Development of two types of hepatocellular carcinoma in transgenic mice carrying the SV40 large T-antigen gene

Abstract

We produced transgenic mice by introducing a fusion gene (ST) comprising of the promoter for human serum amyloid P component (SAP) and the coding region of the simian virus 40 (SV40) large tumor antigen (Tag). The ST transgenic mice developed hepatocellular carcinomas (HCC) between 7 and 12 weeks of age. Clinically and pathologically these HCC were classified into two types: diffuse and focal. In the diffuse type Tag is expressed in almost all hepatocytes and HCC has presumably developed from these T-antigen-positive cells. The focal type, which resembles human HCC, is only Tag positive in the neoplastic nodules. These are surrounded by Tag-negative normal hepatocytes that form normal lobular structures. As the human SAP promoter can direct adult liver-specific expression of heterologous genes, it is assumed that Tag gene expression in the transgenic animals is increased sharply after birth. Interestingly, a similar level of Tag expression was observed in both the cytoplasm and the nucleus. Our results suggest that spatial differences in Tag expression result in the generation of two types of HCC in transgenic mice and that the ST mouse can serve as a model for human hepatocarcinogenesis.