Table 1.
ECM evolution during cancer progression.
| ECM changes | Physiological ECM | Cancer-associated ECM | The pre-metastatic ECM | References |
|---|---|---|---|---|
| ECM determinants | Tissue-resident stroma or resident/infiltrating immune cells, quiescent and metabolically inactive fibroblasts are the primary source of ECM molecules (collagens, PGs, elastins, and GFs) and proteolytic enzymes (MMPs) driving physiological ECM degradation | Pro-tumorigenic, metabolically active CAFs, peritumoral fibroblasts, reactive stroma fibroblasts, and myofibroblasts are the major source of ECM molecules. CAFs secrete high levels of collagen I, FNs, laminin, and HA, increasing matrix stiffness. Cancer cells and immune cells also contribute to ECM changes. |
PMN ECM remodeling by resident stroma and immune cells: - Lung via activation and differentiation into α-SMA myofibroblast or CAF phenotype - Bone fibroblast-like cells - Liver hepatocytes, hepatic stellate cells (HStCs) in the liver - LN fibroblastic reticular cells - Omentum preadipocytes and endothelial cells - Immune resident (macrophages in the liver, microglia in the brain) and infiltrating (MDSCs and inflammation-activated neutrophils) cells |
(22–30) |
| Composition | Tissue-specific composition of diverse glycans (PGs and GAGs) and ECM proteins (collagen, elastin, fibronectin, and laminin) present in physiological ratios HA is an abundant component of the brain ECM, while collagen is less prevalent, and FN is concentrated around the BM |
Increased ECM deposition of collagen (types I, III, and IV), FNs, HA, and altered levels of elastin, as well as PGs (decorin, biglycan, lumican, and fibromodulin) depending on the cancer type Increased TNC impacts tumor growth and metastasis by modulating the interactions of integrins and syndecans with FNs. |
Increased FN deposition in lung, liver, and LN PMNs - Lung: fibronectin- or laminin-rich (S100A4+ fibroblasts); transcriptional regulation for CD44, osteopontin (OPN), collagens, and MMPs -liver: increased collagen I deposition - lung and bone: local LOX disrupts ECM homeostasis -omentum: increased collagen and adhesion molecules -brain: increased HA |
(1, 5, 11, 31–39) |
| Organization, stiffness, and mechanical properties | Highly organized structures with tissue-specific fiber alignments and crosslinking Maintenance of the physiological balance between stiffness and elasticity by FNs and elastins Compliant and flexible ECM - Bone: mineralization of type I collagen resulting in increased strengths) with areas of dense or porous ECM - Brain: maintenance of BBB integrity |
Disorganized ECM Irregular fiber alignments Excessive crosslinking, stiffness ECM is a scaffold for EC migration and tube formation Increased desmoplasia (growth of fibrous and connective tissue) through the upregulation of LOX enzymes |
Altered architecture (increased orthogonal characteristics) Crosslinking of collagen type I and IV by LOX family enzymes, adhesion platform for BMDC infiltration Increased stiffness in the (lung, liver, and LN PMNs) and pro-fibrotic ECM determined by the increased secretion of FNs, collagen, and LOX enzymes that crosslink collagen Altered mechanics perturb the function of mechanosensitive cells Bone—osteogenic environment with bone lesions that promote bone colonization. Osteoclast-mediated bone resorption and osteolytic metastases Brain vascular remodeling and BBB barrier disruption promote angiogenesis |
(4, 6, 24, 28, 29, 35, 40–47) |
| Cellular signaling | Abnormal Provides physiological signaling cues that regulate cell behavior (e.g., proliferation, differentiation, migration) |
Abnormal ECM signaling Release of stored GFs, activation of GF-mediated cellular functions (TGF-β, VEGF, PDGF, EGF, bFGF, and HGF), promote inflammation, angiogenesis HA interactions promote anti-apoptotic pathways, EMT, and invasiveness |
Lung-altered POSTN promotes WNT signaling in the lung PMN - FN-rich areas anchor integrin a4b1+/VEGFR1+ HPCs; VCAN deposition in the lungs and promotion of MET Altered integrin interactions with PMN ECM drive tumor colonization and thrombosis |
(1, 48–51b; 52, 53) |
| Proteolysis | Balanced levels of proteases degrade and modify the ECM depending on tissue requirements | Overexpression of ECM remodeling enzymes Increased secretion and activation of enzymes that degrade the ECM: MMPs (MMP-1, MMP-2, MMP-9, and others), ADAMs (serine and threonine proteases), proteases released by neutrophils, NET formation Dysregulated proteolysis leading to excessive ECM degradation and remodeling, enhanced tumor angiogenesis, invasion, and metastasis |
Proteolytic remodeling by MMPs, MT MMPs, cathepsins, serine protease inhibitors - Lung: EV-mediated MMP-2 and MMP-9 production, which cleaves collagen IV; TIMP-1-mediated cleavage of MMPs - Neutrophil enzymes (neutrophil elastase, cathepsin G) degrade anti-tumorigenic TSP-1 - Brain-serine protease inhibitor (SERPINB1) determines brain tropism via ECM changes - Bone-cathepsin (e.g., cathepsin K), MMPs, and membrane-type MMPs mediate osteoclastogenesis and bone resorption |
(40, 47, 54–62, 172) |
| PTMs (e.g., matrix crosslinking, glycosylation) | Physiological PTMs | Dysregulated glycosylation and collagen crosslinking | Collagen type I and type IV crosslinking by LOX family of enzymes (LOX, LOX-like 2 (LOXL2), and LOXL4) - Omentum-palmitic acid regulated LAMC1 posttranslational regulation |
(13, 17, 30, 40, 41, 63–65) |
| Metabolites | Balanced and regulated | Altered glucose and lipid metabolism Increased release of GF, cytokines, etc. |
- Lung, omentum-altered glucose (lactate production), and lipid metabolism (palmitic acid) promote ECM changes Increased release of GF, cytokines, etc. |
(5, 30, 66, 67) |
| Other physicochemical parameters: hydration, pH, Ca2+ signaling | Hydrated and lubricated Tissue-dependent hydration Physiological pH Homeostatic Ca2+ signaling |
Perturbations of ECM hydration Acidic pH Disrupted Ca2+ signaling |
Decreased hydration due to altered GAG content and increased collagen crosslinking Disrupted levels of extra- and intracellular Ca2+ levels and dysregulated Ca2+ signaling delineated by increased production of Ca2+-binding proteins - Lung, LN: acidification of the ECM |
(17, 35, 42, 66–69) |
ECM, extracellular matrix; PGs, proteoglycans; GFs, growth factors; MMPs, matrix metalloproteinases; CAFs, cancer-associated fibroblasts; FNs, fibronectins; HA, hyaluronic acid; PMN, pre-metastatic niche; LN, lymph node; MDSCs, myeloid-derived suppressor cells; GAGs, glycosaminoglycans; BM, basement membrane; BBB, blood–brain barrier; EC, endothelial cell; BMDC, bone marrow-derived cell; EV, extracellular vesicle.