A guide to the types, structures, and multifaceted functions of matrix metalloproteinases in cancer

Zoi Piperigkou; Sylvia Mangani; Spyros Kremmydas; Nikolaos E Koletsis; Nikos K Karamanos

doi:10.1111/febs.70296

. 2025 Oct 29;293(13):3717–3757. doi: 10.1111/febs.70296

A guide to the types, structures, and multifaceted functions of matrix metalloproteinases in cancer

Zoi Piperigkou ¹, Sylvia Mangani ¹, Spyros Kremmydas ¹, Nikolaos E Koletsis ¹, Nikos K Karamanos ^1,^✉

PMCID: PMC13326533 PMID: 41159838

Abstract

Matrix metalloproteinases (MMPs) represent a diverse family of zinc‐dependent matrix remodeling enzymes that play critical roles in both physiological and pathological processes, including cancer progression. Their enzymatic activity in matrix remodeling underpins key aspects of cellular physiology; however, uncontrolled remodeling determines several pathological conditions, such as osteoarthritis, fibrosis, and cancer. Several cell functional properties, among them cell proliferation, apoptosis, migration, adhesion, and invasion, are affected by certain MMPs. Moreover, MMPs guide critical steps during cancer progression, including cell behavior, epithelial‐to‐mesenchymal transition, pre‐metastatic niche formation, angiogenesis, and immune surveillance. However, the roles of MMPs in cancer are complex and context‐dependent, with certain family members demonstrating opposing functions that vary with tumor stage, anatomic site, enzyme localization, and substrate specificity. These dual roles present both opportunities and challenges for therapeutic targeting and diagnostic applications of MMPs. While early clinical trials of MMP inhibitors (MMPIs) yielded disappointing outcomes, advances in preclinical models have improved our knowledge of MMP biology and continue to inform the design of more effective and selective MMPIs. This guide on the types, structures, and functions of MMPs gives an overview of MMP structural domains, matrix substrates, and specific functions, summarizing their main roles in normal and pathophysiological conditions, with a particular emphasis on cancer progression. New insights into pharmacological targeting, diagnostic applications, and progress on clinical trials are also presented here and critically discussed. This guide revisits the concept of the multifaceted biological functions of MMPs, critically examines the limitations of previous therapeutic attempts, and explores future directions for the development of effective MMP‐based molecular targeting.

Keywords: biomarkers, cancer, extracellular matrix, matrix metalloproteinases, pre‐metastatic niche, proteolytic network

Matrix metalloproteinases (MMPs) orchestrate cancer progression and metastasis through proteolytic and non‐proteolytic actions. By remodeling the tumor microenvironment, enhancing growth factor availability, and modulating cell behavior, MMPs promote proliferation, migration or invasion, and epithelial‐to‐mesenchymal transition. Alongside extracellular vesicles, MMPs support pre‐metastatic niche formation, enabling cancer cell dissemination, dormancy, and metastatic colonization.

graphic file with name FEBS-293-3717-g003.jpg

Abbreviations

3D: three‐dimensional
aa: amino acid
ADAMs: a disintegrin and metalloproteinases
BMDCs: bone marrow‐derived cells
CMTs: chemically modified tetracyclines
CTCs: circulating tumor cells
ECM: extracellular matrix
EGFR: epidermal growth factor receptor
EMT: epithelial‐to‐mesenchymal transition
EVs: extracellular vesicles
FAK: focal adhesion kinase
FGF: fibroblast growth factor
GAG: glycosaminoglycan
GPI: glycosylphosphatidylinositol
HB‐EGF: heparin‐binding EGF‐like growth factor
IGF‐IR: insulin‐like growth factor receptor
MAPK: mitogen‐activated protein kinases
MMP: matrix metalloproteinase
MMPIs: MMPs inhibitors
MT‐MMP: membrane‐type MMP
NCID: notch intracellular domain
NF‐κB: nuclear factor kappa‐B
NGAL: neutrophil gelatinase‐associated lipocalin
OPN: osteopontin
PAR‐1: protease‐activated receptor‐1
PEX: hemopexin
PG: proteoglycan
PI3K: phosphatidylinositol 3‐kinase
PMN: premetastatic niche
SDC: syndecan
TAMs: tumor‐associated macrophages
TGF: transforming growth factor
TIMP: tissue inhibitor of MMPs
TME: tumor microenvironment
VEGF: vascular endothelial growth factor

Introduction

Extracellular matrices (ECMs) constitute three‐dimensional (3D) intercellular macromolecular networks present in all tissues, which provide structural support to the cells within the tissues, while also holding functional roles in regulating cell morphology, signaling, and functional properties [1]. Major matrix components, such as proteoglycans (PGs), collagens, laminins, elastin, and other glycoproteins, form a highly dynamic and responsive network, which serves as a substrate for continuous, highly orchestrated remodeling through matrix degrading enzymes, including, matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs), and cathepsins [2, 3]. MMPs, the critical players of the dynamic proteolytic network, comprise a diverse family of zinc‐dependent, calcium‐containing endopeptidases (belonging to the metzincin superfamily of proteases), involved in the irreversible degradation of complex macromolecules within the ECM, thereby holding crucial roles under both physiological and pathological conditions [4, 5, 6]. Notably, a total of 28 MMPs have been identified in vertebrates to date, with 24 of these (including two equivalent forms encoded by different genes) being expressed in humans [7, 8]. While most MMPs are secreted into the extracellular environment, some of them appear anchored to the cell surface [membrane‐type MMPs (MT‐MMPs)], and others localize intracellularly, such as within the cytosol, mitochondria, sarcomere, or even the nucleus, thus explaining the dynamics in bidirectional cell signaling that forms the so‐called protease web [9, 10].

This guide on the types, structures, and functions of MMPs provides a comprehensive overview of their structural domains, biological roles, and involvement in cancer progression. By redefining the role of MMP signatures in tumor biology, here we promote a holistic approach involving diagnostic innovation, molecular targeting strategies, and translational research. The guide also critically assesses previous therapeutic failures, including off‐target effects, and highlights recent advances in pharmacological development and clinical trials aimed at improving MMP‐based cancer therapies.

Structures of MMPs

Despite their functional differences, almost all MMPs share similar structural characteristics, which include (from the N‐ to C‐terminal region): (a) a signal peptide, (b) a pro‐peptide, (c) a catalytic domain, (d) a linker/hinge region, and (e) a hemopexin C‐terminal domain (Fig. 1) [11]. Particularly, the signal peptide guides MMPs to the secretory pathways, or to the cell membrane (for MT‐MMPs) where they anchor [12]. The pro‐peptide site [approximately 80 amino acids (aa) long] demonstrates a conserved cysteine switch motif (PRCGXPD), in which the cysteine sulfhydryl group chelates the Zn²⁺ within the catalytic domain, thus maintaining the enzyme in its latent, proenzyme/zymogen form (autoinhibitory mechanism) [13, 14]. The catalytic domain (approximately 170 aa long) contains a zinc‐binding motif (HEXXHXXGXXH), in which three conserved histidine residues (H199, H203, and H209) and one conserved glutamate residue stabilize the Zn²⁺. This domain also includes a conserved methionine sequence (methionine‐turn, defined by the sequence XBMX), which further coordinates the structural environment around Zn²⁺ [13, 15]. A hinge domain, rich in proline residues (15–65 aa long), links the catalytic domain with the hemopexin‐like (PEX) region (~200 aa), which plays a crucial role in regulating MMP localization, homo‐ or heterodimerization, activation and inhibition, as well as substrate specificity [12, 13, 16].

Fig. 1 — Major MMPs subtypes with their structural features and functional domains. MMPs can be generally categorized into four distinct subfamilies based on structural composition–organization and target specificity: matrilysins, archetypal, gelatinases, and furin‐activated. Matrilysins (MMP‐7, ‐26) are the simplest organized MMPs, consisting of a signaling peptide, a pro‐peptide domain which contains a cysteine switch motif (PRCGXPD, P, proline; R, arginine; C, cysteine; G, glycine; X, any amino acid; D, aspartate) and a catalytic domain with a Zn²⁺ binding motif (HEXXHXXGXXH, H, histidine; E, glutamate; X, any amino acid; G, glycine). Among these domains, the cysteine switch motif facilitates the retention of the zymogen (pro‐MMP) form through binding of the catalytic zinc ion. All the remaining subfamilies are presented with their additional domains. Archetypal MMPs consist of collagenases (MMP‐1, ‐8, ‐13), stromelysins (MMP‐3, ‐10, ‐11), and other MMPs (MMP‐12, ‐19, ‐20, ‐27) that contain, right after the catalytic domain, a linker peptide (hinge region) and a hemopexin domain. Gelatinases (MMP‐2, ‐9) contain three type‐II fibronectin repeats within the catalytic domain. Furin‐activated secreted MMPs (MMP‐21, ‐28) possess a RX{K/R}R (R, arginine; X, any amino acid; K, lysine) motif after the pro‐peptide, which, upon cleavage, results in the release and intracellular activation of the enzyme. Additionally, the latter subfamily includes membrane type MMPs (type‐I: MMP‐14, ‐15, ‐16, ‐24) and GPI‐anchored (MMP‐17, ‐25) that contain a transmembrane domain and a GPI‐anchored domain, respectively. Finally, type‐II transmembrane MMPs (MMP‐23A/B) lack the hemopexin domain, which is replaced by a cysteine‐rich array and an immunoglobulin‐like proline‐rich domain. Created with BioRender.

Classification of MMPs

Depending on domain composition, structural organization, and substrate specificity, human MMPs can be classified into the following distinct categories (Fig. 1): archetypal MMPs, furin‐activated MMPs, gelatinases (MMP‐2, MMP‐9), and matrilysins (MMP‐7, MMP‐26). Particularly, archetypal MMPs are further categorized in collagenases (MMP‐1, MMP‐8, MMP‐13), stromelysins (MMP‐3, MMP‐10, MMP‐11), and other MMPs (MMP‐12, MMP‐19, MMP‐20, MMP‐27), while furin‐activated MMPs contain type‐I transmembrane MMPs [MMP‐14 (MT1‐MMP), MMP‐15 (MT2‐MMP), MMP‐16 (MT3‐MMP), MMP‐24 (MT5‐MMP)], type‐II transmembrane MMPs (MMP‐23A and MMP‐23B), glycosylphosphatidylinositol (GPI)‐anchored MMPs [MMP‐17 (MT4‐MMP), MMP‐25 (MT6‐MMP)] and secreted MMPs (MMP‐21, MMP‐28) [17, 18, 19].

Synthesis, activation, and target substrates of MMPs

Expression of MMPs is tightly regulated at a cell type‐specific and stimulus‐dependent manner [20]. While appearing not expressed, or expressed at low levels under homeostatic conditions, most MMPs are upregulated in disease conditions [20, 21]. Particularly, MMPs are initially synthesized within the endoplasmic reticulum as inactive zymogens, containing inhibitory pro‐peptide domains, and are subsequently transported to the Golgi apparatus for further post‐translational modifications [12, 14, 16]. MMPs are produced in the latent pro‐MMP form as zymogens and require further activation that can occur intracellularly, in the cell surface, or extracellularly, depending on the MMP family [22]. Upon signal peptide removal, MMP activation is mediated by the cleavage of the cysteine switch, driven by proteolytic enzymes (proteases, furin, plasmin, or other MMPs), and the subsequent detachment of the pro‐peptide domain, in order to produce the active MMP [22, 23]. MMP activation is further facilitated by reactive species (ROS/RNS), temperature, low pH levels, chaotropic factors, etc., which disrupt the Zn²⁺–cysteine interaction within the prodomain [22, 24].

Once activated, MMPs initiate complex proteolytic pathways that mediate ECM remodeling and shedding of bioactive molecules, specifically the proteolysis of matrix substrates (i.e., collagens, gelatin, elastin, glycoproteins, and PGs), as well as non‐matrix substrates (i.e., growth factors, cytokines, plasminogen, and casein) [15, 25, 26]. To this regard, MMPs play a pivotal role in driving ECM remodeling under both homeostatic and pathological conditions, by controlling the availability of matrix components in the surrounding tissue, while also generating signaling molecules and modulating other MMPs activity [10, 20, 21, 27]. The target substrates of human MMPs are shown in detail in Table 1.

Table 1.

MMPs functional classification and their main substrates/targets. ADAM, A disintegrin and metalloproteinase; ADAMTS, A disintegrin and metalloproteinase with thrombospondin motifs; CA‐125, cancer antigen 125; CD44, cluster of differentiation 44; CLEC3A, c‐type lectin domain 3 member A; CSPG, chondroitin sulfate proteoglycan; CTGF, connective tissue growth factor; CXC, cysteine‐X‐cysteine motif; DSPG, dermatan sulfate proteoglycan; EMMPRIN, extracellular matrix metalloproteinase inducer; EphA2, erythropoietin‐producing hepatocellular A2; ERβ, estrogen receptor beta; FasL, Fas ligand; FGF‐R1, fibroblast growth factor receptor 1; HB‐EGF, heparin‐binding epidermal growth factor–like growth factor; HSPG, heparan sulfate proteoglycan; ICAM‐1, intercellular adhesion molecule 1; IFNγ, interferon gamma; IGF‐1, insulin‐like growth factor; IGFBP, IGF‐binding protein; IL, interleukin; LAP, latency‐associated peptide; LRP1, low density lipoprotein receptor‐related protein 1; LTBPs, latent TGF‐β‐binding proteins; MBP, myelin basic protein; MCP‐3 (CCL7), chemokine (C‐C motif) ligand 7; MMP, matrix metalloproteinase; MUC‐1, mucin‐1; NG2 (CSPG4), neural/glial antigen 2; PAR‐1, protease‐activated receptor‐1; PTK‐7, protein‐tyrosine kinase 7; PTX3, Pentraxin‐3; RANKL, receptor activator of nuclear factor κB ligand; SDC, syndecan; SDF‐1, stromal cell‐derived factor 1; SLPI, secretory leukocyte peptidase inhibitor; TGF‐β, transforming growth factor beta; TNF, tumor necrosis factor; VEGFR‐1, vascular endothelial growth factor receptor 1; ZO‐1, zonula occludens‐1.

Category/MMP	Substrate/targets	References
Collagenases
MMP‐1 Collagenase‐1	Collagen type I, II, III, VII, VIII, X and XI, gelatin, fibronectin, vitronectin, nidogen, tenascin‐C, aggrecan, perlecan, versican, L‐selectin, MBP, ovostatin, PTX3, β‐casein, IL‐1, SDF‐1, serpins, IGFBP‐3, ‐5, TNF precursor, TGF‐β LAP, PAR‐1, pro‐MMP‐2, ‐9	[15, 25, 28, 29, 30, 31, 32, 33]
MMP‐8 Collagenase‐2	Collagen type I, II, III, V, VII, VIII, and X, gelatin, elastin, laminin, fibronectin, nidogen, aggrecan, decorin, ovostatin, TGF‐β LAP, ephrin‐B1, dysadherin, pro‐MMP‐8	[15, 25, 28, 29, 34]
MMP‐13 Collagenase‐3	Collagen type I, II, III, IV, IX, X and XIV, gelatin, laminin, fibronectin, fibrillin‐1, large tenascin C, aggrecan, perlecan, SDC‐1, plasminogen, osteonectin, casein, SDF‐1, MCP‐3, PAR‐1, TGF‐β LAP/LTBPs, pro‐MMP‐2 and ‐9	[15, 25, 30, 35, 36, 37]
Gelatinases
MMP‐2 Gelatinase A	Collagen type I, III, IV, V, VII and X, gelatin, elastin, laminin, fibronectin, vitronectin, nidogen, aggrecan, versican, SDC‐1, ‐2, ‐3, ‐4, tenascin, MBP, thrombospondin‐2, galectin‐1 and ‐3, TNF precursor, IL‐1β, MCP‐3, TGF‐β LAP/LTBPs, HB‐EGF, FGFR1, IGFBP‐3 and ‐5, osteopontin, big endothelin‐1, PAR‐1, active MMP‐9 and ‐13	[12, 13, 14, 15, 38, 39, 40, 41, 42]
MMP‐9 Gelatinase B	Collagen type IV, V, VII, X and XIV, gelatin, elastin, fibronectin, vitronectin, laminin, nidogen, aggrecan versican, decorin, SDC‐1, ‐2, ‐3, ‐4, NG2 (CSPG4), MBP, TNF precursor, IL‐1β and ‐8, IL‐2 receptor‐α, casein, HB‐EGF, IGFBPs, TGF‐β, LAP/LTBPs, thrombospondin‐2, osteopontin, galectin‐3, PAR‐1, ICAM‐1, E‐cadherin, claudin‐5, Notch1	[12, 13, 14, 15, 38, 39, 40, 42, 43, 44, 45, 46, 47]
Stromelysins
MMP‐3 Stromelysin‐1	Collagen type I, II, III, IV, V, IX, X and XI, gelatin, laminin, elastin, fibronectin, fibrin, fibrillin, fibulin, fibrinogen, vitronectin, osteonectin, nidogen, aggrecan, perlecan, SDC‐3, decorin, versican, tenascin, MBP, ovostatin, casein, TNF precursor, pro‐IL‐1β, SDF‐1, L‐selectin, plasminogen, TGF‐β LAP/LTBPs, E‐cadherin, RANKL, HB‐EGF, IGFBP‐3, pro‐MMP‐1, ‐2, ‐7, ‐8, ‐9, ‐13	[2, 12, 13, 14, 38, 43, 48, 49, 50]
MMP‐10 Stromelysin‐2	Collagen type III, IV, V, IX and X, gelatin, elastin, laminin, fibronectin, fibrilin‐10, fibulin‐2, nidogen, aggrecan, perlecan, SDC‐4, casein, α₆ integrin, desmocollin‐3, pro‐MMP‐1, ‐8, ‐9, ‐10	[15, 25, 28, 51]
MMP‐11 Stromelysin‐3	Collagen type VI, gelatin, fibronectin, laminin receptor, aggrecan, IGFBP‐1	[15, 25, 28, 52, 53]
Matrilysins
MMP‐7 Matrilysin‐1	Collagen type I, IV and X, gelatin, elastin, fibronectin, laminin, vitronectin, nidogen, osteopontin, aggrecan, decorin, perlecan, SDC‐1, ‐2, plasminogen, casein, tenascin, FasL, pro‐TNF‐α, myelin, IGFBP‐1, ‐2, ‐3, ‐4, ‐5, and ‐6, HB‐EGF, TGF‐β LAP/LTBPs, CLEC3A, RANKL, MUC‐1, E‐cadherin, nephrin, claudin‐7, Notch1/2	[10, 15, 25, 28, 29, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66]
MMP‐26 Matrilysin‐2	Collagen type IV, fibronectin, fibrinogen, gelatin, vitronectin, β‐casein, 2‐macroglobulin and IGFBP‐1, ERβ, pro‐MMP‐2, ‐9, ‐26	[9, 28, 67, 68, 69, 70]
MT‐MMPs
Type‐I transmembrane
MMP‐14 (MT1‐MMP)	Collagen type I, II, and III, gelatin, elastin, fibronectin, fibrilin‐1, fibrin, vitronectin, laminin, tenascin, nidogen, α2‐macroglobulin, aggrecan, SDC‐1, ‐3, NG2 (CSPG4), betaglycan, perlecan, α_v/α_vβ₃ integrin, CD44, pro‐TNF‐α, IL‐8, SDF‐1, casein, galectin‐1 and ‐3, HB‐EGF, TGF‐β LAP/LTBPs, CTGF, VEGFR‐1, EphA2, PTK‐7, PAR‐1, CA‐125, RANKL, Notch1, ICAM‐1, E‐cadherin, EMMPRIN, LRP1, SLPI, ADAM‐9, pro‐MMP‐2, ‐8, ‐13	[15, 25, 26, 28, 29, 30, 36, 61, 71, 72, 73, 74, 75, 76, 77, 78]
MMP‐15 (MT2‐MMP)	Collagen type I and IV, gelatin, laminin, fibrin, fibronectin, vitronectin, nidogen, tenascin, aggrecan, perlecan, E‐cadherin, ZO‐1, pro‐MMP‐2, ‐13	[25, 28, 78, 79, 80]
MMP‐16 (MT3‐MMP)	Collagen type I and III, gelatin, laminin, fibronectin, vitronectin, aggrecan, perlecan, SDC‐1, casein, pro‐MMP‐2, ‐9, ‐13	[25, 26, 28, 78, 80]
MMP‐24 (MT5‐MMP)	Gelatin, fibronectin, fibrin, CSPG, DSPG, N‐cadherin, CD44, pro‐MMP‐2 and ‐13	[28, 78, 81]
Type‐II transmembrane
MMP‐23 A/B (CA‐MMP)	Gelatin	[28]
GPI‐anchored
MMP‐17 (MT4‐MMP)	Gelatin, fibrinogen, fibrin, osteopontin, periostin, α_M‐integrin, pro‐TNFα, LRP, CD44, N‐cadherin, LRP1, ADAMTS‐4, pro‐MMP‐13	[25, 28, 78, 82, 83]
MMP‐25 (MT6‐MMP)	Collagen type IV, gelatin, fibronectin, fibrinogen/fibrin pro‐MMP‐2, galectin‐1, MBP isoforms, vimentin, cystatin C, IGFBP‐7, osteonectin, alpha‐1 proteinase inhibitor	[25, 28, 78, 84]
Secreted
MMP‐21 (Xenopus‐MMP)	No physiological activators or substrates for MMP‐21 have yet been identified	[20]
MMP‐28 Epilysin	Casein, E‐cadherin	[28, 85]
Other MMPs
MMP‐12 Macrophage metalloelastase	Collagen type I, II, IV and V, gelatin, elastin, fibronectin, fibrinogen, fibrillin‐1, laminin, vitronectin, nidogen, osteonectin, aggrecan, CSPGs, HSPGs, MBP, TNF precursor, CXC chemokines, IFNγ, TGF‐β LAP, plasminogen, insulin/IGF‐1, N‐cadherin, ZO‐1, claudin‐5, occludin, E‐cadherin, pro‐MMP‐1, ‐2, ‐3, ‐9	[20, 25, 28, 29, 86, 87, 88, 89, 90, 91]
MMP‐19 RASI‐1/stromelysin‐4	Collagen type I and IV, laminin, fibronectin, nidogen, tenascin‐C, aggrecan, casein, IGFBP‐3, endothelin‐1, pro‐MMP‐9	[25, 28, 92, 93, 94]
MMP‐20 Enamelysin	Collagen type IV, V, gelatin, laminin, fibronectin, nidogen, tenascin‐C, aggrecan, amelogenin	[28, 95]
MMP‐27	Gelatin	[28]

Open in a new tab

MMPs as non‐catalytic effectors

In addition to their well‐known proteolytic roles in ECM remodeling (illustrated in the right panel of Fig. 2), MMPs also possess critical non‐catalytic functions (Fig. 2, left panel) that modulate cell signaling, mechanobiology, and tumor progression (Fig. 2). These functions are mediated through specific structural domains, such as the PEX domain, fibronectin‐like inserts, and the cytoplasmic tails of MT‐MMPs, which engage in protein–protein interactions independent of enzymatic activity. These scaffold‐related, signaling, and stabilizing roles underscore the importance of MMPs as versatile effectors in physiological and pathological processes. For example, the PEX domain of MMP‐9 enables interaction with integrin α_vβ₃ and CD44, facilitating its localization to the cell surface and enhancing cell adhesion and motility in immune and cancer cells [96]. MMP‐9 can also bind to neutrophil gelatinase‐associated lipocalin (NGAL), forming high‐molecular‐weight complexes that stabilize latent MMP‐9 and regulate its bioavailability during inflammation and tumorigenesis [97]. Similarly, MT1‐MMP interacts via its cytoplasmic tail with intracellular effectors, such as Src kinase and focal adhesion kinase (FAK), promoting actin cytoskeleton reorganization, invadopodia formation, and cell invasion [98, 99]. MT1‐MMP is further involved in non‐proteolytic activation of signaling pathways, such as the Hippo signaling pathway–Yes‐associated protein/Transcriptional co‐activator with PDZ‐binding motif (Hippo–YAP/TAZ) and Hypoxia‐Inducible Factor 1 (HIF‐1) axes, which regulate transcriptional pathways linked to proliferation, stemness, and mechanosensation [100]. By altering matrix stiffness and integrin engagement, MMPs indirectly influence mechanotransduction, affecting gene expression in a protease‐independent manner.

Redox‐dependent modulation of MMP activity contributes to non‐catalytic outcomes that influence inflammatory and immune signaling. ROS, including hydrogen peroxide and hypochlorous acid, can oxidize regulatory domains of MMPs, particularly the cysteine switch in latent forms, leading to structural changes that either promote partial activation or alter substrate interactions without complete proteolysis [101]. Such redox‐mediated conformational changes have been shown to influence MMP‐dependent processes such as receptor shedding, immune cell recruitment, and cytokine dynamics, even in the absence of full enzymatic cleavage. MMP‐7, MMP‐12, and MT1‐MMP can shed ectodomains of key immune receptors, such as tumor necrosis factor alpha (TNF‐α) and interleukin‐1 (IL‐1) receptors, thereby modulating downstream nuclear factor kappa‐B (NF‐κB) and mitogen‐activated protein kinases (MAPK) signaling pathways. These proteolysis‐independent or limited‐cleavage events shape chronic inflammatory responses and support immune evasion mechanisms in tumors [102].

Notably, MMP‐12 has emerged as an immunomodulatory protease with antiviral and regulatory properties that extend beyond ECM remodeling. Recent studies demonstrate that MMP‐12 can directly bind membrane receptors and immune mediators, exerting structural and regulatory effects without full enzymatic cleavage [103]. In addition, catalytically inactive pro‐MMPs may function as structural scaffolds. For instance, pro‐MMP‐2 interacts with integrins and growth factors at the tumor–stromal interface, contributing to localized signaling events that influence angiogenesis, immune cell infiltration, and tumor progression. These scaffolding effects expand the repertoire of MMP functions beyond proteolysis, positioning them as key modulators of the tumor microenvironment (TME) [104]. As highlighted in Fig. 2, MT1‐MMP exemplifies this bifunctionality, but here the emphasis is on non‐catalytic functions, which represent emerging therapeutic targets with the potential to circumvent the toxicity and off‐target effects of classical MMP inhibitors (MMPIs).

Functional roles of MMPs under homeostatic conditions

Under physiological conditions, MMPs are key regulators of homeostasis, contributing to several biological processes, including tissue/organ development and wound healing. Notably, they are the main facilitators of ECM remodeling maintaining its stability through the degradation of its structural proteins (i.e., collagens, fibronectin, and laminins) [105, 106]. MMPs are actively engaged in all three phases of wound healing cascade: the inflammatory, proliferative, and maturation phases. Specifically, during the inflammatory phase, MMPs modulate leukocyte migration and chemokine/cytokine activity. Moreover, in the subsequent proliferative and maturation phases, they eliminate damaged ECM components and promote re‐epithelialization and tissue reconstruction [107]. Additionally, MMPs are essential regulators of organ development by mediating ECM remodeling across different developmental stages. During embryogenesis, MMPs coordinate tissue formation, especially in heart and lungs [38]. MMP‐mediated ECM shaping further promotes epithelial branching and mediates cellular functions such as growth and motility, through the secretion of biologically active molecules (i.e., growth factors) that influence cell behavior [39]. Their active roles during adipogenesis, myogenesis, and endochondral ossification have been thoroughly reported [38, 40]. MMPs also participate in vascular tissue remodeling, where they are expressed by multiple cell types and regulate processes such as cell migration, proliferation, differentiation, and angiogenesis [22]. Interestingly, beyond their structural roles, MMPs also facilitate neurogenesis and neuronal plasticity, hence mediating various functions, including memory formation, learning, and long‐term potentiation [43, 48].

Pathophysiological roles of MMPs

Dysregulation of MMPs activity is linked to various pathophysiological conditions, where they promote aberrant tissue degradation, and disrupt normal processes of tissue repair and regeneration [108]. Notably, MMPs are implicated in multiple aspects of arthritis pathogenesis, particularly rheumatoid arthritis, affecting ECM remodeling, oxidative stress, cell invasion/migration, angiogenesis and bone destruction [109]. The aberrant activation of MMPs, driven by pro‐ and/or anti‐inflammatory cytokines, further results in excessive matrix degradation in osteoarthritic cartilage lesions [41]. MMPs also hold crucial roles in structural integrity and remodeling of cardiovascular tissues, while their dysregulated activity has been associated with cardiac hypertrophy, hypertension, atherosclerosis, aortic valve stenosis, heart failure, and aneurysm formation. Apart from ECM remodeling, MMPs are key players in lipoprotein metabolism, and inflammatory signaling pathways [42]. Moreover, the imbalance between MMPs and their endogenous inhibitors, tissue inhibitors of MMPs (TIMPs), is responsible for fibrotic conditions, such as pulmonary, hepatic, pancreatic, renal, intestinal and skin fibrosis, conditions characterized by aberrant ECM deposition [44, 45, 46, 47, 49].

Importantly, MMPs are recognized for their dual roles in both promoting ECM degradation and contributing to ECM accumulation, depending on different stages of fibrosis [49, 50]. MMPs also regulate the progression of neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In addition to their role in ECM remodeling, they can not only impair tight junction integrity at brain barriers but also activate pro‐inflammatory cytokines and free radicals, thereby exacerbating neuroinflammation and contributing to blood–brain barrier disruption [48].

Roles of MMPs in cancer progression

Cancer progression follows a multistep process, which allows cancer cell growth, detachment, spreading and finally, secondary tumor site formation in distant tissues/organs, an event referred to as metastasis [2, 108]. Cancer cells are defined by their ability for aberrant proliferation and apoptosis evasion, enabling them to persist and grow despite normal regulatory mechanisms [110]. Angiogenesis nourishes the primary tumor, while also supporting cancer progression, via allowing cancer cells to disseminate and seed distant metastases [111]. In order to disseminate, cancer cells can undergo epithelial‐to‐mesenchymal transition (EMT), thereby acquiring migratory/invasive properties and stem cell‐like characteristics that allow them to migrate and invade the surrounding tissues (Fig. 3) [112]. Although EMT is considered as a key driver of metastasis, recent evidence has demonstrated that it is not strictly required for metastatic dissemination; EMT hybrid cells, characterized by a blend of epithelial and mesenchymal traits, have emerged as pivotal in metastasis and demonstrate remarkable plasticity, enabling transitions across cellular states crucial for intravasation, survival in circulation, and extravasation at distal sites [113]. Particularly, a high frequency of circulating tumor cells (CTCs), expressing both epithelial and mesenchymal markers, has been noted in patients [114]. Upon dissemination, cancer cells infiltrate the bloodstream or lymphatic vessels, where they travel through the circulatory systems until they exit the vasculature to colonize distant tissues [115]. Following bloodstream intravasation, CTCs must overcome various challenges, including shear stress and immune surveillance. Additionally, the loss of cell–cell and cell–ECM interactions render CTCs vulnerable to apoptosis, particularly via anoikis [116]. Finally, upon extravasation, most cancer cells persist either as single cells or small clusters, which frequently enter a dormant state (Fig. 3). Once they overcome dormancy, often through escaping growth restraints or immune surveillance—they can proliferate into metastatic sites [112].

Fig. 3 — Revisiting the multifaceted roles of MMPs in cancer progression and initiation of metastasis. MMPs are central regulators of key steps of cancer growth and progression via proteolytic and non‐proteolytic actions. In the primary tumor, MMPs released into the stiff ECM modulate cell behavior by promoting local spreading, migration and invasion, influencing cell signaling and promoting epithelial‐to‐mesenchymal transition (EMT). Beyond matrix remodeling, MMPs also reorganize the tumor microenvironment, while modulating cell–cell and cell‐matrix‐cell interactions. There is an enhanced bioavailability of growth factors and cytokines (among other matrix macromolecules) resulting from MMP‐driven secretion and/or surface shedding along with EVs/exosomes release. Additionally, MMPs regulate cancer cell signaling which leads to tumor heterogeneity, and supports different cancer cell phenotypes apart from typical cancer cells, including highly metastatic and hybrid cancer cells. These fundamental changes drive basement membrane cleavage and the intravasation of cancer cells, MMPs and EVs carrying functional matrix components. Once in circulation, circulating cancer cells (CTCs) disseminate systemically, eventually extravasate, where they persist either as single cells or even small clusters. CTCs frequently enter a dormant state, releasing MMPs and afterwards can proliferate into macrometastases. MMPs in association with EVs/exosomes that are extravasated in distant sites contribute to the formation of a pre‐metastatic niche, characterized by matrix remodeling, immune surveillance, hypoxia, autophagy and inflammation. The local microenvironment fosters conditions for the colonization of CTCs, angiogenesis, and finally, the initiation of metastasis. Created with BioRender.

ECM serves as a dynamic platform that supports cell adhesion, survival, and proliferation; thus, ECM remodeling that is primarily driven by MMPs holds a critical role in tumor development and progression [117]. Mechanistically, MMPs degrade matrix macromolecules, and therefore, they create a malignancy‐supporting microenvironment, while also inducing downstream signaling cascades that support tumor growth and survival, EMT, migration/invasion, and ultimately metastasis [22, 35, 108]. Notably, MMPs appear overexpressed both in tumor cells and surrounding stromal cells, promoting more aggressive malignant phenotypes [28, 84]. Beyond that, they can be also found loaded into extracellular vesicles (EVs) [118], where they contribute to cancer progression by either cleaving surrounding TME components or shedding receptors and other surface molecules on recipient cells [119, 120, 121]. Finally, immune cells can modulate pre‐metastatic niche (PMN) formation and establish a favorable environment for the CTCs extravasation, by releasing MMPs (Fig. 3) [122].

Importantly, different MMPs exert multifaceted and context‐dependent influence on cancer development and progression by modulating the TME. By cleaving the surrounding ECM and altering the availability of growth factors, cytokines, and cell‐surface receptors, they impact different stages of cancer propagation, including cancer cell proliferation, migration, invasion, immune evasion, angiogenesis, and metastasis [108]. Dysregulated MMP expression has been implicated across several cancer types, such as breast, prostate, liver, oral, lung, renal, head and neck, colorectal, esophageal, endometrial, bladder, gastric, and thyroid cancers [54, 123]. In the following sections, the roles of MMPs involved in various stages of cancer progression, through modulation the TME and proteolysis of bioactive molecules, will be analyzed.

MMPs in cancer cell proliferation and survival

While they can exert context‐dependent, or even opposing effects in cancer progression, several members of the MMP family—including MMP‐1, ‐2, ‐3, ‐7, ‐8, ‐9, ‐10, ‐ 11, ‐ 12, ‐13, ‐19, ‐21, ‐ 26, ‐28, and MT1‐, MT2‐, MT3‐, MT4‐MMP—have been consistently associated with enhanced cancer cell proliferation across various solid tumor types (Fig. 4; Table 2) [29]. Notably, breast cancer cells transfected with MMP‐26 exhibit enhanced proliferation rate both in vitro and in vivo (in mouse xenografts), whereas MMP‐1 knockdown in colorectal cancer cells (CRC) inhibited their proliferation under both settings [71, 124]. MMP‐11 knockdown was further shown to impair breast cancer cell proliferation and tumor growth in vivo [125], and MMP‐28 knockdown could also restrain the pancreatic adenocarcinoma cell proliferation [126]. Finally, MMP‐10 and MMP‐12 knockdown resulted in suppressed tongue cancer cells proliferation [127] and decreased lung adenocarcinoma cell growth in vitro, respectively [128].

Fig. 4 — MMP‐mediated mechanisms drive cancer cell proliferation. Collagenases (MMP‐1, ‐8, ‐13) enhance tumor cell growth by activating signaling pathways such as NF‐κB and TGF‐β, releasing growth factors like FGF, and degrading IGFBPs to increase IGF availability and activate proliferative signaling. Stromelysins (MMP‐3, ‐11) sustain cancer cell proliferation by promoting HB‐EGF release and EGFR activation, while also stabilizing TGF‐β/Smad signaling and inducing NF‐κB–dependent gene expression that supports cell cycle progression. Other MMPs, including MMP‐12 and MMP‐19, contribute to cancer cell proliferation mainly by modulating IGF and TGF‐β signaling through IGFBP‐3 and LAP cleavage, respectively, thereby enhancing growth factor activity within the tumor microenvironment. Membrane‐type MMPs (MT1‐MMP, MT4‐MMP) promote cancer growth through diverse mechanisms. Notably, MT1‐MMP cleaves HB‐EGF to stimulate EGFR signaling and degrades ECM components such as fibronectin, vitronectin, and SDCs, while MT4‐MMP regulates ligand‐dependent EGFR signaling. Matrilysin MMP‐7 supports cancer cell survival and proliferation by cleaving multiple IGFBPs, releasing HB‐EGF, and inducing CD44v3‐mediated mitogenic signaling and anti‐apoptotic pathways. Gelatinases (MMP‐2, ‐9) exert multifaceted roles by activating IGF and TGF‐β pathways, releasing adhesion molecules such as E‐cadherin, and shedding SDCs. In addition, their nuclear functions can directly regulate histone architecture and transcription, further driving tumor cell proliferation. Together, these MMP‐driven mechanisms lead to enhanced growth factor signaling, disrupt regulatory barriers, and sustain the proliferative capacity of cancer cells. Created with BioRender.

Table 2.

The main functions of major MMPs in cancer growth and progression. All references supporting the data in Table 2 are cited in the corresponding sections of the main text. AKT1, protein kinase B; AXL, receptor tyrosine kinase; BMDC, bone marrow‐derived cell; CA‐125, cancer antigen 125; Cdc42, cell division control protein 42; CD44, cluster of differentiation 44; CLEC3A, c‐type lectin domain 3 member A; CTC, circulating tumor cell; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EMT, epithelial‐to‐mesenchymal transition; EphA2, erythropoietin‐producing hepatocellular A2; ErbB, erythroblastic oncogene B; ERK, extracellular signal‐regulated kinase; FAK, focal adhesion kinase; FasL, Fas ligand; FGF, fibroblast growth factor; HB‐EGF, heparin‐binding epidermal growth factor–like growth factor; H3NT, N‐terminal tail of histone H3; NICD, Notch intracellular domain; IGF‐1, insulin‐like growth factor; IGFBP, IGF‐binding protein; IL‐1β, Interleukin‐1 β; LAP, latency‐associated peptide; LTBPs, latent TGF‐β‐binding proteins; MMP, matrix metalloproteinase; NF‐κB, nuclear factor kappa‐B; OPN, osteopontin; PAR‐1, protease‐activated receptor‐1; PDGFRα, platelet‐derived growth factor receptor alpha; PI3K, phosphatidylinositol 3‐kinase; PMN, premetastatic niche; PTK‐7, protein‐tyrosine kinase 7; RAC1, Ras‐related C3 botulinum toxin substrate 1; RGD, arginine, glycine, and aspartate motif; RhoA, Ras homolog family member A; rRNA, ribosomal RNA; SDC, syndecan; Src, non‐receptor tyrosine kinase protein; TGF‐β, transforming growth factor beta; Tks5, SH3 and PX domain‐containing protein 2A; ZO‐1, zonula occludens‐1.

MMP	Function in cancer progression
Cancer cell proliferation
MMP‐1, ‐2, ‐3, ‐7, ‐9, ‐11, ‐13	IGFBPs degradation; insulin/IGF‐1 signaling
MMP‐3, ‐7, ‐9, MT1‐MMP, MMP‐7/CD44v3	HB‐EGF ectodomain shedding; EGFR signaling
MT1‐MMP	Fibronectin/vitronectin degradation; released RGD motifs induce α_vβ₃‐mediated ERK signaling; Collagen degradation; downregulation of p21^WAF1
MT4‐MMP	Non‐proteolytic regulator of EGFR signaling; cell cycle regulation
MMP‐9	E‐cadherin cleavage; soluble E‐cadherin interaction with IGF‐IR and EGFR H3NT cleavage; transcriptional activation of growth stimulatory genes; Notch cleavage and NICD release
MMP‐2, ‐3, ‐7, ‐8, ‐9, ‐12, ‐13, and MT1‐MMP	LAP or/and LTBPs degradation; TGF‐β activation
MMP‐11	Smad2 stabilization; TGF‐β activation; NF‐κB pathway activation; cyclin D1 expression
MMP‐1	NF‐κB pathway activation
MMP‐13	Active FGF release
MT1‐MMP	Notch 1 degradation and activation
MMP‐2, ‐9, and MT1‐MMP	SDC‐1 cleavage; Akt1 SUMOylation; proliferation
MMP‐2, ‐3, ‐9, and MT1‐MMP	SDC‐3 cleavage; proliferation
MMP‐2	H3NT cleavage; rRNA transcription
MT1‐MMP (cytoplasmic tail)	Hypoxia‐inducible transcription factors activation; proliferation‐related gene expression
Cancer cell apoptosis
MMP‐7	Cleavage of membrane FasL; apoptosis‐resistance
Epithelial‐to‐mesenchymal transition
MMP‐1, ‐2, ‐9, ‐10, ‐11, ‐13, ‐19, ‐20, ‐28, MT1‐, MT3‐, MT4‐MMP	EMT induction; upregulation of epithelial markers, downregulation of mesenchymal markers
MMP‐1, ‐3	NF‐κB pathway activation
MMP‐8, ‐9, ‐28, and MT1‐MMP	Active TGF‐β release
MMP‐3	β‐catenin release from adhesion junctions; Wnt signaling
MMP‐1 (exosomal)	PAR‐1 cleavage and downstream signaling pathway
MMP‐11	PI3K/AKT signaling triggering
MMP‐3, ‐7, ‐9, and MT1‐MMP	E‐cadherin cleavage
MT2‐MMP	E‐cadherin and ZO‐1 shedding, disrupted β‐catenin attachment on cell membrane
MMP‐8	Dysadherin degradation
MMP‐13	Intercellular adhesion disturbance via mechanotransduction pathways
Cancer cell migration and invasion
MMP‐2, ‐9, ‐21, ‐28, MT1‐MMP	Proteolytic degradation of ECM components; physical pathways for cell migration
MMP‐2	Degradation of gelatin, collagen type IV, fibronectin, vitronectin; Active TGF‐β release; signaling; Interaction with α₅β₁ integrin
MMP‐9	Degradation of gelatin, collagen type IV; SDC‐1 and ‐4 shedding, OPN cleavage; Active TGF‐β release; signaling
MT1‐MMP	RAC1 Activation; expression of cell migration‐associated genes; CA‐125 shedding; invasion within sub‐mesothelial matrix; integrin α_v subunit cleavage; FAK activation; fibronectin/vitronectin degradation; RGD motifs induce integrin α_vβ₃‐mediated ERK and FAK signaling; EphA2 cleavage; ErbB signaling or increase in RhoA activity; PTK‐7 shedding, CD44 and E‐cadherin cleavage; SDC‐1 shedding; Active TGF‐β release; Hypoxia‐inducible transcription factors activation; migration/invasion‐related genes expression; RhoA activation; RhoA‐dependent Actin polymerization
MMP‐2, ‐7, ‐9, MT1‐MMP	Actin polymerization and invadopodia formation
MT3‐MMP	Wnt signaling mediator; Inhibition of collagen fiber alignment
MT4‐MMP	Interaction with Tks5 and PDGFRα; Src signaling and activation of Rho and Cdc42 (amoeboid‐like cell movement)
MT6‐MMP	alpha‐1 proteinase inhibitor cleavage
MMP‐7	Basement membrane, E‐cadherin, SDC‐1, perlecan, HB‐EGF, CLEC3A, OPN degradation
MMP‐2, ‐3, ‐13, ‐19, ‐20, MT1‐MMP	Laminin‐332 proteolysis; γ2 chain generation
MMP‐1, ‐2, ‐9, ‐13, MT1‐MMP	PAR‐1 cleavage
MMP‐8	Crosstalk with TGF‐β1; activation of PI3K/Akt/Rac1 signaling
MMP‐3 (nuclear)	Induction of CTGF expression
MMP‐10	AXL (Akt/mTOR/NF‐κB p65) signaling induction
MMP‐11	FAK signaling pathway
MMP‐26	MMP‐9 activation
Intravasation
MMP‐2, ‐9	Basement membrane degradation and vascular wall disruption for tumor cell entry
MMP‐12, MMP‐19	Regulate endothelial junctional integrity and leukocyte transmigration; may facilitate cancer cell intravasation under inflammatory conditions
MT1‐MMP	Supports invasion through type I collagen remodeling, aiding intravasation through the vessel wall
Extravasation and premetastatic niche formation
MMP‐1, ‐2, ‐3, ‐9, ‐10	Vascular permeability; endothelial integrity disruption; CTC extravasation
MMP‐2, ‐9, ‐13	ECM degradation; BMDC and immune cell recruitment; PMN formation
MMP‐2, ‐7, ‐9, ‐13, MT1‐MMP	ECM remodeling; PMN establishment for future CTC colonization
Neoangiogenesis
MMP‐2, ‐9	Vascular basement membrane degradation of and endothelial sprouting
MMP‐3, MMP‐7, MMP‐13	Release of ECM‐bound angiogenic cytokines (i.e., VEGF, IGF‐binding proteins); enhances endothelial recruitment and neovessel formation
MMP‐13, MMP‐16	Carried by tumor‐derived exosomes; reprogram endothelial cells and prime the premetastatic niche
MT1‐MMP	Angiogenic sprouting via activation of pro‐MMP‐2 and localized matrix degradation; Highly expressed at endothelial tip cell protrusions; cleaves ECM and engages VEGFR1/2 signaling, promoting vascular formation and maturation
Immune surveillance
MMP‐2	Cleaves chemokines such as CXCL12 to regulate immune cell trafficking; Promotes T cell recruitment via ECM degradation; facilitates TGF‐β release and regulatory T cell expansion
MMP‐7	Cytokine modification i.e., IL‐1β), immune cell activity modulation; Involved in shedding Fas ligand and syndecan‐1; impacts apoptotic signaling and chemokine presentation
MMP‐7, MMP‐12	Targeting enhances macrophage reprogramming and APC functionality; may improve checkpoint inhibitor efficacy
MMP‐8	Cleaves IL‐8 and CCL3; deficiency linked to increased tumor burden and immune evasion in models
MMP‐12	Degrades elastin; modulates macrophage polarization toward an immunosuppressive phenotype
MT1‐MMP	Perivascular remodeling affecting T cell extravasation

Open in a new tab

MMPs—Growth factors axis in cancer cell proliferation

MMPs proteolytic activity leads to the release of ECM‐sequestered bioactive molecules, modulating growth factor availability and signaling, thereby enhancing cellular responses that drive tumor progression (Fig. 3; Table 2) [82]. Signaling cascades activated by the epidermal growth factor receptor (EGFR) and insulin‐like growth factor receptor (IGF‐IR) regulate the expression of target genes, which in turn modulate essential cell proliferation and survival pathways, holding a pivotal role in cancer progression [129, 130]. Notably, soluble E‐cadherin, generated by MMP‐9‐mediated cleavage of mature E‐cadherin, can interact with IGF‐IR, EGFR, and other members of the human epidermal growth factor receptor (HER) family, thereby leading to downstream activation of MAPK, phosphatidylinositol 3‐kinase (PI3K)/Akt, and mammalian target of rapamycin (mTOR) signaling pathways, which in turn regulate the expression of proteins essential for cell proliferation (Table 2) [131]. Moreover, MMP‐13 has been shown to sequester fibroblast growth factor (FGF), thereby inducing cancer cell proliferation (Fig. 4) [132].

MMPs—IGF axis in cancer cell proliferation

Several MMPs modulate IGF‐IR signaling through the proteolytic cleavage of IGF‐binding proteins (IGFBPs). Notably, stromal cell‐derived MMPs, specifically MMP‐2, ‐3, ‐7, and ‐9, within the pancreatic TME can degrade IGFBPs, thereby enhancing IGF‐1 signaling involved in cell proliferation [133]. Among them, cancer cell‐derived MMP‐7 supports cancer cell survival and proliferation by cleaving IGFBP‐1, ‐2, ‐4, ‐5, and ‐6 (Fig. 4). Similarly, stromal cell‐derived MMP‐2 can cleave IGFBP‐5, further amplifying the anti‐apoptotic/proliferative downstream pathways [55]. In addition to the above, MMP‐1, ‐2, ‐3, and ‐19 mediate IGFBP‐3 proteolysis, thereby increasing the bioavailability of IGF and the activation of downstream signaling pathways associated with cell proliferation [134, 135]. Finally, MMP‐11 has also been reported to cleave IGFBP‐1, leading to the release of IGF‐1 and the subsequent activation of the PI3K/Akt pathway, contributing to breast and pancreatic tumor progression (Fig. 4; Table 2).

MMPs—EGF axis in cancer cell proliferation

Ectodomain shedding of the heparin‐binding EGF‐like growth factor (HB‐EGF) allows the release of soluble HB‐EGF, which mediates EGFR (particularly EGFR1 and EGFR4) signaling (Table 2) [136]. Of note, macrophage‐derived MMP‐9 cleaves HB‐EGF from the macrophage surface, triggering EGFR activation and enhancing proliferation in ovarian cancer cells [137]. Similarly, MMP‐7 is able to trans‐activate EGFR signaling by cleaving HB‐EGF in CRC, while the MMP‐7/cluster of differentiation 44 receptor isoform variant 3 (CD44v3) complex induces a comparable effect, contributing to a substantial mitogenic and proliferative activity of maxillary sinus cancer cells [56, 138]. MMP‐3 further exhibits its tumor‐promoting effects in breast cancer progression by cleaving HB‐EGF, hence driving cancer cell proliferation (Fig. 4; Table 2) [139].

MT‐MMPs roles in cancer cell proliferation

MT‐MMPs have been shown to release EGFR ligands, particularly EGF and transforming growth factor‐alpha (TGF‐α), in several solid tumors, thus affecting cancer cell proliferation (Fig. 4) [140]. Specifically, MT1‐MMP drives the proteolytic processing of HB‐EGF, thereby inducing EGFR signaling and contributing to increased tumor growth in non‐small‐cell lung carcinoma (NSCLC) mouse models [72]. Moreover, MT4‐MMP has emerged as a critical non‐proteolytic regulator of EGFR signaling, enhancing ligand‐dependent EGFR activation and promoting cancer cell proliferation by modulating cell cycle protein expression, as demonstrated in both 3D breast cancer models and mouse xenografts [82, 141]. Further than EGFR signaling, MT1‐MMP has also been reported to drive cancer cell proliferation by degrading fibronectin/vitronectin; the released tripeptide [arginine, glycine, and aspartate (RGD)] motifs induce integrin α_νβ₃‐mediated ERK signaling in 3D collagen matrices [142, 143]. Simultaneously, the degradation of collagen fibrils by MT1‐MMP reverses their inhibitory influence on cell proliferation, leading to downregulation of p21^WAF1 and restoration of tumor cell growth (Table 2) [143]. In addition, MT2‐MMP silencing was shown to decrease 3D multiple myeloma cell proliferation, as well as restrict the growth of plasmacytoma in xenograft models, highlighting the significant role of MT2‐MMP in cancer proliferation [144]. Finally, MT3‐MMP is found highly expressed in gastric cancer patients and appears associated with enhanced gastric cancer cell proliferation (Table 2) [145].

MMPs—TGF‐β axis in cancer cell proliferation

Transforming growth factor beta (TGF‐β) exhibits a dual role in cancer development and advancement, functioning as a tumor suppressor in the early stages of cancer progression, while facilitating tumor propagation in later stages through pro‐oncogenic signaling, affecting, among others, cancer cell proliferation (Fig. 4) [146, 147]. During TGF‐β activation, gelatinases proteolytically cleave the latent TGF‐β‐binding proteins (LTBPs), thereby releasing the latent TGF‐β [29, 82]. Subsequently, stromal MMP‐2, ‐3, ‐7, ‐8, ‐9, ‐12, ‐13, and MT1‐MMP activate the latent TGF‐β via proteolytic cleavage of the latency‐associated peptide (LAP), thus inducing signaling cascades that promote glioblastoma cell proliferation [29]. Furthermore, MMP‐3 and ‐13 have both been implicated in the release of TGF‐β, which further promotes melanoma cell proliferation [36] and colon cancer cell proliferation, respectively [35]. Finally, MMP‐11 promotes breast cancer cell proliferation through stabilization of Smad2 and the concurrent induction of the TGF‐β signaling pathway (Table 2) [125].

MMPs—NF‐κΒ axis in cancer cell proliferation

NF‐κB constitutes a nuclear transcription factor that exhibits a crucial role in cancer development and progression, particularly affecting cancer cell proliferation, among others [148]. Importantly, MMP‐1 induces the activation of the NF‐κB signaling pathway, which further modulates the expression of genes associated with breast cancer cell survival and proliferation [149]. In addition, MMP‐11 was shown to promote thyroid cancer cell proliferation by activating the NF‐κB pathway and altering the expression of cyclin D1 (Fig. 4; Table 2) [150].

MMPs' additional proteolytic actions in cancer cell proliferation

Beyond their previously mentioned primary roles, MMPs also contribute to diverse cellular pathways by proteolytically cleaving cell surface receptors, PGs, as well as through their intracellular functions. Interestingly, MT1‐MMP interacts with and activates Notch1 on the surface of melanoma cells, thereby increasing cell proliferation [57, 151]. Further proteolytic cleavage of Notch by MMP‐7 and MMP‐9 leads to the release of Notch intracellular domain (NICD), which translocates to the nucleus and promotes the transcription of proliferation‐related target genes [57]. Moreover, MMP‐2, –9, and MT1‐MMP may cleave syndecan‐1 (SDC‐1), hence generating two distinct fragments, the extracellular N‐terminal (NTF) and the intracellular C‐terminal (CTF) ones. While both of them have been shown to promote cell proliferation, CTF seems to have a stronger effect, probably by contributing to Akt1 SUMOylation in basal‐like breast cancer cells [73]. MMP‐2, –3, –9, and MT1‐MMP have been further implicated in syndecan‐3 (SDC‐3) shedding; the shed products that are released within the TME affect, among others, cancer cell proliferation (Fig. 4; Table 2) [10].

More recently, gelatinases have been implicated in the proteolytic processing of intracellular proteins [131, 152]. Notably, nuclear MMP‐2 can enhance ribosomal RNA transcription and drive cell proliferation by cleaving the N‐terminal tail of histone H3 (H3NT) in osteosarcoma cells [131], while MMP‐9 can modulate the transcriptional activation of growth stimulatory genes by degrading the H3NT in colon cancer cells [152]. The cytoplasmic tail of MT1‐MMP also mediates cancer cell proliferation by activating HIF factors, which further control the expression of proliferation‐related genes (Fig. 4; Table 2) [153].

MMPs—Fas/FasL axis in cancer progression

Beyond their role in cancer cell proliferation, MMPs can exhibit both pro‐apoptotic and anti‐apoptotic effects depending on their action [154]. Fas signaling, initiated by the interaction between Fas and its ligand (FasL), typically promotes apoptosis, thereby limiting abnormal cell proliferation and supporting programmed cell death. However, when disrupted, FasL can lead to the activation of pro‐survival signaling cascades, including MAPK and NF‐κB, ultimately increasing cancer cell survival and proliferation [155]. Notably, membrane‐bound FasL can be cleaved by MMP‐7, resulting in the release of soluble FasL (sFasL). Unlike its membrane‐bound form, sFasL is incapable of inducing apoptosis, thereby endowing cancer cells with apoptosis resistance and promoting metastasis across various types of cancer by contributing to tumor immune escape (Fig. 4; Table 2) [156, 157].

MMPs in epithelial‐to‐mesenchymal transition

EMT is a crucial biological mechanism involved in many physiological conditions; however, when abnormally activated, it mediates cancer progression by endowing cancer cells with aggressive/metastatic properties (i.e., increased mobility and invasiveness, enhanced stem cell‐like properties, apoptosis escape, resistance to both chemotherapy and immunotherapy) [158, 159]. Increasing evidence supports the role of MMPs in cellular adhesion and EMT, critical steps by which cancer cells disrupt tissue architecture and enable their intravasation into nearby blood vessels [71, 106]. While MMP‐19 constitutes a pure mesenchymal marker, other MMPs that also exhibit a demonstrated role during EMT mainly include MMP‐1, ‐2, ‐3, ‐7, ‐8, ‐9, ‐10, ‐11, ‐13, ‐20, ‐21, ‐28, and MT1‐, MT2‐, MT3‐, MT4‐MMP (Table 2) [2, 132, 160, 161]. The main MMPs functionalities in EMT are given in Fig. 5.

Fig. 5 — Summarizing illustration of the role of MMPs in EMT progression. By cleaving ECM components and cell adhesion molecules such as E‐cadherin, MMPs disrupt epithelial integrity and promote mesenchymal traits including increased motility and invasiveness. Distinct MMP subtypes act through various specific mechanisms: Collagenases (MMP‐1, MMP‐8, MMP‐13): activate NF‐κB signaling, degrade adhesion molecules such as dysadherin, activate TGF‐β and enhance cell motility. Stromelysins (MMP‐3, MMP‐10, MMP‐11): mediate E‐cadherin cleavage, β‐catenin release and PI3K/Akt or AXL pathway activation, contributing to mesenchymal marker upregulation. Matrilysins (MMP‐7): cleave E‐cadherin into soluble fragments, weakening epithelial junctions. Gelatinases (MMP‐2, MMP‐9): reduce E‐cadherin, upregulate mesenchymal markers, and activate TGF‐β signaling through fibronectin and E‐cadherin cleavage. Other archetypal MMPs (MMP‐19, MMP‐20): promote EMT‐associated protein expression, reduce E‐cadherin, regulate gelatinase activity, and enhance motility. Furin‐activated MMPs: GPI‐anchored (MT4‐MMP) promote EMT in tumor‐associated macrophages (TAMs), transmembrane type I (MT1‐MMP, MT2‐MMP, MT3‐MMP) drive TGF‐β activation, E‐cadherin cleavage, β‐catenin redistribution and upregulation of mesenchymal markers such as vimentin and N‐cadherin, secreted MMPs (MMP‐21, MMP‐28) induce EMT *in vivo* and activate Notch3/TGF‐β pathways, increasing transcription factors such as ZEB and Snail. Collectively, these enzymes reshape the TME and promote molecular signaling cascades that enhance cancer cell plasticity and metastatic progression. Created with BioRender.

MMPs‐mediated proteolysis of cell adhesion molecules

MMPs actively promote EMT by ECM remodeling within the TME and triggering signaling cascades that favor mesenchymal transition [84]. MMP‐3, ‐7, ‐9, and MT1‐MMP facilitate the cleavage of E‐cadherin, disrupting epithelial cell adhesion junctions and releasing a bioactive E‐cadherin fragment that further induces cancer cell motility (Fig. 6) [71, 162]. Particularly, MMP‐7 further facilitates the cleavage of E‐cadherin into its soluble form, thus enabling cancer cells to disseminate from the primary tumor during the initial stages of metastasis [54]. MT2‐MMP has also been shown to shed adhesion molecules and tight junction proteins [including E‐cadherin and Zonula Occludens‐1 (ZO‐1)], while also decreasing β‐catenin association with the cell surface, thereby consisting an important EMT mediator [79]. Additionally, MMP‐13 contributes to EMT plasticity via mechanotransduction pathways, as it disturbs intercellular adhesion, thereby leading to a more dispersed arrangement of breast cancer cells [132]. Finally, MMP‐8 can also promote tongue carcinoma cell–cell adhesion junctions through the degradation of dysadherin (Table 2) [34].

Fig. 6 — Schematic representation of the main functions of MT‐MMPs in cancer cell migration and invasion. MT‐MMPs are key mediators of cancer cell migration and invasion through the proteolytic remodeling of ECM and the activation of intracellular signaling pathways. MT1‐MMP degrades ECM components such as fibronectin, vitronectin, and laminin‐332, activates pro‐MMP‐2, and cleaves cell surface molecules including integrins, CD44, and E‐cadherin. These activities facilitate cytoskeletal remodeling and gene expression alterations via RAC1, RhoA, FAK, ERK, and hypoxia‐inducible transcription factors, inducing invasive motility. MT1‐MMP also sheds protein‐tyrosine kinase‐7, EphA2, PAR‐1 and cancer antigen 125 promoting ErbB signaling and cell junction disassembly. MT3‐MMP promotes migration by regulating Wnt signaling and inhibiting collagen fiber alignment, enhancing lymphatic invasion. MT4‐MMP facilitates invadopodia formation and amoeboid‐like motility through dimerization and interactions with Tks5 and PDGFRα, activating Src, Rho, and Cdc42 pathways. MT6‐MMP cleaves alpha‐1 proteinase inhibitor, supporting ECM degradation. Conclusively, MT‐MMPs orchestrate ECM degradation and intracellular signaling cascades to enable cancer cell migration and invasion. Created with BioRender.

MMP‐mediated expression of mesenchymal markers

Beyond their role in shedding intercellular adhesion molecules, MMPs mediate EMT by inducing the transcription of mesenchymal markers (Table 2) [160]. Vimentin, fibronectin, and N‐cadherin constitute some of the main mesenchymal markers, while zinc finger E‐box binding homeobox (ZEB1/2), Snail, Slug, Smug, and Twist1/2 constitute transcription factors related to EMT [163]. Of note, MMP‐1 knockdown has been shown to significantly decrease the expression of N‐cadherin, vimentin, and Twist1, alongside the concurrent increase of E‐cadherin, revealing its role in EMT in colorectal and cervical cancer [124, 164]. MMP‐11 has also been shown to induce CRC EMT by upregulating Slug expression levels [165]. Knockdown of MMP‐19 resulted in significant changes in the expression of EMT‐related proteins, particularly the upregulation of E‐cadherin and the downregulation of N‐cadherin and vimentin, suggesting the role of MMP‐19 in promoting EMT in CRC (Fig. 5) [166].

Gelatinases are among the most commonly cited MMPs implicated in EMT [84, 167]. Notably, MMP‐2 mediates EMT in nasopharyngeal carcinoma by reducing E‐cadherin expression, along with the concurrent increase in N‐cadherin, fibronectin, and Slug levels [161]. Furthermore, MMP‐9 activation can trigger Notch1 signaling, which directly alters the expression of E‐cadherin and leads to the expression of Slug and Snail in CRC [168]. MMP‐20 silencing diminishes the expression levels of gelatinases, as well as increasing the expression of E‐cadherin, along with the reduction of N‐cadherin, vimentin, Snail, and Twist in oral squamous cell carcinoma cells, implicating its role in promoting EMT and cell motility [169].

MMP‐28 has been reported to enhance EMT in hepatocellular carcinoma via Notch3 signaling, by significantly upregulating ZEB‐1, ZEB‐2, N‐cadherin, and Snail, and downregulating E‐cadherin, respectively [170]. Finally, MMP‐10‐mediated EMT of tongue cancer cells includes AXL signaling activation, thus upregulating N‐cadherin, Vimentin, Slug, MMP‐9, and β‐catenin, while suppressing E‐cadherin [127].

MT‐MMPs hold significant roles in inducing EMT and the subsequent enhanced cancer cell motility (Fig. 6). Notably, MT1‐MMP‐driven EMT in squamous cell carcinoma has been linked to elevated expression of ZEB1/2 and Twist, along with the concurrent reduction of E‐cadherin levels [74]. Additionally, MT3‐MMP facilitates hepatocellular carcinoma progression by mediating EMT, thereby upregulating N‐cadherin and Vimentin, while decreasing E‐cadherin at mRNA and protein levels (Table 2) [171].

MMPs—NF‐κΒ axis in EMT induction

Studies have revealed that NF‐κB signaling further enhances cancer cell metastasis by inducing EMT (Fig. 6) [172]. MMP‐1 mediates the NF‐κB pathway, which drives EMT by downstream signaling cascades in hormone‐dependent breast cancer cells [149], while MMP‐3 is also found to promote EMT by inducing ROS that further activate NF‐κB, thereby mediating the transcription of Snail in breast cancer cells (Table 2) [173].

MMPs—TGF‐β and MMP – Wnt axis in EMT induction

Wnt/β‐catenin and TGF‐β pathways are key regulators of EMT in cancer progression [174, 175]. MMP‐8, ‐9, ‐28, and MT1‐MMP have been shown to drive TGF‐β‐induced EMT in various types of solid tumors [2]. Particularly, the interplay between MMP‐8 and TGF‐β1 stimulates EMT and malignant progression of hepatocellular carcinoma, while its high expression has been correlated with poor prognosis of liver and ovarian cancer patients [2, 176]. Additionally, MMP‐9 mediates EMT by cleaving fibronectin, and therefore releasing the active TGF‐β [177, 178], while MMP‐28 also participates in TGF‐β‐mediated EMT of lung cancer cells by releasing the active factor from its complex [35, 179]. Moreover, MT1‐MMP exhibits the ability to boost EMT to the adjacent cells by upregulating the activated TGF‐β [75]; as already mentioned, MT1‐MMP can release the active TGF‐β via proteolytic cleavage of the LTBP‐1 [74]. Furthermore, MMP‐3 functions as an effector of Wnt signaling by releasing β‐catenin from adhesion junctions, thereby mediating the transcription of mesenchymal markers (i.e., Twist, Snail) (Table 2) [106, 180].

TME‐ and exosome‐associated MMPs in EMT induction

As already mentioned, EVs/exosomes contain matrix‐degrading enzymes, including MMPs [118]. Although limited studies directly demonstrate the capacity of exosomal MMPs to promote cancer cell proliferation [181], emerging evidence highlights the complex role of distinct signals from the TME in shaping cancer cell plasticity, and thereby driving EMT during cancer progression [182]. Of note, cancer‐associated fibroblasts (CAFs) released MMP‐11 may induce EMT to promote pancreatic cancer progression through the PI3K/Akt pathway [183]. Furthermore, MT4‐MMP in tumor‐associated macrophages (TAMs) is also associated with hepatocellular carcinoma propagation by inducing EMT [184]. While MMP‐21 did not significantly affect epithelial/mesenchymal markers levels in vitro, its overexpression in mouse xenograft models promoted EMT and cancer progression, suggesting that MMP‐21 probably collaborates with other tumor‐associated cells within the TME in order to indirectly drive cancer advancement [185].

Exosomes (enriched in MMP‐1) derived from highly metastatic cells have been shown to enhance the malignancy of breast cancer cells, potentially by promoting EMT through the protease‐activated receptor‐1 (PAR‐1) signaling pathway [186]. MMP‐13‐enriched exosomes were also shown to promote cell motility by inducing EMT (increase in E‐cadherin and decrease in N‐cadherin and vimentin in the recipient cells) (Table 2) [187, 188].

MMPs in cancer cell migration and invasion

Aberrant EMT is linked with malignant cell properties (enhanced migratory and invasive capacity) that drive cancer progression, while MMPs importantly mediate these properties by degrading components of the pericellular ECM [158]. Several MMPs have been implicated in cancer cell migration and invasion, including MMP‐1, ‐2, ‐3, ‐7, ‐8, ‐9, ‐10, ‐11, ‐12, ‐‐13, ‐19, ‐20, ‐21, ‐26, ‐28, and MT1‐, MT2‐, MT3‐, MT4‐, MT6‐MMP (Table 2) [36, 84, 160, 162, 189, 190, 191, 192]. The migratory and invasive characteristics obtained by cancer cells are importantly influenced by ECM stiffness; thus, they are facilitated through the targeted degradation of specific matrix components and matrix‐related effectors (Fig. 3) [160].

MMP‐mediated proteolytic degradation of basement membranes

The proteolytic degradation of basement membrane and pericellular ECM components mediates cancer cell invasion by generating bioactive peptides or neoepitopes that disrupt cell‐matrix interactions, while also creating physical pathways that facilitate tumor cell migration into surrounding tissues (Fig. 3) [134, 193, 194]. Gelatinases are critically implicated in cancer cell invasion in various cancer types by degrading two major components of the basement membranes, gelatin and collagen type IV (Table 2) [195, 196]. Further than its well‐established proteolytic function, MMP‐2 has also been shown to drive ovarian cancer cell invasion by degrading fibronectin and vitronectin [197]. The cleaved fragments promote the interaction of ovarian cancer cells with mesothelial cells through integrins [198]; ovarian cancer cell spheroids apply mechanical forces across the mesothelial layer, which disrupt the submesothelial basement membrane and enable the subsequent cell invasion into the underlying connective tissue [199]. MMP‐2 was further shown to drive glioma invasion and metastasis by directly interacting with α₅β₁ integrin [200]. MMP‐13‐mediated activation of MMP‐2 and ‐9, as well as MT1‐MMP‐mediated activation of MMP‐2, are actively involved in cancer cell invasion through ECM degradation [35, 201]. Finally, MMP‐21 and MMP‐28 expression is significantly implicated in tumor/vascular invasion and metastasis, mediated through the degradation of ECM components (Table 2) [202].

Roles of less‐studied MMPs in cancer cell migration and invasion

The role of MMP‐10 in pancreatic adenocarcinoma and hepatocellular carcinoma cell migration/invasion is shown through knockdown experiments, with the latter being established both in vitro and in vivo [126, 170]. Respectively, the migratory/invasive role of MMP‐10 was demonstrated in vitro and in vivo, where tongue cancer cell motility is mediated through the receptor tyrosine kinase AXL signaling pathway (Table 2) [127]. MMP‐11 knockdown has further impacted CRC migration and invasion of CRC cells in vitro [165], while its overexpression in oral squamous carcinoma cells increased cell migration in vitro, particularly via the downstream activation of the FAK signaling pathway [203]. Finally, knockdown experiments revealed the crucial role of MMP‐19 and ‐20 in ovarian cancer cell motility and invasion [204], while MMP‐12 knockdown further resulted in reduced invasion of lung carcinoma cells on Matrigel® substrate [128]. MMP‐26 drives NSCLC cell invasion and migration in vitro, particularly through its coordination with MMP‐9 [205]. Notably, it has been shown to proteolytically cleave and activate pro‐MMP‐9, which further cleaves fibronectin and induces pancreatic cancer cell invasion (Table 2) [67]. Moreover, MMP‐26 participates in the malignant phenotype of the less‐invasive MCF‐7 breast cancer cells by inducing enhanced cell dissemination, migration, and invasion [206].

MMPs in invadopodia formation and cancer cell migration

Actin polymerization at the leading edge of the plasma membrane drives the formation of protrusive structures (i.e., lamellipodia, filopodia, podosomes, and invadopodia) in the migrating cells [207]. The maturation of invadopodia involves targeted delivery and exocytosis of MMP‐2, ‐9, and SDC‐1 that contribute to ECM degradation, with MT1‐MMP holding a significant role in basement membrane breakage [207, 208]. MMP‐7 is also found at the invasive protrusions of cancer cells [209]. Interestingly, MMP‐2‐mediated activation of the intracellular p38 MAPK/MK‐2/HSP27 pathway results in actin polymerization, thus driving breast cancer cell migration (Table 2) [210].

MT1‐MMP roles in cancer cell migration and invasion

MT1‐MMP, frequently overexpressed in tumor tissues compared to normal counterparts, is widely recognized as a potent pro‐migratory and pro‐invasive factor that enhances cancer cell migration, invasion, and metastasis [74]. Notably, it has been shown to participate in the degradation of the basement membrane, CD44, and E‐cadherin, respectively (Table 2) [86]. Furthermore, cleavage of the integrin α_ν subunit by MT1‐MMP was reported to induce the activation of FAK and its downstream signaling, thereby mediating breast cancer cell migration on a vitronectin substrate [211]. As previously mentioned for its proliferative role, MT1‐MMP has been demonstrated to promote cancer cell migration by degrading fibronectin/vitronectin; the released RGD motifs induce integrin α_νβ₃‐mediated ERK and FAK signaling in 3D collagen matrices [142, 143]. MT1‐MMP‐mediated cleavage of erythropoietin‐producing hepatocellular receptor‐2 (EphA2) has also been shown to promote ErbB signaling and drive fibrosarcoma and epidermoid carcinoma cell migration [212]. In another study, cleaved EphA2 triggered intracellular EphA2 translocation, with a following increase in RhoA activity and cell junction disassembly, thereby promoting breast cancer cell invasion within a collagen substrate both in vitro and in vivo (mouse xenografts) [213]. Additionally, the release of soluble (shed) protein tyrosine kinase‐7, degraded by MT1‐MMP, causes enhanced cancer cell invasion and polarized motility [74, 214]. MT1‐MMP further mediates melanoma cell dissemination and motility, particularly by activating the cytoskeleton regulator RAC1, which induces the expression of genes regulating cell migration and invasion [215, 216, 217]. Finally, MT1‐MMP‐mediated ectodomain shedding of cancer antigen 125 on ovarian cancer cells regulates their invasive capacity within the collagen‐rich submesothelial matrix [76].

Other MT‐MMPs roles in cancer cell migration and invasion

Other MT‐MMPs also exhibit crucial roles in cancer cell migration and invasion (Table 2). Particularly, MT2‐MMP silencing in multiple myeloma cells significantly decreased their motility and invasion [144]. Additionally, MT3‐MMP has been shown to promote gastric cancer cell migration and invasion, as it stands as a critical mediator of Wnt‐mediated gastric cancer progression and metastasis [145, 171]. MT3‐MMP further enhances the invasive capacity of melanoma cells by inhibiting collagen fiber alignment and inducing lymphatic invasion [171, 218]. Furthermore, MT4‐MMP enhances invadopodia formation and subsequent cell motility in head and neck cancer cells, by interacting with Tks5 and PDGFRα, which induces Src signaling and the subsequent activation of Rho and Cdc42, thus promoting amoeboid‐like movement [219]. MT4‐MMP in TAMs is also linked to hepatocellular carcinoma cell motility and invasion, leading to cancer progression and metastasis [184]. Beyond ECM degradation, MT4‐MMP‐mediated cancer cell migration and invasion in vitro has been attributed to its dimerization through cysteine residues [82]. Finally, MT6‐MMP acts by cleaving and reducing the levels of alpha‐1 proteinase inhibitor, thereby facilitating ECM degradation and the subsequent colon cancer migration and invasion [84]. The various actions and pathways of MT‐MMPs are summarized in Fig. 6.

MMP‐driven adhesion molecules disruption and PGs shedding in tumor invasion

MMP‐7 exhibits a crucial role in basal cell carcinoma invasion by degrading the basement membrane, E‐cadherin, and the HB‐EGF [86]. Furthermore, it induces cancer cell migration and invasion through the degradation of cell surface proteins, the disruption of adhesion molecules (i.e., c‐type lectin domain 3 member A), and thereby facilitating basement membrane breakdown and tumor metastasis [58, 162]. The E‐cadherin/SDC‐1 complex functions as an invasion suppressor; thus, MMP‐7‐mediated cleavage of either component facilitates morphological changes in cancer cells, promoting their migration and invasion [86]. SDC‐1 ectodomain (shed by MT1‐MMP) has been shown to enhance human fibrosarcoma cell migration on collagen substrates [201]. Similarly, MMP‐9‐mediated shedding of SDC‐1 and ‐4 facilitates ECM degradation during cervical cancer cell invasion and ultimately metastasis (Table 2) [220]. Finally, MMP‐7‐mediated cleavage of perlecan was shown to induce FAK downstream signaling, hence driving prostate cancer cell invasion [59].

MMPs—Laminin and MMPs—Osteopontin axis in cancer cell migration and invasion

Laminin‐332 proteolysis (mediated by MMP‐2, ‐3, ‐13, ‐19, ‐20, and MT1‐MMP) and the generation of smaller fragments (i.e., γ2 chain) promote cancer cell migration [92]. Interestingly, laminin‐332 proteolysis mediated by MMP‐13 facilitates melanoma cell invasion, probably through the release of fragments that allow the motility of cancer cells through the ECM [36, 221]. Laminin‐332 γ2 chain cleavage by MT1‐MMP in two different sites was shown to secrete an EGF‐like fragment (Domain III) that activates EGFR and its downstream signaling, resulting, among others, in the increased cancer cell motility and invasion [92, 117, 222]. Furthermore, osteopontin (OPN) can also undergo proteolytic cleavage by MMP‐7 and ‐9 [60]. The resultant OPN fragments have been shown to further promote glioblastoma cell migration [60] and hepatocellular carcinoma cell invasion, respectively (Table 2) [223].

MMPs–PAR‐1 axis in cancer cell migration and invasion

Beyond its role in EMT, PAR‐1 promotes cancer cell migration and invasion by increasing cell adhesion to the surrounding ECM [224]. MMP‐1, ‐2, ‐9, ‐13, and MT1‐MMP have been shown to cleave and activate PAR‐1, while the role of MMP‐1 in driving PAR‐1‐mediated cancer cell migration and invasion is well‐established in many different types of cancer [30, 225]. Of note, tumor‐infiltrating fibroblast‐released MMP‐1 was shown to hold a key role in the activation of PAR‐1 and the downstream induction of breast cancer cell migration and invasion, utilizing a xenograft model (Table 2) [191, 226].

MMPs–TGF‐β axis in cancer cell migration and invasion

Apart from their role in ECM remodeling and physical barrier breakage (i.e., collagen, elastin, fibronectin, and laminin degradation), MMPs are shown to release biologically active molecules (i.e., growth factors or growth factor‐like fragments) that initiate intracellular signaling pathways [54]. As already mentioned, TGF‐β acts as a tumor suppressor in premalignant cells; however, cancer cells utilize TGF‐β's tumorigenic roles to facilitate cancer progression and metastasis [227]. MT1‐MMP and MMP‐2 could proteolytically activate TGF‐β, thus promoting cancer cell migration and invasion [225]. MMP‐9 has also been shown to activate TGF‐β and its downstream Smad signaling, which further induces the invasion and metastasis of CRC [228]. Interestingly, the crosstalk between MMP‐8 and TGF‐β1 promotes hepatocellular carcinoma cell migration and invasion, mainly through the activation of PI3K/Akt/Rac1 signaling (Table 2) [176].

MMPs–CD44 axis in cancer cell migration and invasion

Interactions between CD44 and MMPs guide matrix‐degrading enzymes to the invadopodia of the migrating cancer cells, thereby resulting in the degradation of ECM components [229]. Notably, CD44 serves as a platform for the assembly of various MMPs with their substrates to modulate cell migration [230]. MT1‐MMP guides enhanced CD44 cleavage along with cell migration and invasion of cancer cells [153, 201, 231]. Moreover, the CD44 interaction with MMP‐9 is shown to promote the degradation of collagen IV, and therefore cell migration and invasion [229, 232]. Furthermore, CD44, MT1‐MMP, MMP‐2, ‐9, and TIMP‐2 form a multiprotein complex that attaches to F‐actin intracellularly, thereby influencing cell–cell and cell–matrix interactions and inducing alterations in cancer cell migration (Table 2) [233].

Further than proteolytic degradation, nuclear MMP‐3 induces the expression of the connective tissue growth factor by interacting with heterochromatin protein gamma, which is further involved in glioma cell migration [28]. The cytoplasmic tail of MT1‐MMP further promotes cancer cell motility by activating HIF factors that mediate the expression of migration/invasion‐related genes [153], while it also induces RhoA activation, thereby driving RhoA‐dependent actin polymerization and cancer cell invasion (Table 2) [160, 234].

TME‐associated MMPs in cancer cell migration and invasion

The dynamic intercellular communication within the TME actively drives cancer cell migration and invasion (Fig. 3) [28, 235]. Interestingly, CAF‐released MMP‐1 and ‐9 were shown to mediate the invasion of breast cancer cells [236]. Furthermore, 3D co‐culture models of fibroblasts with low‐aggressiveness breast cancer cells demonstrated that fibroblast‐released MMP‐9 and MT1‐MMP alter collagen architecture, thereby enhancing cancer cell invasiveness [237]. Other studies revealed that cervical and melanoma cancer cells can activate the Schwann cells within the TME to secrete MMP‐2, ‐9, ‐12, and MMP‐1, respectively, thereby degrading the surrounding matrix and driving cancer cell migration and invasion [238, 239]. Moreover, stromal cell‐secreted MMP‐9 has been shown to promote—via its non‐catalytic functions—the rounded‐amoeboid invasion of melanoma cells [240, 241].

Exosomal MMPs in cancer cell migration and invasion

MMPs loaded in EVs/exosomes degrade the basement membranes and other matrix components, driving cell motility and invasion during cancer progression (Fig. 3) [242]. Numerous studies have identified MMPs as integral EV/exosomal cargo and characterized their downstream effects on surrounding matrix and recipient cell behavior. We have already discussed the crucial roles of MMP‐2, ‐9, and MT1‐MMP in mediating the disruption of basement membranes. Notably, EVs secreted from ovarian cancer ascites, enriched in active MMP‐2 and MMP‐9, degrade the ECM to drive tumor invasion on Matrigel^® substrate [243, 244], while EVs from fibrosarcoma and melanoma cells similarly remodel the matrix through MT1‐MMP‐mediated activation of pro‐MMP‐2 [99, 244]. As mentioned before, multiple myeloma‐derived EVs are reported to reprogram monocytes, triggering the secretion of MMP‐9, and thereby enhancing, beyond proliferation, multiple myeloma cell migration [181]. In addition, exosomes derived from metastatic medulloblastoma cells were shown to activate these cells' migration and invasion in vitro, through MMP‐2‐mediated degradation of the surrounding ECM [245]. Furthermore, adipocytes were shown to increase the invasive capacity of lung cancer cells by secreting exosomes with high levels of MMP‐3, that further activates MMP‐9, and thereby promote cancer cell invasion on Matrigel^®, but also in vivo [246].

MMPs in angiogenesis and vascular integrity

Within the TME, cancer cells exploit angiogenic programs to sustain oxygen and nutrient delivery, support metabolic demands, as well as enable metastatic dissemination through leaky and disorganized vasculature that facilitates intravasation, immune evasion, and neovascularization that is a hallmark of tumor progression [247, 248, 249]. Angiogenesis is primarily regulated by vascular endothelial growth factor‐A (VEGF‐A), which drives endothelial proliferation, survival, and migration via VEGFR‐2 signaling. Additionally, FGF‐2 and angiopoietins (Ang1 and Ang2) regulate endothelial activation and vascular stability through FGFR1 and Tie2 receptors, respectively [250]. The interplay among these growth factors, integrin‐mediated adhesion, and ECM remodeling orchestrates the dynamic and spatially regulated nature of tumor‐associated neovascularization.

MMPs exhibit indispensable roles in ECM remodeling during angiogenesis and the intravasation of EMT‐like cancer cells (Fig. 3). Endothelial sprouting from pre‐existing vessels demands precise and localized degradation of basement membranes and interstitial ECM components, processes largely driven by specific MMPs. Key structural ECM constituents, including collagen IV, laminin, and fibronectin, are predominantly degraded by gelatinases, as well as by MT1‐MMP, thereby creating permissive paths for endothelial cell migration and vessel sprouting [54, 193]. MT1‐MMP, highly expressed at endothelial cell protrusions, acts directly on ECM components and concurrently activates pro‐MMP‐2, amplifying proteolytic cascades essential for sustained endothelial invasion [251, 252]. In particular, MT1‐MMP is highly expressed at endothelial tip cell protrusions and not only does it cleave ECM directly, but also engages VEGFR1/2 signaling, promoting vascular formation and maturation [75, 253]. Furthermore, MMP‐dependent proteolysis liberates angiogenic growth factors such as VEGF‐A and FGF‐2 from ECM sequestration, strengthening paracrine signaling pathways critical for endothelial cell chemotaxis and proliferation [254]. MMP‐3, MMP‐7, and MMP‐13 have also been implicated in the release of ECM‐bound angiogenic mediators—such as VEGF and IGFBPs—enhancing endothelial recruitment and neovessel formation across multiple tumor models [54, 255].

In the context of tumor progression, MMP‐mediated ECM remodeling significantly enhances the permeability and structural irregularity of the tumor vasculature. Such structural alterations are crucial for not only facilitating oxygen and nutrient supply but also enabling intravasation (Fig. 3). Intravasation is critically supported by MMP‐driven basement membrane degradation, with MMP‐1, MMP‐2, and MMP‐9 actively contributing to vascular barrier breakdown, promoting tumor cell access to the vascular lumen and enhancing metastatic spread [193, 256]. Recent studies emphasize the role of MMP‐10 and MT1‐MMP in perivascular ECM modification, reinforcing vascular permeability and directly influencing tumor cell extravasation efficiency [193, 257]. Additionally, MMP‐12 and MMP‐19 have been shown to regulate endothelial junctional integrity and leukocyte transmigration, which may indirectly facilitate cancer cell intravasation under inflammatory microenvironmental conditions [93, 258]. This finely regulated balance between ECM degradation and angiogenic factor mobilization underscores the essential yet complex role of MMPs in tumor‐promoting angiogenesis and metastasis.

Dysregulated MMP activity disrupts vascular integrity, contributing to abnormal angiogenesis characterized by increased permeability, impaired perfusion, and reduced responsiveness to anti‐angiogenic therapies [38, 259]. This imbalance is further exacerbated by tumor‐derived exosomes carrying pro‐angiogenic MMPs such as MMP‐13 and MMP‐16 that reprogram endothelial cells and prime the PMN [260]. The integration of these insights into MMP biology is essential for developing more effective therapeutic strategies targeting tumor angiogenesis and metastatic progression.

MMPs in immune surveillance

MMPs dynamically shape immune surveillance through modulation of immune cell migration, signaling, and tumor–immune crosstalk. MMP‐9 and MT1‐MMP, prominently expressed by neutrophils and macrophages, cleave basement membrane components such as laminin, collagen IV, and fibronectin, facilitating diapedesis and interstitial movement of leukocytes [261, 262]. These proteases also regulate ECM mechanics—modifying stiffness, porosity, and integrin engagement—which fine‐tunes chemokine gradients and directs immune cell polarization and motility [261, 263]. Beyond migration, MMP activity at immune synapses promotes receptor clustering and granule secretion, critical for T‐cell cytotoxicity and memory formation [264].

Within the TME, MMPs play multifaceted, context‐dependent roles. Neutrophil‐derived MMP‐9 drives ECM remodeling and vascular permeability, releasing VEGF to support angiogenesis and, paradoxically, fostering both immune infiltration and tumor progression [265, 266]. TAMs express MT1‐MMP, enabling perivascular ECM degradation, angiogenesis, and TGFβ activation, which reinforce immunosuppressive niches and establish physical barriers to CD8⁺ T cell infiltration [267, 268]. MMP‐mediated remodeling can either facilitate T‐cell entry or, when dysregulated, reinforce stromal exclusion in desmoplastic tumors. MMP‐10 has been implicated in coordinating ECM remodeling at metastatic niches, further influencing immune timing and access [269]. Additionally, MMP‐8 (neutrophil collagenase) modulates inflammatory responses through cleavage of IL‐8 and CCL3, and its deficiency has been associated with increased tumor burden and immune surveillance in preclinical models [270]. MMP‐12 (macrophage metalloelastase), primarily expressed by TAMs, degrades elastin and modulates macrophage polarization toward an immunosuppressive phenotype [258]. MMP‐2 not only facilitates T‐cell recruitment through ECM degradation but also promotes the release of latent TGF‐β, facilitating regulatory T‐cell expansion and immune tolerance in the TME, whereas MMP‐7 is involved in the shedding of FasL and SDC‐1, impacting apoptotic signaling and chemokine presentation [271, 272].

MMPs additionally modulate immune signaling networks. Particularly, MMP‐2 and MMP‐9 cleave chemokines such as CCL2 and CXCL8, altering leukocyte recruitment and inflammatory tone, while MMP‐7, which can associate with cell‐surface PGs, and MT1‐MMP regulate immune responses by cleaving key receptors such as Fas, thereby influencing NF‐κB and MAPK signaling cascades in immune and cancer cells [262, 273].

Crucially, MMPs have emerged as pivotal regulators of immunotherapy response. Elevated MMP activity is linked to immune‐excluded tumors with poor T‐cell localization, reduced antigen presentation, and checkpoint resistance. Genetic ablation or pharmacologic inhibition of specific MMPs (notably MMP‐9 or MT1MMP) has been shown to normalize ECM, reduce matrix stiffness, and enhance CD8⁺ T cell infiltration, synergizing with anti‐PD‐1 and anti‐CTLA‐4 treatments in preclinical cancer models [191, 264]. Recent studies also suggest that targeting MMP‐12 and MMP‐7 may enhance macrophage reprogramming and antigen‐presenting cell functionality, potentially improving checkpoint inhibitor efficacy in immunologically cold tumors [264]. Such evidence highlights MMPIs as powerful adjuncts in combination immunotherapeutic strategies, especially for tumors characterized by dense stroma or immune exclusion.

MMPs in pre‐metastatic niche formation

Tumors can influence distant organ sites by inducing molecular and cellular mechanisms that establish a permissive environment even before metastatic cells arrive, a process known as PMN formation. PMN is a tumor‐conditioned, cancer cell‐free microenvironment that supports future colonization by CTCs, playing a key role in the initial steps of metastasis [274, 275]. The formation of the PMN is a dynamic, multistage process that can generally be divided into three main phases: initiation, development, and colonization. During the initial phase, primary tumor sites release EVs and tumor‐derived secreted factors, triggering alterations in specific distant organs. In the development phase, secondary sites undergo modifications, including metabolic reprogramming of cells, immunosuppression, angiogenesis, ECM remodeling, and inflammation, which collectively reshape the microenvironment to support future colonization by CTCs [269, 276, 277, 278].

MMPs appear to be key facilitators in establishing this tumor‐promoting environment at secondary sites in the body [279]. More precisely, MMPs serve as key regulators of CTC extravasation by degrading vascular endothelial barriers (Table 2) [280]. In breast cancer, MMP‐1 co‐expression with MMP‐2, epiregulin, and cyclooxygenase‐2 (COX‐2) increases vascular permeability and promotes lung metastasis [274]. Additionally, upregulation of MMP‐3 and MMP‐10 is linked to disruption of vascular integrity in premetastatic lungs, acting synergistically with Αng2 and promoting CTCs' extravasation [269, 274, 279, 281, 282]. MMP‐9 is also highly expressed in PMNs, increasing vascular permeability by degrading the vascular basement membrane and sequestering VEGF and TGF‐β [283]. Moreover, MMP‐9 produced by recruited Gr1⁺CD11b⁺ myeloid cells reduces pericyte coverage and disrupts VE‐cadherin‐mediated junctions in the vascular endothelium, leading to abnormal and leaky vasculature in the premetastatic lungs (Table 2) [269].

The recruitment of bone marrow‐derived cells (BMDCs) and other immune cells is a key step for the development of the PMN [278]. MMP‐2 expression by BMDCs degrades collagen IV, leading to the production of collagen IV peptides that act as chemoattractants, promoting BMDC recruitment to the niche [281, 282]. MMP‐9 is highly expressed in endothelial and MAC1+/VEGFR1+ myeloid cells in the PMN, promoting tumor invasion and BMDC recruitment by releasing soluble factors such as Kit‐ligand [281]. The role of MMP‐13, which activates pro‐MMP‐9 and further promotes BMDC and immune cell recruitment to the niche, is also very crucial (Table 2) [35].

The inhibition of inflammatory monocyte recruitment via the CCL2‐CCR2 axis in CCR2‐DTR mice with pre‐metastatic lungs significantly reduces MMP‐9 expression and cancer cell extravasation, indicating that primary tumor‐driven recruitment of monocytes and subsequent macrophage infiltration are key drivers of MMP‐9 upregulation in the lung PMN. Additionally, secretion of both gelatinases by TAMs further contributes to ECM remodeling during PMN formation [277]. In CRC‐associated liver metastasis, immature myeloid cells are recruited to the liver PMN, where they secrete MMP‐2 and MMP‐9 to degrade the liver ECM (Table 2) [284].

Exosome‐derived factors also contribute to MMP expression in PMN, with heat shock protein 90 carried by tumor‐derived exosomes inducing MMP‐2 expression in the niche. Additionally, proteomic analyses of ascites‐derived exosomes from ovarian and breast cancer have identified both latent and active MMP‐2 and MMP‐9, with emerging evidence suggesting that MT1‐MMP may activate exosome pro‐MMP‐2 to enhance collagen I remodeling [281]. Moreover, exosomes containing MMP‐13 also contribute to the remodeling of ECM at future metastatic sites through the degradation of structural components like collagen and fibronectin [35]. Finally, other studies have demonstrated that MMP‐7 production is promoted in Kupffer cells in response to miR‐135a‐5p‐containing EVs released by hypoxic CRC cells within the liver PMN (Table 2) [285].

Novel insights into MMPs targeting and MMP‐based diagnostics

Next‐generation MMP inhibitors

Early efforts to inhibit MMPs in clinical settings were dominated by broad‐spectrum small molecules that functioned primarily through Zn²⁺ chelation at the catalytic site. These compounds, including batimastat and marimastat, showed initial potential in preclinical models; however, they failed in clinical trials because of dose‐limiting toxicities—most notably musculoskeletal pain—and lack of selectivity, which led to off‐target effects across the MMP family [286, 287]. Beyond toxicity, these failures also highlighted two critical issues: functional redundancy among MMPs, which allowed compensatory activity when one protease was blocked, and the absence of predictive biomarkers for patient stratification, meaning inhibitors were tested in unselected populations where MMP activity might not have been the main driver of disease [40].

To overcome these limitations, next‐generation inhibitors have focused on increased specificity by mimicking natural substrates or targeting noncatalytic domains. Peptidomimetic inhibitors are engineered to resemble the transition state of enzymatic cleavage and can achieve high selectivity for individual MMPs. For instance, WAY‐170523 selectively inhibits MMP‐13 with minimal cross‐reactivity, offering a template for arthritis and cancer‐related applications [288]. These inhibitors benefit from rational design approaches based on high‐resolution crystal structures and computational modeling of active sites. In parallel, nonpeptidomimetic small molecules—including pyrimidinetrione‐ and thiirane‐based scaffolds—have been developed with improved pharmacokinetic and metabolic profiles, enhanced tissue penetration, and favorable oral bioavailability [289]. Such compounds exploit distinct exosites or hydrophobic pockets outside the catalytic Zn²⁺‐binding cleft, providing opportunities for allosteric modulation and reduced off‐target inhibition. Nevertheless, despite promising biochemical selectivity, very few of these molecules have advanced beyond early‐phase clinical trials, underscoring the translational gap between preclinical efficacy and clinical benefit [290].

Over the past decade, the field has progressed toward the selective inhibition strategies targeting MMP‐9 and MT1‐MMP, both upregulated in tumor‐associated vasculature. For example, the humanized allosteric monoclonal antibody GS‐5745 exhibits potent and specific MMP‐9 inhibition, suppressing tumor growth and metastasis in CRC models without causing musculoskeletal syndrome—offering a therapeutic window for vascular normalization and angiogenesis blockade [291]. Parallel efforts have yielded selective MT1‐MMP antibodies (i.e., DX‐2400) and small molecules that bind exosites or noncatalytic regions, successfully impairing endothelial cell invasion and lumen formation, and synergizing with anti‐VEGF agents in breast cancer xenografts [292]. Preclinical and early‐phase trials are now pairing MMPIs with anti‐VEGF therapies and immune checkpoint inhibitors, aiming to overcome compensatory mechanisms mediated by aberrant ECM remodeling and immune exclusion [293, 294]. For instance, the combination of anti‐angiogenic agents with checkpoint antibodies has shown enhanced vascular normalization and immune cell infiltration—suggesting an optimal context for MMP‐targeted cotherapies [295]. Overall, future success hinges on precise MMP targeting, spatial‐temporal control of protease inhibition, and rational combinatorial regimens.

Chemically modified tetracyclines

Chemically modified tetracyclines (CMTs) represent a promising class of non‐antimicrobial agents with potent MMP‐inhibitory properties. Unlike traditional tetracyclines, CMTs such as COL‐3 (also known as incyclinide) lack antibiotic activity due to the removal of the C4 dimethylamino group but retain the ability to chelate divalent metal ions, thereby inhibiting MMP catalytic activity [296, 297]. In addition to direct enzyme inhibition, CMTs downregulate MMP expression at the transcriptional level, possibly through interference with NF‐κB signaling and AP‐1 transcriptional complexes [298]. These compounds exhibit both anti‐invasive and anti‐inflammatory effects, making them attractive candidates for modulating tissue remodeling in cancer, infectious diseases, and pulmonary injury [299]. In preclinical sepsis‐induced acute respiratory distress syndrome models, COL‐3 significantly reduced lung inflammation, improved histopathological outcomes, and lowered mortality by modulating MMP activity and dampening neutrophilic infiltration [300]. Moreover, recent bioinformatics and in vitro studies suggest that COL3 can reverse lung injury‐associated gene expression signatures—particularly those involving inflammatory (i.e., TNF, MAPK, chemokines) and proteolytic (i.e., MT1‐MMP) pathways—highlighting its potential as an antilung injury agent [301]. The continuous development of CMTs may benefit from biomarker‐guided patient stratification and combination strategies with antifibrotic or immunomodulatory agents to enhance therapeutic efficacy.

Natural inhibitors of MMPs

Due to their potent tissue‐degrading properties, the activity of MMPs is tightly regulated [302]. Particularly, their regulation involves multiple steps, including transcriptional (regulated by hormones, growth factors, and cytokines, among others) and post‐translational controls, conversion of the inactive zymogen into the active enzyme, compartmentalization, as well as inhibition by TIMPs [4, 302, 303]. The TIMPs family includes four members (TIMP‐1, ‐2, ‐3, ‐4) that block the enzymatic activity of MMPs by binding directly to their catalytic sites, forming 1:1 stoichiometric inhibitory complexes [302, 304]. Many TIMPs can interact with and inhibit several different MMPs, with each TIMP exhibiting distinct expression patterns and substrate specificities [302]. TIMP‐1 can inhibit MMP‐1, ‐3, ‐7, and ‐9; TIMP‐3 exhibits a broad inhibitory profile, inhibiting all MMPs, while TIMP‐4 inhibits MMP‐2, ‐26, and MT1‐MMP [38, 305, 306, 307]. Notably, TIMP‐2 exerts a dual role, constituting a potent inhibitor of most MMPs (particularly MMP‐2), while also facilitating the activation of MMP‐2 by forming a ternary complex consisting of a MT1‐MMP dimer, TIMP‐2, and pro‐MMP‐2 [201, 308].

Beyond TIMPs, additional endogenous inhibitors contribute to MMP regulation. α2‐Macroglobulin, a broad‐spectrum protease inhibitor abundant in plasma, sequesters MMPs through bait region cleavage followed by conformational entrapment, effectively clearing them from circulation [4]. Another key modulator is the membrane‐anchored glycoprotein, reversion‐inducing cysteine‐rich protein with Kazal motifs (RECK), which suppresses the activity of MMP‐2, MMP‐9, and MT1‐MMP, and is frequently downregulated in aggressive tumors [309, 310]. RECK stabilizes the basement membrane and inhibits tumor cell invasion, angiogenesis, and metastasis. The coordinated actions of these natural inhibitors underscore the importance of spatial and temporal control over MMP function in both physiological tissue remodeling (i.e., wound healing, morphogenesis) and pathological contexts such as cancer, fibrosis, and inflammation. Disruption of this regulatory network—via TIMP downregulation, protease overexpression, or loss of RECK—has been linked to enhanced tumor progression and poor clinical outcomes, emphasizing their significance as prognostic markers and therapeutic targets.

Targeting non‐catalytic MMP functions

In recent years, the paradigm of MMP inhibition has evolved to encompass their non‐proteolytic roles, creating novel opportunities for therapeutic intervention. Instead of reiterating their structural scaffolding and signaling functions (see Section MMPs as non‐catalytic effectors), emphasis here is placed on how these interactions can be pharmacologically disrupted. For instance, interference with the MT1‐MMP/CD44 axis impairs lamellipodial localization and Rho GTPase‐driven signaling, thereby reducing invasion and intravasation without disturbing physiological ECM turnover [311, 312]. Likewise, modulation of pro‐MMP‐9/NGAL complexes highlights the potential to regulate extracellular stability and chemokine activity [313].

Emerging research also demonstrates the utility of RNAi to suppress pathogenic MMP functions. For instance, systemic delivery of MMP‐2 siRNA via nanoparticle carriers has been shown to reduce ECM degradation and protect chondrocytes in osteoarthritis models, suggesting a strategy for tissue‐specific MMP silencing [314]. Additionally, siRNA‐mediated knockdown of TIMP‐2 in ovarian cancer cells has unexpectedly upregulated MT1‐MMP while reducing MMP‐2, altering cells' invasive phenotype, hence highlighting the complexity of MMP/TIMP network modulation and its therapeutic potential [315].

Therapeutically, strategies targeting non‐catalytic domains, such as monoclonal antibodies or small molecules that disrupt PEX domain interactions or MT1‐MMP cytoplasmic tail, offer higher specificity and reduced systemic toxicity compared to Zn²⁺‐chelating inhibitors. As our understanding of MMP scaffolding, localization, and receptor engagement deepens, these functionally selective inhibitors and gene‐silencing approaches may emerge as powerful tools in combinatorial cancer and tissue‐preserving therapies. For example, the monoclonal antibody DX‐2400 (MT1‐MMP‐specific) demonstrated robust inhibition of angiogenesis and tumor invasion in preclinical xenografts but has yet to demonstrate efficacy in clinical trials [290]. Similarly, GS‐5745 (andecaliximab), a humanized MMP‐9 antibody, showed encouraging safety in phase I/II studies but failed to improve survival when added to chemotherapy in gastric cancer (phase III), underscoring the challenge of translating noncatalytic targeting into clinical efficacy [316].

Diagnostic applications

MMPs have emerged as promising diagnostic and prognostic biomarkers due to their dysregulated expression and activity in cancer and inflammatory diseases. Notably, elevated levels of MMP‐2, MMP‐9, and MT1‐MMP correlate with tumor aggressiveness, invasiveness, and poor clinical outcomes across a wide range of malignancies, including breast, colorectal, and lung cancer. Immunohistochemistry and immunofluorescence techniques applied to formalin‐fixed paraffin‐embedded tumor tissues enable spatial localization of MMPs and provide insights into their compartment‐specific expression patterns within the TME [317, 318]. Quantitative assays such as real‐time PCR and ELISA are routinely employed to detect mRNA transcripts and soluble forms of TIMPs in serum, plasma, or tissue lysates [319, 320]. The ratio of circulating MMPs to TIMPs (i.e., MMP‐9/TIMP‐1) has shown prognostic value and reflects the net proteolytic potential within the tumor niche, potentially guiding therapeutic stratification [321]. Moreover, molecular imaging strategies have enabled in vivo visualization of MMP activity using protease‐activatable cell‐penetrating peptides, which remain inactive until cleaved by tumor‐associated MMPs. Upon activation, these peptides penetrate nearby cells and accumulate, enabling high‐resolution, real‐time imaging of MMP activity using modalities such as near‐infrared fluorescence and magnetic resonance imaging (MRI) [322].

Despite this promise, translation into clinical diagnostics has been limited. Most MMP assays lack assay standardization, tumor‐type specificity, and prospective validation in large patient cohorts. Importantly, no MMP‐based biomarker has yet received regulatory approval for routine clinical use. Molecular imaging probes—such as AVB‐620—have advanced only to early‐phase clinical testing, with the majority of MMP‐targeted imaging agents still confined to preclinical development due to challenges including signal specificity, delivery efficiency, and regulatory hurdles [323]. Thus, while MMP signatures are compelling candidates for precision oncology, their current utility is restricted to research or exploratory clinical settings.

Collectively, the integration of MMP‐based diagnostic platforms with standard clinical tools may refine precision oncology by enhancing early detection, real‐time disease mapping, and tailored therapeutic decision‐making. However, significant work remains to bridge the gap from correlative biomarker studies and experimental imaging to validated, clinically actionable diagnostic tools.

Gaps and challenges in clinical translation

Despite extensive preclinical and early‐phase clinical research, the successful translation of MMP inhibitors into effective therapies has proven elusive. Considerable broad‐spectrum inhibitors, including marimastat and prinomastat, demonstrated potent anti‐invasive activity in vitro and in animal models, but ultimately failed in clinical trials due to dose‐limiting toxicities, musculoskeletal side effects, and poor efficacy in unselected patient populations [324, 325]. These shortcomings were largely attributed to the non‐selective inhibition of multiple MMPs, some of which are essential for tissue homeostasis, immune regulation, and angiogenesis. Importantly, these early failures tempered enthusiasm for the field and created a perception that MMPs were ‘undruggable’, which still influences current clinical development strategies [290].

One of the primary challenges is the functional redundancy and pleiotropy among MMP family members. Many MMPs share overlapping substrates and biological roles, making MMP‐specific inhibition difficult to achieve without affecting physiological matrix remodeling or immune responses [326]. Moreover, compensatory upregulation of alternative proteolytic pathways, such as ADAMs or serine proteases, can circumvent MMP inhibition and restore tumor‐promoting proteolysis [325]. Poor tissue penetration and pharmacokinetic limitations further complicate drug delivery, particularly in solid tumors characterized by dense stromal matrices or elevated interstitial pressure. Another critical barrier is the lack of robust biomarkers to guide patient selection and monitor therapeutic response. The absence of predictive biomarkers likely contributed to the failure of previous trials, where heterogeneous patient populations may have masked benefits in responsive subgroups. While exploratory studies (e.g., circulating MMP‐9/TIMP‐1 ratios, exosomal MMP content) have shown promise, none have yet been prospectively validated or integrated into trial design [327].

It is noteworthy that most MMP‐targeted interventions were deployed as monotherapies, whereas mounting evidence suggests that MMPs act synergistically with other tumor‐promoting pathways, such as VEGF signaling or immune checkpoint evasion [328, 329]. Future translational success will require a paradigm shift toward precision approaches. These include the development of MMP‐selective inhibitors targeting exosites or non‐catalytic domains, spatially and temporally controlled delivery systems (e.g., nanoparticles or protease‐activated prodrugs), and integration with combination regimens involving anti‐angiogenic agents or immunotherapies. For instance, preclinical combinations of MMP inhibition with anti‐VEGF or PD‐1 blockade have shown additive effects on vascular normalization and T cell infiltration, suggesting that rational cotargeting may overcome past failures [330].

The incorporation of real‐time MMP activity imaging and multi‐omic biomarker platforms may further enhance stratification and therapeutic precision. Despite extensive efforts, clinical trials targeting MMPs have largely failed to translate into effective therapies (Table 3; Table 4), primarily due to the fundamental gap in the MMP‐targeting concept. Previous approaches have focused on inhibiting individual MMP activity, without accounting for the complex nature of the MMP activation network. Recently, Kollet et al. addressed this limitation by proposing a novel framework that targets specific activators, linkers, and executioners within the MMP proteolytic cascade [10]. This network‐based approach aims to selectively disrupt pathological proteolysis, while minimizing off‐target effects, offering renewed therapeutic potential for MMP inhibition in disease. Ultimately, progress will depend not only on better inhibitors, but on integrating biomarker‐guided trial design, timing of intervention, and combinatorial regimens that reflect the multifactorial role of MMPs in tumor biology.

Table 3.

Summary of MMPs as diagnostic biomarkers and pharmacological targets in various types of solid tumors.

MMP	Clinical trial ID (recruitment status)	Cancer type	Details
MMP‐1	NCT05049408 (Completed)	Cancer oral squamous cell carcinoma (OSCC)	Measurement of salivary MMP‐1 using ELISA assay as an adjunctive tool to aid in diagnosis of OSCC
MMP‐1	NCT03722628 (Unknown)	Hepatocellular Carcinoma (HCC)	Determination of MMP‐1 gene polymorphism as a risk factor for HCC in Chronic Hepatitis C (HCV) patients with liver cirrhosis
MMP‐2/ MMP‐9	NCT01493219 (Completed)	Glioblastoma (GBM)	Detection of MMP‐2, ‐9 and neutrophil gelatinase‐associated lipocalin (NGAL) in blood and urine as potential biomarkers for GBM
	NCT03526822 (Recruiting)	GBM	Analysis of MMP‐2 and MMP‐9 expression and correlation to Neuro‐imaging features, in patients with newly diagnosed GBM
	NCT03185039 (Unknown)	Kidney cancer	Evaluation of MMP‐2 and MMP‐9 as potential biomarkers in metastatic kidney cancer patients treated with the anti‐angiogenic agents Sunitinib/Pazopanib
MMP‐7	NCT01570452 (Completed)	Colorectal cancer (CRC)	Evaluation of MMP‐7 expression in different stages (0‐iV) of patients with CRC as a potential biomarker
MMP‐7	NCT03151759 (Completed)	Rectal cancer	Effect of short‐ and long‐term Neoadjuvant radiotherapy on MMP‐7 level in patients with rectal cancer
MMP‐8	NCT06701058 (Completed)	Oropharyngeal cancers	Evaluation of active MMP‐8 in oral fluid for the detection of patients with oropharyngeal cancers
MMP‐14 (ΜΤ1‐MMP)	NCT06719856 (Not yet recruiting)	Solid tumors	Development of a noninvasive approach using 68Ga‐labeled bicyclic peptide radiotracer to detect MT1‐MMP expression in patients with solid tumors and identification of patients benefiting from MT1‐MMP targeting treatment
MMP‐14 (ΜΤ1‐MMP)	NCT06955767 (Not yet recruiting)	CRC	Measurement of MT1‐MMP protein levels in plasma exosomes, as a novel biomarker for CRC detection

Open in a new tab

Table 4.

Summary of MMP inhibitors used in pharmacological targeting in clinical trials.

MMP	Inhibitor	Mechanism of action	Clinical trial (code, details & recruitment status)
All MMPs	COL‐3 (NSC‐683551)	Chemically modified tetracycline derivative	NCT00001683: Phase I clinical study of oral COL‐3 (NSC‐683551) in patients with refractory metastatic cancer (completed)
All MMPs	Prinomastat (AG3340)	Synthetic hydroxamic acid derivative	NCT00004200: Phase II clinical study of MMP inhibitor Primomastat in combination with Temozolomide following radiation, in patients with newly diagnosed GBM (completed)
All MMPs	Prinomastat (AG3340)	Synthetic hydroxamic acid derivative	NCT00004199: Phase III clinical study of MMP inhibitor Primomastat in combination with cisplatin and gemcitabine, in patients with metastatic or recurrent NSCLC (completed)
All MMPs	Prinomastat (AG3340)	Synthetic hydroxamic acid derivative	NCT00003343: Phase III clinical study of MMP inhibitor Primomastat in combination with mitoxantrone and prednisone, in patients with metastatic prostate cancer (completed)
MMP‐9	GS5745	Monoclonal antibody	NCT03631836: Phase I clinical study of MMP‐9 inhibitor GS5745, in combination with Bevacizumab in patients with recurrent GBM (unknown)
MMP‐14/MT1‐MMP	BT1718	Bicycle drug conjugate	NCT03486730: Phase I/IIa clinical trial of BT1718, in patients with advanced solid tumors (completed)

Open in a new tab

Concluding remarks and future perspectives

MMPs are recognized as key mediators in both physiological remodeling and pathological matrix remodeling. This guide has revisited the intricate roles of MMPs across diverse biological contexts, with a particular focus on their multifaceted involvement in cancer progression. From modulating TME dynamics and promoting EMT to facilitating angiogenesis, immune evasion, and PMN formation, MMPs act not only as degrading matrix enzymes, but also as central regulators of intercellular communication and matrix‐mediated signaling. Despite early setbacks in clinical translation due to the lack of isoform specificity and adverse effects of broad‐spectrum MMPIs, recent advances have focused interest on MMP‐targeted strategies. The development of next‐generation MMPIs, including monoclonal antibodies, allosteric modulators, and chemically modified tetracyclines, has yielded more refined tools with improved specificity, reduced toxicity, and potential for combinatorial therapeutic approaches. Moreover, emerging insights into the non‐catalytic functions of MMPs highlight therapeutic avenues beyond enzymatic inhibition. Going a step forward, the integration of MMP‐based diagnostics with precision medicine platforms could enhance early detection and patient stratification, particularly through liquid biopsies and exosome‐based assays. Furthermore, expanding our understanding of MMP interactions within complex tissue microenvironments will be critical to unlocking new therapeutic eras. Future research should also aim to clarify the temporal and spatial regulation of MMPs across cancer stages, enabling more context‐sensitive interventions. Collectively, by embracing new perspectives that consider the multifaceted actions of MMPs, basic and applied research may move closer to their full diagnostic and therapeutic potential. The coming era of MMP research holds promise for insights into the development of innovative, tailored interventions in oncology and beyond.

Conflict of interest

The authors declare no conflicts of interest.

Author contributions

ZP, SM, SK, NEK: interpretation and review of reported data, writing original draft; ZP, SM, SK, NEK: writing—review and editing, figures' conceptual design and preparation; NKK: conceptual design, interpretation, writing—review, and editing. All authors have read and approved the final version for publication.

Acknowledgements

ZP and NKK acknowledge funding by the European Union under the action HORIZON‐MSCA‐2022‐SE‐01 (CARES). Project ID: 101130985. ZP acknowledges the funding programme “MEDICUS” of the University of Patras, and FEBS as a funding contributor (FEBS Booster Fund 2024).

Zoi Piperigkou and Sylvia Mangani contributed equally to this work.

References

1. Karamanos NK, Theocharis AD, Piperigkou Z, Manou D, Passi A, Skandalis SS, Vynios DH, Orian‐Rousseau V, Ricard‐Blum S, Schmelzer CEH et al. (2021) A guide to the composition and functions of the extracellular matrix. FEBS J 288, 6850–6912. [DOI] [PubMed] [Google Scholar]
2. Piperigkou Z, Kyriakopoulou K, Koutsakis C, Mastronikolis S & Karamanos NK (2021) Key matrix remodeling enzymes: functions and targeting in cancer. Cancer 13, 1441. [DOI] [PMC free article] [PubMed] [Google Scholar]
3. Karamanos NK (2019) Extracellular matrix: key structural and functional meshwork in health and disease. FEBS J 286, 2826–2829. [DOI] [PubMed] [Google Scholar]
4. Gaffney J, Solomonov I, Zehorai E & Sagi I (2015) Multilevel regulation of matrix metalloproteinases in tissue homeostasis indicates their molecular specificity in vivo. Matrix Biol 44–46, 191–199. [DOI] [PubMed] [Google Scholar]
5. Kulesza M, Kicman A, Motyka J, Guszczyn T & Ławicki S (2023) Importance of metalloproteinase enzyme Group in Selected Skeletal System Diseases. Int J Mol Sci 24, 17139. [DOI] [PMC free article] [PubMed] [Google Scholar]
6. Cuffaro D, Nuti E, D'Andrea F & Rossello A (2020) Developments in carbohydrate‐based Metzincin inhibitors. Pharmaceuticals 13, 376. [DOI] [PMC free article] [PubMed] [Google Scholar]
7. Gonzalez‐Avila G, Sommer B, García‐Hernández AA & Ramos C (2020) Matrix Metalloproteinases' role in tumor microenvironment. In Tumor Microenvironment (Birbrair A, ed.), pp. 97–131. Springer International Publishing, Cham. [DOI] [PubMed] [Google Scholar]
8. Tseng Y‐T, Chen M, John JS & Ekberg J (2021) Targeting matrix Metalloproteinases: a potential strategy for improving cell transplantation for nervous system repair. Cell Transplant 30, 09636897211012909. [DOI] [PMC free article] [PubMed] [Google Scholar]
9. Bassiouni W, Ali MAM & Schulz R (2021) Multifunctional intracellular matrix metalloproteinases: implications in disease. FEBS J 288, 7162–7182. [DOI] [PubMed] [Google Scholar]
10. Kollet O, Das A, Karamanos N, Auf Dem Keller U & Sagi I (2023) Redefining metalloproteases specificity through network proteolysis. Trends Mol Med 30, 147–163. [DOI] [PMC free article] [PubMed] [Google Scholar]
11. Alaseem A, Alhazzani K, Dondapati P, Alobid S, Bishayee A & Rathinavelu A (2019) Matrix Metalloproteinases: a challenging paradigm of cancer management. Semin Cancer Biol 56, 100–115. [DOI] [PubMed] [Google Scholar]
12. Gonzalez‐Avila G, Sommer B, García‐Hernandez AA, Ramos C & Flores‐Soto E (2022) Nanotechnology and matrix Metalloproteinases in cancer diagnosis and treatment. Front Mol Biosci 9, 918789. [DOI] [PMC free article] [PubMed] [Google Scholar]
13. Almutairi S, Kalloush HM, Manoon NA & Bardaweel SK (2023) Matrix Metalloproteinases inhibitors in cancer treatment: An updated review (2013–2023). Molecules 28, 5567. [DOI] [PMC free article] [PubMed] [Google Scholar]
14. Hey S & Linder S (2024) Matrix metalloproteinases at a glance. J Cell Sci 137, jcs261898. [DOI] [PubMed] [Google Scholar]
15. Cui N, Hu M & Khalil RA (2017) Biochemical and biological attributes of matrix Metalloproteinases. Progress Molec Biol Translat Sci 147, 1–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
16. Hey S, Ratt A & Linder S (2022) There and back again: intracellular trafficking, release and recycling of matrix metalloproteinases. Biochimica et Biophysica Acta (BBA) 1869, 119189. [DOI] [PubMed] [Google Scholar]
17. Pompili S, Latella G, Gaudio E, Sferra R & Vetuschi A (2021) The charming world of the extracellular matrix: a dynamic and protective network of the Intestinal Wall. Front Med 8, 610189. [DOI] [PMC free article] [PubMed] [Google Scholar]
18. Khalid U, Dimov D & Vlaykova T (2023) Matrix metalloproteinases in COVID‐19: underlying significance. Biotechnol Biotechnol Equip 37, 295–301. [Google Scholar]
19. Moracho N, Learte AIR, Muñoz‐Sáez E, Marchena MA, Cid MA, Arroyo AG & Sánchez‐Camacho C (2022) Emerging roles of MT‐MMPs in embryonic development. Dev Dyn 251, 240–275. [DOI] [PubMed] [Google Scholar]
20. De Almeida LGN, Thode H, Eslambolchi Y, Chopra S, Young D, Gill S, Devel L & Dufour A (2022) Matrix Metalloproteinases: from molecular mechanisms to physiology, pathophysiology, and pharmacology. Pharmacol Rev 74, 714–770. [DOI] [PubMed] [Google Scholar]
21. Sak K (2024) The low expression of matrix metalloproteinases: a key to longevity? Exp Ther Med 158–166.38476893 [Google Scholar]
22. Wang X & Khalil RA (2018) Matrix Metalloproteinases, vascular remodeling, and vascular disease. Adv Pharmacol 81, 241–330. [DOI] [PMC free article] [PubMed] [Google Scholar]
23. Marcianò G, Vocca C, Rania V, Citraro R, De Sarro G & Gallelli L (2023) Metalloproteases in pain generation and persistence: a possible target? Biomolecules 13, 268. [DOI] [PMC free article] [PubMed] [Google Scholar]
24. Prado AF, Batista RIM, Tanus‐Santos JE & Gerlach RF (2021) Matrix Metalloproteinases and arterial hypertension: role of oxidative stress and nitric oxide in vascular functional and structural alterations. Biomolecules 11, 585. [DOI] [PMC free article] [PubMed] [Google Scholar]
25. Laronha H & Caldeira J (2020) Structure and function of human matrix Metalloproteinases. Cells 9, 1076. [DOI] [PMC free article] [PubMed] [Google Scholar]
26. Piperigkou Z, Mohr B, Karamanos N & Götte M (2016) Shed proteoglycans in tumor stroma. Cell Tissue Res 365, 643–655. [DOI] [PubMed] [Google Scholar]
27. Ioannou P, Katsoulieris E & Afratis NA (2025) Matrix dynamics and microbiome crosstalk: matrix Metalloproteinases as key players in disease and therapy. Int J Mol Sci 26, 3621. [DOI] [PMC free article] [PubMed] [Google Scholar]
28. Tampa M, Georgescu SR, Mitran MI, Mitran CI, Matei C, Caruntu A, Scheau C, Nicolae I, Matei A, Caruntu C et al. (2021) Current perspectives on the role of matrix Metalloproteinases in the pathogenesis of basal cell carcinoma. Biomolecules 11, 903. [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Towner RA, Smith N, Saunders D, Brown CA, Cai X, Ziegler J, Mallory S, Dozmorov MG, Coutinho De Souza P, Wiley G et al. (2019) OKN‐007 increases temozolomide (TMZ) sensitivity and suppresses TMZ‐resistant glioblastoma (GBM) tumor growth. Transl Oncol 12, 320–335. [DOI] [PMC free article] [PubMed] [Google Scholar]
30. Liu X, Yu J, Song S, Yue X & Li Q (2017) Protease‐activated receptor‐1 (PAR‐1): a promising molecular target for cancer. Oncotarget 8, 107334–107345. [DOI] [PMC free article] [PubMed] [Google Scholar]
31. Alipour H, Raz A, Zakeri S & Dinparast Djadid N (2016) Therapeutic applications of collagenase (metalloproteases): a review. Asian Pac J Trop Biomed 6, 975–981. [Google Scholar]
32. Christopoulou M‐E, Papakonstantinou E & Stolz D (2023) Matrix Metalloproteinases in chronic obstructive pulmonary disease. Int J Mol Sci 24, 3786. [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Dai L, Mugaanyi J, Cai X, Dong M, Lu C & Lu C (2022) Comprehensive bioinformatic analysis of MMP1 in hepatocellular carcinoma and establishment of relevant prognostic model. Sci Rep 12, 13639. [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Juurikka K, Dufour A, Pehkonen K, Mainoli B, Campioni Rodrigues P, Solis N, Klein T, Nyberg P, Overall CM, Salo T et al. (2021) MMP8 increases tongue carcinoma cell–cell adhesion and diminishes migration via cleavage of anti‐adhesive FXYD5. Oncogene 10, 44. [DOI] [PMC free article] [PubMed] [Google Scholar]
35. Li S, Pritchard DM & Yu L‐G (2022) Regulation and function of matrix Metalloproteinase‐13 in cancer progression and metastasis. Cancer 14, 3263. [DOI] [PMC free article] [PubMed] [Google Scholar]
36. Szczygielski O, Dąbrowska E, Niemyjska S, Przylipiak A & Zajkowska M (2024) Targeting matrix Metalloproteinases and their inhibitors in melanoma. Int J Mol Sci 25, 13558. [DOI] [PMC free article] [PubMed] [Google Scholar]
37. Manon‐Jensen T, Multhaupt HAB & Couchman JR (2013) Mapping of matrix metalloproteinase cleavage sites on syndecan‐1 and syndecan‐4 ectodomains. FEBS J 280, 2320–2331. [DOI] [PubMed] [Google Scholar]
38. Cabral‐Pacheco GA, Garza‐Veloz I, Castruita‐De La Rosa C, Ramirez‐Acuña JM, Perez‐Romero BA, Guerrero‐Rodriguez JF, Martinez‐Avila N & Martinez‐Fierro ML (2020) The roles of matrix Metalloproteinases and their inhibitors in human diseases. Int J Mol Sci 21, 9739. [DOI] [PMC free article] [PubMed] [Google Scholar]
39. Bonnans C, Chou J & Werb Z (2014) Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 15, 786–801. [DOI] [PMC free article] [PubMed] [Google Scholar]
40. Molière S, Jaulin A, Tomasetto C‐L & Dali‐Youcef N (2023) Roles of matrix Metalloproteinases and their natural inhibitors in metabolism: insights into health and disease. Int J Mol Sci 24, 10649. [DOI] [PMC free article] [PubMed] [Google Scholar]
41. Mukherjee A & Das B (2024) The role of inflammatory mediators and matrix metalloproteinases (MMPs) in the progression of osteoarthritis. Biomater Biosyst 13, 100090. [DOI] [PMC free article] [PubMed] [Google Scholar]
42. Tanase DM, Valasciuc E, Anton I‐B, Gosav EM, Dima N, Cucu AI, Costea CF, Floria DE, Hurjui LL, Tarniceriu CC et al. (2025) Matrix Metalloproteinases: pathophysiologic implications and potential therapeutic targets in cardiovascular disease. Biomolecules 15, 598. [DOI] [PMC free article] [PubMed] [Google Scholar]
43. Small C & Crawford B (2016) Matrix metalloproteinases in neural development: a phylogenetically diverse perspective. Neural Regen Res 11, 357. [DOI] [PMC free article] [PubMed] [Google Scholar]
44. Chuliá‐Peris L, Carreres‐Rey C, Gabasa M, Alcaraz J, Carretero J & Pereda J (2022) Matrix Metalloproteinases and their inhibitors in pulmonary fibrosis: EMMPRIN/CD147 comes into play. Int J Mol Sci 23, 6894. [DOI] [PMC free article] [PubMed] [Google Scholar]
45. Shan L, Wang F, Zhai D, Meng X, Liu J & Lv X (2023) Matrix metalloproteinases induce extracellular matrix degradation through various pathways to alleviate hepatic fibrosis. Biomed Pharmacother 161, 114472. [DOI] [PubMed] [Google Scholar]
46. Soboleva AG, Sobolev VV, Karapetyan MM, Mezentsev A, Rud'ko OI, Davydova ED, Mogulevtseva JA, Zhukova OV & Korsunskaya IM (2023) Laser therapy changes the expression of matrix Metalloproteinases in Bleomycin‐induced skin fibrosis. Life 13, 810. [DOI] [PMC free article] [PubMed] [Google Scholar]
47. Manjari, KS , Nallari, Pratibha & Venkateshwari, A (2017) Matrix metalloproteinases in pancreatitis: current insights. Met Med 4, 15–23. [Google Scholar]
48. Behl T, Kaur G, Sehgal A, Bhardwaj S, Singh S, Buhas C, Judea‐Pusta C, Uivarosan D, Munteanu MA & Bungau S (2021) Multifaceted role of matrix Metalloproteinases in neurodegenerative diseases: pathophysiological and therapeutic perspectives. Int J Mol Sci 22, 1413. [DOI] [PMC free article] [PubMed] [Google Scholar]
49. Afratis NA, Klepfish M, Karamanos NK & Sagi I (2018) The apparent competitive action of ECM proteases and cross‐linking enzymes during fibrosis: applications to drug discovery. Adv Drug Deliv Rev 129, 4–15. [DOI] [PubMed] [Google Scholar]
50. Sabir U, Gu H & Zhang D (2023) Extracellular matrix turnover: phytochemicals target and modulate the dual role of matrix metalloproteinases (MMPs) in liver fibrosis. Phytother Res 37, 4932–4962. [DOI] [PubMed] [Google Scholar]
51. Schlage P, Kockmann T, Sabino F, Kizhakkedathu Jayachandran N & Auf Dem Keller U (2015) Matrix metalloproteinase 10 Degradomics in keratinocytes and epidermal tissue identifies bioactive substrates with pleiotropic functions*. Mol Cell Proteomics 14, 3234–3246. [DOI] [PMC free article] [PubMed] [Google Scholar]
52. Zhang X, Huang S, Guo J, Zhou L, You L, Zhang T & Zhao Y (2016) Insights into the distinct roles of MMP‐11 in tumor biology and future therapeutics (review). Int J Oncol 48, 1783–1793. [DOI] [PubMed] [Google Scholar]
53. Alcantara MC, Suzuki K, Acebedo AR, Kajioka D, Hirohata S, Kaisho T, Hatano Y, Yamagata K, Takahashi S & Yamada G (2022) Androgen‐regulated MafB drives cell migration via MMP11‐dependent extracellular matrix remodeling in mice. iScience 25, 105609. [DOI] [PMC free article] [PubMed] [Google Scholar]
54. Mustafa S, Koran S & AlOmair L (2022) Insights into the role of matrix Metalloproteinases in cancer and its various therapeutic aspects: a review. Front Mol Biosci 9, 896099. [DOI] [PMC free article] [PubMed] [Google Scholar]
55. Waters JA, Urbano I, Robinson M & House CD (2022) Insulin‐like growth factor binding protein 5: diverse roles in cancer. Front Oncol 12, 1052457. [DOI] [PMC free article] [PubMed] [Google Scholar]
56. Thongiratama GW, Dhananjaya GAD, Mulya HK & Ruma IMW (2024) Activity of matrix Metalloproteinase‐7 (MMP‐7) related to heparin‐binding epidermal growth factor (HB‐EGF) activation in squamous cell as diagnostic biomarker for early detection and treatment of Maxilarian cancer: review article. Indones J Cancer 18, 89–98. [Google Scholar]
57. Hernole J & Narayanappa R (2023) Interactions between notch and matrix metalloproteinases: the role in cancer. Nowotwory J Oncol 73, 354–361. [Google Scholar]
58. Tsunezumi J, Higashi S & Miyazaki K (2009) Matrilysin (MMP‐7) cleaves C‐type lectin domain family 3 member a (CLEC3A) on tumor cell surface and modulates its cell adhesion activity. J Cell Biochem 106, 693–702. [DOI] [PubMed] [Google Scholar]
59. Grindel BJ, Martinez JR, Tellman TV, Harrington DA, Zafar H, Nakhleh L, Chung LW & Farach‐Carson MC (2018) Matrilysin/MMP‐7 cleavage of Perlecan/HSPG2 complexed with Semaphorin 3A supports FAK‐mediated stromal invasion by prostate cancer cells. Sci Rep 8, 7262. [DOI] [PMC free article] [PubMed] [Google Scholar]
60. Kariya Y & Kariya Y (2022) Osteopontin in cancer: mechanisms and therapeutic targets. Int J Transl Med 2, 419–447. [Google Scholar]
61. Tauro M & Lynch C (2018) Cutting to the chase: how matrix Metalloproteinase‐2 activity controls breast‐cancer‐to‐bone metastasis. Cancer 10, 185. [DOI] [PMC free article] [PubMed] [Google Scholar]
62. Yu W‐H, Wu E, Li Y, Hou H‐H, Yu SC, Huang P‐T, Kuo W‐H, Qi D & Yu C‐J (2020) Matrix Metalloprotease‐7 mediates nucleolar assembly and intra‐nucleolar cleaving p53 in Gefitinib‐resistant cancer stem cells. iScience 23, 101600. [DOI] [PMC free article] [PubMed] [Google Scholar]
63. Jin L, Shen F, Weinfeld M & Sergi C (2020) Insulin growth factor binding protein 7 (IGFBP7)‐related cancer and IGFBP3 and IGFBP7 crosstalk. Front Oncol 10, 727. [DOI] [PMC free article] [PubMed] [Google Scholar]
64. Liu Z, Tan RJ & Liu Y (2020) The many faces of matrix Metalloproteinase‐7 in kidney diseases. Biomolecules 10, 960. [DOI] [PMC free article] [PubMed] [Google Scholar]
65. Xiao Y, Lian H, Zhong XS, Krishnachaitanya SS, Cong Y, Dashwood RH, Savidge TC, Powell DW, Liu X & Li Q (2022) Matrix metalloproteinase 7 contributes to intestinal barrier dysfunction by degrading tight junction protein Claudin‐7. Front Immunol 13, 1020902. [DOI] [PMC free article] [PubMed] [Google Scholar]
66. Van Doren SR (2022) MMP‐7 marks severe pancreatic cancer and alters tumor cell signaling by proteolytic release of ectodomains. Biochem Soc Trans 50, 839–851. [DOI] [PMC free article] [PubMed] [Google Scholar]
67. Piskór BM, Przylipiak A, Dąbrowska E, Niczyporuk M & Ławicki S (2020) Matrilysins and Stromelysins in pathogenesis and diagnostics of cancers. Cancer Manag Res 12, 10949–10964. [DOI] [PMC free article] [PubMed] [Google Scholar]
68. Guo J, Guo C, He Z, Cai X & Mou Y (2018) High MMP‐26 expression in glioma is correlated with poor clinical outcome of patients. Oncol Lett 16, 2237–2242. [DOI] [PMC free article] [PubMed] [Google Scholar]
69. Silva RLD, Paes FLA, Silva SMSD, Santos F, Santana ESD & Silva Neto JDC (2025) Specific immunohistochemical expression of Mmp‐26 in prostatic adenocarcinoma. An Acad Bras Cienc 97, e20231380. [DOI] [PubMed] [Google Scholar]
70. Khamis ZI, Iczkowski KA, Man Y‐G, Bou‐Dargham MJ & Sang Q‐XA (2016) Evidence for a Proapoptotic role of matrix Metalloproteinase‐26 in human prostate cancer cells and tissues. J Cancer 7, 80–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
71. Gonzalez‐Avila G, Sommer B, Mendoza‐Posada DA, Ramos C, Garcia‐Hernandez AA & Falfan‐Valencia R (2019) Matrix metalloproteinases participation in the metastatic process and their diagnostic and therapeutic applications in cancer. Crit Rev Oncol Hematol 137, 57–83. [DOI] [PubMed] [Google Scholar]
72. Stawowczyk M, Wellenstein MD, Lee SB, Yomtoubian S, Durrans A, Choi H, Narula N, Altorki NK, Gao D & Mittal V (2017) Matrix metalloproteinase 14 promotes lung cancer by cleavage of heparin‐binding EGF‐like growth factor. Neoplasia 19, 55–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
73. Nadanaka S, Bai Y & Kitagawa H (2021) Cleavage of Syndecan‐1 promotes the proliferation of the basal‐like breast cancer cell line BT‐549 via Akt SUMOylation. Front Cell Dev Biol 9, 659428. [DOI] [PMC free article] [PubMed] [Google Scholar]
74. Knapinska AM & Fields GB (2019) The expanding role of MT1‐MMP in cancer progression. Pharmaceuticals 12, 77. [DOI] [PMC free article] [PubMed] [Google Scholar]
75. Liu J, Li Y, Lian X, Zhang C, Feng J, Tao H & Wang Z (2025) Potential target within the tumor microenvironment – MT1‐MMP. Front Immunol 16, 1517519. [DOI] [PMC free article] [PubMed] [Google Scholar]
76. Bruney L, Conley KC, Moss NM, Liu Y & Stack MS (2014) Membrane‐type I matrix metalloproteinase‐dependent ectodomain shedding of mucin16/ CA‐125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium. Biol Chem 395, 1221–1231. [DOI] [PMC free article] [PubMed] [Google Scholar]
77. Tanaka N & Sakamoto T (2023) MT1‐MMP as a key regulator of metastasis. Cells 12, 2187. [DOI] [PMC free article] [PubMed] [Google Scholar]
78. Itoh Y (2015) Membrane‐type matrix metalloproteinases: their functions and regulations. Matrix Biol 44–46, 207–223. [DOI] [PubMed] [Google Scholar]
79. Liu Y, Sun X, Feng J, Deng L‐L, Liu Y, Li B, Zhu M, Lu C & Zhou L (2016) MT2‐MMP induces proteolysis and leads to EMT in carcinomas. Oncotarget 7, 48193–48205. [DOI] [PMC free article] [PubMed] [Google Scholar]
80. Cui X, Jing X, Yi Q, Long C, Tian J & Zhu J (2017) Clinicopathological and prognostic significance of SDC1 overexpression in breast cancer. Oncotarget 8, 111444–111455. [DOI] [PMC free article] [PubMed] [Google Scholar]
81. Cloud AS, Vargheese AM, Gunewardena S, Shimak RM, Ganeshkumar S, Kumaraswamy E, Jensen RA & Chennathukuzhi VM (2022) Loss of REST in breast cancer promotes tumor progression through estrogen sensitization, MMP24 and CEMIP overexpression. BMC Cancer 22, 180. [DOI] [PMC free article] [PubMed] [Google Scholar]
82. Muñoz‐Sáez E, Moracho N, Learte AIR, Collignon A, Arroyo AG, Noel A, Sounni NE & Sánchez‐Camacho C (2023) Molecular mechanisms driven by MT4‐MMP in cancer progression. Int J Mol Sci 24, 9944. [DOI] [PMC free article] [PubMed] [Google Scholar]
83. Yip C, Foidart P, Noël A & Sounni NE (2019) MT4‐MMP: the GPI‐anchored membrane‐type matrix metalloprotease with multiple functions in diseases. Int J Mol Sci 20, 354. [DOI] [PMC free article] [PubMed] [Google Scholar]
84. Scheau C, Badarau IA, Costache R, Caruntu C, Mihai GL, Didilescu AC, Constantin C & Neagu M (2019) The role of matrix Metalloproteinases in the epithelial‐mesenchymal transition of hepatocellular carcinoma. Anal Cell Pathol 2019, 1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
85. Spinale FG (2013) Epilysin (matrix Metalloproteinase‐28) joins the matrix metalloproteinase team on the field of Postmyocardial infarction remodeling. Circ Res 112, 579–582. [DOI] [PubMed] [Google Scholar]
86. Pittayapruek P, Meephansan J, Prapapan O, Komine M & Ohtsuki M (2016) Role of matrix Metalloproteinases in Photoaging and Photocarcinogenesis. Int J Mol Sci 17, 868. [DOI] [PMC free article] [PubMed] [Google Scholar]
87. Lamort A‐S, Gravier R, Laffitte A, Juliano L, Zani M‐L & Moreau T (2016) New insights into the substrate specificity of macrophage elastase MMP‐12. Biol Chem 397, 469–484. [DOI] [PubMed] [Google Scholar]
88. Veeravalli KK (2024) Implications of MMP‐12 in the pathophysiology of ischaemic stroke. Stroke Vasc Neurol 9, 97–107. [DOI] [PMC free article] [PubMed] [Google Scholar]
89. Jiang L, Yang M, He S, Li Z, Li H, Niu T, Xie D, Mei Y, He X, Wei L et al. (2021) MMP12 knockout prevents weight and muscle loss in tumor‐bearing mice. BMC Cancer 21, 1297. [DOI] [PMC free article] [PubMed] [Google Scholar]
90. Arruri V, Chokkalla AK, Jeong S, Chelluboina B, Mehta SL, Veeravalli KK & Vemuganti R (2022) MMP‐12 knockdown prevents secondary brain damage after ischemic stroke in mice. Neurochem Int 161, 105432. [DOI] [PMC free article] [PubMed] [Google Scholar]
91. Park J‐H, Shin J‐M, Yang H‐W, Kim TH, Lee SH, Shin OS & Park I‐H (2024) Matrix metalloproteinase‐12 by M2 macrophages induced epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyps. PLoS One 19, e0313097. [DOI] [PMC free article] [PubMed] [Google Scholar]
92. Yasuda H, Nakagawa M, Kiyokawa H, Yoshida E, Yoshimura T, Koshikawa N, Itoh F & Seiki M (2019) Unique biological activity and potential role of monomeric Laminin‐γ2 as a novel biomarker for hepatocellular carcinoma: a review. Int J Mol Sci 20, 226. [DOI] [PMC free article] [PubMed] [Google Scholar]
93. Zhao W, Wang L, Yang J, Chen X, Guo X, Xu K, Wang N, Zhao W, Xia C, Lian H et al. (2023) Endothelial cell‐derived MMP19 promotes pulmonary fibrosis by inducing E(nd)MT and monocyte infiltration. Cell Commun Signal 21, 56. [DOI] [PMC free article] [PubMed] [Google Scholar]
94. Ma B, Zeng Q, Yang F, Yang H, Li W, Fu R, Cai Z, Zhu G, Shu C, Luo M et al. (2025) MMP19 in vascular smooth muscle cells protects against thoracic aortic aneurysm and dissection via the MMP19/Aggrecan/Wnt/β‐catenin axis. J Mol Cell Cardiol 202, 35–49. [DOI] [PubMed] [Google Scholar]
95. Mezentsev A, Nikolaev A & Bruskin S (2014) Matrix metalloproteinases and their role in psoriasis. Gene 540, 1–10. [DOI] [PubMed] [Google Scholar]
96. Alford VM, Kamath A, Ren X, Kumar K, Gan Q, Awwa M, Tong M, Seeliger MA, Cao J, Ojima I et al. (2017) Targeting the Hemopexin‐like domain of latent matrix Metalloproteinase‐9 (proMMP‐9) with a Small molecule inhibitor prevents the formation of focal adhesion junctions. ACS Chem Biol 12, 2788–2803. [DOI] [PMC free article] [PubMed] [Google Scholar]
97. Che K, Han W, Zhang M & Niu H (2020) Role of neutrophil gelatinase‐associated lipocalin in renal cell carcinoma (review). Oncol Lett 21, 148. [DOI] [PMC free article] [PubMed] [Google Scholar]
98. Castro‐Castro A, Marchesin V, Monteiro P, Lodillinsky C, Rossé C & Chavrier P (2016) Cellular and molecular mechanisms of MT1‐MMP‐dependent cancer cell invasion. Annu Rev Cell Dev Biol 32, 555–576. [DOI] [PubMed] [Google Scholar]
99. Suárez H, López‐Martín S, Toribio V, Zamai M, Hernández‐Riquer MV, Genís L, Arroyo AG & Yáñez‐Mó M (2020) Regulation of MT1‐MMP activity through its association with ERMs. Cells 9, 348. [DOI] [PMC free article] [PubMed] [Google Scholar]
100. Venghateri JB, Dassa B, Morgenstern D, Shreberk‐Shaked M, Oren M & Geiger B (2023) Deciphering the involvement of the hippo pathway co‐regulators, YAP/TAZ in invadopodia formation and matrix degradation. Cell Death Dis 14, 290. [DOI] [PMC free article] [PubMed] [Google Scholar]
101. Divvela SSK, Gallorini M, Gellisch M, Patel GD, Saso L & Brand‐Saberi B (2025) Navigating redox imbalance: the role of oxidative stress in embryonic development and long‐term health outcomes. Front Cell Dev Biol 13, 1521336. [DOI] [PMC free article] [PubMed] [Google Scholar]
102. Wang K, Xuan Z, Liu X, Zheng M, Yang C & Wang H (2022) Immunomodulatory role of metalloproteinase ADAM17 in tumor development. Front Immunol 13, 1059376. [DOI] [PMC free article] [PubMed] [Google Scholar]
103. Xie Z, Wang X, Ren X & Ge X (2024) MMP12 disrupts epithelial barrier integrity in oral lichen planus by degrading fibronectin. Sci Rep 14, 27511. [DOI] [PMC free article] [PubMed] [Google Scholar]
104. Yosef G, Arkadash V & Papo N (2018) Targeting the MMP‐14/MMP‐2/integrin αvβ3 axis with multispecific N‐TIMP2–based antagonists for cancer therapy. J Biol Chem 293, 13310–13326. [DOI] [PMC free article] [PubMed] [Google Scholar]
105. Mittal R, Patel AP, Debs LH, Nguyen D, Patel K, Grati M, Mittal J, Yan D, Chapagain P & Liu XZ (2016) Intricate functions of matrix Metalloproteinases in physiological and pathological conditions. J Cell Physiol 231, 2599–2621. [DOI] [PubMed] [Google Scholar]
106. Khalili‐Tanha G, Radisky ES, Radisky DC & Shoari A (2025) Matrix metalloproteinase‐driven epithelial‐mesenchymal transition: implications in health and disease. J Transl Med 23, 436. [DOI] [PMC free article] [PubMed] [Google Scholar]
107. Kandhwal M, Behl T, Singh S, Sharma N, Arora S, Bhatia S, Al‐Harrasi A, Sachdeva M & Bungau S (2022) Role of matrix metalloproteinase in wound healing. Am J Transl Res 14, 4391–4405. [PMC free article] [PubMed] [Google Scholar]
108. Gialeli C, Theocharis AD & Karamanos NK (2011) Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J 278, 16–27. [DOI] [PubMed] [Google Scholar]
109. Bian Y, Xiang Z, Wang Y, Ren Q, Chen G, Xiang B, Wang J, Zhang C, Pei S, Guo S et al. (2023) Immunomodulatory roles of metalloproteinases in rheumatoid arthritis. Front Pharmacol 14, 1285455. [DOI] [PMC free article] [PubMed] [Google Scholar]
110. Brown JS, Amend SR, Austin RH, Gatenby RA, Hammarlund EU & Pienta KJ (2023) Updating the definition of cancer. Mol Cancer Res 21, 1142–1147. [DOI] [PMC free article] [PubMed] [Google Scholar]
111. Zhang Q‐Z, Zhu Y‐P, Rahat MA & Kzhyshkowska J (2023) Editorial: angiogenesis and tumor metastasis. Front Oncol 12, 1129736. [DOI] [PMC free article] [PubMed] [Google Scholar]
112. Castaneda M, Den Hollander P, Kuburich NA, Rosen JM & Mani SA (2022) Mechanisms of cancer metastasis. Semin Cancer Biol 87, 17–31. [DOI] [PubMed] [Google Scholar]
113. Hariri A, Mirian M, Khosravi A, Zarepour A, Iravani S & Zarrabi A (2024) Intersecting pathways: the role of hybrid E/M cells and circulating tumor cells in cancer metastasis and drug resistance. Drug Resist Updat 76, 101119. [DOI] [PubMed] [Google Scholar]
114. Liao T‐T & Yang M‐H (2020) Hybrid epithelial/mesenchymal state in cancer metastasis: clinical significance and regulatory mechanisms. Cells 9, 623. [DOI] [PMC free article] [PubMed] [Google Scholar]
115. Leong SP & Witte MH (2024) Cancer metastasis through the lymphatic versus blood vessels. Clin Exp Metastasis 41, 387–402. [DOI] [PMC free article] [PubMed] [Google Scholar]
116. Heeke S, Mograbi B, Alix‐Panabières C & Hofman P (2019) Never travel alone: the crosstalk of circulating tumor cells and the blood microenvironment. Cells 8, 714. [DOI] [PMC free article] [PubMed] [Google Scholar]
117. Popova NV & Jücker M (2022) The functional role of extracellular matrix proteins in cancer. Cancer 14, 238. [DOI] [PMC free article] [PubMed] [Google Scholar]
118. Karampoga A, Tzaferi K, Koutsakis C, Kyriakopoulou K & Karamanos NK (2022) Exosomes and the extracellular matrix: a dynamic interplay in cancer progression. Int J Dev Biol 66, 97–102. [DOI] [PubMed] [Google Scholar]
119. Shimoda M & Khokha R (2017) Metalloproteinases in extracellular vesicles. Biochimica et Biophysica Acta (BBA) 1864, 1989–2000. [DOI] [PubMed] [Google Scholar]
120. Thuault S, Ghossoub R, David G & Zimmermann P (2022) A journey on extracellular vesicles for matrix Metalloproteinases: a mechanistic perspective. Front Cell Dev Biol 10, 886381. [DOI] [PMC free article] [PubMed] [Google Scholar]
121. Guo S, Huang J, Li G, Chen W, Li Z & Lei J (2023) The role of extracellular vesicles in circulating tumor cell‐mediated distant metastasis. Mol Cancer 22, 193. [DOI] [PMC free article] [PubMed] [Google Scholar]
122. Hu C, Long L, Lou J, Leng M, Yang Q, Xu X & Zhou X (2024) CTC‐neutrophil interaction: a key driver and therapeutic target of cancer metastasis. Biomed Pharmacother 180, 117474. [DOI] [PubMed] [Google Scholar]
123. Gobin E, Bagwell K, Wagner J, Mysona D, Sandirasegarane S, Smith N, Bai S, Sharma A, Schleifer R & She J‐X (2019) A pan‐cancer perspective of matrix metalloproteases (MMP) gene expression profile and their diagnostic/prognostic potential. BMC Cancer 19, 581. [DOI] [PMC free article] [PubMed] [Google Scholar]
124. Wang K, Zheng J, Yu J, Wu Y, Guo J, Xu Z & Sun X (2020) Knockdown of MMP‐1 inhibits the progression of colorectal cancer by suppressing the PI3K/Akt/c‐myc signaling pathway and EMT. Oncol Rep 43, 1103–1112. [DOI] [PMC free article] [PubMed] [Google Scholar]
125. Zhuang Y, Li X, Zhan P, Pi G & Wen G (2021) MMP11 promotes the proliferation and progression of breast cancer through stabilizing Smad2 protein. Oncol Rep 45, 16. [DOI] [PMC free article] [PubMed] [Google Scholar]
126. Liu N, Zhong L, Ni G, Lin J, Xie L, Li T, Dan H & Chen Q (2021) High matrix metalloproteinase 28 expression is associated with poor prognosis in pancreatic adenocarcinoma. OncoTargets Ther 14, 4391–4406. [DOI] [PMC free article] [PubMed] [Google Scholar]
127. Dharavath B, Butle A, Pal A, Desai S, Upadhyay P, Rane A, Khandelwal R, Manavalan S, Thorat R, Sonawane K et al. (2023) Role of miR‐944/MMP10/AXL‐ axis in lymph node metastasis in tongue cancer. Commun Biol 6, 57. [DOI] [PMC free article] [PubMed] [Google Scholar]
128. Lv F‐Z, Wang J‐L, Wu Y, Chen H‐F & Shen X‐Y (2015) Knockdown of MMP12 inhibits the growth and invasion of lung adenocarcinoma cells. Int J Immunopathol Pharmacol 28, 77–84. [DOI] [PubMed] [Google Scholar]
129. Sigismund S, Avanzato D & Lanzetti L (2018) Emerging functions of the egfr in cancer. Mol Oncol 12, 3–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
130. Soni UK, Jenny L & Hegde RS (2023) IGF‐1R targeting in cancer – does sub‐cellular localization matter? J Exp Clin Cancer Res 42, 273. [DOI] [PMC free article] [PubMed] [Google Scholar]
131. Augoff K, Hryniewicz‐Jankowska A, Tabola R & Stach K (2022) MMP9: a tough target for targeted therapy for cancer. Cancer 14, 1847. [DOI] [PMC free article] [PubMed] [Google Scholar]
132. Sun X & Hu X (2025) Unveiling matrix metalloproteinase 13's dynamic role in breast cancer: a link to physical changes and prognostic modulation. Int J Mol Sci 26, 3083. [DOI] [PMC free article] [PubMed] [Google Scholar]
133. Thomas D & Radhakrishnan P (2020) Role of tumor and stroma‐derived IGF/IGFBPs in pancreatic cancer. Cancer 12, 1228. [DOI] [PMC free article] [PubMed] [Google Scholar]
134. Roy R, Morad G, Jedinak A & Moses MA (2020) Metalloproteinases and their roles in human cancer. Anat Rec 303, 1557–1572. [DOI] [PubMed] [Google Scholar]
135. Gligorijević N, Dobrijević Z, Šunderić M, Robajac D, Četić D, Penezić A, Miljuš G & Nedić O (2022) The insulin‐like growth factor system and colorectal cancer. Life 12, 1274. [DOI] [PMC free article] [PubMed] [Google Scholar]
136. Dao DT, Anez‐Bustillos L, Adam RM, Puder M & Bielenberg DR (2018) Heparin‐binding epidermal growth factor–like growth factor as a critical mediator of tissue repair and regeneration. Am J Pathol 188, 2446–2456. [DOI] [PMC free article] [PubMed] [Google Scholar]
137. Carroll MJ, Kapur A, Felder M, Patankar MS & Kreeger PK (2016) M2 macrophages induce ovarian cancer cell proliferation via a heparin binding epidermal growth factor/matrix metalloproteinase 9 intercellular feedback loop. Oncotarget 7, 86608–86620. [DOI] [PMC free article] [PubMed] [Google Scholar]
138. Pezeshkian Z, Nobili S, Peyravian N, Shojaee B, Nazari H, Soleimani H, Asadzadeh‐Aghdaei H, Ashrafian Bonab M, Nazemalhosseini‐Mojarad E & Mini E (2021) Insights into the role of matrix Metalloproteinases in precancerous conditions and in colorectal cancer. Cancer 13, 6226. [DOI] [PMC free article] [PubMed] [Google Scholar]
139. Suhaimi SA, Chan SC & Rosli R (2020) Matrix metallopeptidase 3 polymorphisms: emerging genetic markers in human breast cancer metastasis. J Breast Cancer 23, 1–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
140. Figueroa CD, Molina L, Bhoola KD & Ehrenfeld P (2018) Overview of tissue kallikrein and kallikrein‐related peptidases in breast cancer. Biol Chem 399, 937–957. [DOI] [PubMed] [Google Scholar]
141. Paye A, Truong A, Yip C, Cimino J, Blacher S, Munaut C, Cataldo D, Foidart JM, Maquoi E, Collignon J et al. (2014) EGFR activation and signaling in cancer cells are enhanced by the membrane‐bound metalloprotease MT4‐MMP. Cancer Res 74, 6758–6770. [DOI] [PubMed] [Google Scholar]
142. Strouhalova K, Tolde O, Rosel D & Brábek J (2023) Cytoplasmic tail of MT1‐MMP: a hub of MT1‐MMP regulation and function. Int J Mol Sci 24, 5068. [DOI] [PMC free article] [PubMed] [Google Scholar]
143. Takino T, Tsuge H, Ozawa T & Sato H (2010) MT1‐MMP promotes cell growth and ERK activation through c‐Src and paxillin in three‐dimensional collagen matrix. Biochem Biophys Res Commun 396, 1042–1047. [DOI] [PubMed] [Google Scholar]
144. Fakhari S, Jalili A, Nikkhoo B, Ghaderi B, Boshagh MA, Mirzaie S & Moradzad M (2022) MT2‐MMP is differentially expressed in multiple myeloma cells and mediates their growth and progression. Cell Signal 92, 110248. [DOI] [PubMed] [Google Scholar]
145. Cao L, Chen C, Zhu H, Gu X, Deng D, Tian X, Liu J & Xiao Q (2016) MMP16 is a marker of poor prognosis in gastric cancer promoting proliferation and invasion. Oncotarget 7, 51865–51874. [DOI] [PMC free article] [PubMed] [Google Scholar]
146. Haque S & Morris JC (2017) Transforming growth factor‐β: a therapeutic target for cancer. Hum Vaccin Immunother 13, 1741–1750. [DOI] [PMC free article] [PubMed] [Google Scholar]
147. Baba AB, Rah B, Bhat GR, Mushtaq I, Parveen S, Hassan R, Hameed Zargar M & Afroze D (2022) Transforming growth factor‐Beta (TGF‐β) signaling in cancer‐a betrayal within. Front Pharmacol 13, 791272. [DOI] [PMC free article] [PubMed] [Google Scholar]
148. Khan A, Zhang Y, Ma N, Shi J & Hou Y (2024) NF‐κB role on tumor proliferation, migration, invasion and immune escape. Cancer Gene Ther 31, 1599–1610. [DOI] [PubMed] [Google Scholar]
149. Chen L, Cen Y, Qian K, Yang W, Zhou W & Yang Y (2025) MMP1‐induced NF‐κB activation promotes epithelial–mesenchymal transition and sacituzumab govitecan resistance in hormone receptor‐positive breast cancer. Cell Death Dis 16, 346. [DOI] [PMC free article] [PubMed] [Google Scholar]
150. Zhang Z, Dong T, Fu Y, Zhou W, Tian X, Chen G & Liu S (2019) MMP‐11 promotes papillary thyroid cell proliferation and invasion via the NF‐κB pathway. J Cell Biochem 120, 1860–1868. [DOI] [PubMed] [Google Scholar]
151. Ma J, Tang X, Wong P, Jacobs B, Borden EC & Bedogni B (2014) Noncanonical activation of Notch1 protein by membrane type 1 matrix metalloproteinase (MT1‐MMP) controls melanoma cell proliferation. J Biol Chem 289, 8442–8449. [DOI] [PMC free article] [PubMed] [Google Scholar]
152. Shin Y, Kim S, Liang G & An W (2024) mmp ‐9‐dependent proteolysis of the histone h3 N‐terminal tail: a critical epigenetic step in driving oncogenic transcription and colon tumorigenesis. Mol Oncol 18, 2001–2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
153. Sakamoto T & Seiki M (2017) Integrated functions of membrane‐type 1 matrix metalloproteinase in regulating cancer malignancy: beyond a proteinase. Cancer Sci 108, 1095–1100. [DOI] [PMC free article] [PubMed] [Google Scholar]
154. Jabłońska‐Trypuć A, Matejczyk M & Rosochacki S (2016) Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem 31, 177–183. [DOI] [PubMed] [Google Scholar]
155. Hu L, Lu J, Fan H, Niu C, Han Y, Caiyin Q, Wu H & Qiao J (2025) FAS mediates apoptosis, inflammation, and treatment of pathogen infection. Front Cell Infect Microbiol 15, 1561102. [DOI] [PMC free article] [PubMed] [Google Scholar]
156. Haymour L, Jean M, Smulski C & Legembre P (2023) CD95 (Fas) and CD95L (FasL)‐mediated non‐canonical signaling pathways. Biochimica et Biophysica Acta (BBA) 1878, 189004. [DOI] [PubMed] [Google Scholar]
157. Ababneh O, Nishizaki D, Kato S & Kurzrock R (2024) Tumor necrosis factor superfamily signaling: life and death in cancer. Cancer Metastasis Rev 43, 1137–1163. [DOI] [PMC free article] [PubMed] [Google Scholar]
158. Huang Y, Hong W & Wei X (2022) The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol 15, 129. [DOI] [PMC free article] [PubMed] [Google Scholar]
159. Mittal V (2018) Epithelial mesenchymal transition in tumor metastasis. Annu Rev Pathol Mech Dis 13, 395–412. [DOI] [PubMed] [Google Scholar]
160. Niland S, Riscanevo AX & Eble JA (2021) Matrix Metalloproteinases shape the tumor microenvironment in cancer progression. Int J Mol Sci 23, 146. [DOI] [PMC free article] [PubMed] [Google Scholar]
161. Li S & Luo W (2019) Matrix metalloproteinase 2 contributes to aggressive phenotype, epithelial‐mesenchymal transition and poor outcome in nasopharyngeal carcinoma. OncoTargets Ther 12, 5701–5711. [DOI] [PMC free article] [PubMed] [Google Scholar]
162. Liao H‐Y, Da C‐M, Liao B & Zhang H‐H (2021) Roles of matrix metalloproteinase‐7 (MMP‐7) in cancer. Clin Biochem 92, 9–18. [DOI] [PubMed] [Google Scholar]
163. Kanwal R, Esposito JE, Jawed B, Zakir SK, Pulcini R, Martinotti R, Botteghi M, Gaudio F, Martinotti S & Toniato E (2025) Exploring the role of epithelial–mesenchymal transcriptional factors involved in hematological malignancy and solid tumors: a systematic review. Cancer 17, 529. [DOI] [PMC free article] [PubMed] [Google Scholar]
164. Tian R, Li X, Gao Y, Li Y, Yang P & Wang K (2018) Identification and validation of the role of matrix metalloproteinase‐1 in cervical cancer. Int J Oncol 52, 1198–1208. [DOI] [PMC free article] [PubMed] [Google Scholar]
165. Pan C, Dai J, Wei Y, Yang L, Ding Z, Wang X & He J (2024) Matrix metalloproteinase 11 promotes migration and invasion of colorectal cancer by elevating slug protein. Int J Med Sci 21, 2170–2188. [DOI] [PMC free article] [PubMed] [Google Scholar]
166. Wang L, Li N, Chen Y, Qiao Y, Song Y, Zhang X, Zhao H, Ran W, Li G & Xing X (2025) GPSM1 interacts and cooperates with MMP19 to promote proliferation and EMT in colorectal cancer cells. Biochimica et Biophysica Acta (BBA) 1872, 119903. [DOI] [PubMed] [Google Scholar]
167. Chen S, Shen Z, Gao L, Yu S, Zhang P, Han Z & Kang M (2021) TPM3 mediates epithelial‐mesenchymal transition in esophageal cancer via MMP2/MMP9. Ann Transl Med 9, 1338. [DOI] [PMC free article] [PubMed] [Google Scholar]
168. Zhang H, Hang W, Jing Z, Liu B, Wang X, Li Y, Luo H, Lv H, Tao X, Timashev P et al. (2025) The role of notch signaling pathway in cancer: mechanistic insights, therapeutic potential, and clinical progress. Front Immunol 16, 1567524. [DOI] [PMC free article] [PubMed] [Google Scholar]
169. Aseervatham J & Ogbureke KUE (2020) Effects of DSPP and MMP20 silencing on adhesion, metastasis, angiogenesis, and epithelial‐mesenchymal transition proteins in Oral squamous cell carcinoma cells. Int J Mol Sci 21, 4734. [DOI] [PMC free article] [PubMed] [Google Scholar]
170. Zhou J, Zheng X, Feng M, Mo Z, Shan Y, Wang Y & Jin J (2019) Upregulated MMP28 in hepatocellular carcinoma promotes metastasis via Notch3 signaling and predicts unfavorable prognosis. Int J Biol Sci 15, 812–825. [DOI] [PMC free article] [PubMed] [Google Scholar]
171. Shen Z, Wang X, Yu X, Zhang Y & Qin L (2017) MMP16 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma. Oncotarget 8, 72197–72204. [DOI] [PMC free article] [PubMed] [Google Scholar]
172. Mirzaei S, Saghari S, Bassiri F, Raesi R, Zarrabi A, Hushmandi K, Sethi G & Tergaonkar V (2022) NF‐κB as a regulator of cancer metastasis and therapy response: a focus on epithelial–mesenchymal transition. J Cell Physiol 237, 2770–2795. [DOI] [PubMed] [Google Scholar]
173. Cichon MA & Radisky DC (2014) ROS‐induced epithelial‐mesenchymal transition in mammary epithelial cells is mediated by NF‐κB‐dependent activation of snail. Oncotarget 5, 2827–2838. [DOI] [PMC free article] [PubMed] [Google Scholar]
174. Luo W, Shi Q, Han M, Zhang Z, Reiter RJ, Ashrafizadeh M, Nabavi N, Sethi G, Nicot C & Mao Y (2025) TGF‐β‐driven EMT in cancer progression and drug resistance. Cytokine Growth Factor Rev 85, S1359610125000504. [DOI] [PubMed] [Google Scholar]
175. Sun L, Xing J, Zhou X, Song X & Gao S (2024) Wnt/β‐catenin signalling, epithelial‐mesenchymal transition and crosslink signalling in colorectal cancer cells. Biomed Pharmacother 175, 116685. [DOI] [PubMed] [Google Scholar]
176. Qin G, Luo M, Chen J, Dang Y, Chen G, Li L, Zeng J, Lu Y & Yang J (2016) Reciprocal activation between MMP‐8 and TGF‐β1 stimulates EMT and malignant progression of hepatocellular carcinoma. Cancer Lett 374, 85–95. [DOI] [PubMed] [Google Scholar]
177. Bai X, Li Y, Zhang H, Wang F, He H, Yao J, Liu L & Li S (2017) Role of matrix metalloproteinase‐9 in transforming growth factor‐&β1‐induced epithelial–mesenchymal transition in esophageal squamous cell carcinoma. OncoTargets Ther 10, 2837–2847. [DOI] [PMC free article] [PubMed] [Google Scholar]
178. Carey P, Low E, Harper E & Stack MS (2021) Metalloproteinases in ovarian cancer. Int J Mol Sci 22, 3403. [DOI] [PMC free article] [PubMed] [Google Scholar]
179. Illman SA, Lehti K, Keski‐Oja J & Lohi J (2006) Epilysin (MMP‐28) induces TGF‐β mediated epithelial to mesenchymal transition in lung carcinoma cells. J Cell Sci 119, 3856–3865. [DOI] [PubMed] [Google Scholar]
180. Lei Y, Chen L, Zhang G, Shan A, Ye C, Liang B, Sun J, Liao X, Zhu C, Chen Y et al. (2020) MicroRNAs target the Wnt/β‐catenin signaling pathway to regulate epithelial‐mesenchymal transition in cancer (review). Oncol Rep 44, 1299–1313. [DOI] [PMC free article] [PubMed] [Google Scholar]
181. Sheridan R, Brennan K, Bazou D, O'Gorman P, Matallanas D & Mc Gee MM (2024) Multiple myeloma derived extracellular vesicle uptake by monocyte cells stimulates IL‐6 and MMP‐9 secretion and promotes cancer cell migration and proliferation. Cancer 16, 1011. [DOI] [PMC free article] [PubMed] [Google Scholar]
182. Hass R, Von Der Ohe J & Ungefroren H (2020) The intimate relationship among EMT, MET and TME: a T(ransdifferentiation) E(nhancing) M(ix) to Be exploited for therapeutic purposes. Cancer 12, 3674. [DOI] [PMC free article] [PubMed] [Google Scholar]
183. Wang Z, Guo X, Li X, Wang J, Zhang N, Amin B, Xu G & Zhu B (2025) Cancer‐associated fibroblast‐derived mmp11 promotes tumor progression in pancreatic cancer. Cancer Sci 116, 643–655. [DOI] [PMC free article] [PubMed] [Google Scholar]
184. Qi F, Li J, Guo M, Yang B & Xia J (2020) MT4‐MMP in tumor‐associated macrophages is linked to hepatocellular carcinoma aggressiveness and recurrence. Clin Transl Med 10, e162. [DOI] [PMC free article] [PubMed] [Google Scholar]
185. Zhou J, Liu L, Hu X, Feng R, Zhao N, Zhang L, Hu W, Zhang J, Huang S, Liu L et al. (2023) Matrix metalloproteinase‐21 promotes metastasis via increasing the recruitment and M2 polarization of macrophages in HCC. Cancer Sci 114, 423–435. [DOI] [PMC free article] [PubMed] [Google Scholar]
186. Zhu Y, Tao Z, Chen Y, Lin S, Zhu M, Ji W, Liu X, Li T & Hu X (2022) Exosomal MMP‐1 transfers metastasis potential in triple‐negative breast cancer through PAR1‐mediated EMT. Breast Cancer Res Treat 193, 65–81. [DOI] [PubMed] [Google Scholar]
187. You Y, Shan Y, Chen J, Yue H, You B, Shi S, Li X & Cao X (2015) Matrix metalloproteinase 13‐containing exosomes promote nasopharyngeal carcinoma metastasis. Cancer Sci 106, 1669–1677. [DOI] [PMC free article] [PubMed] [Google Scholar]
188. Mashouri L, Yousefi H, Aref AR, Ahadi AM, Molaei F & Alahari SK (2019) Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol Cancer 18, 75. [DOI] [PMC free article] [PubMed] [Google Scholar]
189. Gonzalez‐Avila G, Sommer B, Flores‐Soto E & Aquino‐Galvez A (2023) Hypoxic effects on matrix Metalloproteinases' expression in the tumor microenvironment and therapeutic perspectives. Int J Mol Sci 24, 16887. [DOI] [PMC free article] [PubMed] [Google Scholar]
190. Liang M, Wang J, Wu C, Wu M, Hu J, Dai J, Ruan H, Xiong S & Dong C (2021) Targeting matrix metalloproteinase MMP3 greatly enhances oncolytic virus mediated tumor therapy. Transl Oncol 14, 101221. [DOI] [PMC free article] [PubMed] [Google Scholar]
191. Kwon MJ (2023) Matrix metalloproteinases as therapeutic targets in breast cancer. Front Oncol 12, 1108695. [DOI] [PMC free article] [PubMed] [Google Scholar]
192. Deborde S & Wong RJ (2022) The role of Schwann cells in cancer. Adv Biol 6, 2200089. [DOI] [PMC free article] [PubMed] [Google Scholar]
193. Quintero‐Fabián S, Arreola R, Becerril‐Villanueva E, Torres‐Romero JC, Arana‐Argáez V, Lara‐Riegos J, Ramírez‐Camacho MA & Alvarez‐Sánchez ME (2019) Role of matrix Metalloproteinases in angiogenesis and cancer. Front Oncol 9, 1370. [DOI] [PMC free article] [PubMed] [Google Scholar]
194. Dzobo K & Dandara C (2023) The extracellular matrix: its composition, function, remodeling, and role in tumorigenesis. Biomimetics 8, 146. [DOI] [PMC free article] [PubMed] [Google Scholar]
195. Shoari A, Ashja Ardalan A, Dimesa AM & Coban MA (2024) Targeting invasion: the role of MMP‐2 and MMP‐9 inhibition in colorectal cancer therapy. Biomolecules 15, 35. [DOI] [PMC free article] [PubMed] [Google Scholar]
196. Shoari A (2024) Potential of MMP‐2 and MMP‐9 gelatinase blockade as a therapeutic strategy in Fibrosarcoma treatment: a decadal review. Targets 2, 104–125. [Google Scholar]
197. Worzfeld T, Pogge Von Strandmann E, Huber M, Adhikary T, Wagner U, Reinartz S & Müller R (2017) The unique molecular and cellular microenvironment of ovarian cancer. Front Oncol 7, 24. [DOI] [PMC free article] [PubMed] [Google Scholar]
198. Kenny HA, Kaur S, Coussens LM & Lengyel E (2008) The initial steps of ovarian cancer cell metastasis are mediated by MMP‐2 cleavage of vitronectin and fibronectin. J Clin Invest 118, 1367–1379. [DOI] [PMC free article] [PubMed] [Google Scholar]
199. Iwanicki MP, Davidowitz RA, Ng MR, Besser A, Muranen T, Merritt M, Danuser G, Ince T & Brugge JS (2011) Ovarian cancer spheroids use myosin‐generated force to clear the mesothelium. Cancer Discov 1, 144–157. [DOI] [PMC free article] [PubMed] [Google Scholar]
200. Wolosowicz M, Prokopiuk S & Kaminski TW (2024) The complex role of matrix Metalloproteinase‐2 (MMP‐2) in health and disease. Int J Mol Sci 25, 13691. [DOI] [PMC free article] [PubMed] [Google Scholar]
201. Gifford V & Itoh Y (2019) MT1‐MMP‐dependent cell migration: proteolytic and non‐proteolytic mechanisms. Biochem Soc Trans 47, 811–826. [DOI] [PMC free article] [PubMed] [Google Scholar]
202. Zhang J, Pan Q, Yan W, Wang Y, He X & Zhao Z (2018) Overexpression of MMP21 and MMP28 is associated with gastric cancer progression and poor prognosis. Oncol Lett 15, 7776–7782. [DOI] [PMC free article] [PubMed] [Google Scholar]
203. Hsin C‐H, Chou Y‐E, Yang S‐F, Su S‐C, Chuang Y‐T, Lin S‐H & Lin C‐W (2017) MMP‐11 promoted the oral cancer migration and FAK/Src activation. Oncotarget 8, 32783–32793. [DOI] [PMC free article] [PubMed] [Google Scholar]
204. Wang S, Jia J, Liu D, Wang M, Wang Z, Li X, Wang H, Rui Y, Liu Z, Guo W et al. (2019) Matrix metalloproteinase expressions play important role in prediction of ovarian cancer outcome. Sci Rep 9, 11677. [DOI] [PMC free article] [PubMed] [Google Scholar]
205. Zheng L (2011) Non‐small cell lung cancer invasion and metastasis promoted by MMP‐26. Mol Med Rep 4, 1201–1209. [DOI] [PubMed] [Google Scholar]
206. Yang H, Wang Y, Li Y, Zhang L, Deng Y, Qi D, Li Y & Li W (2012) Roles of matrix metalloproteinase‐26 in the growth, invasion and angiogenesis of breast cancer. Oncol Lett 4, 832–836. [DOI] [PMC free article] [PubMed] [Google Scholar]
207. Masi I, Caprara V, Bagnato A & Rosanò L (2020) Tumor cellular and microenvironmental cues controlling Invadopodia formation. Front Cell Dev Biol 8, 584181. [DOI] [PMC free article] [PubMed] [Google Scholar]
208. Hao Z, Zhang M, Du Y, Liu J, Zeng G, Li H & Peng X (2025) Invadopodia in cancer metastasis: dynamics, regulation, and targeted therapies. J Transl Med 23, 548. [DOI] [PMC free article] [PubMed] [Google Scholar]
209. Guan P‐P, Yu X, Guo J‐J, Wang Y, Wang T, Li J‐Y, Konstantopoulos K, Wang Z‐Y & Wang P (2015) By activating matrix metalloproteinase‐7, shear stress promotes chondrosarcoma cell motility, invasion and lung colonization. Oncotarget 6, 9140–9159. [DOI] [PMC free article] [PubMed] [Google Scholar]
210. Das K, Prasad R, Ansari SA, Roy A, Mukherjee A & Sen P (2018) Matrix metalloproteinase‐2: a key regulator in coagulation proteases mediated human breast cancer progression through autocrine signaling. Biomed Pharmacother 105, 395–406. [DOI] [PubMed] [Google Scholar]
211. Deryugina EI, Ratnikov BI, Postnova TI, Rozanov DV & Strongin AY (2002) Processing of integrin αv subunit by membrane type 1 matrix metalloproteinase stimulates migration of breast carcinoma cells on Vitronectin and enhances tyrosine phosphorylation of focal adhesion kinase. J Biol Chem 277, 9749–9756. [DOI] [PubMed] [Google Scholar]
212. Koshikawa N, Hoshino D, Taniguchi H, Minegishi T, Tomari T, Nam S‐O, Aoki M, Sueta T, Nakagawa T, Miyamoto S et al. (2015) Proteolysis of EphA2 converts it from a tumor suppressor to an Oncoprotein. Cancer Res 75, 3327–3339. [DOI] [PMC free article] [PubMed] [Google Scholar]
213. Sugiyama N, Gucciardo E, Tatti O, Varjosalo M, Hyytiäinen M, Gstaiger M & Lehti K (2013) EphA2 cleavage by MT1‐MMP triggers single cancer cell invasion via homotypic cell repulsion. J Cell Biol 201, 467–484. [DOI] [PMC free article] [PubMed] [Google Scholar]
214. Golubkov VS, Chekanov AV, Cieplak P, Aleshin AE, Chernov AV, Zhu W, Radichev IA, Zhang D, Dong PD & Strongin AY (2010) The Wnt/planar cell polarity protein‐tyrosine Kinase‐7 (PTK7) is a highly efficient proteolytic target of membrane Type‐1 matrix metalloproteinase. J Biol Chem 285, 35740–35749. [DOI] [PMC free article] [PubMed] [Google Scholar]
215. Thakur V & Bedogni B (2016) The membrane tethered matrix metalloproteinase MT1‐MMP at the forefront of melanoma cell invasion and metastasis. Pharmacol Res 111, 17–22. [DOI] [PubMed] [Google Scholar]
216. Shaverdashvili K, Wong P, Ma J, Zhang K, Osman I & Bedogni B (2014) mt 1‐ mmp modulates melanoma cell dissemination and metastasis through activation of mmp 2 and rac 1. Pigment Cell Melanoma Res 27, 287–296. [DOI] [PubMed] [Google Scholar]
217. Colón‐Bolea P, García‐Gómez R & Casar B (2021) RAC1 activation as a potential therapeutic option in metastatic cutaneous melanoma. Biomolecules 11, 1554. [DOI] [PMC free article] [PubMed] [Google Scholar]
218. Tatti O, Gucciardo E, Pekkonen P, Holopainen T, Louhimo R, Repo P, Maliniemi P, Lohi J, Rantanen V, Hautaniemi S et al. (2015) MMP16 mediates a proteolytic switch to promote cell–cell adhesion, collagen alignment, and lymphatic invasion in melanoma. Cancer Res 75, 2083–2094. [DOI] [PubMed] [Google Scholar]
219. Yan X, Cao N, Chen Y, Lan H‐Y, Cha J‐H, Yang W‐H & Yang M‐H (2020) MT4‐MMP promotes invadopodia formation and cell motility in FaDu head and neck cancer cells. Biochem Biophys Res Commun 522, 1009–1014. [DOI] [PubMed] [Google Scholar]
220. Jang B, Kim A, Hwang J, Song H‐K, Kim Y & Oh E‐S (2020) Emerging role of Syndecans in extracellular matrix remodeling in cancer. J Histochem Cytochem 68, 863–870. [DOI] [PMC free article] [PubMed] [Google Scholar]
221. Zhao X, Sun B, Li Y, Liu Y, Zhang D, Wang X, Gu Q, Zhao J, Dong X, Liu Z et al. (2015) Dual effects of collagenase‐3 on melanoma: metastasis promotion and disruption of vasculogenic mimicry. Oncotarget 6, 8890–8899. [DOI] [PMC free article] [PubMed] [Google Scholar]
222. Rousselle P & Scoazec JY (2020) Laminin 332 in cancer: when the extracellular matrix turns signals from cell anchorage to cell movement. Semin Cancer Biol 62, 149–165. [DOI] [PubMed] [Google Scholar]
223. Moorman HR, Poschel D, Klement JD, Lu C, Redd PS & Liu K (2020) Osteopontin: a key regulator of tumor progression and immunomodulation. Cancer 12, 3379. [DOI] [PMC free article] [PubMed] [Google Scholar]
224. Kothari A & Flick MJ (2021) Coagulation signaling through PAR1 as a therapeutic target in pancreatic ductal adenocarcinoma. Int J Mol Sci 22, 5138. [DOI] [PMC free article] [PubMed] [Google Scholar]
225. Covic L & Kuliopulos A (2018) Protease‐activated receptor 1 as therapeutic target in breast, lung, and ovarian cancer: Pepducin approach. Int J Mol Sci 19, 2237. [DOI] [PMC free article] [PubMed] [Google Scholar]
226. Boire A, Covic L, Agarwal A, Jacques S, Sherifi S & Kuliopulos A (2005) PAR1 is a matrix Metalloprotease‐1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120, 303–313. [DOI] [PubMed] [Google Scholar]
227. Liu S, Ren J & Ten Dijke P (2021) Targeting TGFβ signal transduction for cancer therapy. Signal Transduct Target Ther 6, 8. [DOI] [PMC free article] [PubMed] [Google Scholar]
228. Ma L, Dong L & Chang P (2019) CD44v6 engages in colorectal cancer progression. Cell Death Dis 10, 30. [DOI] [PMC free article] [PubMed] [Google Scholar]
229. Medrano‐González PA, Rivera‐Ramírez O, Montaño LF & Rendón‐Huerta EP (2021) Proteolytic processing of CD44 and its implications in cancer. Stem Cells Int 2021, 1–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
230. Cauwe B, Van Den Steen PE & Opdenakker G (2007) The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix Metalloproteinases. Crit Rev Biochem Mol Biol 42, 113–185. [DOI] [PubMed] [Google Scholar]
231. Kung C‐I, Chen C‐Y, Yang C‐C, Lin C‐Y, Chen T‐H & Wang H‐S (2012) Enhanced membrane‐type 1 matrix metalloproteinase expression by hyaluronan oligosaccharides in breast cancer cells facilitates CD44 cleavage and tumor cell migration. Oncol Rep 28, 1808–1814. [DOI] [PubMed] [Google Scholar]
232. Merdad A, Karim S, Schulten H‐J, Dallol A, Buhmeida A, Al‐Thubaity F, Gari MA, Chaudhary AG, Abuzenadah AM & Al‐Qahtani MH (2014) Expression of matrix metalloproteinases (MMPs) in primary human breast cancer: MMP‐9 as a potential biomarker for cancer invasion and metastasis. Anticancer Res 34, 1355–1366. [PubMed] [Google Scholar]
233. Wöhner B, Li W, Hey S, Drobny A, Werny L, Becker‐Pauly C, Lucius R, Zunke F, Linder S & Arnold P (2023) Proteolysis of CD44 at the cell surface controls a downstream protease network. Front Mol Biosci 10, 1026810. [DOI] [PMC free article] [PubMed] [Google Scholar]
234. Lawson CD & Ridley AJ (2018) Rho GTPase signaling complexes in cell migration and invasion. J Cell Biol 217, 447–457. [DOI] [PMC free article] [PubMed] [Google Scholar]
235. Yamaguchi H & Sakai R (2015) Direct interaction between carcinoma cells and cancer associated fibroblasts for the regulation of cancer invasion. Cancer 7, 2054–2062. [DOI] [PMC free article] [PubMed] [Google Scholar]
236. Li Y, Wang C, Huang T, Yu X & Tian B (2023) The role of cancer‐associated fibroblasts in breast cancer metastasis. Front Oncol 13, 1194835. [DOI] [PMC free article] [PubMed] [Google Scholar]
237. Fernández‐Nogueira P, Fuster G, Gutierrez‐Uzquiza Á, Gascón P, Carbó N & Bragado P (2021) Cancer‐associated fibroblasts in breast cancer treatment response and metastasis. Cancer 13, 3146. [DOI] [PMC free article] [PubMed] [Google Scholar]
238. Shurin GV, Kruglov O, Ding F, Lin Y, Hao X, Keskinov AA, You Z, Lokshin AE, LaFramboise WA, Falo LD et al. (2019) Melanoma‐induced reprogramming of Schwann cell signaling aids tumor growth. Cancer Res 79, 2736–2747. [DOI] [PMC free article] [PubMed] [Google Scholar]
239. Huang T, Fan Q, Wang Y, Cui Y, Wang Z, Yang L, Sun X & Wang Y (2020) Schwann cell‐derived CCL2 promotes the Perineural invasion of cervical cancer. Front Oncol 10, 19. [DOI] [PMC free article] [PubMed] [Google Scholar]
240. Orgaz JL, Pandya P, Dalmeida R, Karagiannis P, Sanchez‐Laorden B, Viros A, Albrengues J, Nestle FO, Ridley AJ, Gaggioli C et al. (2014) Diverse matrix metalloproteinase functions regulate cancer amoeboid migration. Nat Commun 5, 4255. [DOI] [PMC free article] [PubMed] [Google Scholar]
241. Pandya P, Orgaz JL & Sanz‐Moreno V (2017) Modes of invasion during tumour dissemination. Mol Oncol 11, 5–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
242. Patel B, Gaikwad S & Prasad S (2025) Exploring the significance of extracellular vesicles: key players in advancing cancer and possible theranostic tools. Cancer Pathog Ther 3, 109–119. [DOI] [PMC free article] [PubMed] [Google Scholar]
243. Graves LE, Ariztia EV, Navari JR, Matzel HJ, Stack MS & Fishman DA (2004) Proinvasive properties of ovarian cancer ascites‐derived membrane vesicles. Cancer Res 64, 7045–7049. [DOI] [PubMed] [Google Scholar]
244. Rilla K, Mustonen A‐M, Arasu UT, Härkönen K, Matilainen J & Nieminen P (2019) Extracellular vesicles are integral and functional components of the extracellular matrix. Matrix Biol 75–76, 201–219. [DOI] [PubMed] [Google Scholar]
245. Jackson HK, Mitoko C, Linke F, Macarthur D, Kerr ID & Coyle B (2023) Extracellular vesicles potentiate Medulloblastoma metastasis in an EMMPRIN and MMP‐2 dependent manner. Cancer 15, 2601. [DOI] [PMC free article] [PubMed] [Google Scholar]
246. Wang J, Wu Y, Guo J, Fei X, Yu L & Ma S (2017) Adipocyte‐derived exosomes promote lung cancer metastasis by increasing MMP9 activity via transferring MMP3 to lung cancer cells. Oncotarget 8, 81880–81891. [DOI] [PMC free article] [PubMed] [Google Scholar]
247. Hanahan D (2022) Hallmarks of cancer: new dimensions. Cancer Discov 12, 31–46. [DOI] [PubMed] [Google Scholar]
248. Lugano R, Ramachandran M & Dimberg A (2020) Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci 77, 1745–1770. [DOI] [PMC free article] [PubMed] [Google Scholar]
249. Anderson NM & Simon MC (2020) The tumor microenvironment. Curr Biol 30, R921–R925. [DOI] [PMC free article] [PubMed] [Google Scholar]
250. Liu Z‐L, Chen H‐H, Zheng L‐L, Sun L‐P & Shi L (2023) Angiogenic signaling pathways and anti‐angiogenic therapy for cancer. Signal Transduct Target Ther 8, 198. [DOI] [PMC free article] [PubMed] [Google Scholar]
251. Muñoz‐Sáez E, Moracho N, Learte AIR, Arroyo AG & Sánchez‐Camacho C (2021) Dynamic expression of membrane type 1‐matrix metalloproteinase (Mt1‐mmp/Mmp14) in the mouse embryo. Cells 10, 2448. [DOI] [PMC free article] [PubMed] [Google Scholar]
252. Maybee DV, Ink NL & Ali MAM (2022) Novel roles of MT1‐MMP and MMP‐2: beyond the extracellular milieu. Int J Mol Sci 23, 9513. [DOI] [PMC free article] [PubMed] [Google Scholar]
253. Esteban S, Clemente C, Koziol A, Gonzalo P, Rius C, Martínez F, Linares PM, Chaparro M, Urzainqui A, Andrés V et al. (2020) Endothelial MT1‐MMP targeting limits intussusceptive angiogenesis and colitis via TSP1/nitric oxide axis. EMBO Mol Med 12, e10862. [DOI] [PMC free article] [PubMed] [Google Scholar]
254. Di Martino JS, Akhter T & Bravo‐Cordero JJ (2021) Remodeling the ECM: implications for metastasis and tumor dormancy. Cancer 13, 4916. [DOI] [PMC free article] [PubMed] [Google Scholar]
255. Winkler J, Abisoye‐Ogunniyan A, Metcalf KJ & Werb Z (2020) Concepts of extracellular matrix remodelling in tumour progression and metastasis. Nat Commun 11, 5120. [DOI] [PMC free article] [PubMed] [Google Scholar]
256. Mao S, Xia A, Tao X, Ye D, Qu J, Sun M, Wei H & Li G (2023) A pan‐cancer analysis of the prognostic and immunological roles of matrix metalloprotease‐1 (MMP1) in human tumors. Front Oncol 12, 1089550. [DOI] [PMC free article] [PubMed] [Google Scholar]
257. Grafinger OR, Hayward JJ, Meng Y, Geddes‐McAlister J, Li Y, Mar S, Sheng M, Su B, Thillainadesan G, Lipsman N et al. (2024) Cancer cell extravasation requires iplectin‐mediated delivery of MT1‐MMP at invadopodia. Br J Cancer 131, 931–943. [DOI] [PMC free article] [PubMed] [Google Scholar]
258. Aristorena M, Gallardo‐Vara E, Vicen M, De Las Casas‐Engel M, Ojeda‐Fernandez L, Nieto C, Blanco FJ, Valbuena‐Diez AC, Botella LM, Nachtigal P et al. (2019) MMP‐12, secreted by pro‐inflammatory macrophages, targets Endoglin in human macrophages and endothelial cells. Int J Mol Sci 20, 3107. [DOI] [PMC free article] [PubMed] [Google Scholar]
259. Hellenthal KEM, Brabenec L & Wagner N‐M (2022) Regulation and dysregulation of endothelial permeability during systemic inflammation. Cells 11, 1935. [DOI] [PMC free article] [PubMed] [Google Scholar]
260. Lin Y, Zheng Z‐H, Wang J‐X, Zhao Z & Peng T‐Y (2021) Tumor cell‐derived Exosomal Circ‐0072088 suppresses migration and invasion of hepatic carcinoma cells through regulating MMP‐16. Front Cell Dev Biol 9, 726323. [DOI] [PMC free article] [PubMed] [Google Scholar]
261. McMahon M, Ye S, Pedrina J, Dlugolenski D & Stambas J (2021) Extracellular matrix enzymes and immune cell biology. Front Mol Biosci 8, 703868. [DOI] [PMC free article] [PubMed] [Google Scholar]
262. Lee HS & Kim WJ (2022) The role of matrix metalloproteinase in inflammation with a focus on infectious diseases. Int J Mol Sci 23, 10546. [DOI] [PMC free article] [PubMed] [Google Scholar]
263. Ye Y, Kuang X, Xie Z, Liang L, Zhang Z, Zhang Y, Ma F, Gao Q, Chang R, Lee H‐H et al. (2020) Small‐molecule MMP2/MMP9 inhibitor SB‐3CT modulates tumor immune surveillance by regulating PD‐L1. Genome Med 12, 83. [DOI] [PMC free article] [PubMed] [Google Scholar]
264. Wang Q, Wang K, Tan X, Li Z & Wang H (2022) Immunomodulatory role of metalloproteases in cancers: current progress and future trends. Front Immunol 13, 1064033. [DOI] [PMC free article] [PubMed] [Google Scholar]
265. McFarlane AJ, Fercoq F, Coffelt SB & Carlin LM (2021) Neutrophil dynamics in the tumor microenvironment. J Clin Invest 131, e143759. [DOI] [PMC free article] [PubMed] [Google Scholar]
266. Cai N, Cheng K, Ma Y, Liu S, Tao R, Li Y, Li D, Guo B, Jia W, Liang H et al. (2024) Targeting MMP9 in CTNNB1 mutant hepatocellular carcinoma restores CD8⁺ T cell‐mediated antitumour immunity and improves anti‐PD‐1 efficacy. Gut 73, 985–999. [DOI] [PMC free article] [PubMed] [Google Scholar]
267. Wang G, Zhong K, Wang Z, Zhang Z, Tang X, Tong A & Zhou L (2022) Tumor‐associated microglia and macrophages in glioblastoma: from basic insights to therapeutic opportunities. Front Immunol 13, 964898. [DOI] [PMC free article] [PubMed] [Google Scholar]
268. Makutani Y, Kawakami H, Tsujikawa T, Yoshimura K, Chiba Y, Ito A, Kawamura J, Haratani K & Nakagawa K (2022) Contribution of MMP14‐expressing cancer‐associated fibroblasts in the tumor immune microenvironment to progression of colorectal cancer. Front Oncol 12, 956270. [DOI] [PMC free article] [PubMed] [Google Scholar]
269. Wang H, Pan J, Barsky L, Jacob JC, Zheng Y, Gao C, Wang S, Zhu W, Sun H, Lu L et al. (2021) Characteristics of pre‐metastatic niche: the landscape of molecular and cellular pathways. Mol Biomed 2, 3. [DOI] [PMC free article] [PubMed] [Google Scholar]
270. Decock J, Hendrickx W, Thirkettle S, Gutiérrez‐Fernández A, Robinson SD & Edwards DR (2015) Pleiotropic functions of the tumor‐ and metastasis‐suppressing matrix metalloproteinase‐8 in mammary cancer in MMTV‐PyMT transgenic mice. Breast Cancer Res 17, 38. [DOI] [PMC free article] [PubMed] [Google Scholar]
271. Muniz‐Bongers LR, McClain CB, Saxena M, Bongers G, Merad M & Bhardwaj N (2021) MMP2 and TLRs modulate immune responses in the tumor microenvironment. JCI Insight 6, e144913. [DOI] [PMC free article] [PubMed] [Google Scholar]
272. Krstic J & Santibanez JF (2014) Transforming growth factor‐beta and matrix metalloproteinases: functional interactions in tumor stroma‐infiltrating myeloid cells. ScientificWorldJ 2014, 521754. [DOI] [PMC free article] [PubMed] [Google Scholar]
273. Kenji SF, Kurma K, Collet B, Oblet C, Debure L, Di Primo C, Minder L, Vérité F, Danger Y, Jean M et al. (2022) MMP7 cleavage of amino‐terminal CD95 death receptor switches signaling toward non‐apoptotic pathways. Cell Death Dis 13, 895. [DOI] [PMC free article] [PubMed] [Google Scholar]
274. Liu Y & Cao X (2016) Characteristics and significance of the pre‐metastatic niche. Cancer Cell 30, 668–681. [DOI] [PubMed] [Google Scholar]
275. Peinado H, Zhang H, Matei IR, Costa‐Silva B, Hoshino A, Rodrigues G, Psaila B, Kaplan RN, Bromberg JF, Kang Y et al. (2017) Pre‐metastatic niches: organ‐specific homes for metastases. Nat Rev Cancer 17, 302–317. [DOI] [PubMed] [Google Scholar]
276. Qi Y, Sun D, Zhai X, Chen F, Niu J & Zhu H (2025) Macrophages in the premetastatic and metastatic niche: key functions and therapeutic directions. J Transl Med 23, 602. [DOI] [PMC free article] [PubMed] [Google Scholar]
277. Wang Y, Jia J, Wang F, Fang Y, Yang Y, Zhou Q, Yuan W, Gu X, Hu J & Yang S (2024) Pre‐metastatic niche: formation, characteristics and therapeutic implication. Signal Transduct Target Ther 9, 236. [DOI] [PMC free article] [PubMed] [Google Scholar]
278. Li Y, Li M, Su K, Zong S, Zhang H & Xiong L (2023) Pre‐metastatic niche: from revealing the molecular and cellular mechanisms to the clinical applications in breast cancer metastasis. Theranostics 13, 2301–2318. [DOI] [PMC free article] [PubMed] [Google Scholar]
279. Shuman Moss LA, Jensen‐Taubman S & Stetler‐Stevenson WG (2012) Matrix metalloproteinases. Am J Pathol 181, 1895–1899. [DOI] [PMC free article] [PubMed] [Google Scholar]
280. Liu Y, Zhang Y, Ding Y & Zhuang R (2021) Platelet‐mediated tumor metastasis mechanism and the role of cell adhesion molecules. Crit Rev Oncol Hematol 167, 103502. [DOI] [PubMed] [Google Scholar]
281. Shay G, Lynch CC & Fingleton B (2015) Moving targets: emerging roles for MMPs in cancer progression and metastasis. Matrix Biol 44–46, 200–206. [DOI] [PMC free article] [PubMed] [Google Scholar]
282. Cai R, Tressler CM, Cheng M, Sonkar K, Tan Z, Paidi SK, Ayyappan V, Barman I & Glunde K (2023) Primary breast tumor induced extracellular matrix remodeling in premetastatic lungs. Sci Rep 13, 18566. [DOI] [PMC free article] [PubMed] [Google Scholar]
283. Wang Y, Ding Y, Guo N & Wang S (2019) MDSCs: key criminals of tumor pre‐metastatic niche formation. Front Immunol 10, 172. [DOI] [PMC free article] [PubMed] [Google Scholar]
284. Patras L, Paul D & Matei IR (2023) Weaving the nest: extracellular matrix roles in pre‐metastatic niche formation. Front Oncol 13, 1163786. [DOI] [PMC free article] [PubMed] [Google Scholar]
285. Sun H, Meng Q, Shi C, Yang H, Li X, Wu S, Familiari G, Relucenti M, Aschner M, Wang X et al. (2021) Hypoxia‐inducible exosomes facilitate liver‐tropic Premetastatic niche in colorectal cancer. Hepatology 74, 2633–2651. [DOI] [PubMed] [Google Scholar]
286. Alves R, Pires A, Jorge J, Balça‐Silva J, Gonçalves AC & Sarmento‐Ribeiro AB (2024) Batimastat induces cytotoxic and cytostatic effects in in vitro models of hematological tumors. Int J Mol Sci 25, 4554. [DOI] [PMC free article] [PubMed] [Google Scholar]
287. Laronha H, Carpinteiro I, Portugal J, Azul A, Polido M, Petrova KT, Salema‐Oom M & Caldeira J (2020) Challenges in matrix Metalloproteinases inhibition. Biomolecules 10, 717. [DOI] [PMC free article] [PubMed] [Google Scholar]
288. Zhu B‐L, Long Y, Luo W, Yan Z, Lai Y‐J, Zhao L‐G, Zhou W‐H, Wang Y‐J, Shen L‐L, Liu L et al. (2019) MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation. Brain 142, 176–192. [DOI] [PMC free article] [PubMed] [Google Scholar]
289. Wang L‐L, Zhang B, Zheng M‐H, Xie Y‐Z, Wang C‐J & Jin J‐Y (2020) Matrix Metalloproteinases (MMPs) in targeted drug delivery: synthesis of a potent and highly selective inhibitor against matrix Metalloproteinase‐7. Curr Top Med Chem 20, 2459–2471. [DOI] [PubMed] [Google Scholar]
290. Fields GB (2019) Mechanisms of action of novel drugs targeting angiogenesis‐promoting matrix Metalloproteinases. Front Immunol 10, 1278. [DOI] [PMC free article] [PubMed] [Google Scholar]
291. Bendell J, Sharma S, Patel MR, Windsor KS, Wainberg ZA, Gordon M, Chaves J, Berlin J, Brachmann CB, Zavodovskaya M et al. (2020) Safety and efficacy of Andecaliximab (GS‐5745) plus gemcitabine and nab‐paclitaxel in patients with advanced pancreatic adenocarcinoma: results from a phase I study. Oncologist 25, 954–962. [DOI] [PMC free article] [PubMed] [Google Scholar]
292. Das N, Benko C, Gill SE & Dufour A (2020) The pharmacological TAILS of matrix Metalloproteinases and their inhibitors. Pharmaceuticals 14, 31. [DOI] [PMC free article] [PubMed] [Google Scholar]
293. Xu Q & Shao D (2024) Leveraging the synergy between anti‐angiogenic therapy and immune checkpoint inhibitors to treat digestive system cancers. Front Immunol 15, 1487610. [DOI] [PMC free article] [PubMed] [Google Scholar]
294. Lee WS, Yang H, Chon HJ & Kim C (2020) Combination of anti‐angiogenic therapy and immune checkpoint blockade normalizes vascular‐immune crosstalk to potentiate cancer immunity. Exp Mol Med 52, 1475–1485. [DOI] [PMC free article] [PubMed] [Google Scholar]
295. Granet‐Vaissiere E, Lefort F, Domblides C, Larroquette M, Ravaud A, Bernhard J‐C & Gross‐Goupil M (2023) Combinations of anti‐Angiogenic agents and immune checkpoint inhibitors in renal cell carcinoma: best option? Cancer 15, 1048. [DOI] [PMC free article] [PubMed] [Google Scholar]
296. Jain S, Annett SL, Morgan MP & Robson T (2021) The cancer stem cell niche in ovarian cancer and its impact on immune surveillance. Int J Mol Sci 22, 4091. [DOI] [PMC free article] [PubMed] [Google Scholar]
297. Protasoni M, Kroon AM & Taanman J‐W (2018) Mitochondria as oncotarget: a comparison between the tetracycline analogs doxycycline and COL‐3. Oncotarget 9, 33818–33831. [DOI] [PMC free article] [PubMed] [Google Scholar]
298. Ferreira Junior NC, Dos Santos Pereira M, Francis N, Ramirez P, Martorell P, González‐Lizarraga F, Figadère B, Chehin R, Del Bel E, Raisman‐Vozari R et al. (2021) The chemically‐modified tetracycline COL‐3 and its parent compound doxycycline prevent microglial inflammatory responses by reducing glucose‐mediated oxidative stress. Cells 10, 2163. [DOI] [PMC free article] [PubMed] [Google Scholar]
299. Rahmani M, Negro Álvarez SE & Hernández EB (2022) The potential use of tetracyclines in neurodegenerative diseases and the role of nano‐based drug delivery systems. Eur J Pharm Sci 175, 106237. [DOI] [PubMed] [Google Scholar]
300. Garrido‐Mesa J, Adams K, Galvez J & Garrido‐Mesa N (2022) Repurposing tetracyclines for acute respiratory distress syndrome (ARDS) and severe COVID‐19: a critical discussion of recent publications. Expert Opin Investig Drugs 31, 475–482. [DOI] [PMC free article] [PubMed] [Google Scholar]
301. He B & Garmire L (2020) Prediction of repurposed drugs for treating lung injury in COVID‐19. F1000Res 9, 609. [DOI] [PMC free article] [PubMed] [Google Scholar]
302. Muri L, Leppert D, Grandgirard D & Leib SL (2019) MMPs and ADAMs in neurological infectious diseases and multiple sclerosis. Cell Mol Life Sci 76, 3097–3116. [DOI] [PMC free article] [PubMed] [Google Scholar]
303. He L, Kang Q, Chan KI, Zhang Y, Zhong Z & Tan W (2023) The immunomodulatory role of matrix metalloproteinases in colitis‐associated cancer. Front Immunol 13, 1093990. [DOI] [PMC free article] [PubMed] [Google Scholar]
304. Radisky ES, Raeeszadeh‐Sarmazdeh M & Radisky DC (2017) Therapeutic potential of matrix metalloproteinase inhibition in breast cancer. J Cell Biochem 118, 3531–3548. [DOI] [PMC free article] [PubMed] [Google Scholar]
305. Fan D & Kassiri Z (2020) Biology of tissue inhibitor of metalloproteinase 3 (TIMP3), and its therapeutic implications in cardiovascular pathology. Front Physiol 11, 661. [DOI] [PMC free article] [PubMed] [Google Scholar]
306. Nikolov A, Popovski N & Hristova I (2020) Collagenases MMP‐1, MMP‐13, and tissue inhibitors TIMP‐1, TIMP‐2: their role in healthy and complicated pregnancy and potential as preeclampsia biomarkers—a brief review. Appl Sci 10, 7731. [Google Scholar]
307. Boumiza S, Chahed K, Tabka Z, Jacob M‐P, Norel X & Ozen G (2021) MMPs and TIMPs levels are correlated with anthropometric parameters, blood pressure, and endothelial function in obesity. Sci Rep 11, 20052. [DOI] [PMC free article] [PubMed] [Google Scholar]
308. Sarkar P, Li Z, Ren W, Wang S, Shao S, Sun J, Ren X, Perkins NG, Guo Z, Chang C‐EA et al. (2020) Inhibiting matrix Metalloproteinase‐2 activation by perturbing protein–protein interactions using a cyclic peptide. J Med Chem 63, 6979–6990. [DOI] [PMC free article] [PubMed] [Google Scholar]
309. Mendes SR, Amo‐Maestro LD, Marino‐Puertas L, Diego ID, Goulas T & Gomis‐Rüth FX (2020) Analysis of the inhibiting activity of reversion‐inducing cysteine‐rich protein with Kazal motifs (RECK) on matrix metalloproteinases. Sci Rep 10, 6317. [DOI] [PMC free article] [PubMed] [Google Scholar]
310. Russell JJ, Grisanti LA, Brown SM, Bailey CA, Bender SB & Chandrasekar B (2021) Reversion inducing cysteine rich protein with Kazal motifs and cardiovascular diseases: the RECKlessness of adverse remodeling. Cell Signal 83, 109993. [DOI] [PMC free article] [PubMed] [Google Scholar]
311. Mori H, Tomari T, Koshikawa N, Kajita M, Itoh Y, Sato H, Tojo H, Yana I & Seiki M (2002) CD44 directs membrane‐type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin‐like domain. EMBO J 21, 3949–3959. [DOI] [PMC free article] [PubMed] [Google Scholar]
312. Yosef G, Hayun H & Papo N (2021) Simultaneous targeting of CD44 and MMP9 catalytic and hemopexin domains as a therapeutic strategy. Biochem J 478, 1139–1157. [DOI] [PMC free article] [PubMed] [Google Scholar]
313. Charzewski Ł, Krzyśko KA & Lesyng B (2021) Structural characterisation of inhibitory and non‐inhibitory MMP‐9–TIMP‐1 complexes and implications for regulatory mechanisms of MMP‐9. Sci Rep 11, 13376. [DOI] [PMC free article] [PubMed] [Google Scholar]
314. Conte R, Finicelli M, Borrone A, Margarucci S, Peluso G, Calarco A & Bosetti M (2023) MMP‐2 silencing through siRNA loaded positively‐charged nanoparticles (AcPEI‐NPs) counteracts chondrocyte De‐differentiation. Polymers 15, 1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
315. Escalona RM, Chu S, Kadife E, Kelly JK, Kannourakis G, Findlay JK & Ahmed N (2022) Knock down of TIMP‐2 by siRNA and CRISPR/Cas9 mediates diverse cellular reprogramming of metastasis and chemosensitivity in ovarian cancer. Cancer Cell Int 22, 422. [DOI] [PMC free article] [PubMed] [Google Scholar]
316. Shah MA, Bodoky G, Starodub A, Cunningham D, Yip D, Wainberg ZA, Bendell J, Thai D, He J, Bhargava P et al. (2021) Phase III study to evaluate efficacy and safety of Andecaliximab with mFOLFOX6 as first‐line treatment in patients with advanced gastric or GEJ adenocarcinoma (GAMMA‐1). J Clin Oncol 39, 990–1000. [DOI] [PMC free article] [PubMed] [Google Scholar]
317. Wang Y, Wei Y, Huang J, Li X, You D, Wang L & Ma X (2024) Prognostic value of matrix metalloproteinase‐2 protein and matrix metalloproteinase‐9 protein in colorectal cancer: a meta‐analysis. BMC Cancer 24, 1065. [DOI] [PMC free article] [PubMed] [Google Scholar]
318. Jiang H & Li H (2021) Prognostic values of tumoral MMP2 and MMP9 overexpression in breast cancer: a systematic review and meta‐analysis. BMC Cancer 21, 149. [DOI] [PMC free article] [PubMed] [Google Scholar]
319. Maurya S, Swati K, Ghosh M & Yadav PK (2025) Matrix metalloproteases as diagnostic and prognostic biomarkers in cancer. In Pathophysiological Aspects of Proteases in Cancerpp. 205–222. Academic Press, Amsterdam, the Netherlands. [Google Scholar]
320. Böckelman C, Beilmann‐Lehtonen I, Kaprio T, Koskensalo S, Tervahartiala T, Mustonen H, Stenman U‐H, Sorsa T & Haglund C (2018) Serum MMP‐8 and TIMP‐1 predict prognosis in colorectal cancer. BMC Cancer 18, 679. [DOI] [PMC free article] [PubMed] [Google Scholar]
321. Jonsson A, Hjalmarsson C, Falk P & Ivarsson M‐L (2016) Levels of matrix metalloproteinases differ in plasma and serum – aspects regarding analysis of biological markers in cancer. Br J Cancer 115, 703–706. [DOI] [PMC free article] [PubMed] [Google Scholar]
322. Mortaja M, Cheng MM, Ali A, Lesperance J, Hingorani DV, Allevato MM, Dhawan K, Camargo MF, McKay RR, Adams SR et al. (2024) Tumor‐targeted cell‐penetrating peptides reveal that monomethyl Auristatin E temporally modulates the tumor immune microenvironment. Molecules 29, 5618. [DOI] [PMC free article] [PubMed] [Google Scholar]
323. Seah D, Cheng Z & Vendrell M (2023) Fluorescent probes for imaging in humans: where are we now? ACS Nano 17, 19478–19490. [DOI] [PMC free article] [PubMed] [Google Scholar]
324. Winer A, Adams S & Mignatti P (2018) Matrix metalloproteinase inhibitors in cancer therapy: turning past failures into future successes. Mol Cancer Ther 17, 1147–1155. [DOI] [PMC free article] [PubMed] [Google Scholar]
325. Cathcart J, Pulkoski‐Gross A & Cao J (2015) Targeting matrix metalloproteinases in cancer: bringing new life to old ideas. Genes Dis 2, 26–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
326. Fields GB (2019) The rebirth of matrix metalloproteinase inhibitors: moving beyond the dogma. Cells 8, 984. [DOI] [PMC free article] [PubMed] [Google Scholar]
327. Ghosh S, Rajendran RL, Mahajan AA, Chowdhury A, Bera A, Guha S, Chakraborty K, Chowdhury R, Paul A, Jha S et al. (2024) Harnessing exosomes as cancer biomarkers in clinical oncology. Cancer Cell Int 24, 278. [DOI] [PMC free article] [PubMed] [Google Scholar]
328. Amar S & Fields GB (2015) Potential clinical implications of recent matrix metalloproteinase inhibitor design strategies. Expert Rev Proteomics 12, 445–447. [DOI] [PMC free article] [PubMed] [Google Scholar]
329. Vandenbroucke RE & Libert C (2014) Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat Rev Drug Discov 13, 904–927. [DOI] [PubMed] [Google Scholar]
330. Melaiu O, Vanni G, Portarena I, Pistolese CA, Anemona L, Pomella S, Bei R, Buonomo OC, Roselli M, Mauriello A et al. (2023) The combination of immune checkpoint blockade with tumor vessel normalization as a promising therapeutic strategy for breast cancer: An overview of preclinical and clinical studies. Int J Mol Sci 24, 3226. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0001] 1. Karamanos NK, Theocharis AD, Piperigkou Z, Manou D, Passi A, Skandalis SS, Vynios DH, Orian‐Rousseau V, Ricard‐Blum S, Schmelzer CEH et al. (2021) A guide to the composition and functions of the extracellular matrix. FEBS J 288, 6850–6912. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0002] 2. Piperigkou Z, Kyriakopoulou K, Koutsakis C, Mastronikolis S & Karamanos NK (2021) Key matrix remodeling enzymes: functions and targeting in cancer. Cancer 13, 1441. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0003] 3. Karamanos NK (2019) Extracellular matrix: key structural and functional meshwork in health and disease. FEBS J 286, 2826–2829. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0004] 4. Gaffney J, Solomonov I, Zehorai E & Sagi I (2015) Multilevel regulation of matrix metalloproteinases in tissue homeostasis indicates their molecular specificity in vivo. Matrix Biol 44–46, 191–199. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0005] 5. Kulesza M, Kicman A, Motyka J, Guszczyn T & Ławicki S (2023) Importance of metalloproteinase enzyme Group in Selected Skeletal System Diseases. Int J Mol Sci 24, 17139. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0006] 6. Cuffaro D, Nuti E, D'Andrea F & Rossello A (2020) Developments in carbohydrate‐based Metzincin inhibitors. Pharmaceuticals 13, 376. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0007] 7. Gonzalez‐Avila G, Sommer B, García‐Hernández AA & Ramos C (2020) Matrix Metalloproteinases' role in tumor microenvironment. In Tumor Microenvironment (Birbrair A, ed.), pp. 97–131. Springer International Publishing, Cham. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0008] 8. Tseng Y‐T, Chen M, John JS & Ekberg J (2021) Targeting matrix Metalloproteinases: a potential strategy for improving cell transplantation for nervous system repair. Cell Transplant 30, 09636897211012909. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0009] 9. Bassiouni W, Ali MAM & Schulz R (2021) Multifunctional intracellular matrix metalloproteinases: implications in disease. FEBS J 288, 7162–7182. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0010] 10. Kollet O, Das A, Karamanos N, Auf Dem Keller U & Sagi I (2023) Redefining metalloproteases specificity through network proteolysis. Trends Mol Med 30, 147–163. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0011] 11. Alaseem A, Alhazzani K, Dondapati P, Alobid S, Bishayee A & Rathinavelu A (2019) Matrix Metalloproteinases: a challenging paradigm of cancer management. Semin Cancer Biol 56, 100–115. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0012] 12. Gonzalez‐Avila G, Sommer B, García‐Hernandez AA, Ramos C & Flores‐Soto E (2022) Nanotechnology and matrix Metalloproteinases in cancer diagnosis and treatment. Front Mol Biosci 9, 918789. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0013] 13. Almutairi S, Kalloush HM, Manoon NA & Bardaweel SK (2023) Matrix Metalloproteinases inhibitors in cancer treatment: An updated review (2013–2023). Molecules 28, 5567. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0014] 14. Hey S & Linder S (2024) Matrix metalloproteinases at a glance. J Cell Sci 137, jcs261898. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0015] 15. Cui N, Hu M & Khalil RA (2017) Biochemical and biological attributes of matrix Metalloproteinases. Progress Molec Biol Translat Sci 147, 1–73. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0016] 16. Hey S, Ratt A & Linder S (2022) There and back again: intracellular trafficking, release and recycling of matrix metalloproteinases. Biochimica et Biophysica Acta (BBA) 1869, 119189. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0017] 17. Pompili S, Latella G, Gaudio E, Sferra R & Vetuschi A (2021) The charming world of the extracellular matrix: a dynamic and protective network of the Intestinal Wall. Front Med 8, 610189. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0018] 18. Khalid U, Dimov D & Vlaykova T (2023) Matrix metalloproteinases in COVID‐19: underlying significance. Biotechnol Biotechnol Equip 37, 295–301. [Google Scholar]

[febs70296-bib-0019] 19. Moracho N, Learte AIR, Muñoz‐Sáez E, Marchena MA, Cid MA, Arroyo AG & Sánchez‐Camacho C (2022) Emerging roles of MT‐MMPs in embryonic development. Dev Dyn 251, 240–275. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0020] 20. De Almeida LGN, Thode H, Eslambolchi Y, Chopra S, Young D, Gill S, Devel L & Dufour A (2022) Matrix Metalloproteinases: from molecular mechanisms to physiology, pathophysiology, and pharmacology. Pharmacol Rev 74, 714–770. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0021] 21. Sak K (2024) The low expression of matrix metalloproteinases: a key to longevity? Exp Ther Med 158–166.38476893 [Google Scholar]

[febs70296-bib-0022] 22. Wang X & Khalil RA (2018) Matrix Metalloproteinases, vascular remodeling, and vascular disease. Adv Pharmacol 81, 241–330. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0023] 23. Marcianò G, Vocca C, Rania V, Citraro R, De Sarro G & Gallelli L (2023) Metalloproteases in pain generation and persistence: a possible target? Biomolecules 13, 268. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0024] 24. Prado AF, Batista RIM, Tanus‐Santos JE & Gerlach RF (2021) Matrix Metalloproteinases and arterial hypertension: role of oxidative stress and nitric oxide in vascular functional and structural alterations. Biomolecules 11, 585. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0025] 25. Laronha H & Caldeira J (2020) Structure and function of human matrix Metalloproteinases. Cells 9, 1076. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0026] 26. Piperigkou Z, Mohr B, Karamanos N & Götte M (2016) Shed proteoglycans in tumor stroma. Cell Tissue Res 365, 643–655. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0027] 27. Ioannou P, Katsoulieris E & Afratis NA (2025) Matrix dynamics and microbiome crosstalk: matrix Metalloproteinases as key players in disease and therapy. Int J Mol Sci 26, 3621. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0028] 28. Tampa M, Georgescu SR, Mitran MI, Mitran CI, Matei C, Caruntu A, Scheau C, Nicolae I, Matei A, Caruntu C et al. (2021) Current perspectives on the role of matrix Metalloproteinases in the pathogenesis of basal cell carcinoma. Biomolecules 11, 903. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0029] 29. Towner RA, Smith N, Saunders D, Brown CA, Cai X, Ziegler J, Mallory S, Dozmorov MG, Coutinho De Souza P, Wiley G et al. (2019) OKN‐007 increases temozolomide (TMZ) sensitivity and suppresses TMZ‐resistant glioblastoma (GBM) tumor growth. Transl Oncol 12, 320–335. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0030] 30. Liu X, Yu J, Song S, Yue X & Li Q (2017) Protease‐activated receptor‐1 (PAR‐1): a promising molecular target for cancer. Oncotarget 8, 107334–107345. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0031] 31. Alipour H, Raz A, Zakeri S & Dinparast Djadid N (2016) Therapeutic applications of collagenase (metalloproteases): a review. Asian Pac J Trop Biomed 6, 975–981. [Google Scholar]

[febs70296-bib-0032] 32. Christopoulou M‐E, Papakonstantinou E & Stolz D (2023) Matrix Metalloproteinases in chronic obstructive pulmonary disease. Int J Mol Sci 24, 3786. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0033] 33. Dai L, Mugaanyi J, Cai X, Dong M, Lu C & Lu C (2022) Comprehensive bioinformatic analysis of MMP1 in hepatocellular carcinoma and establishment of relevant prognostic model. Sci Rep 12, 13639. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0034] 34. Juurikka K, Dufour A, Pehkonen K, Mainoli B, Campioni Rodrigues P, Solis N, Klein T, Nyberg P, Overall CM, Salo T et al. (2021) MMP8 increases tongue carcinoma cell–cell adhesion and diminishes migration via cleavage of anti‐adhesive FXYD5. Oncogene 10, 44. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0035] 35. Li S, Pritchard DM & Yu L‐G (2022) Regulation and function of matrix Metalloproteinase‐13 in cancer progression and metastasis. Cancer 14, 3263. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0036] 36. Szczygielski O, Dąbrowska E, Niemyjska S, Przylipiak A & Zajkowska M (2024) Targeting matrix Metalloproteinases and their inhibitors in melanoma. Int J Mol Sci 25, 13558. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0037] 37. Manon‐Jensen T, Multhaupt HAB & Couchman JR (2013) Mapping of matrix metalloproteinase cleavage sites on syndecan‐1 and syndecan‐4 ectodomains. FEBS J 280, 2320–2331. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0038] 38. Cabral‐Pacheco GA, Garza‐Veloz I, Castruita‐De La Rosa C, Ramirez‐Acuña JM, Perez‐Romero BA, Guerrero‐Rodriguez JF, Martinez‐Avila N & Martinez‐Fierro ML (2020) The roles of matrix Metalloproteinases and their inhibitors in human diseases. Int J Mol Sci 21, 9739. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0039] 39. Bonnans C, Chou J & Werb Z (2014) Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 15, 786–801. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0040] 40. Molière S, Jaulin A, Tomasetto C‐L & Dali‐Youcef N (2023) Roles of matrix Metalloproteinases and their natural inhibitors in metabolism: insights into health and disease. Int J Mol Sci 24, 10649. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0041] 41. Mukherjee A & Das B (2024) The role of inflammatory mediators and matrix metalloproteinases (MMPs) in the progression of osteoarthritis. Biomater Biosyst 13, 100090. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0042] 42. Tanase DM, Valasciuc E, Anton I‐B, Gosav EM, Dima N, Cucu AI, Costea CF, Floria DE, Hurjui LL, Tarniceriu CC et al. (2025) Matrix Metalloproteinases: pathophysiologic implications and potential therapeutic targets in cardiovascular disease. Biomolecules 15, 598. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0043] 43. Small C & Crawford B (2016) Matrix metalloproteinases in neural development: a phylogenetically diverse perspective. Neural Regen Res 11, 357. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0044] 44. Chuliá‐Peris L, Carreres‐Rey C, Gabasa M, Alcaraz J, Carretero J & Pereda J (2022) Matrix Metalloproteinases and their inhibitors in pulmonary fibrosis: EMMPRIN/CD147 comes into play. Int J Mol Sci 23, 6894. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0045] 45. Shan L, Wang F, Zhai D, Meng X, Liu J & Lv X (2023) Matrix metalloproteinases induce extracellular matrix degradation through various pathways to alleviate hepatic fibrosis. Biomed Pharmacother 161, 114472. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0046] 46. Soboleva AG, Sobolev VV, Karapetyan MM, Mezentsev A, Rud'ko OI, Davydova ED, Mogulevtseva JA, Zhukova OV & Korsunskaya IM (2023) Laser therapy changes the expression of matrix Metalloproteinases in Bleomycin‐induced skin fibrosis. Life 13, 810. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0047] 47. Manjari, KS , Nallari, Pratibha & Venkateshwari, A (2017) Matrix metalloproteinases in pancreatitis: current insights. Met Med 4, 15–23. [Google Scholar]

[febs70296-bib-0048] 48. Behl T, Kaur G, Sehgal A, Bhardwaj S, Singh S, Buhas C, Judea‐Pusta C, Uivarosan D, Munteanu MA & Bungau S (2021) Multifaceted role of matrix Metalloproteinases in neurodegenerative diseases: pathophysiological and therapeutic perspectives. Int J Mol Sci 22, 1413. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0049] 49. Afratis NA, Klepfish M, Karamanos NK & Sagi I (2018) The apparent competitive action of ECM proteases and cross‐linking enzymes during fibrosis: applications to drug discovery. Adv Drug Deliv Rev 129, 4–15. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0050] 50. Sabir U, Gu H & Zhang D (2023) Extracellular matrix turnover: phytochemicals target and modulate the dual role of matrix metalloproteinases (MMPs) in liver fibrosis. Phytother Res 37, 4932–4962. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0051] 51. Schlage P, Kockmann T, Sabino F, Kizhakkedathu Jayachandran N & Auf Dem Keller U (2015) Matrix metalloproteinase 10 Degradomics in keratinocytes and epidermal tissue identifies bioactive substrates with pleiotropic functions*. Mol Cell Proteomics 14, 3234–3246. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0052] 52. Zhang X, Huang S, Guo J, Zhou L, You L, Zhang T & Zhao Y (2016) Insights into the distinct roles of MMP‐11 in tumor biology and future therapeutics (review). Int J Oncol 48, 1783–1793. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0053] 53. Alcantara MC, Suzuki K, Acebedo AR, Kajioka D, Hirohata S, Kaisho T, Hatano Y, Yamagata K, Takahashi S & Yamada G (2022) Androgen‐regulated MafB drives cell migration via MMP11‐dependent extracellular matrix remodeling in mice. iScience 25, 105609. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0054] 54. Mustafa S, Koran S & AlOmair L (2022) Insights into the role of matrix Metalloproteinases in cancer and its various therapeutic aspects: a review. Front Mol Biosci 9, 896099. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0055] 55. Waters JA, Urbano I, Robinson M & House CD (2022) Insulin‐like growth factor binding protein 5: diverse roles in cancer. Front Oncol 12, 1052457. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0056] 56. Thongiratama GW, Dhananjaya GAD, Mulya HK & Ruma IMW (2024) Activity of matrix Metalloproteinase‐7 (MMP‐7) related to heparin‐binding epidermal growth factor (HB‐EGF) activation in squamous cell as diagnostic biomarker for early detection and treatment of Maxilarian cancer: review article. Indones J Cancer 18, 89–98. [Google Scholar]

[febs70296-bib-0057] 57. Hernole J & Narayanappa R (2023) Interactions between notch and matrix metalloproteinases: the role in cancer. Nowotwory J Oncol 73, 354–361. [Google Scholar]

[febs70296-bib-0058] 58. Tsunezumi J, Higashi S & Miyazaki K (2009) Matrilysin (MMP‐7) cleaves C‐type lectin domain family 3 member a (CLEC3A) on tumor cell surface and modulates its cell adhesion activity. J Cell Biochem 106, 693–702. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0059] 59. Grindel BJ, Martinez JR, Tellman TV, Harrington DA, Zafar H, Nakhleh L, Chung LW & Farach‐Carson MC (2018) Matrilysin/MMP‐7 cleavage of Perlecan/HSPG2 complexed with Semaphorin 3A supports FAK‐mediated stromal invasion by prostate cancer cells. Sci Rep 8, 7262. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0060] 60. Kariya Y & Kariya Y (2022) Osteopontin in cancer: mechanisms and therapeutic targets. Int J Transl Med 2, 419–447. [Google Scholar]

[febs70296-bib-0061] 61. Tauro M & Lynch C (2018) Cutting to the chase: how matrix Metalloproteinase‐2 activity controls breast‐cancer‐to‐bone metastasis. Cancer 10, 185. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0062] 62. Yu W‐H, Wu E, Li Y, Hou H‐H, Yu SC, Huang P‐T, Kuo W‐H, Qi D & Yu C‐J (2020) Matrix Metalloprotease‐7 mediates nucleolar assembly and intra‐nucleolar cleaving p53 in Gefitinib‐resistant cancer stem cells. iScience 23, 101600. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0063] 63. Jin L, Shen F, Weinfeld M & Sergi C (2020) Insulin growth factor binding protein 7 (IGFBP7)‐related cancer and IGFBP3 and IGFBP7 crosstalk. Front Oncol 10, 727. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0064] 64. Liu Z, Tan RJ & Liu Y (2020) The many faces of matrix Metalloproteinase‐7 in kidney diseases. Biomolecules 10, 960. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0065] 65. Xiao Y, Lian H, Zhong XS, Krishnachaitanya SS, Cong Y, Dashwood RH, Savidge TC, Powell DW, Liu X & Li Q (2022) Matrix metalloproteinase 7 contributes to intestinal barrier dysfunction by degrading tight junction protein Claudin‐7. Front Immunol 13, 1020902. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0066] 66. Van Doren SR (2022) MMP‐7 marks severe pancreatic cancer and alters tumor cell signaling by proteolytic release of ectodomains. Biochem Soc Trans 50, 839–851. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0067] 67. Piskór BM, Przylipiak A, Dąbrowska E, Niczyporuk M & Ławicki S (2020) Matrilysins and Stromelysins in pathogenesis and diagnostics of cancers. Cancer Manag Res 12, 10949–10964. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0068] 68. Guo J, Guo C, He Z, Cai X & Mou Y (2018) High MMP‐26 expression in glioma is correlated with poor clinical outcome of patients. Oncol Lett 16, 2237–2242. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0069] 69. Silva RLD, Paes FLA, Silva SMSD, Santos F, Santana ESD & Silva Neto JDC (2025) Specific immunohistochemical expression of Mmp‐26 in prostatic adenocarcinoma. An Acad Bras Cienc 97, e20231380. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0070] 70. Khamis ZI, Iczkowski KA, Man Y‐G, Bou‐Dargham MJ & Sang Q‐XA (2016) Evidence for a Proapoptotic role of matrix Metalloproteinase‐26 in human prostate cancer cells and tissues. J Cancer 7, 80–87. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0071] 71. Gonzalez‐Avila G, Sommer B, Mendoza‐Posada DA, Ramos C, Garcia‐Hernandez AA & Falfan‐Valencia R (2019) Matrix metalloproteinases participation in the metastatic process and their diagnostic and therapeutic applications in cancer. Crit Rev Oncol Hematol 137, 57–83. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0072] 72. Stawowczyk M, Wellenstein MD, Lee SB, Yomtoubian S, Durrans A, Choi H, Narula N, Altorki NK, Gao D & Mittal V (2017) Matrix metalloproteinase 14 promotes lung cancer by cleavage of heparin‐binding EGF‐like growth factor. Neoplasia 19, 55–64. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0073] 73. Nadanaka S, Bai Y & Kitagawa H (2021) Cleavage of Syndecan‐1 promotes the proliferation of the basal‐like breast cancer cell line BT‐549 via Akt SUMOylation. Front Cell Dev Biol 9, 659428. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0074] 74. Knapinska AM & Fields GB (2019) The expanding role of MT1‐MMP in cancer progression. Pharmaceuticals 12, 77. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0075] 75. Liu J, Li Y, Lian X, Zhang C, Feng J, Tao H & Wang Z (2025) Potential target within the tumor microenvironment – MT1‐MMP. Front Immunol 16, 1517519. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0076] 76. Bruney L, Conley KC, Moss NM, Liu Y & Stack MS (2014) Membrane‐type I matrix metalloproteinase‐dependent ectodomain shedding of mucin16/ CA‐125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium. Biol Chem 395, 1221–1231. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0077] 77. Tanaka N & Sakamoto T (2023) MT1‐MMP as a key regulator of metastasis. Cells 12, 2187. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0078] 78. Itoh Y (2015) Membrane‐type matrix metalloproteinases: their functions and regulations. Matrix Biol 44–46, 207–223. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0079] 79. Liu Y, Sun X, Feng J, Deng L‐L, Liu Y, Li B, Zhu M, Lu C & Zhou L (2016) MT2‐MMP induces proteolysis and leads to EMT in carcinomas. Oncotarget 7, 48193–48205. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0080] 80. Cui X, Jing X, Yi Q, Long C, Tian J & Zhu J (2017) Clinicopathological and prognostic significance of SDC1 overexpression in breast cancer. Oncotarget 8, 111444–111455. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0081] 81. Cloud AS, Vargheese AM, Gunewardena S, Shimak RM, Ganeshkumar S, Kumaraswamy E, Jensen RA & Chennathukuzhi VM (2022) Loss of REST in breast cancer promotes tumor progression through estrogen sensitization, MMP24 and CEMIP overexpression. BMC Cancer 22, 180. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0082] 82. Muñoz‐Sáez E, Moracho N, Learte AIR, Collignon A, Arroyo AG, Noel A, Sounni NE & Sánchez‐Camacho C (2023) Molecular mechanisms driven by MT4‐MMP in cancer progression. Int J Mol Sci 24, 9944. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0083] 83. Yip C, Foidart P, Noël A & Sounni NE (2019) MT4‐MMP: the GPI‐anchored membrane‐type matrix metalloprotease with multiple functions in diseases. Int J Mol Sci 20, 354. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0084] 84. Scheau C, Badarau IA, Costache R, Caruntu C, Mihai GL, Didilescu AC, Constantin C & Neagu M (2019) The role of matrix Metalloproteinases in the epithelial‐mesenchymal transition of hepatocellular carcinoma. Anal Cell Pathol 2019, 1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0085] 85. Spinale FG (2013) Epilysin (matrix Metalloproteinase‐28) joins the matrix metalloproteinase team on the field of Postmyocardial infarction remodeling. Circ Res 112, 579–582. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0086] 86. Pittayapruek P, Meephansan J, Prapapan O, Komine M & Ohtsuki M (2016) Role of matrix Metalloproteinases in Photoaging and Photocarcinogenesis. Int J Mol Sci 17, 868. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0087] 87. Lamort A‐S, Gravier R, Laffitte A, Juliano L, Zani M‐L & Moreau T (2016) New insights into the substrate specificity of macrophage elastase MMP‐12. Biol Chem 397, 469–484. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0088] 88. Veeravalli KK (2024) Implications of MMP‐12 in the pathophysiology of ischaemic stroke. Stroke Vasc Neurol 9, 97–107. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0089] 89. Jiang L, Yang M, He S, Li Z, Li H, Niu T, Xie D, Mei Y, He X, Wei L et al. (2021) MMP12 knockout prevents weight and muscle loss in tumor‐bearing mice. BMC Cancer 21, 1297. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0090] 90. Arruri V, Chokkalla AK, Jeong S, Chelluboina B, Mehta SL, Veeravalli KK & Vemuganti R (2022) MMP‐12 knockdown prevents secondary brain damage after ischemic stroke in mice. Neurochem Int 161, 105432. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0091] 91. Park J‐H, Shin J‐M, Yang H‐W, Kim TH, Lee SH, Shin OS & Park I‐H (2024) Matrix metalloproteinase‐12 by M2 macrophages induced epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyps. PLoS One 19, e0313097. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0092] 92. Yasuda H, Nakagawa M, Kiyokawa H, Yoshida E, Yoshimura T, Koshikawa N, Itoh F & Seiki M (2019) Unique biological activity and potential role of monomeric Laminin‐γ2 as a novel biomarker for hepatocellular carcinoma: a review. Int J Mol Sci 20, 226. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0093] 93. Zhao W, Wang L, Yang J, Chen X, Guo X, Xu K, Wang N, Zhao W, Xia C, Lian H et al. (2023) Endothelial cell‐derived MMP19 promotes pulmonary fibrosis by inducing E(nd)MT and monocyte infiltration. Cell Commun Signal 21, 56. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0094] 94. Ma B, Zeng Q, Yang F, Yang H, Li W, Fu R, Cai Z, Zhu G, Shu C, Luo M et al. (2025) MMP19 in vascular smooth muscle cells protects against thoracic aortic aneurysm and dissection via the MMP19/Aggrecan/Wnt/β‐catenin axis. J Mol Cell Cardiol 202, 35–49. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0095] 95. Mezentsev A, Nikolaev A & Bruskin S (2014) Matrix metalloproteinases and their role in psoriasis. Gene 540, 1–10. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0096] 96. Alford VM, Kamath A, Ren X, Kumar K, Gan Q, Awwa M, Tong M, Seeliger MA, Cao J, Ojima I et al. (2017) Targeting the Hemopexin‐like domain of latent matrix Metalloproteinase‐9 (proMMP‐9) with a Small molecule inhibitor prevents the formation of focal adhesion junctions. ACS Chem Biol 12, 2788–2803. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0097] 97. Che K, Han W, Zhang M & Niu H (2020) Role of neutrophil gelatinase‐associated lipocalin in renal cell carcinoma (review). Oncol Lett 21, 148. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0098] 98. Castro‐Castro A, Marchesin V, Monteiro P, Lodillinsky C, Rossé C & Chavrier P (2016) Cellular and molecular mechanisms of MT1‐MMP‐dependent cancer cell invasion. Annu Rev Cell Dev Biol 32, 555–576. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0099] 99. Suárez H, López‐Martín S, Toribio V, Zamai M, Hernández‐Riquer MV, Genís L, Arroyo AG & Yáñez‐Mó M (2020) Regulation of MT1‐MMP activity through its association with ERMs. Cells 9, 348. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0100] 100. Venghateri JB, Dassa B, Morgenstern D, Shreberk‐Shaked M, Oren M & Geiger B (2023) Deciphering the involvement of the hippo pathway co‐regulators, YAP/TAZ in invadopodia formation and matrix degradation. Cell Death Dis 14, 290. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0101] 101. Divvela SSK, Gallorini M, Gellisch M, Patel GD, Saso L & Brand‐Saberi B (2025) Navigating redox imbalance: the role of oxidative stress in embryonic development and long‐term health outcomes. Front Cell Dev Biol 13, 1521336. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0102] 102. Wang K, Xuan Z, Liu X, Zheng M, Yang C & Wang H (2022) Immunomodulatory role of metalloproteinase ADAM17 in tumor development. Front Immunol 13, 1059376. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0103] 103. Xie Z, Wang X, Ren X & Ge X (2024) MMP12 disrupts epithelial barrier integrity in oral lichen planus by degrading fibronectin. Sci Rep 14, 27511. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0104] 104. Yosef G, Arkadash V & Papo N (2018) Targeting the MMP‐14/MMP‐2/integrin αvβ3 axis with multispecific N‐TIMP2–based antagonists for cancer therapy. J Biol Chem 293, 13310–13326. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0105] 105. Mittal R, Patel AP, Debs LH, Nguyen D, Patel K, Grati M, Mittal J, Yan D, Chapagain P & Liu XZ (2016) Intricate functions of matrix Metalloproteinases in physiological and pathological conditions. J Cell Physiol 231, 2599–2621. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0106] 106. Khalili‐Tanha G, Radisky ES, Radisky DC & Shoari A (2025) Matrix metalloproteinase‐driven epithelial‐mesenchymal transition: implications in health and disease. J Transl Med 23, 436. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0107] 107. Kandhwal M, Behl T, Singh S, Sharma N, Arora S, Bhatia S, Al‐Harrasi A, Sachdeva M & Bungau S (2022) Role of matrix metalloproteinase in wound healing. Am J Transl Res 14, 4391–4405. [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0108] 108. Gialeli C, Theocharis AD & Karamanos NK (2011) Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J 278, 16–27. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0109] 109. Bian Y, Xiang Z, Wang Y, Ren Q, Chen G, Xiang B, Wang J, Zhang C, Pei S, Guo S et al. (2023) Immunomodulatory roles of metalloproteinases in rheumatoid arthritis. Front Pharmacol 14, 1285455. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0110] 110. Brown JS, Amend SR, Austin RH, Gatenby RA, Hammarlund EU & Pienta KJ (2023) Updating the definition of cancer. Mol Cancer Res 21, 1142–1147. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0111] 111. Zhang Q‐Z, Zhu Y‐P, Rahat MA & Kzhyshkowska J (2023) Editorial: angiogenesis and tumor metastasis. Front Oncol 12, 1129736. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0112] 112. Castaneda M, Den Hollander P, Kuburich NA, Rosen JM & Mani SA (2022) Mechanisms of cancer metastasis. Semin Cancer Biol 87, 17–31. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0113] 113. Hariri A, Mirian M, Khosravi A, Zarepour A, Iravani S & Zarrabi A (2024) Intersecting pathways: the role of hybrid E/M cells and circulating tumor cells in cancer metastasis and drug resistance. Drug Resist Updat 76, 101119. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0114] 114. Liao T‐T & Yang M‐H (2020) Hybrid epithelial/mesenchymal state in cancer metastasis: clinical significance and regulatory mechanisms. Cells 9, 623. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0115] 115. Leong SP & Witte MH (2024) Cancer metastasis through the lymphatic versus blood vessels. Clin Exp Metastasis 41, 387–402. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0116] 116. Heeke S, Mograbi B, Alix‐Panabières C & Hofman P (2019) Never travel alone: the crosstalk of circulating tumor cells and the blood microenvironment. Cells 8, 714. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0117] 117. Popova NV & Jücker M (2022) The functional role of extracellular matrix proteins in cancer. Cancer 14, 238. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0118] 118. Karampoga A, Tzaferi K, Koutsakis C, Kyriakopoulou K & Karamanos NK (2022) Exosomes and the extracellular matrix: a dynamic interplay in cancer progression. Int J Dev Biol 66, 97–102. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0119] 119. Shimoda M & Khokha R (2017) Metalloproteinases in extracellular vesicles. Biochimica et Biophysica Acta (BBA) 1864, 1989–2000. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0120] 120. Thuault S, Ghossoub R, David G & Zimmermann P (2022) A journey on extracellular vesicles for matrix Metalloproteinases: a mechanistic perspective. Front Cell Dev Biol 10, 886381. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0121] 121. Guo S, Huang J, Li G, Chen W, Li Z & Lei J (2023) The role of extracellular vesicles in circulating tumor cell‐mediated distant metastasis. Mol Cancer 22, 193. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0122] 122. Hu C, Long L, Lou J, Leng M, Yang Q, Xu X & Zhou X (2024) CTC‐neutrophil interaction: a key driver and therapeutic target of cancer metastasis. Biomed Pharmacother 180, 117474. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0123] 123. Gobin E, Bagwell K, Wagner J, Mysona D, Sandirasegarane S, Smith N, Bai S, Sharma A, Schleifer R & She J‐X (2019) A pan‐cancer perspective of matrix metalloproteases (MMP) gene expression profile and their diagnostic/prognostic potential. BMC Cancer 19, 581. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0124] 124. Wang K, Zheng J, Yu J, Wu Y, Guo J, Xu Z & Sun X (2020) Knockdown of MMP‐1 inhibits the progression of colorectal cancer by suppressing the PI3K/Akt/c‐myc signaling pathway and EMT. Oncol Rep 43, 1103–1112. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0125] 125. Zhuang Y, Li X, Zhan P, Pi G & Wen G (2021) MMP11 promotes the proliferation and progression of breast cancer through stabilizing Smad2 protein. Oncol Rep 45, 16. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0126] 126. Liu N, Zhong L, Ni G, Lin J, Xie L, Li T, Dan H & Chen Q (2021) High matrix metalloproteinase 28 expression is associated with poor prognosis in pancreatic adenocarcinoma. OncoTargets Ther 14, 4391–4406. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0127] 127. Dharavath B, Butle A, Pal A, Desai S, Upadhyay P, Rane A, Khandelwal R, Manavalan S, Thorat R, Sonawane K et al. (2023) Role of miR‐944/MMP10/AXL‐ axis in lymph node metastasis in tongue cancer. Commun Biol 6, 57. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0128] 128. Lv F‐Z, Wang J‐L, Wu Y, Chen H‐F & Shen X‐Y (2015) Knockdown of MMP12 inhibits the growth and invasion of lung adenocarcinoma cells. Int J Immunopathol Pharmacol 28, 77–84. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0129] 129. Sigismund S, Avanzato D & Lanzetti L (2018) Emerging functions of the egfr in cancer. Mol Oncol 12, 3–20. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0130] 130. Soni UK, Jenny L & Hegde RS (2023) IGF‐1R targeting in cancer – does sub‐cellular localization matter? J Exp Clin Cancer Res 42, 273. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0131] 131. Augoff K, Hryniewicz‐Jankowska A, Tabola R & Stach K (2022) MMP9: a tough target for targeted therapy for cancer. Cancer 14, 1847. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0132] 132. Sun X & Hu X (2025) Unveiling matrix metalloproteinase 13's dynamic role in breast cancer: a link to physical changes and prognostic modulation. Int J Mol Sci 26, 3083. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0133] 133. Thomas D & Radhakrishnan P (2020) Role of tumor and stroma‐derived IGF/IGFBPs in pancreatic cancer. Cancer 12, 1228. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0134] 134. Roy R, Morad G, Jedinak A & Moses MA (2020) Metalloproteinases and their roles in human cancer. Anat Rec 303, 1557–1572. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0135] 135. Gligorijević N, Dobrijević Z, Šunderić M, Robajac D, Četić D, Penezić A, Miljuš G & Nedić O (2022) The insulin‐like growth factor system and colorectal cancer. Life 12, 1274. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0136] 136. Dao DT, Anez‐Bustillos L, Adam RM, Puder M & Bielenberg DR (2018) Heparin‐binding epidermal growth factor–like growth factor as a critical mediator of tissue repair and regeneration. Am J Pathol 188, 2446–2456. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0137] 137. Carroll MJ, Kapur A, Felder M, Patankar MS & Kreeger PK (2016) M2 macrophages induce ovarian cancer cell proliferation via a heparin binding epidermal growth factor/matrix metalloproteinase 9 intercellular feedback loop. Oncotarget 7, 86608–86620. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0138] 138. Pezeshkian Z, Nobili S, Peyravian N, Shojaee B, Nazari H, Soleimani H, Asadzadeh‐Aghdaei H, Ashrafian Bonab M, Nazemalhosseini‐Mojarad E & Mini E (2021) Insights into the role of matrix Metalloproteinases in precancerous conditions and in colorectal cancer. Cancer 13, 6226. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0139] 139. Suhaimi SA, Chan SC & Rosli R (2020) Matrix metallopeptidase 3 polymorphisms: emerging genetic markers in human breast cancer metastasis. J Breast Cancer 23, 1–9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0140] 140. Figueroa CD, Molina L, Bhoola KD & Ehrenfeld P (2018) Overview of tissue kallikrein and kallikrein‐related peptidases in breast cancer. Biol Chem 399, 937–957. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0141] 141. Paye A, Truong A, Yip C, Cimino J, Blacher S, Munaut C, Cataldo D, Foidart JM, Maquoi E, Collignon J et al. (2014) EGFR activation and signaling in cancer cells are enhanced by the membrane‐bound metalloprotease MT4‐MMP. Cancer Res 74, 6758–6770. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0142] 142. Strouhalova K, Tolde O, Rosel D & Brábek J (2023) Cytoplasmic tail of MT1‐MMP: a hub of MT1‐MMP regulation and function. Int J Mol Sci 24, 5068. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0143] 143. Takino T, Tsuge H, Ozawa T & Sato H (2010) MT1‐MMP promotes cell growth and ERK activation through c‐Src and paxillin in three‐dimensional collagen matrix. Biochem Biophys Res Commun 396, 1042–1047. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0144] 144. Fakhari S, Jalili A, Nikkhoo B, Ghaderi B, Boshagh MA, Mirzaie S & Moradzad M (2022) MT2‐MMP is differentially expressed in multiple myeloma cells and mediates their growth and progression. Cell Signal 92, 110248. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0145] 145. Cao L, Chen C, Zhu H, Gu X, Deng D, Tian X, Liu J & Xiao Q (2016) MMP16 is a marker of poor prognosis in gastric cancer promoting proliferation and invasion. Oncotarget 7, 51865–51874. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0146] 146. Haque S & Morris JC (2017) Transforming growth factor‐β: a therapeutic target for cancer. Hum Vaccin Immunother 13, 1741–1750. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0147] 147. Baba AB, Rah B, Bhat GR, Mushtaq I, Parveen S, Hassan R, Hameed Zargar M & Afroze D (2022) Transforming growth factor‐Beta (TGF‐β) signaling in cancer‐a betrayal within. Front Pharmacol 13, 791272. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0148] 148. Khan A, Zhang Y, Ma N, Shi J & Hou Y (2024) NF‐κB role on tumor proliferation, migration, invasion and immune escape. Cancer Gene Ther 31, 1599–1610. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0149] 149. Chen L, Cen Y, Qian K, Yang W, Zhou W & Yang Y (2025) MMP1‐induced NF‐κB activation promotes epithelial–mesenchymal transition and sacituzumab govitecan resistance in hormone receptor‐positive breast cancer. Cell Death Dis 16, 346. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0150] 150. Zhang Z, Dong T, Fu Y, Zhou W, Tian X, Chen G & Liu S (2019) MMP‐11 promotes papillary thyroid cell proliferation and invasion via the NF‐κB pathway. J Cell Biochem 120, 1860–1868. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0151] 151. Ma J, Tang X, Wong P, Jacobs B, Borden EC & Bedogni B (2014) Noncanonical activation of Notch1 protein by membrane type 1 matrix metalloproteinase (MT1‐MMP) controls melanoma cell proliferation. J Biol Chem 289, 8442–8449. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0152] 152. Shin Y, Kim S, Liang G & An W (2024) mmp ‐9‐dependent proteolysis of the histone h3 N‐terminal tail: a critical epigenetic step in driving oncogenic transcription and colon tumorigenesis. Mol Oncol 18, 2001–2019. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0153] 153. Sakamoto T & Seiki M (2017) Integrated functions of membrane‐type 1 matrix metalloproteinase in regulating cancer malignancy: beyond a proteinase. Cancer Sci 108, 1095–1100. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0154] 154. Jabłońska‐Trypuć A, Matejczyk M & Rosochacki S (2016) Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem 31, 177–183. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0155] 155. Hu L, Lu J, Fan H, Niu C, Han Y, Caiyin Q, Wu H & Qiao J (2025) FAS mediates apoptosis, inflammation, and treatment of pathogen infection. Front Cell Infect Microbiol 15, 1561102. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0156] 156. Haymour L, Jean M, Smulski C & Legembre P (2023) CD95 (Fas) and CD95L (FasL)‐mediated non‐canonical signaling pathways. Biochimica et Biophysica Acta (BBA) 1878, 189004. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0157] 157. Ababneh O, Nishizaki D, Kato S & Kurzrock R (2024) Tumor necrosis factor superfamily signaling: life and death in cancer. Cancer Metastasis Rev 43, 1137–1163. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0158] 158. Huang Y, Hong W & Wei X (2022) The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol 15, 129. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0159] 159. Mittal V (2018) Epithelial mesenchymal transition in tumor metastasis. Annu Rev Pathol Mech Dis 13, 395–412. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0160] 160. Niland S, Riscanevo AX & Eble JA (2021) Matrix Metalloproteinases shape the tumor microenvironment in cancer progression. Int J Mol Sci 23, 146. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0161] 161. Li S & Luo W (2019) Matrix metalloproteinase 2 contributes to aggressive phenotype, epithelial‐mesenchymal transition and poor outcome in nasopharyngeal carcinoma. OncoTargets Ther 12, 5701–5711. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0162] 162. Liao H‐Y, Da C‐M, Liao B & Zhang H‐H (2021) Roles of matrix metalloproteinase‐7 (MMP‐7) in cancer. Clin Biochem 92, 9–18. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0163] 163. Kanwal R, Esposito JE, Jawed B, Zakir SK, Pulcini R, Martinotti R, Botteghi M, Gaudio F, Martinotti S & Toniato E (2025) Exploring the role of epithelial–mesenchymal transcriptional factors involved in hematological malignancy and solid tumors: a systematic review. Cancer 17, 529. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0164] 164. Tian R, Li X, Gao Y, Li Y, Yang P & Wang K (2018) Identification and validation of the role of matrix metalloproteinase‐1 in cervical cancer. Int J Oncol 52, 1198–1208. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0165] 165. Pan C, Dai J, Wei Y, Yang L, Ding Z, Wang X & He J (2024) Matrix metalloproteinase 11 promotes migration and invasion of colorectal cancer by elevating slug protein. Int J Med Sci 21, 2170–2188. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0166] 166. Wang L, Li N, Chen Y, Qiao Y, Song Y, Zhang X, Zhao H, Ran W, Li G & Xing X (2025) GPSM1 interacts and cooperates with MMP19 to promote proliferation and EMT in colorectal cancer cells. Biochimica et Biophysica Acta (BBA) 1872, 119903. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0167] 167. Chen S, Shen Z, Gao L, Yu S, Zhang P, Han Z & Kang M (2021) TPM3 mediates epithelial‐mesenchymal transition in esophageal cancer via MMP2/MMP9. Ann Transl Med 9, 1338. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0168] 168. Zhang H, Hang W, Jing Z, Liu B, Wang X, Li Y, Luo H, Lv H, Tao X, Timashev P et al. (2025) The role of notch signaling pathway in cancer: mechanistic insights, therapeutic potential, and clinical progress. Front Immunol 16, 1567524. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0169] 169. Aseervatham J & Ogbureke KUE (2020) Effects of DSPP and MMP20 silencing on adhesion, metastasis, angiogenesis, and epithelial‐mesenchymal transition proteins in Oral squamous cell carcinoma cells. Int J Mol Sci 21, 4734. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0170] 170. Zhou J, Zheng X, Feng M, Mo Z, Shan Y, Wang Y & Jin J (2019) Upregulated MMP28 in hepatocellular carcinoma promotes metastasis via Notch3 signaling and predicts unfavorable prognosis. Int J Biol Sci 15, 812–825. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0171] 171. Shen Z, Wang X, Yu X, Zhang Y & Qin L (2017) MMP16 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma. Oncotarget 8, 72197–72204. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0172] 172. Mirzaei S, Saghari S, Bassiri F, Raesi R, Zarrabi A, Hushmandi K, Sethi G & Tergaonkar V (2022) NF‐κB as a regulator of cancer metastasis and therapy response: a focus on epithelial–mesenchymal transition. J Cell Physiol 237, 2770–2795. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0173] 173. Cichon MA & Radisky DC (2014) ROS‐induced epithelial‐mesenchymal transition in mammary epithelial cells is mediated by NF‐κB‐dependent activation of snail. Oncotarget 5, 2827–2838. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0174] 174. Luo W, Shi Q, Han M, Zhang Z, Reiter RJ, Ashrafizadeh M, Nabavi N, Sethi G, Nicot C & Mao Y (2025) TGF‐β‐driven EMT in cancer progression and drug resistance. Cytokine Growth Factor Rev 85, S1359610125000504. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0175] 175. Sun L, Xing J, Zhou X, Song X & Gao S (2024) Wnt/β‐catenin signalling, epithelial‐mesenchymal transition and crosslink signalling in colorectal cancer cells. Biomed Pharmacother 175, 116685. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0176] 176. Qin G, Luo M, Chen J, Dang Y, Chen G, Li L, Zeng J, Lu Y & Yang J (2016) Reciprocal activation between MMP‐8 and TGF‐β1 stimulates EMT and malignant progression of hepatocellular carcinoma. Cancer Lett 374, 85–95. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0177] 177. Bai X, Li Y, Zhang H, Wang F, He H, Yao J, Liu L & Li S (2017) Role of matrix metalloproteinase‐9 in transforming growth factor‐&β1‐induced epithelial–mesenchymal transition in esophageal squamous cell carcinoma. OncoTargets Ther 10, 2837–2847. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0178] 178. Carey P, Low E, Harper E & Stack MS (2021) Metalloproteinases in ovarian cancer. Int J Mol Sci 22, 3403. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0179] 179. Illman SA, Lehti K, Keski‐Oja J & Lohi J (2006) Epilysin (MMP‐28) induces TGF‐β mediated epithelial to mesenchymal transition in lung carcinoma cells. J Cell Sci 119, 3856–3865. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0180] 180. Lei Y, Chen L, Zhang G, Shan A, Ye C, Liang B, Sun J, Liao X, Zhu C, Chen Y et al. (2020) MicroRNAs target the Wnt/β‐catenin signaling pathway to regulate epithelial‐mesenchymal transition in cancer (review). Oncol Rep 44, 1299–1313. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0181] 181. Sheridan R, Brennan K, Bazou D, O'Gorman P, Matallanas D & Mc Gee MM (2024) Multiple myeloma derived extracellular vesicle uptake by monocyte cells stimulates IL‐6 and MMP‐9 secretion and promotes cancer cell migration and proliferation. Cancer 16, 1011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0182] 182. Hass R, Von Der Ohe J & Ungefroren H (2020) The intimate relationship among EMT, MET and TME: a T(ransdifferentiation) E(nhancing) M(ix) to Be exploited for therapeutic purposes. Cancer 12, 3674. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0183] 183. Wang Z, Guo X, Li X, Wang J, Zhang N, Amin B, Xu G & Zhu B (2025) Cancer‐associated fibroblast‐derived mmp11 promotes tumor progression in pancreatic cancer. Cancer Sci 116, 643–655. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0184] 184. Qi F, Li J, Guo M, Yang B & Xia J (2020) MT4‐MMP in tumor‐associated macrophages is linked to hepatocellular carcinoma aggressiveness and recurrence. Clin Transl Med 10, e162. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0185] 185. Zhou J, Liu L, Hu X, Feng R, Zhao N, Zhang L, Hu W, Zhang J, Huang S, Liu L et al. (2023) Matrix metalloproteinase‐21 promotes metastasis via increasing the recruitment and M2 polarization of macrophages in HCC. Cancer Sci 114, 423–435. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0186] 186. Zhu Y, Tao Z, Chen Y, Lin S, Zhu M, Ji W, Liu X, Li T & Hu X (2022) Exosomal MMP‐1 transfers metastasis potential in triple‐negative breast cancer through PAR1‐mediated EMT. Breast Cancer Res Treat 193, 65–81. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0187] 187. You Y, Shan Y, Chen J, Yue H, You B, Shi S, Li X & Cao X (2015) Matrix metalloproteinase 13‐containing exosomes promote nasopharyngeal carcinoma metastasis. Cancer Sci 106, 1669–1677. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0188] 188. Mashouri L, Yousefi H, Aref AR, Ahadi AM, Molaei F & Alahari SK (2019) Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol Cancer 18, 75. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0189] 189. Gonzalez‐Avila G, Sommer B, Flores‐Soto E & Aquino‐Galvez A (2023) Hypoxic effects on matrix Metalloproteinases' expression in the tumor microenvironment and therapeutic perspectives. Int J Mol Sci 24, 16887. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0190] 190. Liang M, Wang J, Wu C, Wu M, Hu J, Dai J, Ruan H, Xiong S & Dong C (2021) Targeting matrix metalloproteinase MMP3 greatly enhances oncolytic virus mediated tumor therapy. Transl Oncol 14, 101221. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0191] 191. Kwon MJ (2023) Matrix metalloproteinases as therapeutic targets in breast cancer. Front Oncol 12, 1108695. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0192] 192. Deborde S & Wong RJ (2022) The role of Schwann cells in cancer. Adv Biol 6, 2200089. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0193] 193. Quintero‐Fabián S, Arreola R, Becerril‐Villanueva E, Torres‐Romero JC, Arana‐Argáez V, Lara‐Riegos J, Ramírez‐Camacho MA & Alvarez‐Sánchez ME (2019) Role of matrix Metalloproteinases in angiogenesis and cancer. Front Oncol 9, 1370. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0194] 194. Dzobo K & Dandara C (2023) The extracellular matrix: its composition, function, remodeling, and role in tumorigenesis. Biomimetics 8, 146. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0195] 195. Shoari A, Ashja Ardalan A, Dimesa AM & Coban MA (2024) Targeting invasion: the role of MMP‐2 and MMP‐9 inhibition in colorectal cancer therapy. Biomolecules 15, 35. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0196] 196. Shoari A (2024) Potential of MMP‐2 and MMP‐9 gelatinase blockade as a therapeutic strategy in Fibrosarcoma treatment: a decadal review. Targets 2, 104–125. [Google Scholar]

[febs70296-bib-0197] 197. Worzfeld T, Pogge Von Strandmann E, Huber M, Adhikary T, Wagner U, Reinartz S & Müller R (2017) The unique molecular and cellular microenvironment of ovarian cancer. Front Oncol 7, 24. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0198] 198. Kenny HA, Kaur S, Coussens LM & Lengyel E (2008) The initial steps of ovarian cancer cell metastasis are mediated by MMP‐2 cleavage of vitronectin and fibronectin. J Clin Invest 118, 1367–1379. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0199] 199. Iwanicki MP, Davidowitz RA, Ng MR, Besser A, Muranen T, Merritt M, Danuser G, Ince T & Brugge JS (2011) Ovarian cancer spheroids use myosin‐generated force to clear the mesothelium. Cancer Discov 1, 144–157. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0200] 200. Wolosowicz M, Prokopiuk S & Kaminski TW (2024) The complex role of matrix Metalloproteinase‐2 (MMP‐2) in health and disease. Int J Mol Sci 25, 13691. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0201] 201. Gifford V & Itoh Y (2019) MT1‐MMP‐dependent cell migration: proteolytic and non‐proteolytic mechanisms. Biochem Soc Trans 47, 811–826. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0202] 202. Zhang J, Pan Q, Yan W, Wang Y, He X & Zhao Z (2018) Overexpression of MMP21 and MMP28 is associated with gastric cancer progression and poor prognosis. Oncol Lett 15, 7776–7782. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0203] 203. Hsin C‐H, Chou Y‐E, Yang S‐F, Su S‐C, Chuang Y‐T, Lin S‐H & Lin C‐W (2017) MMP‐11 promoted the oral cancer migration and FAK/Src activation. Oncotarget 8, 32783–32793. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0204] 204. Wang S, Jia J, Liu D, Wang M, Wang Z, Li X, Wang H, Rui Y, Liu Z, Guo W et al. (2019) Matrix metalloproteinase expressions play important role in prediction of ovarian cancer outcome. Sci Rep 9, 11677. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0205] 205. Zheng L (2011) Non‐small cell lung cancer invasion and metastasis promoted by MMP‐26. Mol Med Rep 4, 1201–1209. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0206] 206. Yang H, Wang Y, Li Y, Zhang L, Deng Y, Qi D, Li Y & Li W (2012) Roles of matrix metalloproteinase‐26 in the growth, invasion and angiogenesis of breast cancer. Oncol Lett 4, 832–836. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0207] 207. Masi I, Caprara V, Bagnato A & Rosanò L (2020) Tumor cellular and microenvironmental cues controlling Invadopodia formation. Front Cell Dev Biol 8, 584181. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0208] 208. Hao Z, Zhang M, Du Y, Liu J, Zeng G, Li H & Peng X (2025) Invadopodia in cancer metastasis: dynamics, regulation, and targeted therapies. J Transl Med 23, 548. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0209] 209. Guan P‐P, Yu X, Guo J‐J, Wang Y, Wang T, Li J‐Y, Konstantopoulos K, Wang Z‐Y & Wang P (2015) By activating matrix metalloproteinase‐7, shear stress promotes chondrosarcoma cell motility, invasion and lung colonization. Oncotarget 6, 9140–9159. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0210] 210. Das K, Prasad R, Ansari SA, Roy A, Mukherjee A & Sen P (2018) Matrix metalloproteinase‐2: a key regulator in coagulation proteases mediated human breast cancer progression through autocrine signaling. Biomed Pharmacother 105, 395–406. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0211] 211. Deryugina EI, Ratnikov BI, Postnova TI, Rozanov DV & Strongin AY (2002) Processing of integrin αv subunit by membrane type 1 matrix metalloproteinase stimulates migration of breast carcinoma cells on Vitronectin and enhances tyrosine phosphorylation of focal adhesion kinase. J Biol Chem 277, 9749–9756. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0212] 212. Koshikawa N, Hoshino D, Taniguchi H, Minegishi T, Tomari T, Nam S‐O, Aoki M, Sueta T, Nakagawa T, Miyamoto S et al. (2015) Proteolysis of EphA2 converts it from a tumor suppressor to an Oncoprotein. Cancer Res 75, 3327–3339. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0213] 213. Sugiyama N, Gucciardo E, Tatti O, Varjosalo M, Hyytiäinen M, Gstaiger M & Lehti K (2013) EphA2 cleavage by MT1‐MMP triggers single cancer cell invasion via homotypic cell repulsion. J Cell Biol 201, 467–484. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0214] 214. Golubkov VS, Chekanov AV, Cieplak P, Aleshin AE, Chernov AV, Zhu W, Radichev IA, Zhang D, Dong PD & Strongin AY (2010) The Wnt/planar cell polarity protein‐tyrosine Kinase‐7 (PTK7) is a highly efficient proteolytic target of membrane Type‐1 matrix metalloproteinase. J Biol Chem 285, 35740–35749. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0215] 215. Thakur V & Bedogni B (2016) The membrane tethered matrix metalloproteinase MT1‐MMP at the forefront of melanoma cell invasion and metastasis. Pharmacol Res 111, 17–22. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0216] 216. Shaverdashvili K, Wong P, Ma J, Zhang K, Osman I & Bedogni B (2014) mt 1‐ mmp modulates melanoma cell dissemination and metastasis through activation of mmp 2 and rac 1. Pigment Cell Melanoma Res 27, 287–296. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0217] 217. Colón‐Bolea P, García‐Gómez R & Casar B (2021) RAC1 activation as a potential therapeutic option in metastatic cutaneous melanoma. Biomolecules 11, 1554. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0218] 218. Tatti O, Gucciardo E, Pekkonen P, Holopainen T, Louhimo R, Repo P, Maliniemi P, Lohi J, Rantanen V, Hautaniemi S et al. (2015) MMP16 mediates a proteolytic switch to promote cell–cell adhesion, collagen alignment, and lymphatic invasion in melanoma. Cancer Res 75, 2083–2094. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0219] 219. Yan X, Cao N, Chen Y, Lan H‐Y, Cha J‐H, Yang W‐H & Yang M‐H (2020) MT4‐MMP promotes invadopodia formation and cell motility in FaDu head and neck cancer cells. Biochem Biophys Res Commun 522, 1009–1014. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0220] 220. Jang B, Kim A, Hwang J, Song H‐K, Kim Y & Oh E‐S (2020) Emerging role of Syndecans in extracellular matrix remodeling in cancer. J Histochem Cytochem 68, 863–870. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0221] 221. Zhao X, Sun B, Li Y, Liu Y, Zhang D, Wang X, Gu Q, Zhao J, Dong X, Liu Z et al. (2015) Dual effects of collagenase‐3 on melanoma: metastasis promotion and disruption of vasculogenic mimicry. Oncotarget 6, 8890–8899. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0222] 222. Rousselle P & Scoazec JY (2020) Laminin 332 in cancer: when the extracellular matrix turns signals from cell anchorage to cell movement. Semin Cancer Biol 62, 149–165. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0223] 223. Moorman HR, Poschel D, Klement JD, Lu C, Redd PS & Liu K (2020) Osteopontin: a key regulator of tumor progression and immunomodulation. Cancer 12, 3379. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0224] 224. Kothari A & Flick MJ (2021) Coagulation signaling through PAR1 as a therapeutic target in pancreatic ductal adenocarcinoma. Int J Mol Sci 22, 5138. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0225] 225. Covic L & Kuliopulos A (2018) Protease‐activated receptor 1 as therapeutic target in breast, lung, and ovarian cancer: Pepducin approach. Int J Mol Sci 19, 2237. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0226] 226. Boire A, Covic L, Agarwal A, Jacques S, Sherifi S & Kuliopulos A (2005) PAR1 is a matrix Metalloprotease‐1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120, 303–313. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0227] 227. Liu S, Ren J & Ten Dijke P (2021) Targeting TGFβ signal transduction for cancer therapy. Signal Transduct Target Ther 6, 8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0228] 228. Ma L, Dong L & Chang P (2019) CD44v6 engages in colorectal cancer progression. Cell Death Dis 10, 30. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0229] 229. Medrano‐González PA, Rivera‐Ramírez O, Montaño LF & Rendón‐Huerta EP (2021) Proteolytic processing of CD44 and its implications in cancer. Stem Cells Int 2021, 1–12. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0230] 230. Cauwe B, Van Den Steen PE & Opdenakker G (2007) The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix Metalloproteinases. Crit Rev Biochem Mol Biol 42, 113–185. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0231] 231. Kung C‐I, Chen C‐Y, Yang C‐C, Lin C‐Y, Chen T‐H & Wang H‐S (2012) Enhanced membrane‐type 1 matrix metalloproteinase expression by hyaluronan oligosaccharides in breast cancer cells facilitates CD44 cleavage and tumor cell migration. Oncol Rep 28, 1808–1814. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0232] 232. Merdad A, Karim S, Schulten H‐J, Dallol A, Buhmeida A, Al‐Thubaity F, Gari MA, Chaudhary AG, Abuzenadah AM & Al‐Qahtani MH (2014) Expression of matrix metalloproteinases (MMPs) in primary human breast cancer: MMP‐9 as a potential biomarker for cancer invasion and metastasis. Anticancer Res 34, 1355–1366. [PubMed] [Google Scholar]

[febs70296-bib-0233] 233. Wöhner B, Li W, Hey S, Drobny A, Werny L, Becker‐Pauly C, Lucius R, Zunke F, Linder S & Arnold P (2023) Proteolysis of CD44 at the cell surface controls a downstream protease network. Front Mol Biosci 10, 1026810. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0234] 234. Lawson CD & Ridley AJ (2018) Rho GTPase signaling complexes in cell migration and invasion. J Cell Biol 217, 447–457. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0235] 235. Yamaguchi H & Sakai R (2015) Direct interaction between carcinoma cells and cancer associated fibroblasts for the regulation of cancer invasion. Cancer 7, 2054–2062. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0236] 236. Li Y, Wang C, Huang T, Yu X & Tian B (2023) The role of cancer‐associated fibroblasts in breast cancer metastasis. Front Oncol 13, 1194835. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0237] 237. Fernández‐Nogueira P, Fuster G, Gutierrez‐Uzquiza Á, Gascón P, Carbó N & Bragado P (2021) Cancer‐associated fibroblasts in breast cancer treatment response and metastasis. Cancer 13, 3146. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0238] 238. Shurin GV, Kruglov O, Ding F, Lin Y, Hao X, Keskinov AA, You Z, Lokshin AE, LaFramboise WA, Falo LD et al. (2019) Melanoma‐induced reprogramming of Schwann cell signaling aids tumor growth. Cancer Res 79, 2736–2747. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0239] 239. Huang T, Fan Q, Wang Y, Cui Y, Wang Z, Yang L, Sun X & Wang Y (2020) Schwann cell‐derived CCL2 promotes the Perineural invasion of cervical cancer. Front Oncol 10, 19. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0240] 240. Orgaz JL, Pandya P, Dalmeida R, Karagiannis P, Sanchez‐Laorden B, Viros A, Albrengues J, Nestle FO, Ridley AJ, Gaggioli C et al. (2014) Diverse matrix metalloproteinase functions regulate cancer amoeboid migration. Nat Commun 5, 4255. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0241] 241. Pandya P, Orgaz JL & Sanz‐Moreno V (2017) Modes of invasion during tumour dissemination. Mol Oncol 11, 5–27. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0242] 242. Patel B, Gaikwad S & Prasad S (2025) Exploring the significance of extracellular vesicles: key players in advancing cancer and possible theranostic tools. Cancer Pathog Ther 3, 109–119. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0243] 243. Graves LE, Ariztia EV, Navari JR, Matzel HJ, Stack MS & Fishman DA (2004) Proinvasive properties of ovarian cancer ascites‐derived membrane vesicles. Cancer Res 64, 7045–7049. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0244] 244. Rilla K, Mustonen A‐M, Arasu UT, Härkönen K, Matilainen J & Nieminen P (2019) Extracellular vesicles are integral and functional components of the extracellular matrix. Matrix Biol 75–76, 201–219. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0245] 245. Jackson HK, Mitoko C, Linke F, Macarthur D, Kerr ID & Coyle B (2023) Extracellular vesicles potentiate Medulloblastoma metastasis in an EMMPRIN and MMP‐2 dependent manner. Cancer 15, 2601. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0246] 246. Wang J, Wu Y, Guo J, Fei X, Yu L & Ma S (2017) Adipocyte‐derived exosomes promote lung cancer metastasis by increasing MMP9 activity via transferring MMP3 to lung cancer cells. Oncotarget 8, 81880–81891. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0247] 247. Hanahan D (2022) Hallmarks of cancer: new dimensions. Cancer Discov 12, 31–46. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0248] 248. Lugano R, Ramachandran M & Dimberg A (2020) Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci 77, 1745–1770. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0249] 249. Anderson NM & Simon MC (2020) The tumor microenvironment. Curr Biol 30, R921–R925. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0250] 250. Liu Z‐L, Chen H‐H, Zheng L‐L, Sun L‐P & Shi L (2023) Angiogenic signaling pathways and anti‐angiogenic therapy for cancer. Signal Transduct Target Ther 8, 198. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0251] 251. Muñoz‐Sáez E, Moracho N, Learte AIR, Arroyo AG & Sánchez‐Camacho C (2021) Dynamic expression of membrane type 1‐matrix metalloproteinase (Mt1‐mmp/Mmp14) in the mouse embryo. Cells 10, 2448. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0252] 252. Maybee DV, Ink NL & Ali MAM (2022) Novel roles of MT1‐MMP and MMP‐2: beyond the extracellular milieu. Int J Mol Sci 23, 9513. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0253] 253. Esteban S, Clemente C, Koziol A, Gonzalo P, Rius C, Martínez F, Linares PM, Chaparro M, Urzainqui A, Andrés V et al. (2020) Endothelial MT1‐MMP targeting limits intussusceptive angiogenesis and colitis via TSP1/nitric oxide axis. EMBO Mol Med 12, e10862. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0254] 254. Di Martino JS, Akhter T & Bravo‐Cordero JJ (2021) Remodeling the ECM: implications for metastasis and tumor dormancy. Cancer 13, 4916. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0255] 255. Winkler J, Abisoye‐Ogunniyan A, Metcalf KJ & Werb Z (2020) Concepts of extracellular matrix remodelling in tumour progression and metastasis. Nat Commun 11, 5120. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0256] 256. Mao S, Xia A, Tao X, Ye D, Qu J, Sun M, Wei H & Li G (2023) A pan‐cancer analysis of the prognostic and immunological roles of matrix metalloprotease‐1 (MMP1) in human tumors. Front Oncol 12, 1089550. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0257] 257. Grafinger OR, Hayward JJ, Meng Y, Geddes‐McAlister J, Li Y, Mar S, Sheng M, Su B, Thillainadesan G, Lipsman N et al. (2024) Cancer cell extravasation requires iplectin‐mediated delivery of MT1‐MMP at invadopodia. Br J Cancer 131, 931–943. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0258] 258. Aristorena M, Gallardo‐Vara E, Vicen M, De Las Casas‐Engel M, Ojeda‐Fernandez L, Nieto C, Blanco FJ, Valbuena‐Diez AC, Botella LM, Nachtigal P et al. (2019) MMP‐12, secreted by pro‐inflammatory macrophages, targets Endoglin in human macrophages and endothelial cells. Int J Mol Sci 20, 3107. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0259] 259. Hellenthal KEM, Brabenec L & Wagner N‐M (2022) Regulation and dysregulation of endothelial permeability during systemic inflammation. Cells 11, 1935. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0260] 260. Lin Y, Zheng Z‐H, Wang J‐X, Zhao Z & Peng T‐Y (2021) Tumor cell‐derived Exosomal Circ‐0072088 suppresses migration and invasion of hepatic carcinoma cells through regulating MMP‐16. Front Cell Dev Biol 9, 726323. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0261] 261. McMahon M, Ye S, Pedrina J, Dlugolenski D & Stambas J (2021) Extracellular matrix enzymes and immune cell biology. Front Mol Biosci 8, 703868. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0262] 262. Lee HS & Kim WJ (2022) The role of matrix metalloproteinase in inflammation with a focus on infectious diseases. Int J Mol Sci 23, 10546. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0263] 263. Ye Y, Kuang X, Xie Z, Liang L, Zhang Z, Zhang Y, Ma F, Gao Q, Chang R, Lee H‐H et al. (2020) Small‐molecule MMP2/MMP9 inhibitor SB‐3CT modulates tumor immune surveillance by regulating PD‐L1. Genome Med 12, 83. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0264] 264. Wang Q, Wang K, Tan X, Li Z & Wang H (2022) Immunomodulatory role of metalloproteases in cancers: current progress and future trends. Front Immunol 13, 1064033. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0265] 265. McFarlane AJ, Fercoq F, Coffelt SB & Carlin LM (2021) Neutrophil dynamics in the tumor microenvironment. J Clin Invest 131, e143759. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0266] 266. Cai N, Cheng K, Ma Y, Liu S, Tao R, Li Y, Li D, Guo B, Jia W, Liang H et al. (2024) Targeting MMP9 in CTNNB1 mutant hepatocellular carcinoma restores CD8⁺ T cell‐mediated antitumour immunity and improves anti‐PD‐1 efficacy. Gut 73, 985–999. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0267] 267. Wang G, Zhong K, Wang Z, Zhang Z, Tang X, Tong A & Zhou L (2022) Tumor‐associated microglia and macrophages in glioblastoma: from basic insights to therapeutic opportunities. Front Immunol 13, 964898. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0268] 268. Makutani Y, Kawakami H, Tsujikawa T, Yoshimura K, Chiba Y, Ito A, Kawamura J, Haratani K & Nakagawa K (2022) Contribution of MMP14‐expressing cancer‐associated fibroblasts in the tumor immune microenvironment to progression of colorectal cancer. Front Oncol 12, 956270. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0269] 269. Wang H, Pan J, Barsky L, Jacob JC, Zheng Y, Gao C, Wang S, Zhu W, Sun H, Lu L et al. (2021) Characteristics of pre‐metastatic niche: the landscape of molecular and cellular pathways. Mol Biomed 2, 3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0270] 270. Decock J, Hendrickx W, Thirkettle S, Gutiérrez‐Fernández A, Robinson SD & Edwards DR (2015) Pleiotropic functions of the tumor‐ and metastasis‐suppressing matrix metalloproteinase‐8 in mammary cancer in MMTV‐PyMT transgenic mice. Breast Cancer Res 17, 38. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0271] 271. Muniz‐Bongers LR, McClain CB, Saxena M, Bongers G, Merad M & Bhardwaj N (2021) MMP2 and TLRs modulate immune responses in the tumor microenvironment. JCI Insight 6, e144913. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0272] 272. Krstic J & Santibanez JF (2014) Transforming growth factor‐beta and matrix metalloproteinases: functional interactions in tumor stroma‐infiltrating myeloid cells. ScientificWorldJ 2014, 521754. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0273] 273. Kenji SF, Kurma K, Collet B, Oblet C, Debure L, Di Primo C, Minder L, Vérité F, Danger Y, Jean M et al. (2022) MMP7 cleavage of amino‐terminal CD95 death receptor switches signaling toward non‐apoptotic pathways. Cell Death Dis 13, 895. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0274] 274. Liu Y & Cao X (2016) Characteristics and significance of the pre‐metastatic niche. Cancer Cell 30, 668–681. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0275] 275. Peinado H, Zhang H, Matei IR, Costa‐Silva B, Hoshino A, Rodrigues G, Psaila B, Kaplan RN, Bromberg JF, Kang Y et al. (2017) Pre‐metastatic niches: organ‐specific homes for metastases. Nat Rev Cancer 17, 302–317. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0276] 276. Qi Y, Sun D, Zhai X, Chen F, Niu J & Zhu H (2025) Macrophages in the premetastatic and metastatic niche: key functions and therapeutic directions. J Transl Med 23, 602. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0277] 277. Wang Y, Jia J, Wang F, Fang Y, Yang Y, Zhou Q, Yuan W, Gu X, Hu J & Yang S (2024) Pre‐metastatic niche: formation, characteristics and therapeutic implication. Signal Transduct Target Ther 9, 236. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0278] 278. Li Y, Li M, Su K, Zong S, Zhang H & Xiong L (2023) Pre‐metastatic niche: from revealing the molecular and cellular mechanisms to the clinical applications in breast cancer metastasis. Theranostics 13, 2301–2318. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0279] 279. Shuman Moss LA, Jensen‐Taubman S & Stetler‐Stevenson WG (2012) Matrix metalloproteinases. Am J Pathol 181, 1895–1899. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0280] 280. Liu Y, Zhang Y, Ding Y & Zhuang R (2021) Platelet‐mediated tumor metastasis mechanism and the role of cell adhesion molecules. Crit Rev Oncol Hematol 167, 103502. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0281] 281. Shay G, Lynch CC & Fingleton B (2015) Moving targets: emerging roles for MMPs in cancer progression and metastasis. Matrix Biol 44–46, 200–206. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0282] 282. Cai R, Tressler CM, Cheng M, Sonkar K, Tan Z, Paidi SK, Ayyappan V, Barman I & Glunde K (2023) Primary breast tumor induced extracellular matrix remodeling in premetastatic lungs. Sci Rep 13, 18566. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0283] 283. Wang Y, Ding Y, Guo N & Wang S (2019) MDSCs: key criminals of tumor pre‐metastatic niche formation. Front Immunol 10, 172. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0284] 284. Patras L, Paul D & Matei IR (2023) Weaving the nest: extracellular matrix roles in pre‐metastatic niche formation. Front Oncol 13, 1163786. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0285] 285. Sun H, Meng Q, Shi C, Yang H, Li X, Wu S, Familiari G, Relucenti M, Aschner M, Wang X et al. (2021) Hypoxia‐inducible exosomes facilitate liver‐tropic Premetastatic niche in colorectal cancer. Hepatology 74, 2633–2651. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0286] 286. Alves R, Pires A, Jorge J, Balça‐Silva J, Gonçalves AC & Sarmento‐Ribeiro AB (2024) Batimastat induces cytotoxic and cytostatic effects in in vitro models of hematological tumors. Int J Mol Sci 25, 4554. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0287] 287. Laronha H, Carpinteiro I, Portugal J, Azul A, Polido M, Petrova KT, Salema‐Oom M & Caldeira J (2020) Challenges in matrix Metalloproteinases inhibition. Biomolecules 10, 717. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0288] 288. Zhu B‐L, Long Y, Luo W, Yan Z, Lai Y‐J, Zhao L‐G, Zhou W‐H, Wang Y‐J, Shen L‐L, Liu L et al. (2019) MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation. Brain 142, 176–192. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0289] 289. Wang L‐L, Zhang B, Zheng M‐H, Xie Y‐Z, Wang C‐J & Jin J‐Y (2020) Matrix Metalloproteinases (MMPs) in targeted drug delivery: synthesis of a potent and highly selective inhibitor against matrix Metalloproteinase‐7. Curr Top Med Chem 20, 2459–2471. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0290] 290. Fields GB (2019) Mechanisms of action of novel drugs targeting angiogenesis‐promoting matrix Metalloproteinases. Front Immunol 10, 1278. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0291] 291. Bendell J, Sharma S, Patel MR, Windsor KS, Wainberg ZA, Gordon M, Chaves J, Berlin J, Brachmann CB, Zavodovskaya M et al. (2020) Safety and efficacy of Andecaliximab (GS‐5745) plus gemcitabine and nab‐paclitaxel in patients with advanced pancreatic adenocarcinoma: results from a phase I study. Oncologist 25, 954–962. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0292] 292. Das N, Benko C, Gill SE & Dufour A (2020) The pharmacological TAILS of matrix Metalloproteinases and their inhibitors. Pharmaceuticals 14, 31. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0293] 293. Xu Q & Shao D (2024) Leveraging the synergy between anti‐angiogenic therapy and immune checkpoint inhibitors to treat digestive system cancers. Front Immunol 15, 1487610. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0294] 294. Lee WS, Yang H, Chon HJ & Kim C (2020) Combination of anti‐angiogenic therapy and immune checkpoint blockade normalizes vascular‐immune crosstalk to potentiate cancer immunity. Exp Mol Med 52, 1475–1485. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0295] 295. Granet‐Vaissiere E, Lefort F, Domblides C, Larroquette M, Ravaud A, Bernhard J‐C & Gross‐Goupil M (2023) Combinations of anti‐Angiogenic agents and immune checkpoint inhibitors in renal cell carcinoma: best option? Cancer 15, 1048. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0296] 296. Jain S, Annett SL, Morgan MP & Robson T (2021) The cancer stem cell niche in ovarian cancer and its impact on immune surveillance. Int J Mol Sci 22, 4091. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0297] 297. Protasoni M, Kroon AM & Taanman J‐W (2018) Mitochondria as oncotarget: a comparison between the tetracycline analogs doxycycline and COL‐3. Oncotarget 9, 33818–33831. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0298] 298. Ferreira Junior NC, Dos Santos Pereira M, Francis N, Ramirez P, Martorell P, González‐Lizarraga F, Figadère B, Chehin R, Del Bel E, Raisman‐Vozari R et al. (2021) The chemically‐modified tetracycline COL‐3 and its parent compound doxycycline prevent microglial inflammatory responses by reducing glucose‐mediated oxidative stress. Cells 10, 2163. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0299] 299. Rahmani M, Negro Álvarez SE & Hernández EB (2022) The potential use of tetracyclines in neurodegenerative diseases and the role of nano‐based drug delivery systems. Eur J Pharm Sci 175, 106237. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0300] 300. Garrido‐Mesa J, Adams K, Galvez J & Garrido‐Mesa N (2022) Repurposing tetracyclines for acute respiratory distress syndrome (ARDS) and severe COVID‐19: a critical discussion of recent publications. Expert Opin Investig Drugs 31, 475–482. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0301] 301. He B & Garmire L (2020) Prediction of repurposed drugs for treating lung injury in COVID‐19. F1000Res 9, 609. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0302] 302. Muri L, Leppert D, Grandgirard D & Leib SL (2019) MMPs and ADAMs in neurological infectious diseases and multiple sclerosis. Cell Mol Life Sci 76, 3097–3116. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0303] 303. He L, Kang Q, Chan KI, Zhang Y, Zhong Z & Tan W (2023) The immunomodulatory role of matrix metalloproteinases in colitis‐associated cancer. Front Immunol 13, 1093990. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0304] 304. Radisky ES, Raeeszadeh‐Sarmazdeh M & Radisky DC (2017) Therapeutic potential of matrix metalloproteinase inhibition in breast cancer. J Cell Biochem 118, 3531–3548. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0305] 305. Fan D & Kassiri Z (2020) Biology of tissue inhibitor of metalloproteinase 3 (TIMP3), and its therapeutic implications in cardiovascular pathology. Front Physiol 11, 661. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0306] 306. Nikolov A, Popovski N & Hristova I (2020) Collagenases MMP‐1, MMP‐13, and tissue inhibitors TIMP‐1, TIMP‐2: their role in healthy and complicated pregnancy and potential as preeclampsia biomarkers—a brief review. Appl Sci 10, 7731. [Google Scholar]

[febs70296-bib-0307] 307. Boumiza S, Chahed K, Tabka Z, Jacob M‐P, Norel X & Ozen G (2021) MMPs and TIMPs levels are correlated with anthropometric parameters, blood pressure, and endothelial function in obesity. Sci Rep 11, 20052. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0308] 308. Sarkar P, Li Z, Ren W, Wang S, Shao S, Sun J, Ren X, Perkins NG, Guo Z, Chang C‐EA et al. (2020) Inhibiting matrix Metalloproteinase‐2 activation by perturbing protein–protein interactions using a cyclic peptide. J Med Chem 63, 6979–6990. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0309] 309. Mendes SR, Amo‐Maestro LD, Marino‐Puertas L, Diego ID, Goulas T & Gomis‐Rüth FX (2020) Analysis of the inhibiting activity of reversion‐inducing cysteine‐rich protein with Kazal motifs (RECK) on matrix metalloproteinases. Sci Rep 10, 6317. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0310] 310. Russell JJ, Grisanti LA, Brown SM, Bailey CA, Bender SB & Chandrasekar B (2021) Reversion inducing cysteine rich protein with Kazal motifs and cardiovascular diseases: the RECKlessness of adverse remodeling. Cell Signal 83, 109993. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0311] 311. Mori H, Tomari T, Koshikawa N, Kajita M, Itoh Y, Sato H, Tojo H, Yana I & Seiki M (2002) CD44 directs membrane‐type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin‐like domain. EMBO J 21, 3949–3959. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0312] 312. Yosef G, Hayun H & Papo N (2021) Simultaneous targeting of CD44 and MMP9 catalytic and hemopexin domains as a therapeutic strategy. Biochem J 478, 1139–1157. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0313] 313. Charzewski Ł, Krzyśko KA & Lesyng B (2021) Structural characterisation of inhibitory and non‐inhibitory MMP‐9–TIMP‐1 complexes and implications for regulatory mechanisms of MMP‐9. Sci Rep 11, 13376. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0314] 314. Conte R, Finicelli M, Borrone A, Margarucci S, Peluso G, Calarco A & Bosetti M (2023) MMP‐2 silencing through siRNA loaded positively‐charged nanoparticles (AcPEI‐NPs) counteracts chondrocyte De‐differentiation. Polymers 15, 1172. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0315] 315. Escalona RM, Chu S, Kadife E, Kelly JK, Kannourakis G, Findlay JK & Ahmed N (2022) Knock down of TIMP‐2 by siRNA and CRISPR/Cas9 mediates diverse cellular reprogramming of metastasis and chemosensitivity in ovarian cancer. Cancer Cell Int 22, 422. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0316] 316. Shah MA, Bodoky G, Starodub A, Cunningham D, Yip D, Wainberg ZA, Bendell J, Thai D, He J, Bhargava P et al. (2021) Phase III study to evaluate efficacy and safety of Andecaliximab with mFOLFOX6 as first‐line treatment in patients with advanced gastric or GEJ adenocarcinoma (GAMMA‐1). J Clin Oncol 39, 990–1000. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0317] 317. Wang Y, Wei Y, Huang J, Li X, You D, Wang L & Ma X (2024) Prognostic value of matrix metalloproteinase‐2 protein and matrix metalloproteinase‐9 protein in colorectal cancer: a meta‐analysis. BMC Cancer 24, 1065. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0318] 318. Jiang H & Li H (2021) Prognostic values of tumoral MMP2 and MMP9 overexpression in breast cancer: a systematic review and meta‐analysis. BMC Cancer 21, 149. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0319] 319. Maurya S, Swati K, Ghosh M & Yadav PK (2025) Matrix metalloproteases as diagnostic and prognostic biomarkers in cancer. In Pathophysiological Aspects of Proteases in Cancerpp. 205–222. Academic Press, Amsterdam, the Netherlands. [Google Scholar]

[febs70296-bib-0320] 320. Böckelman C, Beilmann‐Lehtonen I, Kaprio T, Koskensalo S, Tervahartiala T, Mustonen H, Stenman U‐H, Sorsa T & Haglund C (2018) Serum MMP‐8 and TIMP‐1 predict prognosis in colorectal cancer. BMC Cancer 18, 679. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0321] 321. Jonsson A, Hjalmarsson C, Falk P & Ivarsson M‐L (2016) Levels of matrix metalloproteinases differ in plasma and serum – aspects regarding analysis of biological markers in cancer. Br J Cancer 115, 703–706. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0322] 322. Mortaja M, Cheng MM, Ali A, Lesperance J, Hingorani DV, Allevato MM, Dhawan K, Camargo MF, McKay RR, Adams SR et al. (2024) Tumor‐targeted cell‐penetrating peptides reveal that monomethyl Auristatin E temporally modulates the tumor immune microenvironment. Molecules 29, 5618. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0323] 323. Seah D, Cheng Z & Vendrell M (2023) Fluorescent probes for imaging in humans: where are we now? ACS Nano 17, 19478–19490. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0324] 324. Winer A, Adams S & Mignatti P (2018) Matrix metalloproteinase inhibitors in cancer therapy: turning past failures into future successes. Mol Cancer Ther 17, 1147–1155. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0325] 325. Cathcart J, Pulkoski‐Gross A & Cao J (2015) Targeting matrix metalloproteinases in cancer: bringing new life to old ideas. Genes Dis 2, 26–34. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0326] 326. Fields GB (2019) The rebirth of matrix metalloproteinase inhibitors: moving beyond the dogma. Cells 8, 984. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0327] 327. Ghosh S, Rajendran RL, Mahajan AA, Chowdhury A, Bera A, Guha S, Chakraborty K, Chowdhury R, Paul A, Jha S et al. (2024) Harnessing exosomes as cancer biomarkers in clinical oncology. Cancer Cell Int 24, 278. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0328] 328. Amar S & Fields GB (2015) Potential clinical implications of recent matrix metalloproteinase inhibitor design strategies. Expert Rev Proteomics 12, 445–447. [DOI] [PMC free article] [PubMed] [Google Scholar]

[febs70296-bib-0329] 329. Vandenbroucke RE & Libert C (2014) Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat Rev Drug Discov 13, 904–927. [DOI] [PubMed] [Google Scholar]

[febs70296-bib-0330] 330. Melaiu O, Vanni G, Portarena I, Pistolese CA, Anemona L, Pomella S, Bei R, Buonomo OC, Roselli M, Mauriello A et al. (2023) The combination of immune checkpoint blockade with tumor vessel normalization as a promising therapeutic strategy for breast cancer: An overview of preclinical and clinical studies. Int J Mol Sci 24, 3226. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

A guide to the types, structures, and multifaceted functions of matrix metalloproteinases in cancer

Zoi Piperigkou

Sylvia Mangani

Spyros Kremmydas

Nikolaos E Koletsis

Nikos K Karamanos

Abstract

Abbreviations

Introduction

Structures of MMPs

Fig. 1.

Classification of MMPs

Synthesis, activation, and target substrates of MMPs

Table 1.

MMPs as non‐catalytic effectors

Fig. 2.

Functional roles of MMPs under homeostatic conditions

Pathophysiological roles of MMPs

Roles of MMPs in cancer progression

Fig. 3.

MMPs in cancer cell proliferation and survival

Fig. 4.

Table 2.

MMPs—Growth factors axis in cancer cell proliferation

MMPs—IGF axis in cancer cell proliferation

MMPs—EGF axis in cancer cell proliferation

MT‐MMPs roles in cancer cell proliferation

MMPs—TGF‐β axis in cancer cell proliferation

MMPs—NF‐κΒ axis in cancer cell proliferation

MMPs' additional proteolytic actions in cancer cell proliferation

MMPs—Fas/FasL axis in cancer progression

MMPs in epithelial‐to‐mesenchymal transition

Fig. 5.

MMPs‐mediated proteolysis of cell adhesion molecules

Fig. 6.

MMP‐mediated expression of mesenchymal markers

MMPs—NF‐κΒ axis in EMT induction

MMPs—TGF‐β and MMP – Wnt axis in EMT induction

TME‐ and exosome‐associated MMPs in EMT induction

MMPs in cancer cell migration and invasion

MMP‐mediated proteolytic degradation of basement membranes

Roles of less‐studied MMPs in cancer cell migration and invasion

MMPs in invadopodia formation and cancer cell migration

MT1‐MMP roles in cancer cell migration and invasion

Other MT‐MMPs roles in cancer cell migration and invasion

MMP‐driven adhesion molecules disruption and PGs shedding in tumor invasion

MMPs—Laminin and MMPs—Osteopontin axis in cancer cell migration and invasion

MMPs–PAR‐1 axis in cancer cell migration and invasion

MMPs–TGF‐β axis in cancer cell migration and invasion

MMPs–CD44 axis in cancer cell migration and invasion

TME‐associated MMPs in cancer cell migration and invasion

Exosomal MMPs in cancer cell migration and invasion

MMPs in angiogenesis and vascular integrity

MMPs in immune surveillance

MMPs in pre‐metastatic niche formation

Novel insights into MMPs targeting and MMP‐based diagnostics

Next‐generation MMP inhibitors

Chemically modified tetracyclines

Natural inhibitors of MMPs

Targeting non‐catalytic MMP functions

Diagnostic applications

Gaps and challenges in clinical translation

Table 3.

Table 4.

Concluding remarks and future perspectives

Conflict of interest

Author contributions

Acknowledgements

References

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases