Hepatic stellate cells activated by acidic tumor microenvironment promote the metastasis of hepatocellular carcinoma via osteopontin.

Extracellular pH of solid tumor is generally acidic due to excessive glycolysis and poor perfusion. But whether acidic tumor microenvironment influenced the stromal cells infiltrating in tumor remains unknown. As the predominant progenitor of stromal cells in liver, the number of activated hepatic stellate cells (HSCs) was found positively correlated to the acidification level in the tumor tissues of HCC patients in our study. Whereas, in vitro acidic culture condition and in vivo co-implanting xenograft model were adopted to study the response of HSCs and its influence on HCC progression. HSCs were activated under acidic culture condition depending on the phosphorylation of cellular signal-regulated kinase (ERK). Acidity-activated HSCs promoted HCC metastasis in vitro and in vivo. Osteopontin (OPN) excretion from HSCs was increased under acidic condition and proved to promote the migration of HCC cells. Furthermore, the expression level of OPN was significantly associated with myofibroblasts and the combination of α-SMA with OPN was a powerful predictor for poor prognosis of HCC patients. Activation of HSCs in acidic tumor microenvironment represents a novel mechanism for HCC metastasis and provides a potential therapeutic strategy for HCC.

Song J ，Ge Z ，Yang X ，Luo Q ，Wang C ，You H ，Ge T ，Deng Y ，Lin H ，Cui Y ，Chu W ，Yao M ，Zhang Z ，Gu J ，Fan J ，Qin W ... -  《-》

Activated hepatic stellate cells promote hepatocellular carcinoma development in immunocompetent mice.

Activated hepatic stellate cells (HSCs) play a central role in the hepatic fibrosis and cirrhosis. Recently, HSCs were reported to have strong immune modulatory activities. However, the role of HSCs in hepatocellular carcinoma (HCC) remains unclear. In this study, we showed that HSCs could promote HCC growth both in vitro and in vivo. We examined the HSC-mediated inhibition of T-cell proliferation and the ability of conditioned medium from activated HSCs to promote the growth of murine HCC cell lines in vitro. We also assessed the immune suppression by HSCs during the development of HCC in immunocompetent mice. Cotransplantation of HSCs promoted HCC growth and progression by enhancing tumor angiogenesis and tumor cell proliferation and by creating an immunosuppressed microenvironment. Cotransplanted HSCs inhibited the lymphocyte infiltration in tumors and the spleens of mice bearing tumors, induced apoptosis of infiltrating mononuclear cells, and enhanced the expression of B7H1 and CD4(+) CD25(+) Treg cells. The immune modulation by HSCs seemed to be systemic. In conclusion, our data provide new information to support an integral role for HSCs in promoting HCC progression in part via their immune regulatory activities, and suggest that HSCs may serve as a therapeutic target in HCC.

Zhao W ，Zhang L ，Yin Z ，Su W ，Ren G ，Zhou C ，You J ，Fan J ，Wang X ... -  《-》

Hepatocellular carcinoma cells and their fibrotic microenvironment modulate bone marrow-derived mesenchymal stromal cell migration in vitro and in vivo.

Garcia MG ，Bayo J ，Bolontrade MF ，Sganga L ，Malvicini M ，Alaniz L ，Aquino JB ，Fiore E ，Rizzo MM ，Rodriguez A ，Lorenti A ，Andriani O ，Podhajcer O ，Mazzolini G ... -  《-》

Activated hepatic stellate cells promote hepatocellular carcinoma cell migration and invasion via the activation of FAK-MMP9 signaling.

Han S ，Han L ，Yao Y ，Sun H ，Zan X ，Liu Q ... -  《-》

Hepatic stellate cells stimulate HCC cell migration via laminin-5 production.

Santamato A ，Fransvea E ，Dituri F ，Caligiuri A ，Quaranta M ，Niimi T ，Pinzani M ，Antonaci S ，Giannelli G ... -  《-》