Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells

Abstract

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;)

Lung Extracellular Matrix and Fibroblast Function

“…Besides influencing cellular behavior based on specific molecular signaling, dimensionality and biomechanical cues in the lung clearly impact the effect of ECM on interstitial cell phenotype (8)(9)(10)(11)(12)(13)(14)(15). Although traditional in vitro studies of cell-matrix interactions usually rely on matrix-coated culture dishes, these artificial environments do not truly recapitulate the in vivo conditions under which cells reside.…”

Review: Mechanotransduction in ovarian cancer: Shearing into the unknown

“…[83][84][85][86] Numerous studies have proven that stiffer substrates enhance the metastatic phenotypes of cancer cells. [87][88][89][90][91] However, within the field of ovarian cancer, studies have resulted in contradictory findings.…”

Intrahepatic recurrence of hepatocellular carcinoma 13 years after orthotopic liver transplantation for hepatitis C-related cirrhosis with occult hepatocellular carcinoma: A case report

“…Recent studies have suggested an important role for mechanical factors in the induction and maintenance of tumor cell dormancy. Schrader et al 6 showed that a soft physiological environment (eg, that encountered in the bone marrow niche) induces HCC cell dormancy, whereas increased matrix stiffness may be responsible for the reactivation of dormant tumor cells. This would explain the increased frequency of HCC recurrence in fibrotic allografts and may help to explain the very late recurrence seen in this patient after a long evolution of chronic HCV in the allograft resulted in increased fibrosis.…”

“…This would explain the increased frequency of HCC recurrence in fibrotic allografts and may help to explain the very late recurrence seen in this patient after a long evolution of chronic HCV in the allograft resulted in increased fibrosis. The process of reactivation from dormancy, which may involve the mesenchymal-to-epithelial transition, after the epithelial-tomesenchymal transition undergone by the malignant cells to enter the dormancy state 6 could explain the loss of HepPar1 staining in the recurrent HCC. Welldifferentiated HCCs are almost universally positive for HepPar1, but this hepatocytic differentiation marker has, to our knowledge, not been studied in the context of intrahepatic recurrences of HCCs.…”