The main objective of this project is to define the genetic determinants for the initiation stage in hepatocarcinogenesis and subsequent evolution of liver tumors that are brought about by chemical carcinogens and other cancer causing agents. The principal lesions that develop in the rat liver as a result of initiation-promotion protocols are foci of altered hepatocytes. Initiation of these foci by a variety of hepatocarcinogens has been shown to follow an apparent first order dose response, suggesting that the foci are a clonal expansion of the initiated cell. Consequently the phenotype of initiation should be completely represented by the foci of altered hepatocytes. To test this hypothesis we have started a series of experiments in which activated retroviral-associated oncogenes are transfected into a nontumorigenic rat liver epithelial cell line and primary rat hepatocytes, and the phenotypic changes determined. The research is currently focused on: (1) transfecting rat liver cells with retroviral associated oncogenes, (2) construction of a retroviral vector-based transfection system to introduce selected oncogenes into primary hepatocytes, and (3) construction of cDNA libraries from normal and neoplastic rat liver.
