Vascular plasticity in the gastric cancer environment: mechanisms, prognostic significance, and concepts of therapeutic interventions

Abstract

Gastric cancer (GC) remains a major global health problem because of its aggressive behavior and frequent development of therapeutic resistance. In GC, as in other malignancies, blood vessels are essential for Tumor-cell survival and dissemination, thereby facilitating metastasis to distant organs. As tumors grow, they remodel the surrounding microenvironment, generating hypoxic, acidic, nutrient-poor conditions with elevated interstitial fluid pressure. Reactive oxygen species further support tumor growth, glycolytic metabolism, and neovascularization. Highly aggressive cancer cells can also form endothelial cell-independent vascular-like networks defined as vasculogenic mimicry (VM), which may facilitate access to oxygen and nutrients. Many molecular markers and mechanisms underlying VM in GC remain insufficiently defined, while the presence of VM is associated with aggressive tumor behavior, metastatic potential, therapeutic resistance, and poor prognosis. Therefore, new therapeutic strategies are needed that complement conventional treatment and target the heterogeneous vascular compartments of GC. Nanomedicine may contribute to this goal by improving targeted drug delivery, local drug concentration, bioavailability, and controlled release while reducing systemic adverse effects.

Background

Gastric cancer

Gastric cancer (GC), with more than 968.000 new cases worldwide and over 660.000 deaths annually, is the fifth most common cancer and the fifth leading cause of cancer-related mortality globally [1]. GC is particularly common in Eastern Europe and Asia in both men and women. According to tumor location, GC can be classified as non-cardia or distal GC (lower stomach) and cardia or proximal GC (upper stomach). Predisposition to GC is strongly associated with chronic infection by the Gram-negative bacterium Helicobacter pylori, which is responsible for the majority of non-cardia GC [2, 3]. Other risk factors include genetic susceptibility and environmental exposures to high salt intake, alcohol consumption, and tobacco smoking, all of which may contribute to dysbiosis and impaired gastric barrier homeostasis. An increasing incidence of GC among younger individuals has been reported in both low- and high-risk populations and may be associated with gastrointestinal disorders and disrupted gastric homeostasis [4–6].

Several preventive strategies have been proposed to reduce the risk of GC. The most effective approach is the eradication of H. pylori infection combined with early cancer detection. Standard diagnostic procedures include endoscopic examination, imaging when clinically indicated, and collection of multiple biopsies for histopathological assessment [7]. Given the importance of H. pylori infection in GC development, European and international organizations, including the World Health Organization (WHO) and the International Agency for Research on Cancer (IARC), emphasize early detection and treatment of H. pylori infection as an important component of GC prevention [5, 8].

Standard treatment of resectable GC includes surgical resection combined with perioperative chemotherapy, with radiotherapy used in selected settings [9]. For advanced disease, systemic treatment depends on tumor stage and molecular characteristics and may include fluoropyrimidine- and platinum-based chemotherapy, the 5-fluorouracil/leucovorin, oxaliplatin, and docetaxel (FLOT) regimen, targeted therapy, and immune checkpoint inhibitors. Anti-angiogenic treatment includes ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor 2 (VEGFR-2), whereas pembrolizumab and nivolumab target programmed cell death protein 1 (PD-1) [7, 10, 11].

The extensive interpatient and intratumoral heterogeneity of GC makes the development of uniformly effective therapies difficult. Tumors may also respond differently to chemotherapy and immunotherapy, and the accumulation of genetic or epigenetic alterations during prolonged treatment can compromise therapeutic efficacy [12, 13]. Multidrug resistance (MDR) mechanisms in GC include increased drug efflux, enhanced DNA-repair capacity, and resistance to apoptosis. GC stem cells (GCSCs) can further promote drug resistance by remodeling the tumor microenvironment (TME), altering drug pharmacokinetics, and enhancing invasiveness and metastasis through epithelial-to-mesenchymal transition (EMT). Diagnosis at advanced stage additionally limits therapeutic options [14]. Consequently, modern therapeutic approaches focus on identifying new clinically actionable targets and on understanding interactions among the TME, immune components, and heterogeneous GC cell populations [10]. Antibody–drug conjugates (ADCs), receptor-targeted antibodies, tyrosine kinase inhibitors (TKIs), and chimeric antigen receptor T-cell (CAR-T) strategies are among the approaches currently being investigated or implemented in selected GC subgroups [15–18].

Given the importance of H. pylori infection in GC development and progression, improved preventive and therapeutic anti-H. pylori strategies remain important [8, 19].

The enhanced permeability and retention (EPR) effect has contributed to the development of nanomedicine-based therapeutic concepts by enabling passive accumulation of some macromolecular and nanoscale agents within tumors. However, the magnitude and consistency of the EPR effect vary substantially among tumors and patients, and this variability must be considered when designing nanoformulations [20].

Concluding perspective

GC represents an important health, economic, and social burden. Its pathogenesis is complex and heterogeneous, reflecting host genetic background, infectious agents such as H. pylori, alterations in the microbiota, and other environmental factors. Both conventional endothelial angiogenesis and alternative vascularization mechanisms can support the survival and expansion of GC cells. Therefore, modern therapeutic strategies should combine the identification of new vascular and tumor-cell targets with improved drug-delivery systems. Nanotechnology may facilitate drug protection, local delivery, and combination treatment, but its therapeutic value should be considered in the context of the heterogeneous vascular biology of GC.

Introduction to GC angiogenesis and vasculogenesis

Tumor vascularization is required for the progression of GC, yet the biological context in which vascular remodeling occurs appears to differ from that of several other solid tumors. In many non-cardia gastric adenocarcinomas, particularly of the intestinal histological subtype, tumor development occurs against a background of chronic mucosal inflammation, frequently associated with H. pylori infection [21]. In this setting, vascular remodeling may reflect a progressive component of chronic mucosal injury and repair rather than a late, abrupt “angiogenic switch” [22]. Angiogenic activation has been reported in premalignant lesions, although its magnitude, spatial organization, and functional impact across histological and molecular GC subtypes have not been systematically characterized. Notably, the association of inflammatory and angiogenesis-related biomarkers with survival outcomes further suggests that vascular heterogeneity may carry clinical relevance beyond simple vessel density measurements [23].

Accordingly, GC vascularization should be interpreted within the broader framework of chronic inflammation, epithelial transformation, and stromal reprogramming. Whether these processes converge into reproducible, subtype-specific vascular phenotypes remains a central question for understanding disease biology and for interpreting therapeutic response.

Initiation of tumor vascularization in gastric cancer and its therapeutic relevance

Intestinal-type gastric adenocarcinoma is commonly described as developing through the multistep progression outlined in Correa’s cascade, involving chronic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, and invasive carcinoma [24]. While this framework is well established histopathologically, its vascular implications have received less attention. Several studies have reported increased microvessel density and/or elevated expression of pro-angiogenic mediators in premalignant gastric lesions, including intestinal metaplasia and dysplasia [25]. If reproducible across cohorts, these observations indicate that vascular remodeling may accompany progressive mucosal transformation rather than emerging exclusively at the stage of invasion. However, the magnitude and spatial distribution of these early vascular changes remain insufficiently quantified.

Chronic H. pylori-associated inflammation provides a coherent mechanism for early angiogenic priming. Persistent infection activates nuclear factor kappa B (NF-κB)-dependent inflammatory programs and sustains cytokine and chemokine production, including interleukin (IL)−8 [26]. Experimental work in other tumor systems indicates that IL-8 can enhance endothelial proliferation and migration and amplify VEGF signaling [27]. Whether this inflammatory-angiogenic coupling is demonstrable in human gastric mucosa across premalignant progression has not been conclusively established. Inflammatory infiltrates, including macrophages and neutrophils, may further contribute to local sources of VEGF and matrix-remodeling enzymes. Tumor-associated macrophage density correlates with angiogenic markers in invasive GC [28], yet similar analyses in earlier lesions remain limited.

Vascular initiation in GC may also involve qualitative alterations in vessel organization, not only changes in density. Descriptions of irregular vascular architecture in early lesions raise the possibility that heterogeneous vessel caliber, and potentially altered mural coverage, emerge during the transition from chronic inflammation to dysplasia. Targeted assessment of mural coverage and basement membrane organization in premalignant gastric lesions would help establish whether vessel instability is an early feature or a later consequence of tumor growth.

Diffuse-type GC, which does not strictly conform to Correa’s cascade, may exhibit distinct vascular remodeling linked to its infiltrative growth pattern and stromal composition. Whether these differences translate into reproducible vascular phenotypes remains to be clarified. These early cues may shape the endothelial states that emerge in established tumors.

Molecular and cellular diversity of vascular heterogeneity

Tumor vascularization in GC likely reflects the integration of multiple processes, including sprouting angiogenesis, intussusceptive remodeling, and recruitment of bone marrow-derived cells. Evidence from multiple solid tumors indicates that tumor endothelial cells are transcriptionally heterogeneous and functionally specialized rather than a uniform VEGF-responsive population [29], with subsets linked to angiogenesis, extracellular matrix remodeling, metabolic adaptation, and immunomodulatory functions.

Single-cell analyses of solid tumors, including datasets containing GC samples [29, 30], suggest that endothelial heterogeneity may also be present in GC. Available datasets indicate endothelial diversification in GC, though its reproducibility across subtypes remains to be validated. If confirmed, this would indicate that vascular abnormalities in GC reflect coexisting endothelial states with distinct barrier properties, metabolic configurations, and immune interactions.

Vasculogenic inputs, including recruitment of pro-angiogenic myeloid populations or bone marrow-derived endothelial progenitors, may further contribute, although their quantitative relevance in GC remains uncertain.

Hypoxia is a more firmly supported driver of endothelial diversification. Elevated Hypoxia-Inducible Factor 1-Alpha (HIF-1α) expression has been associated with aggressive features and poor prognosis in GC [31, 32], indicating activation of hypoxia-responsive programs in a subset of tumors. Hypoxia may promote endothelial proliferation and metabolic reprogramming while contributing to vessel instability and immune modulation. The relative contribution of these effects on vascular architecture and function in GC has not been systematically dissected. Beyond intrinsic endothelial states, immune cells and endothelium form a coupled system that can further diversify vascular behavior.

Immune-vascular interactions in the GC microenvironment

GC frequently develops within an inflammatory microenvironment characterized by substantial immune infiltration. Beyond serving as sources of pro-angiogenic mediators such as VEGF and cytokines, immune cells may actively shape vascular phenotypes. Tumor-associated macrophages (TAMs) and other myeloid populations can influence endothelial activation, sprouting behavior, and barrier integrity through both soluble mediators and matrix remodeling.

Conversely, the tumor endothelium is not a passive conduit for immune trafficking. Endothelial activation states determine adhesion molecule expression, barrier function, and the selective recruitment or exclusion of immune subsets. In other malignancies, specialized tumor endothelial programs have been implicated in immune suppression and impaired T-cell infiltration. Whether comparable endothelial immune-regulatory states operate in GC and how they relate to histological or molecular subtypes remain to be determined. Recent analyses linking inflammatory and angiogenic features of the GC microenvironment with clinical outcome [23] underscore the potential relevance of immune–vascular coupling for stratification. Such coupling would also be expected to translate into spatially uneven vascular function.

Functional implications for vascular heterogeneity in GC

The molecular and cellular heterogeneity described above is expected to manifest as spatial variability in vascular function. Endothelial states shaped by inflammatory signaling, hypoxia, and stromal interactions are unlikely to generate a uniformly perfused network. Instead, regions of increased permeability may coexist with areas of unstable flow or relative hypoperfusion within the same tumor. In GCs characterized by stromal expansion and fibroblast activation, alterations in extracellular matrix composition may further influence vascular architecture and flow dynamics. Although quantitative mapping of permeability and perfusion heterogeneity in GC is limited, endothelial diversification, hypoxia-responsive pathways, and matrix remodeling together argue for intrinsically uneven vascular function. Such spatial variability is expected to influence intratumoral drug distribution and contribute to heterogeneous therapeutic responses.

Concluding perspective

Tumor vascularization in GC should not be reduced to increased vessel density. Particularly in intestinal-type disease, vascular remodeling may be initiated within a chronically inflamed mucosa and subsequently shaped by hypoxia, stromal activation, and immune interactions. Core principles of tumor angiogenesis are well established. What remains less resolved is how uniformly these mechanisms operate across GC histological and molecular subtypes. Defining GC-specific vascular features will be important for interpreting therapeutic response and developing strategies to improve intratumoral drug distribution.

Vasculogenic mimicry in detail

Characteristics of vasculogenic mimicry

Tumor-cell vasculogenic mimicry (VM) is defined as the de novo formation of vascular-like, endothelial cell-independent networks by highly aggressive and phenotypically plastic tumor cells, a phenomenon originally described by Maniotis et al. [33]. Two major morphological types of VM have been described: tubular VM (type 1) and patterned-matrix VM (type 2) [34–36]. Tubular VM consists of channel-like structures whose luminal surface is formed predominantly by tumor cells, whereas patterned-matrix VM is characterized by extracellular matrix-rich networks containing fibronectin, collagen, and laminin surrounding tumor-cell clusters. Kim et al. confirmed the presence of tubular-type VM in gastric adenocarcinoma tissues [37].

Since the original description by Maniotis et al. [33], VM has been identified in multiple malignancies, including gastric adenocarcinoma, and has emerged as a potential therapeutic target [38]. Reliable identification remains challenging because the cells and structures contributing to tumor vascularization are highly heterogeneous. VM is one of several vascularization patterns that can coexist within tumors [39]. Importantly, VM channels should not be generalized as intrinsically “leaky.” VM may rather connect with conventional or abnormal tumor vessels and participate in fluid-conducting networks whose permeability and functional characteristics vary according to vascular architecture and the surrounding microenvironment. Therefore, microvessels and VM-like structures in GC should be assessed according to morphology, endothelial-marker status, and clinical or therapeutic significance.

Historically, VM has been identified as periodic acid-Schiff (PAS)-positive and endothelial-marker-negative, most commonly CD31- and/or CD34-negative, vascular-like structures [33]. The concept of mosaic vessels was subsequently introduced to describe channels in which tumor cells and CD31- or CD34-positive endothelial cells coexist [37]. These observations emphasize the diversity of tumor-associated vascular structures and the potential coexistence of VM channels, mosaic vessels, and conventional endothelial vessels within the same tumor. Their morphology may change in response to the microenvironment. Advances in molecular and imaging techniques have enabled increasingly detailed investigation of the mechanisms responsible for VM development.

Mechanisms of tumor-driven VM

As a tumor expands, oxygen and nutrient availability decrease, while glycolytic metabolites contribute to extracellular acidification and increased interstitial pressure. Under these conditions, VM-prone cells may acquire endothelial-like characteristics through epithelial-to-endothelial transition (EET), a plasticity program related to, but distinct from, EMT. EET is associated with loss of epithelial polarity and increased expression of endothelial-associated markers such as VE-cadherin, CD31, tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1), and platelet endothelial cell adhesion molecule 1 (PECAM1), accompanied by reduced epithelial features. VM-forming tumor cells may also express tissue factor pathway inhibitors (TFPI)−1/2 [40, 41]. The developmental resemblance of VM to embryonic vascular patterning further supports the concept that highly aggressive cancer cells can reactivate primitive, plastic cellular programs [42].

VM formation is currently understood to involve cancer stem-like cells (CSCs), EMT/EET, extracellular matrix (ECM) remodeling, and regulatory non-coding RNAs. Hypoxia is one of the best-characterized VM-inducing conditions. Hypoxia-responsive transcriptional programs can promote the transition of adaptable CSC-like subpopulations toward an endothelial-like phenotype. In parallel, matrix metalloproteinases (MMPs) degrade and reorganize ECM components, thereby facilitating the formation of vascular-like channels and promoting tumor progression [43, 44].

Attempts to suppress conventional tumor angiogenesis may intensify hypoxia in poorly perfused regions. In some tumor models, this selective pressure can enhance VM and favor more plastic and therapy-resistant tumor-cell phenotypes. This mechanism may contribute to the limited efficacy of anti-angiogenic monotherapy in tumors capable of switching between different vascularization programs.

Tumor microenvironment and VM

The tumor microenvironment (TME) is a complex and dynamic network that promotes therapeutic resistance and can facilitate immune escape. It comprises stromal cells, cancer-associated fibroblasts (CAFs), epithelial cells, vascular cells, myeloid-derived suppressor cells, tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), extracellular matrix components, cytokines, and growth factors. Inflammation strongly shapes TME composition by recruiting immune cells and reprogramming resident cells toward states that may support tumor progression [45].

In GC, CAFs may originate from resident fibroblasts, bone marrow-derived mesenchymal stem cells, and pericytes [46, 47]. Although many CAF populations promote tumor progression, selected subsets can exert tumor-suppressive functions [45]. CAFs contribute to excessive ECM deposition, matrix remodeling, and collagen cross-linking, while reciprocal interactions with tumor cells shape CAF transcriptional states [48, 49]. Wang et al. reported that FGF2 levels derived from CAFs and endothelial cells were significantly higher in GC tissues containing VM than in VM-negative tissues and correlated with MMP-2, N-cadherin (CDH2), VE-cadherin (CDH5), vimentin, and TWIST1. Paracrine FGF2 signaling can enhance urokinase-type plasminogen activator and MMP production, promoting ECM remodeling. Downregulation of FGF2 inhibited VM formation in GC models both in vitro and in vivo [50].

Hepatocyte growth factor (HGF), which can be produced by fibroblasts, regulates cell growth, migration, morphogenesis, and tissue repair, and can also promote VM and mosaic-vessel formation in GC. HGF increases the expression of MMP-1, MMP-2, VE-cadherin, and TFPI2 in GC cells, whereas inhibition of PI3K/AKT and ERK1/2 signaling suppresses these effects [51].

Extracellular vesicles (EVs) released by CAFs can influence multiple TME components, including immune cells. In addition to lipids and proteins, EVs carry non-coding RNAs that can modulate TAM polarization. For example, CAF-derived miRNAs have been implicated in shifting macrophages from a pro-inflammatory/antitumor (M1-like) phenotype toward an anti-inflammatory/protumor (M2-like) state [52]. M2-like TAMs can support CSC niches, EMT/EET, ECM remodeling, angiogenesis, and metastatic progression, and these functions have been demonstrated in GC [43, 53]. Such macrophage programs may therefore indirectly favor the development of heterogeneous microvascular networks, potentially including VM. CAF-derived EVs can also promote CSC-associated traits. However, direct evidence defining EV-dependent regulation of VM in GC remains limited.

In addition to angiogenesis, TAMs can promote lymphangiogenesis through the release of TGF-β, VEGF, PDGF, and chemokines. Correlations between VEGF/VEGF-C levels and TAM abundance have been reported in cancer specimens [54]. Park et al. demonstrated that CD163-positive TAMs enhance angiogenesis and increase C-X-C motif chemokine ligand 12 (CXCL12) expression in GC, thereby facilitating recruitment of additional TAMs [55].

Mast cells also contribute to angiogenesis and lymphangiogenesis by releasing VEGFA, CXCL8, and MMP-9. A correlation has been shown between the extent of angiogenesis, tumor malignancy grade, and mast cell infiltration [56, 57]. Tryptase-positive mast cells were more prevalent than chymase-positive ones in GC specimens; however, all mast cells express tryptase, which degrades gelatin, as MMP-9 does, to facilitate angiogenesis.

The expression of cyclooxygenase-2 (COX-2), often abundant in GC tissues, correlates with increased angiogenesis and is associated with higher tumor-cell proliferation and lymph node metastasis. COX-2 also influences apoptosis, affecting overall prognosis. It primarily promotes angiogenesis by regulating the release of VEGF and basic fibroblast growth factor. Inhibitors of COX-2 can significantly reduce angiogenesis, suppress tumor proliferation, and decrease invasiveness. Besides stimulating neovascularization and cancer progression, COX-2 and inducible nitric oxide synthase (iNOS) can serve as biomarkers for GC patient survival [58–60].

VM signaling pathways

Hypoxia and growth factor signaling in VM

Activated CAFs produce multiple mediators that influence the TME, including FGF2, HGF, VEGFs, platelet-derived growth factors (PDGFs), interleukins, and TGF-β [45]. Hypoxia is a major upstream regulator: stabilization of HIF-1α promotes its nuclear translocation, heterodimerization with HIF-1β, and transcription of genes involved in vascular adaptation (including VEGF, PDGF-B, MMP-2, and MMP-9), glycolytic metabolism (GLUT1 and LDHA), cell survival, and EMT-associated plasticity (including TWIST, SNAIL, and ZEB1). VEGF-A expression can also be enhanced through the lncRNA PVT1/STAT3 axis [61]. In the gastric microenvironment, gastrin can stimulate angiogenesis under both normoxic and hypoxic conditions through β-catenin/VEGF and HIF-1α/β-catenin/VEGF signaling, respectively [62]. These pathways converge on tumor-cell plasticity and acquisition of endothelial-like features. Growth-factor signaling acts in parallel with these hypoxia-dependent mechanisms and further connects the TME with VM-associated tumor-cell plasticity.

FGF2 binds FGFR1/2 on tumor cells and activates PI3K/AKT and ERK1/2 signaling. These pathways enhance tumor-cell plasticity, promote mesenchymal features, and increase MMP-2 and MMP-9 expression [63, 64]. FGF2 can also increase VEGF-A production and promote functional interactions between FGFR and VEGFR1, thereby supporting VM in aggressive tumors [65]. A related growth-factor axis involves HGF/c-MET signaling, which further links EMT, stem-like properties, and VM.

HGF promotes nuclear translocation of metastasis-associated in colon cancer 1 (MACC1), a transcriptional activator of the MET gene. MACC1 can drive EMT through TWIST1/2, and HGF/c-MET/MACC1/TWIST signaling has been implicated in VM [66, 67]. HMGA2 represents an additional upstream regulator of TWIST1. Although normally expressed at low levels in adult tissues, HMGA2 is reactivated in several tumors and can increase cell motility, invasion, and VM. Mechanistically, HMGA2 binds the TWIST1 promoter and enhances TWIST1 and VE-cadherin expression [68]. TWIST1 also links EMT with stem-like properties and chemoresistance by regulating apoptosis-associated proteins, including BCL-2 and BAX [68].

LOX-PDGF/PDGFR signaling and extracellular matrix remodeling

LOX is functionally connected with the PDGF-PDGFR axis during VM formation in GC rather than acting through a simple direct interaction with the PDGF ligand. LOX catalyzes oxidative deamination of lysine and hydroxylysine residues in collagen and elastin and is therefore an important regulator of ECM remodeling. In GC tissues, LOX expression correlates positively with VM and with PDGFRα/β expression. In GC cells, exogenous LOX increases PDGFRα/β expression, whereas inhibition of LOX with β-aminopropionitrile decreases PDGFR expression. Pharmacological inhibition of PDGFRα or PDGFRβ reduces VM formation, while exogenous LOX can partially restore the VM phenotype. These findings indicate that LOX promotes VM at least partly through modulation of PDGF-PDGFR signaling, while additional LOX-dependent mechanisms may also contribute [69].

Inflammatory, chemokine and developmental signaling

Among stromal cytokines, IL-8 acts on tumor cells mainly through CXCR1 and CXCR2. Enhanced IL-8/CXCR2 signaling promotes VM, whereas CXCR2 downregulation inhibits VM formation in AGS cells. Mechanistically, CXCR2-dependent activation of PI3K/AKT increases the expression of VM-associated markers [70]. Other chemokine pathways may also contribute to vascular plasticity. CXCR7 regulates VEGF release and participates in tumor-cell proliferation, adhesion, invasion, and angiogenesis [71], whereas CXCR4 can promote GC angiogenesis through JAK2/STAT3-dependent VEGF upregulation [72]. Additional inflammatory mediators, including IL-1α, IL-17, and soluble IL-2 receptor-associated signaling, can further support angiogenesis [73]. Beyond inflammatory and chemokine signaling, developmental pathways provide an additional regulatory layer connecting cellular plasticity with VM.

TGF-β binding to its receptors triggers phosphorylation of Smad2 and Smad3, which form complexes with Smad4 and translocate to the nucleus to regulate genes involved in EMT and vascular-like tube formation. Alterations affecting mediators of TGF-β signaling are common in gastrointestinal cancers [74]. Nodal, another member of the TGF-β superfamily, provides an additional link between developmental plasticity and VM. In breast cancer, Nodal promotes VM through Smad2/3-dependent induction of EMT, while studies in aggressive melanoma demonstrate functional cross-talk between Nodal and Notch signaling [75, 76]. These findings support a broader role for reactivated embryonic signaling programs in VM-associated plasticity; however, direct evidence defining the Nodal-Notch-Smad axis in GC-specific VM remains limited and represents an important research gap.

EphA2-PI3K/AKT signaling

CAFs may also enhance VM formation in GC cells through activation of ephrin type-A receptor 2 (EphA2), a receptor tyrosine kinase linked to PI3K/AKT signaling. AGS cells with high EphA2 expression form VM structures on Matrigel, whereas selective EphA2 inhibition reduces VM development. EphA2 knockdown also decreases MMP-2 and VE-cadherin expression, linking this pathway to invasion, ECM remodeling, and endothelial-like differentiation [77].

VE-cadherin as a central effector of vasculogenic mimicry

VE-cadherin (CDH5) is one of the most consistently reported markers of the endothelial-like phenotype acquired by VM-forming tumor cells. In GC, its expression is linked to FGF2- and HGF-dependent signaling, TWIST1-mediated plasticity, and EphA2/PI3K/AKT activity [50, 51, 68, 77]. VE-cadherin can facilitate tumor-cell organization into vascular-like networks and therefore represents an important convergence point for several VM-inducing pathways. Nevertheless, VE-cadherin expression alone is not sufficient to establish VM and should be interpreted together with tissue morphology, PAS staining, and endothelial marker assessment such as CD31/CD34 [33, 77].

Non-coding RNAs and additional regulators of vascular plasticity

Non-coding RNAs further regulate vascular plasticity in GC. CAF-derived exosomal miR-29b-1-5p has been associated with modulation of VM and EMT/EET-related markers, including N-cadherin and vimentin, through the VSIG1/ZO-1 axis. Experimental downregulation of CAF-derived exosomal miR-29b-1-5p has been associated with inhibition of GC growth and altered VM-related phenotypes [78].

Additional regulators of vascular plasticity include p53, the urokinase plasminogen activator system, and multiple miRNAs. Abnormal p53 signaling can promote angiogenesis by increasing VEGF and decreasing thrombospondin-1 [79], while the urokinase plasminogen activator system can increase VEGF expression and support invasion [80]. In GC, miR-616-3p promotes angiogenesis and EMT through the PTEN/AKT/mTOR pathway [81], whereas miR-130a and miR-495 suppress RUNX3 and thereby enhance cell proliferation and angiogenic signaling [82].

Other GC-associated regulators include REG Iα, which promotes cancer-cell growth and exerts anti-apoptotic effects on endothelial cells [83], and α-fetoprotein (AFP)-associated signaling, which is linked to increased neovascularization and poor clinical outcome [84]. AFP-positive tumors can express high levels of angiopoietin-like 6 (ANGPTL6), which promotes tube formation and endothelial cell migration through ERK1/2 and AKT [85]. CEACAM6 can enhance GC metastasis, angiogenesis, and VM through focal adhesion kinase (FAK) signaling [86]. Placental growth factor (PlGF) is associated with vascularization, nodal metastasis, serosal invasion, and clinical outcome [87]. Additional regulators include survivin, FOXM1b, KLF8, CRYAB, PTEN, and the oncogenic lncRNA MALAT1, which can influence VE-cadherin, MMPs, ERK, β-catenin, FAK, and paxillin signaling [88–91].

Collectively, these mechanisms regulate phenotypic plasticity and promote acquisition of endothelial-like features by tumor cells. Despite their diversity, many pathways converge on a limited set of VM effectors, particularly VE-cadherin, EphA2, MMPs, EMT/EET-associated transcription factors, and ECM-remodeling programs. This networked organization helps explain why inhibition of a single angiogenic pathway may be insufficient and highlights VM-associated signaling as a source of complementary therapeutic targets (Fig. 1).

Fig. 1.

Schematic overview of major pathways regulating vasculogenic mimicry (VM) and its therapeutic relevance. Hypoxia/HIF-1α, CAF-derived growth factors, LOX-PDGF/PDGFR signaling, IL-8/CXCR signaling, TGF-β/Nodal-Smad/Notch pathways, EphA2/VE-cadherin, and MMP-mediated ECM remodeling converge on tumor-cell plasticity and endothelial-like differentiation. VM may contribute to alternative perfusion, invasion, heterogeneous drug distribution, and therapeutic resistance. Foslinanib (CVM-1118) is shown as a clinical proof-of-concept for direct pharmacological targeting of VM, although clinical efficacy has not yet been established in GC [69, 70, 75–77, 92–94]. Created in BioRender. Mikolajczyk-Chmiela, M. (2026) https://BioRender.com/r8s1w5b

Cancer drug resistance

Functionally, VM provides an alternative tumor-cell-derived perfusion route that is not directly dependent on endothelial VEGF signaling and may therefore reduce the efficacy of therapies directed exclusively against conventional angiogenesis. The distinction was demonstrated by van der Schaft et al., who showed that anginex, TNP-470, and endostatin markedly inhibited vascular network formation by endothelial cells, whereas VM-like networks formed by aggressive melanoma cells were relatively unaffected [92]. Although these experiments were performed in melanoma rather than GC, they provide an important mechanistic proof-of-principle that endothelial-directed angiogenesis inhibitors may leave tumor-cell-derived VM intact.

Tumor-cell phenotypic plasticity is central to VM-associated therapeutic resistance. VM-forming cells can activate PI3K/AKT, Wnt/β-catenin, Notch, TGF-β/Smad, and developmental programs such as Nodal signaling, thereby supporting survival under therapeutic stress, stem-like properties, and adaptive cell-state switching [33, 36, 75, 76]. Nodal is particularly relevant because it links embryonic plasticity with EMT and VM formation and therefore complements the Smad- and Notch-associated mechanisms discussed above.

The TME, particularly under hypoxic conditions, plays a critical role in both VM induction and drug resistance. Stabilization of HIF-1α activates genes involved in metabolic adaptation, alternative vascularization, and cell survival. VM may also coexist with poorly organized endothelial vessels, contributing to spatially heterogeneous perfusion and drug distribution and thereby generating regions exposed to subtherapeutic drug concentrations [36, 95, 96].

VM is also associated with ECM remodeling and increased MMP activity, which facilitate invasion and can create protective microenvironments that limit therapeutic penetration. Interactions among tumor cells, ECM components, fibroblasts, and immune cells further reinforce resistant niches [97, 98]. Clinically, VM is associated with aggressive tumor behavior, increased metastatic potential, and poorer prognosis. Because VM can coexist with conventional angiogenesis, tumors may retain redundant or adaptable perfusion mechanisms that complicate vascular targeting [99].

Concluding perspective

In summary, VM contributes to cancer progression and therapeutic resistance through endothelial-independent perfusion, enhanced cellular plasticity and stem-like properties, adaptation to hypoxia and metabolic stress, heterogeneous drug exposure, and formation of protective niches within the TME. These observations support the development of strategies that target VM together with conventional angiogenesis rather than treating the two vascular programs as interchangeable processes.

The role of infectious agents in the vasculogenic processes

Carcinogenic microorganisms

Several bacterial, viral, fungal, and parasitic agents have been associated with carcinogenesis. Established or suspected cancer-promoting microorganisms include H. pylori; human papillomavirus (HPV); Epstein-Barr virus (EBV); hepatitis B and C viruses (HBV and HCV); human immunodeficiency virus (HIV); human T-cell lymphotropic virus type 1 (HTLV-1); and parasites such as Schistosoma haematobium and Opisthorchis viverrini [100].

Among bacteria, H. pylori is classified as a group 1 carcinogen [101]. This Gram-negative, microaerophilic bacterium colonizes the human gastric mucosa and can cause chronic gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma, and GC in a subset of infected individuals [102]. The pathogenesis of H. pylori-associated GC is complex; virulence factors such as cytotoxin-associated gene A (CagA) protein, together with host inflammatory mediators, contribute to gastric carcinogenesis [103]. H. pylori urease and lipopolysaccharide (LPS) can increase oxidative stress and DNA damage, while regenerative epithelial proliferation may increase the probability of genetic abnormalities [104]. The bacterium can also evade phagocytosis, natural-killer-cell activity, and T-cell responses, thereby promoting chronic persistence [105–107].

Among viruses, HPV is a well-established etiological factor in cervical cancer and contributes to selected anogenital and head-and-neck malignancies [100, 108]. Beyond established microbial carcinogens, the host microbiome can influence physiological processes and cancer-associated inflammation [109]. The gut microbiota includes representatives of the Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria phyla, although composition varies considerably among individuals [110, 111]. The healthy gut mycobiota may include genera such as Saccharomyces, Candida, and Cladosporium [112]. Dysbiosis caused by diet, antibiotics, disease, or other factors can reduce microbial diversity and promote pathobiont expansion, chronic inflammation, metabolic disturbance, and potentially carcinogenesis [111]. Microorganisms associated with cancer development include Fusobacterium nucleatum, Porphyromonas gingivalis, Candida albicans, genotoxic Escherichia coli, enterotoxigenic Bacteroides fragilis, and selected Salmonella species [113–122].

Pro-angiogenic properties of microorganisms

Microorganisms can modulate angiogenesis in multiple tissue niches [123]. Pathogens reported to promote host angiogenic responses include Bartonella henselae, Bartonella bacilliformis, Mycobacterium tuberculosis, Candida albicans, Kaposi sarcoma-associated herpesvirus, cytomegalovirus, HCV, HPV, and Schistosoma mansoni [124, 125].

Recent studies suggest that effects of the gut microbiota and microbial metabolites on obesity, diabetes, cardiovascular disease, systemic inflammation, and cancer can involve classical angiogenesis or lymphangiogenesis [125, 126]. Microbial stimuli can induce IL-1, IL-8, and TNF-α, recruit immune cells, and increase pro-angiogenic factors such as VEGF and EGF, sometimes in cooperation with host- or microbe-derived MMP-9 [127–130]. H. pylori can alter expression of angiogenesis-associated genes, including ANGPT2 and miR-203a, in AGS GC cells [131]. Bartonella bacilliformis produces the pro-angiogenic BafA autotransporter, while S. mansoni egg-derived products can promote hepatic neovascularization through VEGF-related mechanisms [132, 133]. Oncogenic viruses and microbiota-associated signals may also modulate HIF-1α, PI3K/AKT, MAPK, and STAT3/ERK1/2 pathways [124, 134, 135]. Microbial products such as LPS and unmethylated CpG motifs can stimulate vascular responses through pattern-recognition receptors and Toll-like-receptor signaling [136, 137]. Our recent experimental work further indicates that H. pylori LPS and CagA can promote VM-like structures in AGS cells through VEGF/VEGFR-associated mechanisms (submitted data), while H. pylori LPS may sustain chronic inflammation and interfere with IL-33-dependent regenerative signaling [138].

Anti-angiogenic properties of microorganisms and their products

Inhibition of neovascularization by microorganisms can have context-dependent consequences. Reduced vascularization may create hypoxic niches that facilitate persistence of selected pathogens, but it may also limit inflammatory tissue damage or pathogen dissemination [134]. Ocular microbiota, for example, can promote pathological angiogenesis in sterile corneal injury, whereas depletion of commensal bacteria suppresses neovascularization [139]. Evidence linking microbiota with ovarian-cancer treatment response is emerging but remains heterogeneous. In the gut, a high baseline abundance of Phascolarctobacterium was independently associated with longer progression-free survival in BRCA1/2-mutation-negative ovarian-cancer patients receiving PARP-inhibitor maintenance therapy; Bifidobacterium, Roseburia, Dialister, Butyricicoccus, and Bilophila were enriched among long-term responders with BRCA1/2 mutations, although no individual genus remained independently associated with progression-free survival in multivariable analysis [140]. In the vaginal microbiota, primary platinum resistance was associated with reduced Lactobacillus dominance and a higher frequency of Escherichia-dominated communities [141]. By contrast, evidence identifying specific uterine microbial taxa as validated determinants of ovarian-cancer treatment response remains insufficient. Accordingly, microbiota-treatment associations should currently be interpreted as emerging biomarkers or mechanistic hypotheses rather than established causal predictors [140–142].

Anti-angiogenic effects can be achieved pharmacologically, but selected microbial products can also inhibit angiogenic signaling by neutralizing VEGF or FGF, blocking growth-factor receptors, or affecting endothelial-cell survival. Reported examples include Bacillus anthracis protective antigen, fumagillin from Aspergillus fumigatus, metabolites from Streptomyces species, citrinin from Penicillium citrinum, prodigiosin from Serratia marcescens, and pyocyanin from Pseudomonas aeruginosa [143–147]. Probiotic strains can also exhibit anti-angiogenic or antitumor effects through apoptosis-associated mechanisms or delivery of anti-angiogenic factors [148–152]. Elaiophylin from Streptomyces species reduces VEGF production by inhibiting HIF-1α accumulation [153]. Diet may additionally influence angiogenesis through microbial metabolites; dietary fiber promotes production of short-chain fatty acids (SCFAs), including butyrate, propionate, and acetate, which modulate inflammation and immune-cell activity [127].

Concluding perspective

Recent multicenter and mechanistic studies have strengthened the link between the human microbiota, chronic inflammation, and tumor-promoting microenvironments. Microorganisms and their products can either stimulate or inhibit vascularization through inflammatory mediators, growth-factor signaling, extracellular-matrix remodeling, and microbial metabolites. Because the strength of evidence varies markedly among microbial taxa and cancer types, future studies should distinguish established carcinogenic microorganisms from microbiota associations that remain correlative and should define whether specific microbial signatures have reproducible predictive value for treatment response.

Angiogenesis inhibitors and mechanisms mediating therapeutic effect

Angiogenesis inhibitors exert antitumor activity through complementary mechanisms that disrupt tumor vascularization, limit oxygen and nutrient supply, and modulate the TME. These effects are mediated primarily by monoclonal antibodies, TKIs, and receptor fusion proteins targeting the VEGF/VEGFR axis. In GC, however, classical angiogenesis coexists with vascular heterogeneity and alternative vascularization mechanisms such as VM; consequently, endothelial-directed therapy alone may be insufficient, and drug-delivery strategies should be designed with this biological redundancy in mind.

The core mechanism of action involves inhibition of VEGF/VEGFR signaling, leading to suppression of endothelial cell proliferation, migration, and survival. Monoclonal antibodies (e.g., bevacizumab) neutralize VEGF-A, receptor fusion proteins (e.g., aflibercept) act as ligand traps, and TKIs (e.g., sunitinib, sorafenib) inhibit intracellular kinase activity of VEGF receptors and related pathways. This results in reduced neovascularization and inhibition of tumor growth [154, 155].

Beyond suppressing new vessel formation, anti-angiogenic agents can induce regression and pruning of immature tumor vessels, thereby decreasing microvessel density and altering tumor perfusion [156]. Novel drug-delivery systems (NDDS) may potentiate these effects by increasing local drug exposure through passive accumulation and active targeting strategies [157].

A more nuanced therapeutic mechanism is vascular normalization, a transient process in which anti-angiogenic therapy remodels structurally abnormal tumor vessels into a more organized and functionally efficient network. This can reduce vascular permeability and interstitial fluid pressure, alleviate hypoxia, and improve delivery of cytotoxic agents. Nanoparticle-based systems may exploit this normalization window by enhancing intratumoral drug penetration and retention [158, 159].

Anti-angiogenic therapy can also modulate the immune microenvironment. Inhibition of VEGF signaling may reduce immunosuppression, facilitate cytotoxic T-cell infiltration, and decrease regulatory T cells and myeloid-derived suppressor cells. NDDS may further enhance these effects by co-delivering immunomodulatory agents or nucleic acids that target pro-angiogenic and immunosuppressive pathways [160, 161].

Importantly, in GC, where VM and vascular heterogeneity can contribute to therapeutic resistance, angiogenesis inhibitors alone may be insufficient. Nanoparticle-based systems may improve drug distribution, support sustained or controlled release, and facilitate simultaneous targeting of endothelial cells, VM-forming tumor cells, and ECM-remodeling pathways [162].

Monoclonal antibodies

Monoclonal antibodies primarily inhibit ligand-receptor interactions. Bevacizumab is a humanized IgG1 antibody that binds VEGF-A and prevents its interaction with VEGFR-1 and VEGFR-2, thereby suppressing new vessel formation and contributing to regression or normalization of immature vessels. Ramucirumab is a fully human IgG1 antibody that directly targets VEGFR-2 and is an established second-line option for advanced GC [163, 164].

Clinical trials of bevacizumab combined with chemotherapy have shown improvements in response rate and progression-free survival in selected settings, but consistent overall-survival benefit in GC has not been established. Limited efficacy may reflect GC molecular heterogeneity, compensatory activation of alternative pro-angiogenic pathways, and alternative vascularization mechanisms such as VM [165–167].

The efficacy of antibody-based anti-angiogenic therapy may also be limited by poor penetration of high-molecular-weight agents and uneven intratumoral distribution. Nanoparticle delivery systems can potentially improve local retention, pharmacokinetics, and receptor-directed delivery of therapeutic macromolecules [168, 169].

Tyrosine kinase inhibitors

TKIs are an important class of anti-angiogenic agents investigated in advanced GC. Unlike monoclonal antibodies, which act extracellularly, TKIs enter cells and inhibit intracellular signaling downstream of receptor tyrosine kinases (RTKs). Depending on their selectivity, they may inhibit VEGFR, PDGFR, FGFR, MET, RAF, or other kinases, thereby suppressing receptor autophosphorylation, endothelial activation, and tumor-associated vascular signaling [170, 171].

Apatinib is a selective VEGFR-2 TKI that inhibits receptor phosphorylation and has been used in previously treated advanced GC. Multitarget TKIs, including sorafenib, sunitinib, pazopanib, and fruquintinib, simultaneously inhibit several RTKs or downstream kinases, such as VEGFR, PDGFR, and RAF family members [170, 171].

MET-directed TKIs, including savolitinib, tepotinib, capmatinib, and crizotinib, inhibit MET signaling, which can contribute to tumor progression and vascular regulation. Their potential value in GC is greatest in molecularly selected tumors with MET activation or amplification, particularly when alternative RTK signaling contributes to resistance [172–174].

Receptor fusion proteins

Receptor fusion proteins inhibit angiogenesis by sequestering circulating ligands rather than directly blocking cell-surface receptors or intracellular kinases. These agents combine ligand-binding receptor domains with an immunoglobulin Fc fragment. Aflibercept, for example, contains extracellular domains of VEGFR-1 and VEGFR-2 fused to human IgG1 Fc and binds VEGF-A, VEGF-B, and PlGF with high affinity.

Receptor fusion proteins are established in selected malignancies, particularly colorectal cancer, and may show greater efficacy when combined with chemotherapy or other targeted therapies. Their broader implementation in GC remains limited by biological heterogeneity, delivery, and pharmacokinetic considerations. Nanoparticle-based systems could potentially protect fusion proteins from degradation, modify their pharmacokinetics, and facilitate tumor-directed delivery [175–178].

Mechanisms of resistance to anti-angiogenic therapy in GC

Despite the activity of anti-angiogenic therapies in selected GC settings, acquired and intrinsic resistance remain major clinical challenges. VEGF/VEGFR inhibition can be bypassed through alternative pro-angiogenic pathways involving FGF, PDGF, angiopoietins, and HGF/MET. Hypoxia-induced signaling may further enhance metastatic potential and therapeutic resistance. Importantly, VM represents an additional VEGF-independent or partially VEGF-independent vascular adaptation because tumor cells themselves can generate vascular-like networks. This functional redundancy limits the efficacy of strategies directed at a single endothelial pathway.

The TME also contributes to resistance by recruiting stromal and immune populations, including myeloid-derived suppressor cells and CAFs, that can restore pro-angiogenic signaling despite therapy. Abnormal vascular architecture, elevated interstitial fluid pressure, and dense ECM can further restrict drug penetration. Nanoparticle-based systems may help overcome some of these delivery barriers by improving drug stability, bioavailability, and intratumoral accumulation, but they do not eliminate the need to target the biological mechanisms that sustain VM and alternative vascularization [179–181].

Vasculogenic mimicry as a complementary therapeutic target

VM remains a therapeutically relevant target even when anti-angiogenic and nanoparticle-based approaches are considered. Unlike conventional angiogenesis, VM is generated by phenotypically plastic tumor cells and therefore cannot be expected to disappear solely after inhibition of endothelial VEGF/VEGFR signaling. Moreover, strong suppression of angiogenesis can increase hypoxic selective pressure and may favor alternative vascularization programs in susceptible tumors. An optimal vascular-targeting strategy may therefore require simultaneous inhibition or normalization of endothelial angiogenesis together with suppression of VM-associated tumor-cell plasticity, ECM remodeling, and endothelial-like differentiation [92].

Foslinanib (CVM-1118) illustrates the translational potential of direct VM targeting. Its major active metabolite, CVM-1125, binds the mitochondrial chaperone TRAP1, reduces cellular succinate, destabilizes HIF-1α, promotes apoptosis, and inhibits VM formation [93]. In 2026, a Phase IIa study of oral CVM-1118 in advanced well-differentiated neuroendocrine tumors reported a median progression-free survival of 10.5 months and a disease-control rate of 77% in the efficacy-evaluable population [94]. These results do not establish efficacy in GC, but they provide clinical proof-of-concept that VM-associated biology can be pharmacologically targeted and reinforce the rationale for evaluating VM-directed approaches in GC.

Concluding perspective

The therapeutic effects of angiogenesis inhibitors include VEGF-pathway blockade, suppression of endothelial cell function and neovascularization, regression or normalization of tumor vasculature, and modulation of the TME and immune response. In GC, these mechanisms should be considered together with alternative vascularization programs. A rational strategy may therefore combine endothelial-directed anti-angiogenic therapy with interventions targeting VM-forming tumor cells, while nanocarriers can serve as delivery platforms for such multi-compartment approaches.

Nanocarriers in anti-angiogenic therapy against GC

Vascular heterogeneity in GC has direct therapeutic implications for drug distribution and resistance and provides a rationale for nanoparticle-based delivery approaches. Importantly, nanocarriers should be viewed as delivery platforms rather than as substitutes for biological target selection; their value may be greatest when they enable simultaneous targeting of conventional angiogenesis, VM-associated tumor-cell plasticity, and the surrounding TME.

Nanoparticle-based drug-delivery systems employ nanoscale carriers composed of lipids, polymers, metals, or other inorganic materials. Their size, shape, and surface chemistry can be engineered to improve drug stability, circulation time, tumor accumulation, and targeting specificity [182]. Polymeric nanoparticles offer tunable physicochemical properties, while liposomes can encapsulate chemically diverse agents and support controlled release. Nevertheless, nonspecific accumulation, heterogeneous tumor delivery, and potential nanomaterial toxicity require careful design and rigorous safety evaluation [183]. Representative nanoparticle-based strategies for anti-angiogenic therapy in GC are summarized in Table 1.

Table 1.

Nanoparticle-based strategies for anti-angiogenic therapy in gastric cancer

Nanoparticles	Drugs	Targeting	Angiogenesis mechanism	References
Bevacizumab-PLGA NPs	Bevacizumab	Passive targeting	Reduction of VEGF signaling and decreased tumor vascularization	[184]
PLGA-PEG-COOH and PLGA-MPEG NPs (Apatinib + Salidroside)	Apatinib + Salidroside	Passive targeting	Inhibition of VEGFR-2 signaling combined with hypoxia modulation	[185]
Fucose-chitosan PEG-chitosan NPs	EGCG	Fucose-mediated active targeting	Reduction of VEGF expression in tumor tissue	[186]
cRGD-PEGylated liposomes	Apatinib	Integrin αvβ3 targeting	Inhibition of VEGFR-2 signaling pathway	[187]
Solid lipid NPs (FC-SLN-CS-FA)	Farnesiferol C	Folic acid targeting	Reduction of VEGF and VEGFR expression with decreased vessel formation in CAM assay	[188]
Exosome (HGF siRNA)	HGF siRNA	Natural exosome-mediated delivery	Reduction of pro-angiogenic signaling pathways	[189]
SALL4-targeted exosome	si-SALL4	Exosome-mediated targeting	Reduction of VEGF-A, VEGF-B, and VEGF-C expression with inhibition of tube formation	[190]
Green synthesized AuNPs	Intrinsic AuNP	Passive targeting	Reduction of Ang-1/Tie2 signaling pathway; suppression of vessel formation in CAM assay	[191]
Ca-AuNPs	Intrinsic AuNP	Passive targeting	Significant reduction of blood vessel formation in CAM assay	[192]
GNP–VGB3	VGB3 peptide	VEGFR1/VEGFR2 targeting	Dual inhibition of VEGFR1 and VEGFR2 resulting in reduced endothelial cell proliferation	[193]
Gold nanoparticles + Ramucirumab	Ramucirumab	VEGFR-2 antibody targeting	Inhibition of VEGFR-2 signaling and enhanced receptor-mediated anti-angiogenic activity	[194]
HA-PLGA + Ag NPs	Apatinib	Hyaluronic acid-CD44 targeting	Inhibition of VEGFR-2 signaling pathway	[195]
HA-Prussian Blue hybrid	Apatinib + Gamabufotalin	Hyaluronic acid-CD44 targeting	Inhibition of VEGFR-2-mediated angiogenic signaling	[196]
Platelet membrane-coated MSN	Combretastatin A4 + Apatinib	Platelet membrane-mediated targeting	Vascular disruption combined with VEGFR-2 inhibition	[197]
PMMA-AA/ZnO composite	Curcumin	pH-responsive delivery	Tumor microenvironment-responsive suppression of angiogenic signaling	[198]
LA-GO-CS-FA	Lawsone	Folate receptor targeting	Reduction of VEGF expression and decreased vessel length	[199]
Ging-GO-CS-FA	6-Gingerol	Folate receptor targeting	Reduction of VEGF and VEGFR expression levels	[200]
SWNT conjugate	Anti-VEGF therapeutic strategy	Active nano-delivery	Suppression of VEGF signaling pathway	[201]

Polymeric nanoparticles

Polymeric nanoparticles (NPs) can provide controlled drug release and reduce off-target exposure. Sousa et al. used poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles to encapsulate bevacizumab (Avastin®), an anti-VEGF antibody [184]. The formulation was internalized by macrophages and altered the tissue distribution of bevacizumab after intranasal administration in mice. Although this model was not a GC model, it illustrates how polymeric carriers can modify the pharmacokinetics and tissue exposure of anti-angiogenic biologics.

Most polymeric DDS are based on polyethylene glycol (PEG)–based polymers or copolymers [202–204] since it is a gold standard for improving the blood circulation of nanocarriers. Nevertheless, reports indicate that most of the population has antibodies against PEGylated therapeutics [205]. Various NPs based on PLGA-PEG-COOH or monomethoxy poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PLGA-MPEG) [185], and PEG-chitosan [186] were used in anti-angiogenic therapy. Zhang et al. developed a complex DDS based on the PLGA NPs co-loaded with salidroside (Sal) and apatinib (Apa) and surface covered with tumor-homing peptide (iVR1 peptide), which inhibits the neovascularization [185]. The effectiveness of the nanocarriers which was tested against MDR cancer cells (MKN-45 and MKN-45/MDR cell lines) and tumor-bearing mice was higher for iVR1 functionalized NPs due to the ability to escape lysozyme degradation. The treatment with iVR1-NPs-Apa/Sal results in the lowest tumor growth rate and the highest survival rate in MDR tumor-bearing mice. Lin et al. proposed a formulation based on fucose-chitosan (FCS), PEG-chitosan (PCS), and gelatin for the construction of NPs loaded with epigallocatechin-3-gallate (EGCG), a green tea extract [186]. The optimal formulation of NPs was resistant in acidic environment. In addition, the release of EGCG varies with pH and the addition of pepsin (simulating gastric acid pH), with the highest release at pH 6.8, when the NPs are unstable due to chitosan protonation. The obtained NPs can not only be easily internalized by MKN45 cells but also effectively inhibit VEGF expression, a marker of neovascularization. As a result, the prepared NPs were able to highly suppress tumor growth compared with blank NPs and free EGCG.

Lipid/polymeric-based nanocarriers

Song et al. described the DDS based on the cyclic arginylglycylaspartic acid (cRGD) and PEG-modified liposomes (cRGD-Lipo-PEG) for the encapsulation and delivery of Apa [187]. Two formulations were prepared: the first, built from soybean phosphatidylcholine (SPC)/cholesterol/1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (DSPE-PEG2000) without a targeting moiety; and the second, SPC/cholesterol/cRGD-DSPE-PEG2000, bearing a high-affinity integrin αvβ3 receptor antagonist. The particles remained stable for 12 days of incubation in a 5% (w/v) glucose solution. Drug release was pH-dependent, with the highest at pH 5.6; however, there was only a slight difference between the formulations. The RGD-containing formulation was most effective in vitro and in vivo, resulting in the lowest tumor volume in HCT116 tumor-bearing nude mice. Moreover, Tabrizi et al. proposed solid lipid NPs covered by chitosan functionalized with folic acid and loaded with farnesiferol C (FC) [188]. The release of FC from the NPs’ interior lasts for 144 h, reaching above 40% of the drug. The effectiveness of nanocarriers was tested against the following human cancer cell lines: PANC, AGS, HT-29, MCF7, and A549. The obtained NPs decrease the viability of AGS GC and PANC pancreatic carcinoma cells. The chicken chorioallantoic membrane (CAM) assay indicated that the number and length of blood vessels were decreased by the obtained NPs, which was further confirmed by low expression of VEGF and VEGFR.

Bioorganic exosome-based systems

Exosomes are a distinct class of extracellular vesicles of endosomal origin that mediate intercellular communication and can be engineered as carriers of drugs, proteins, and RNA. Zhang et al. developed HEK293T-derived exosomes loaded with HGF siRNA [189]. These vesicles fused with SGC-7901 cells and reduced HGF and VEGF expression in a dose-dependent manner. In tumor-bearing mice, treatment decreased tumor size and weight and reduced HGF/VEGF expression; CD31 immunohistochemistry confirmed reduced tumor vessel density [189]. In another study, Abouelnazar et al. [190] used exosome-based delivery of SALL4-targeting siRNA and thalidomide (THAL) (Fig. 2). Among the tested formulations, combined THAL and SALL4 targeting produced the strongest anti-angiogenic effect in MGC-803 cells.

Fig. 2.

Proposed model of the role of SALL4 in gastric cancer angiogenesis and its inhibition by exosome-based therapy. SALL4 promotes the transcriptional activation of vascular endothelial growth factor (VEGF)-A, VEGF-B, and VEGF-C, thereby supporting angiogenic signaling in gastric cancer cells. Exosome-mediated delivery of SALL4-targeting siRNA (si-SALL4-B), combined with thalidomide (THAL), suppresses SALL4 expression and downstream VEGF production, leading to inhibition of tumor angiogenesis. Adapted and graphically modified from Abouelnazar FA et al. [190], Cancer Cell International. 2023;23:149, under the Creative Commons Attribution 4.0 International License (CC BY 4.0). The schematic was recreated using BioRender.com. Mikolajczyk-Chmiela, M. (2026) https://BioRender.com/aiklbg1. THAL, thalidomide; GC, gastric cancer; VEGF, vascular endothelial growth factor

Metal/metal oxides

Metal and metal-oxide NPs have attracted interest as anti-angiogenic and anticancer platforms because of their tunable size, surface reactivity, and capacity to modulate intracellular signaling. In CAM models, green-synthesized AuNPs have shown anti-angiogenic activity associated with reduced neovascularization and modulation of Ang-1/Tie2 signaling [192]. Gold NPs can also function as transporters for vascular-targeting ligands. For example, VEGFR1/VEGFR2-targeting peptide-conjugated AuNPs showed enhanced binding to receptor-expressing endothelial and tumor cells and stronger inhibition of endothelial proliferation and migration than the free peptide [193]. Gold-based nanocarriers have additionally been investigated to enhance the activity of anti-angiogenic antibodies, including ramucirumab, by increasing cellular uptake and tumor targeting [194].

Hybrid/composite

Composite or hybrid nanocarriers combine multiple materials and therapeutic functions within a single platform and may support anti-angiogenic combination strategies in GC. Examples include hyaluronic acid-modified PLGA systems co-delivering apatinib and chitosan-stabilized silver NPs, in which apatinib suppresses VEGFR-2 signaling while silver NPs enhance oxidative stress and ferroptotic mechanisms [195]. Other hybrid systems combine apatinib with additional anticancer agents or integrate biomimetic coatings to improve tumor targeting [196, 201]. Such platforms may enable controlled release and simultaneous modulation of tumor growth and vascular signaling, but their translational value depends on reproducible pharmacokinetics, toxicity, and evidence that the selected targets remain relevant in the heterogeneous GC microenvironment.

Carbon-based nanoparticles

Carbon-based nanomaterials, including graphene oxide (GO) and carbon nanotubes, offer high surface area and extensive opportunities for functionalization. GO-based systems modified with chitosan and folate have been used to deliver natural products to GC cells and have shown anti-angiogenic activity in CAM assays, including reductions in vessel number and expression of VEGF-related genes [199, 200]. Functionalized carbon nanotubes have also been investigated for delivery of VEGF-targeted siRNA in endothelial models. These studies support the feasibility of carbon-based delivery platforms, but most anti-angiogenic evidence derives from vascular or heterologous tumor models rather than direct demonstration of VM inhibition in GC.

Concluding perspective

The available studies demonstrate that polymeric nanoparticles, liposomes, exosomes, metal-based nanoparticles, and graphene-derived composites can support anti-angiogenic strategies through passive or active targeting, controlled release, gene silencing, and combination therapy. Across these systems, VEGF/VEGFR and related pathways remain dominant targets. However, suppression of endothelial angiogenesis should not be equated with suppression of VM. Future nanoparticle strategies should explicitly test whether they affect tumor-cell-derived VM in addition to conventional endothelial vessels and should determine whether combined vascular targeting improves drug distribution and therapeutic response in GC.

Conclusions

The interaction between cancer cells and the surrounding microenvironment is central to GC development and dissemination. Tumor growth generates hypoxic, acidic, and nutrient-poor conditions that promote metabolic adaptation, oxidative stress, and vascular remodeling. In addition to conventional endothelial angiogenesis, aggressive tumor cells can form endothelial-independent vascular-like networks through VM. The presence of VM is associated with tumor-cell plasticity, metastatic potential, and therapeutic resistance and may provide an alternative route of perfusion when conventional angiogenesis is insufficient or therapeutically inhibited.

Although understanding of VM has advanced, many of its molecular drivers in GC remain insufficiently characterized. This gap is particularly important because VM is regulated by interconnected pathways involving hypoxia, growth factors, developmental signaling, VE-cadherin/EphA2, ECM remodeling, and non-coding RNAs. Therapeutic strategies should therefore move beyond a simple distinction between “pro-angiogenic” and “anti-angiogenic” states and account for tumor-cell plasticity and switching between vascularization programs.

Future studies should combine mechanistic investigation of VM with clinically relevant models of vascular heterogeneity and treatment resistance. Nanotechnology-based delivery may complement existing therapy by improving drug exposure and enabling co-targeting of endothelial angiogenesis, VM-forming tumor cells, and the TME. The recent clinical development of direct anti-VM agents further supports VM as a pharmacologically relevant target, although GC-specific clinical evidence remains limited. Integrating vascular biology with nanomedicine and molecular stratification may therefore improve the development of more precise therapies for GC.

Abbreviations

5-FU

5-Fluorouracil

ADCs

Antibody drug conjugates

AFT

α-Fetoprotein

ANGPT2

Angiopoietin 2

ANGPTL6

Angiopoietin-like 6

AuNPs

Gold nanoparticles

Bax

Bcl-2-associated X protein

Bcl-2

B-cell lymphoma 2

CAFs

Tumor-associated fibroblasts

CAM

Chick chorioallantoic membrane

CAR-T

Chimeric antigen receptor T cells

CCs

Cancer stem cells

CMV

Cytomegalovirus

COX-2

Cyclooxygenase-2

CSCs

Cancer stem cells

CXCL12

C-X-C motif chemokine ligand 12

DDS

Drug delivery systems

EBV

Epstein-Barr virus

ECM

Extracellular matrix

EET

Epithelial-endothelial transition process

EMT

Epithelial–mesenchymal transition

EMT

Epithelial-to-mesenchymal transition

EphA2

Ephrin type-A receptor 2

EPR

Enhanced permeability and retention

ERK1/2

Extracellular signal-regulated kinases 1 and 2

EVs

Extracellular vesicles

FAK

Focal adhesion kinase

FGF

Fibroblast growth factor

FLOT

5-Fluorouracil and leucovorin, oxaliplatin, docetaxel

FLOT

Fluorouracil, leucovorin, oxaliplatin, and docetaxel regimen

GC

Gastric cancer

GCSCs

Gastric cancer stem cells

GLUT1

Glucose transporter type 1

GO

Graphene oxide

HBV

Hepatitis B virus

HCV

Hepatitis C virus

HER2

Human epidermal growth factor receptor 2

HGF

Hepatocyte growth factor

HIF-1α

Hypoxia-inducible factor 1-alpha

HIV

Human immunodeficiency virus

Hp

Helicobacter pylori

HPV

Human papilloma virus

HTLV

Human T cell lymphotropic virus type 1

HUVECs

Human umbilical vein endothelial cells

IARC

International Agency for Research on Cancer

IGF2

Insulin-like growth factor 2

IL

Interleukin

KSHV

Kaposi Sarcoma Herpesvirus

LDHA

L-lactate dehydrogenase A chain

LOX

Lysyl oxidase

LPS

Lipopolysaccharide

MAPK

Mitogen-activated protein kinase

MDR

Multi-drug resistance

MHC

Major histocompatibility c

MMP

Metalloproteinase

MOF

Metal-organic framework

NDDS

Novel drug delivery system

NF-κB

Nuclear factor kappa B

NPs

Nanoparticles

PAMPR

Pathogen associated molecular pattern receptors

PAS

Periodic acid–Schiff

PD-1

Programmed cell death protein 1

PDGFs

Platelet-derived growth factor

PECAM1

Platelet endothelial cell ddhesion molecule-1

PI3K/AKT

Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)

PIGF

Placental growth factor

PTEN

Phosphatase and tensin homolog

PVT1

Plasmacytoma variant translocation 1

SCAFA

Short fatty acids

SDF-1

Stromal cell-derived factor 1

SNAIL

Snail family transcriptional repressor 1

STAT3

Signal transducer and activator of transcription 3

TAMs

Tumor-associated macrophages

TFPI-1/2

Tissue factor pathway inhibitors

THAL

Thalidomide

Tie-1

Tyrosine kinase with immunoglobulin-like and EGF-like domains 1

TILs

Tumor-infiltrating lymphocytes

TKIs

Tyrosine kinase inhibitors

TLR

Toll-like receptors

TME

Tumor microenvironment

TNF

Tumor necrosis factors

TWIST

Basic helix-loop-helix (bHLH) transcription factors

VEGF

Vascular endothelial growth factor

VEGFR-2

Vascular endothelial growth factor receptor 2

VM

Vasculogenic mimicry

VSIG1

V-set and immunoglobulin domain-containing 1

ZEB1

Zinc finger E-box-binding homeobox 1

Author contribution

Magdalena Chmiela, Patrycja Jaroniek, Juan Carlos Rodríguez Manzaneque, Ewa Balcerczak, Marek Brzeziński, Agnieszka Jeleń, Saravanan Sandy, Agnieszka Wosiak, Weronika Gonciarz: writing original draft; Magdalena Chmiela and Weronika Gonciarz: conceptualization; Patrycja Jaroniek: article editing; Magdalena Chmiela and Weronika Gonciarz: writing—review and editing.

Funding

Not applicable.

Data availability

No datasets were generated or analyzed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.