Matrix Stiffness Modulates Proliferation, Chemotherapeutic Response and Dormancy in Hepatocellular Carcinoma Cells

By J. Schrader, T. Gordon-Walker, R. Aucott, M. van Deemter, Alexander Quaas, Shaun Walsh, D. Benten, Stuart J. Forbes, R. G. Wells, J. Iredale. Hepatology, 2011

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There is increasing evidence that the physical environment is a critical mediator of tumor behavior. Hepatocellular carcinoma (HCC) develops within an altered biomechanical environment, and increasing matrix stiffness is a strong predictor of HCC development. The aim of this study was to establish whether changes in matrix stiffness, which are characteristic of inflammation and fibrosis, regulate HCC cell proliferation and chemotherapeutic response. Using an in vitro system of “mechanically tunable” matrix‐coated polyacrylamide gels, matrix stiffness was modeled across a pathophysiologically relevant range, corresponding to values encountered in normal and fibrotic livers. Increasing matrix stiffness was found to promote HCC cell proliferation. The proliferative index (assessed by Ki67 staining) of Huh7 and HepG2 cells was 2.7‐fold and 12.2‐fold higher, respectively, when the cells were cultured on stiff (12 kPa) versus soft (1 kPa) supports. This was associated with stiffness‐dependent regulation of basal and hepatocyte growth factor–stimulated mitogenic signaling through extracellular signal‐regulated kinase, protein kinase B (PKB/Akt), and signal transducer and activator of transcription 3. β1‐Integrin and focal adhesion kinase were found to modulate stiffness‐dependent HCC cell proliferation. Following treatment with cisplatin, we observed reduced apoptosis in HCC cells cultured on stiff versus soft (physiological) supports. Interestingly, however, surviving cells from soft supports had significantly higher clonogenic capacity than surviving cells from a stiff microenvironment. This was associated with enhanced expression of cancer stem cell markers, including clusters of differentiation 44 (CD44), CD133, c‐kit, cysteine‐X‐cysteine receptor 4, octamer‐4 (CXCR4), and NANOG. Conclusion: Increasing matrix stiffness promotes proliferation and chemotherapeutic resistance, whereas a soft environment induces reversible cellular dormancy and stem cell characteristics in HCC. This has implications for both the treatment of primary HCC and the prevention of tumor outgrowth from disseminated tumor cells. (HEPATOLOGY 2011;)

Subfields: Cell Biology, Immunology and Allergy, Oncology

View Paper: https://www.semanticscholar.org/paper/f0012dde2e0fb8241f5a2a1d4bf92028b891d879

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Citations in the corpus

Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance (2019, background): “Similarly, whereas hepatocellular carcinoma cells enter into a quiescent state in a soft matrix, they resume proliferation upon interacting with a stiff matrix, which enables integrin β1-dependent activation of FAK (Schrader et al., 2011).”
The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer (2016, background): “for TICs, contributing to their proliferation, resistance to chemotherapy, and dedifferentiation (131).”
Targeting cancer stem cell pathways for cancer therapy (2020, background): “513, 515 Fibronectin, vimentin, collagen, and proteoglycan in the ECM bind to cytokines such as FGF, HGF, VGF, BMP, and TGF-β in the TME and regulate their activities.”
The extracellular matrix modulates the hallmarks of cancer (2014, positive): “Indeed, a stiffened ECM reduces the expression of genes that typically inhibit cell cycle progression [27,48,49].”