Activated hepatic stellate cells promote hepatocellular carcinoma development in immunocompetent mice

• Published in: International journal of cancer Vol. 129; no. 11; pp. 2651 - 2661
• Main Authors: Zhao, Wenxiu, Zhang, Lei, Yin, Zhenyu, Su, Weixue, Ren, Guangli, Zhou, Changsheng, You, Junyong, Fan, Jia, Wang, Xiaomin
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2011; Wiley-Blackwell
• Subjects: Angiogenesis; Animals; Apoptosis; B7-H1 Antigen - metabolism; Biological and medical sciences; Blotting, Western; cancer therapy; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; CD25 antigen; CD4 antigen; Cell Proliferation; Cells, Cultured; Cirrhosis; Culture Media, Conditioned - pharmacology; Data processing; Development; Disease Progression; Enzyme-Linked Immunosorbent Assay; Fibrosis; Flow Cytometry; Fluorescent Antibody Technique; Gastroenterology. Liver. Pancreas. Abdomen; hepatic stellate cells; Hepatic Stellate Cells - immunology; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - transplantation; Hepatocellular carcinoma; Immunoenzyme Techniques; Immunomodulation; immunosuppression; Leukocytes (mononuclear); Liver Neoplasms - immunology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Male; Medical sciences; Metastases; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microenvironments; Spleen; Spleen - immunology; Spleen - metabolism; Spleen - pathology; stellate cells; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tumor cells; Tumors; hepatic stellate cells; Rodentia; Hepatic disease; Hepatocellular carcinoma; Malignant tumor; Carcinogenesis; Liver cancer; Kupffer cell; cancer therapy; Vertebrata; Immunosuppression; Mammalia; Cancerology; Treatment; Mouse; Animal; Digestive diseases; Cancer
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.25920

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.