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 1 CD25 1 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.Hepatocellular carcinoma (HCC), a common malignant tumor worldwide, is a severe public health concern. 1 Carcinogenesis of HCC is a multifactor, multistep and complex process. Recently, many studies have demonstrated that hepatic fibrosis and liver cirrhosis, which are the ultimate results of chronic liver disease, are closely associated with HCC. 2 Liver fibrosis, cirrhosis and HCC all arise from liver parenchymal cells and mesenchymal cells. 3 Genetic and cellular biological studies on malignant tumors have shown that the interaction between parenchymal and stromal cells are important for tumor formation and development. 4 Stromal cells include myofibroblasts and endothelial cells, both of which interact with parenchymal cells via (1) the secretion of cytokines and other chemical factors, (2) extra cellular matrix (ECM)-mediated interaction and (3) direct cell-to-cell contiguity. 5 Stromal cells are closely related to angiogenesis, cancer desmoplasia and tumor immunity and are therefore important players in the progression, growth and spread of tumors. 6 Furthermore, several studies have shown that tumor cells can further induce the expression of tumorigenic factors in tumor-associated stromal cells, 7,8 indicating a mutual interaction between cancer cells and stromal cells. Thus, studies on the role of tumor stroma in the development and progression of cancer will help to clarify the mechanisms of carcinogenic lesions and lead to more effective therapeutic approaches.Hepatic stellate cells (HSCs) are the main collagen-producing cells in the injured liver. 9 Following a chronic liver injury, HSCs play important roles during the development of

The immunosuppressive properties of hepatic stellate cells (HSCs) contribute to the occurrence and development of hepatocellular carcinoma (HCC). The accumulation of cells with immune suppressive activities, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) is a key mechanism for tumor immune evasion. However, the impact of HSCs on immune cell populations in tumor-bearing hosts is unclear. In this study, we established an orthotopic liver tumor mouse model for studying the complex tumor-host interactions in HCC. The activated HSCs promoted HCC growth not only induced tumor angiogenesis and lymphangiogenesis, but also significantly increased the suppressive immune cell population of Tregs and MDSCs in the spleen, bone marrow, and tumor tissues of the tumor-bearing mice. Murine HCC cell line H22-activated HSCs also expanded the expression of Tregs and MDSCs in vitro. In conclusion, our study suggests a novel role for HSCs in the HCC microenvironment. HSCs can promote HCC progression by enhancement of the immunosuppressive cell population. Targeting HSCs, which is a new concept in adjuvant immunotherapy, may be introduced in the near future to improve the outcome of patients with HCC.

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Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage, and over the past several decades, many researchers have worked to develop novel effective therapies for HCC patients. The functional contributions of mesenchymal stem cells to human malignancies, including HCC growth and progression, are controversial, and the potential mechanisms underlying these effects are not clear. The aim of this study was to investigate the effect of adipose-derived mesenchymal stem cells (ADSCs) on the growth of HCC cells. In this study, a conditioned medium from ADSCs (ADSC-CM) efficiently inhibited HCC cell proliferation and division, and induced HCC cell death through the downregulation of Akt signaling. These findings indicated that the ADSC-CM could inhibit HCC growth. Thus, the ADSC-CM is a good candidate for the treatment of HCC patients for whom no effective therapy is available.