Target cell populations in virus-associated hepatocarcinogenesis

Studies on the natural course of virus-associated hepatocellular carcinoma (HCC) in high risk areas, particularly hepatitis B virus (HBV), have shown a stage of persistent liver cell hyperplasia characterized by a low level elevation of serum alpha-fetoprotein (AFP). We have recently identified a population of epithelial cells with distinct structure and expression of cytokeratin and AFP in non-neoplastic liver tissues from humans with HBV-associated HCC. These cells were characterized by oval nuclei, scant pale cytoplasm, small cell size, and cross-reactivity to a monoclonal antibody against rat oval cells. These human epithelial cells, putative human oval-type cells, stained strongly positive for cytokeratin 19 and displayed considerable heterogeneity in AFP and albumin expression. These findings suggest that a cell population structurally and phenotypically similar to oval cells seen in the early stages of chemical hepatocarcinogenesis in the rat is also present in humans in regenerating liver lesions observed in HBV-associated HCC. Hepatitis B surface antigen (HBsAg) was detected in 69, 81, and 85% of oval-type cells, transitional cells, and hepatocytes, respectively, but not in bile ducts or ductular cells. Also, high levels of expression of transforming growth factor alpha (TGF-alpha) were frequently seen in oval-type and transitional cells expressing HBsAg. These data suggest the possibility that oval-type cells are a target cell population for HBV infection; in the presence of elevated TGF-alpha expression, these cells may constitute a progenitor population for human HCC.