HEPATITIS C VIRUS INDUCED TUMOR INITIATING CANCER STEM-LIKE CELLS ACTIVATE STROMAL FIBROBLASTS IN XENOGRAFT TUMOR MODEL

摘要

Hepatitis C virus (HCV) often causes persistent infection, and is an increasingly important factor in the etiology of fibrosis/cirrhosis and hepatocellular carcinoma (HCC), although the mechanisms for the disease processes remain unclear. We have shown previously that HCV infection generates epithelial mesenchymal transition state (EMT) and tumor initiating cancer stem-like cells (TISCs) in human hepatocytes. In this study, we investigated whether HCV induced TISC when implanted into mice activate stromal fibroblasts. A number of fibroblast activation markers, including metalloproteinase (MMP) 2 were significantly increased at the mRNA or protein level in the xenograft tumors, suggesting the presence of tumor-associated fibroblasts (TAFs). Fibroblast activation markers of murine origin were specifically increased in tumor, suggesting that fibroblasts are migrated to form stroma. Next, we demonstrated that the conditioned medium (CM) from HCV infected human hepatocytes activates fibrosis related markers in hepatic stellate cells. We further observed that these HCV infected hepatocytes express TGF-β which activates stromal fibroblast markers. Subsequent analysis suggest anti-TGF-β neutralizing antibody, when incubated with CM from HCV infected hepatocytes, inhibits fibrosis marker activation in primary human hepatic stellate cells (HSCs).ConclusionHCV infected hepatocytes induce local fibroblast activation by secretion of TGF-β, and preneoplastic or tumor state of the hepatocytes influences the network for TAF environment.