Insights into the Mechanisms, Regulation, and Therapeutic Implications of Extracellular Matrix Stiffness in Cancer

Overview

Journal Bioeng Transl Med

Date 2025 Jan 13

PMID 39801760

Authors

Ximo Zhang

Abdullah Al-Danakh

Xinqing Zhu

Dan Feng

Linlin Yang

Haotian Wu

Yingying Li

Shujing Wang

Qiwei Chen

Deyong Yang

Affiliations

Soon will be listed here.

Abstract

The tumor microenvironment (TME) is critical for cancer initiation, growth, metastasis, and therapeutic resistance. The extracellular matrix (ECM) is a significant tumor component that serves various functions, including mechanical support, TME regulation, and signal molecule generation. The quantity and cross-linking status of ECM components are crucial factors in tumor development, as they determine tissue stiffness and the interaction between stiff TME and cancer cells, resulting in aberrant mechanotransduction, proliferation, migration, invasion, angiogenesis, immune evasion, and treatment resistance. Therefore, broad knowledge of ECM dysregulation in the TME might aid in developing innovative cancer therapies. This review summarized the available information on major ECM components, their functions, factors that increase and decrease matrix stiffness, and related signaling pathways that interplay between cancer cells and the ECM in TME. Moreover, mechanotransduction alters during tumorogenesis, and current drug therapy based on ECM as targets, as well as future efforts in ECM and cancer, are also discussed.

References

Levental K, Yu H, Kass L, Lakins J, Egeblad M, Erler J . Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009; 139(5):891-906. PMC: 2788004. DOI: 10.1016/j.cell.2009.10.027. View

Yang L, Li J, Zang G, Song S, Sun Z, Li X . Pin1/YAP pathway mediates matrix stiffness-induced epithelial-mesenchymal transition driving cervical cancer metastasis via a non-Hippo mechanism. Bioeng Transl Med. 2023; 8(1):e10375. PMC: 9842039. DOI: 10.1002/btm2.10375. View

Deng B, Zhao Z, Kong W, Han C, Shen X, Zhou C . Biological role of matrix stiffness in tumor growth and treatment. J Transl Med. 2022; 20(1):540. PMC: 9682678. DOI: 10.1186/s12967-022-03768-y. View

Sprowls S, Lathia J . Breaking down the barrier to medulloblastoma treatment: Piezo2 knockout disrupts the BTB and increases vascular permeability. Neuron. 2023; 111(1):3-5. DOI: 10.1016/j.neuron.2022.12.008. View

Peng Y, Chen Z, Chen Y, Li S, Jiang Y, Yang H . ROCK isoforms differentially modulate cancer cell motility by mechanosensing the substrate stiffness. Acta Biomater. 2019; 88:86-101. DOI: 10.1016/j.actbio.2019.02.015. View

Zhang D, Wang G, Yu X, Wei T, Farbiak L, Johnson L . Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy. Nat Nanotechnol. 2022; 17(7):777-787. PMC: 9931497. DOI: 10.1038/s41565-022-01122-3. View

Gill B, Gibbons D, Roudsari L, Saik J, Rizvi Z, Roybal J . A synthetic matrix with independently tunable biochemistry and mechanical properties to study epithelial morphogenesis and EMT in a lung adenocarcinoma model. Cancer Res. 2012; 72(22):6013-23. PMC: 3632398. DOI: 10.1158/0008-5472.CAN-12-0895. View

Wei S, Fattet L, Tsai J, Guo Y, Pai V, Majeski H . Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway. Nat Cell Biol. 2015; 17(5):678-88. PMC: 4452027. DOI: 10.1038/ncb3157. View

Balbin M, Fueyo A, Tester A, Pendas A, Pitiot A, Astudillo A . Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nat Genet. 2003; 35(3):252-7. DOI: 10.1038/ng1249. View

10.

Dey N, Young B, Abramovitz M, Bouzyk M, Barwick B, De P . Differential activation of Wnt-β-catenin pathway in triple negative breast cancer increases MMP7 in a PTEN dependent manner. PLoS One. 2013; 8(10):e77425. PMC: 3797090. DOI: 10.1371/journal.pone.0077425. View

11.

Azzolin L, Panciera T, Soligo S, Enzo E, Bicciato S, Dupont S . YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. Cell. 2014; 158(1):157-70. DOI: 10.1016/j.cell.2014.06.013. View

12.

Anlas A, Nelson C . Soft Microenvironments Induce Chemoresistance by Increasing Autophagy Downstream of Integrin-Linked Kinase. Cancer Res. 2020; 80(19):4103-4113. PMC: 7534696. DOI: 10.1158/0008-5472.CAN-19-4021. View

13.

Liu C, Li M, Dong Z, Jiang D, Li X, Lin S . Heterogeneous microenvironmental stiffness regulates pro-metastatic functions of breast cancer cells. Acta Biomater. 2021; 131:326-340. PMC: 8784164. DOI: 10.1016/j.actbio.2021.07.009. View

14.

Huang S, Ingber D . Cell tension, matrix mechanics, and cancer development. Cancer Cell. 2005; 8(3):175-6. DOI: 10.1016/j.ccr.2005.08.009. View

15.

Higgins D, Kimura K, Bernhardt W, Shrimanker N, Akai Y, Hohenstein B . Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest. 2007; 117(12):3810-20. PMC: 2082142. DOI: 10.1172/JCI30487. View

16.

Astrom P, Juurikka K, Hadler-Olsen E, Svineng G, Cervigne N, Coletta R . The interplay of matrix metalloproteinase-8, transforming growth factor-β1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma. Br J Cancer. 2017; 117(7):1007-1016. PMC: 5625665. DOI: 10.1038/bjc.2017.249. View

17.

Jiang H, Torphy R, Steiger K, Hongo H, Ritchie A, Kriegsmann M . Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix. J Clin Invest. 2020; 130(9):4704-4709. PMC: 7456216. DOI: 10.1172/JCI136760. View

18.

Yang N, Chen T, Wang L, Liu R, Niu Y, Sun L . CXCR4 mediates matrix stiffness-induced downregulation of UBTD1 driving hepatocellular carcinoma progression via YAP signaling pathway. Theranostics. 2020; 10(13):5790-5801. PMC: 7255012. DOI: 10.7150/thno.44789. View

19.

Wei B, Zhou X, Liang C, Zheng X, Lei P, Fang J . Human colorectal cancer progression correlates with LOX-induced ECM stiffening. Int J Biol Sci. 2017; 13(11):1450-1457. PMC: 5715527. DOI: 10.7150/ijbs.21230. View

20.

Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T . Latent TGF-β structure and activation. Nature. 2011; 474(7351):343-9. PMC: 4717672. DOI: 10.1038/nature10152. View