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Review
. 2022 Mar 24;15(1):34.
doi: 10.1186/s13045-022-01252-0.

Targeting extracellular matrix stiffness and mechanotransducers to improve cancer therapy

Yangfu Jiang  1 , Hongying Zhang  2 , Jiao Wang  3 , Yongliang Liu  2 , Ting Luo  4 , Hui Hua  5
Affiliations
Review

Targeting extracellular matrix stiffness and mechanotransducers to improve cancer therapy

Yangfu Jiang et al. J Hematol Oncol. .

Abstract

Cancer microenvironment is critical for tumorigenesis and cancer progression. The extracellular matrix (ECM) interacts with tumor and stromal cells to promote cancer cells proliferation, migration, invasion, angiogenesis and immune evasion. Both ECM itself and ECM stiffening-induced mechanical stimuli may activate cell membrane receptors and mechanosensors such as integrin, Piezo1 and TRPV4, thereby modulating the malignant phenotype of tumor and stromal cells. A better understanding of how ECM stiffness regulates tumor progression will contribute to the development of new therapeutics. The rapidly expanding evidence in this research area suggests that the regulators and effectors of ECM stiffness represent potential therapeutic targets for cancer. This review summarizes recent work on the regulation of ECM stiffness in cancer, the effects of ECM stiffness on tumor progression, cancer immunity and drug resistance. We also discuss the potential targets that may be druggable to intervene ECM stiffness and tumor progression. Based on these advances, future efforts can be made to develop more effective and safe drugs to interrupt ECM stiffness-induced oncogenic signaling, cancer progression and drug resistance.

Keywords: Cancer; Cancer therapy; Drug resistance; ECM stiffness; Extracellular matrix; Mechanotransducer; Piezo.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The regulation of ECM stiffness by tumor and stromal cells. Hypoxia or growth factors such as TGFβ can induce the expression of collagen/elastin cross-linking factors in tumor and stromal cells, leading to increased ECM stiffness. ECM stiffening reciprocally acts on tumor and stromal cells thereby generating a vicious cycling. M∅, macrophage; CAF, cancer-associated fibroblast; MSC, mesenchymal stem cell
Fig. 2
Fig. 2
Regulation of tumor angiogenesis, growth, metastasis, immune evasion and drug resistance by ECM stiffness. ECM stiffening-induced mechanical cues drive tumor cells proliferation, CAFs/stellate cells autophagy and endothelial cells growth, thereby stimulating angiogenesis and tumor growth. ECM stiffening also promotes cancer metastasis by inducing EMT and cancer cells migration. The promotion of macrophage polarization and T cells exhaustion by ECM stiffening contributes to immune evasion in cancer
Fig. 3
Fig. 3
The antagonists of ECM stiffness regulators and mechano-signal transducers. Some of the inhibitors of collagen chaperone Hsp47, lysyl oxidases, mechanosensors Piezo1 and TRPV4, mechanotransducers integrin, ILK, FAK, YAP and TEAD are shown
See this image and copyright information in PMC

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