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Increasing evidence implicates that greater matrix stiffness could have profound effects on cancer progression, including oncogenic intracellular signals activation and upregulation of pro-survival signaling. And matrix stiffness is increasingly appreciated as an important mediator of cancer metastasis and development. As previously reported, matrix stiffness induced mechanical force has been emerged as critical determinant of cancer progression in many solid tumor types. The extracellular matrix in tumor tissues typically consists of abundant levels of collagen and fibrinogen, which could be further crosslinked by soluble mediators, such as lysyl oxidase, eventually generating matrix stiffness. Compelling findings provide evidence that the extracellular matrix could support tumor cells proliferation and epithelial-mesenchymal transition, thereby causing the tumor growth and distant metastasis. Therefore, there is an urgent demand to elucidate the underlying mechanism of tumor occurrence and develop innovative strategy to impair tumor growth.Ĭancer development is bound up with diverse biological factors, including immunosuppression, inflammation reaction, pro-survival cytokines secreted by stromal cells, tumor heterogeneity and extracellular matrix. Currently, the underlying mechanism of liver cancer development remains poorly understood.

Despite the advance of surgical excision and adjuvant chemotherapy, a number of liver cancer patients suffer the sustained tumor growth and tissue infiltration during treatment. The incidence of primary hepatocellular cancer is increasing in several centuries, however, limited clinical interventions are developed for patients with advanced liver cancer. Hepatic carcinoma is one of the most common malignant carcinomas with a high mortality worldwide. Blockade of integrin signals efficiently improved the outcome of chemotherapy, which described an innovative approach for liver cancer treatment. ConclusionĪ higher matrix stiffness equipped tumor cells with enhanced stemness and proliferative characteristics, which was dependent on the activation of integrin β1/FAK/ERK1/2/NF-κB signaling pathway. Combination of chemotherapy and integrin β1 inhibitor suppressed the tumor growth and prolonged survival time in hepatocellular cancer xenografts. Inhibition of ERK1/2, FAK, and NF-κB signaling suppressed the pro-tumor effects induced by matrix stiffness.

Mechanistically, activation of integrin β1/FAK/ ERK1/2/NF-κB signaling pathway was observed in SMMC-7721 cells cultured on high stiffness PA hydrogels. Liver cancer cells cultured on high stiffness PA hydrogels displayed enhanced tumorigenic potential and migrative properties. Our study provided evidence that liver tumor tissues from metastatic patients possessed a higher matrix stiffness, when compared to the non-metastatic group. SMMC-7721 cancer xenografts were established to explore the anticancer effects of integrin inhibitors. We performed MTT, colony formation and transwell assay to examine the tumorigenic and metastatic potential of SMMC-7721 cells cultured on the tunable PA hydrogels. The expression level of integrin β1, phosphorylated FAK, ERK1/2, and NF-κB in SMMC-7721 cells was measured by western blotting analysis. In vitro, we used a tunable Polyacrylamide (PA) hydrogels culture system for liver cancer cells culture. The matrix stiffness of tumor tissues was determined by atomic force microscopy (AFM) analysis. Our purpose was to explore the role of matrix stiffness in liver cancer development. Particularly, a higher matrix stiffness has been demonstrated to promote tumor sustained growth. Cancer development is strictly correlated to composition and physical properties of the extracellular matrix.

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