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Cited by 269Cellular Mechanics and InteractionsCancer Cells and MetastasisTGF-β signaling in diseases

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Extracellular matrix stiffness: mechanisms in tumor progression and therapeutic potential in cancer

Open access
Zhang, Meiling, Zhang, Bin·2025·Experimental Hematology & Oncology
DOI 10.1186/s40164-025-00647-2PMC PMC11984264
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Abstract

Tumor microenvironment (TME) is a complex ecosystem composed of both cellular and non-cellular components that surround tumor tissue. The extracellular matrix (ECM) is a key component of the TME, performing multiple essential functions by providing mechanical support, shaping the TME, regulating metabolism and signaling, and modulating immune responses, all of which profoundly influence cell behavior. The quantity and cross-linking status of stromal components are primary determinants of tissue stiffness. During tumor development, ECM stiffness not only serves as a barrier to hinder drug delivery but also promotes cancer progression by inducing mechanical stimulation that activates cell membrane receptors and mechanical sensors. Thus, a comprehensive understanding of how ECM stiffness regulates tumor progression is crucial for identifying potential therapeutic targets for cancer. This review examines the effects of ECM stiffness on tumor progression, encompassing proliferation, migration, metastasis, drug resistance, angiogenesis, epithelial-mesenchymal transition (EMT), immune evasion, stemness, metabolic reprogramming, and genomic stability. Finally, we explore therapeutic strategies that target ECM stiffness and their implications for tumor progression.

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Crossref · 10.1186/s40164-025-00647-2

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Figures

Fig. 1 Schematic illustration of ECM components in normal tissue (left) and the TME (right). Matrix stiffness is mainly related to excessive collagen and HA. Both cytokines or TGFβ are involved in the ECM stiffness process, and LOX is involved in collagen crosslinking. ECM stiffness interacts with tumor cells and stromal cells, thus creating a vicious cycle
Fig. 1 Schematic illustration of ECM components in normal tissue (left) and the TME (right). Matrix stiffness is mainly related to excessive collagen and HA. Both cytokines or TGFβ are involved in the ECM stiffness process, and LOX is involved in collagen crosslinking. ECM stiffness interacts with tumor cells and stromal cells, thus creating a vicious cycleCC BY · PubMed Central
Fig. 2 Key factors and signaling pathways inducing ECM stiffness. Stiffness activates receptors such as integrin, Piezo, and PDGFR, which sense mechanical signals from the ECM and activate downstream pathways, including FAK/SRC, ERK, AKT, β-catenin, RhoA-ROCK, and YAP/TAZ to induce ECM stiffness enhancement. Stromal cells such as CAF, senescent MSC and factors such as TGFβ and hypoxia play a major role in stiffness-mediated properties
Fig. 2 Key factors and signaling pathways inducing ECM stiffness. Stiffness activates receptors such as integrin, Piezo, and PDGFR, which sense mechanical signals from the ECM and activate downstream pathways, including FAK/SRC, ERK, AKT, β-catenin, RhoA-ROCK, and YAP/TAZ to induce ECM stiffness enhancement. Stromal cells such as CAF, senescent MSC and factors such as TGFβ and hypoxia play a major role in stiffness-mediated propertiesCC BY · PubMed Central
Fig. 3 Regulation of ECM stiffness on CSCs, MSC, invasion, proliferation, metastasis, and EMT. a. ECM stiffness not only affects the stemness of CSCs but also upregulates the expression of Id1 and Id3 via the TGF-β pathway, enhancing the tumor-initiating capacity of GICs. Additionally, under high-stiffness conditions, MSCs can be induced to an osteogenic phenotype. b. ECM stiffness primarily promotes tumor invasion and proliferation by increasing and activating the FAK/SRC phosphorylation and PI3K signaling pathways. Besides ECM stiffness, the composition of ECM, such as collagen, HA, and FN, can also regulate the migration patterns of tumor cells. c. ECM stiffness promotes tumor metastasis by facilitating the nuclear localization of TWIST1 and the CD36-AKT-E2F3-FGF-2 pathway. Additionally, CAFs, ECs and BMDCs promote the colonization of cancer cells in distant organs by secreting growth factors, angiogenic factors, and MMPs. d. During EMT, the expression of N-cadherin, zinc finger transcription factor family members such as Snail, Slug, and Twist, and MMPs is upregulated, while the expression of E-cadherin is downregulated. ECM stiffness induces Snail expression through multiple signaling pathways, including S100A11 membrane translocation, eIF4E phosphorylation, and TGF-β1 autocrine signaling, thereby promoting EMT effects
Fig. 3 Regulation of ECM stiffness on CSCs, MSC, invasion, proliferation, metastasis, and EMT. a. ECM stiffness not only affects the stemness of CSCs but also upregulates the expression of Id1 and Id3 via the TGF-β pathway, enhancing the tumor-initiating capacity of GICs. Additionally, under high-stiffness conditions, MSCs can be induced to an osteogenic phenotype. b. ECM stiffness primarily promotes tumor invasion and proliferation by increasing and activating the FAK/SRC phosphorylation and PI3K signaling pathways. Besides ECM stiffness, the composition of ECM, such as collagen, HA, and FN, can also regulate the migration patterns of tumor cells. c. ECM stiffness promotes tumor metastasis by facilitating the nuclear localization of TWIST1 and the CD36-AKT-E2F3-FGF-2 pathway. Additionally, CAFs, ECs and BMDCs promote the colonization of cancer cells in distant organs by secreting growth factors, angiogenic factors, and MMPs. d. During EMT, the expression of N-cadherin, zinc finger transcription factor family members such as Snail, Slug, and Twist, and MMPs is upregulated, while the expression of E-cadherin is downregulated. ECM stiffness induces Snail expression through multiple signaling pathways, including S100A11 membrane translocation, eIF4E phosphorylation, and TGF-β1 autocrine signaling, thereby promoting EMT effectsCC BY · PubMed Central
Fig. 4 Regulation of ECM stiffness on Angiogenesis, Drug Resistance, Immune Escape and Metabolic Reprogramming. a. ECM stiffness supports the growth and survival of ECs mainly by enhancing the expression of VEGF and its receptors; On the contrary, ECM stiffness can also act as a barrier to ECs migration, and ECM protein fragmentation can also act as an anti-angiogenic agent. b. Matrix stiffness actively removes chemotherapeutic drugs from cancer cells by enhancing the functional activity of MRP1, ABC transporters on the cell membrane, and also acts as a barrier to block drug delivery c. EC stiffness not only acts as a physical barrier to block the infiltration of immune cells into the TME, but also limits the contact of anti-apcs with T cells and regulates the polarization of macrophages. d. Matrix stiffness regulates glycolysis, amino acid metabolism, and lipid metabolism in tumors through multiple mechanisms
Fig. 4 Regulation of ECM stiffness on Angiogenesis, Drug Resistance, Immune Escape and Metabolic Reprogramming. a. ECM stiffness supports the growth and survival of ECs mainly by enhancing the expression of VEGF and its receptors; On the contrary, ECM stiffness can also act as a barrier to ECs migration, and ECM protein fragmentation can also act as an anti-angiogenic agent. b. Matrix stiffness actively removes chemotherapeutic drugs from cancer cells by enhancing the functional activity of MRP1, ABC transporters on the cell membrane, and also acts as a barrier to block drug delivery c. EC stiffness not only acts as a physical barrier to block the infiltration of immune cells into the TME, but also limits the contact of anti-apcs with T cells and regulates the polarization of macrophages. d. Matrix stiffness regulates glycolysis, amino acid metabolism, and lipid metabolism in tumors through multiple mechanismsCC BY · PubMed Central
Fig. 5 The diagram of ECM-targeting treatment. a. Targeting ECM components to reduce matrix stiffness, thereby improving drug delivery and enhancing the infiltration of immune cells within the tumor. b. Blocking downstream receptors associated with ECM stiffness to treat tumors
Fig. 5 The diagram of ECM-targeting treatment. a. Targeting ECM components to reduce matrix stiffness, thereby improving drug delivery and enhancing the infiltration of immune cells within the tumor. b. Blocking downstream receptors associated with ECM stiffness to treat tumorsCC BY · PubMed Central

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Metadata

Authors
Zhang, M., & Zhang, B.
Affiliations
China Three Gorges University (CN)
Corresponding author
Zhang, Bin
ORCID
Venue
Experimental Hematology & Oncology
Publisher
Springer Science and Business Media LLC
Published
2025-04-10
Volume
14
Issue
1
Pages
54-54
ISSN
2162-3619 (ISSN-L)
DOI
10.1186/s40164-025-00647-2
PMC
PMC11984264
OpenAlex
W4409339209
Cited by
269
References
205
Citations by year
2026: 199 · 2025: 70
FWCI
32.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental Hematology and Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
extracellular matrix stiffness, tumor microenvironment, tumor progression, mechanotransduction, metastasis, drug resistance, angiogenesis, epithelial-mesenchymal transition, immune evasion, cancer stemness, metabolic reprogramming, genome stability

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