OVAL CELL-PROLIFERATION IN EARLY STAGES OF HEPATOCARCINOGENESIS IN SIMIAN VIRUS-40 LARGE T-TRANSGENIC MICE

In transgenic mice bearing the Simian Virus 40 large T antigen under t he control of the human antithrombin III regulatory sequences, a stepw ise progression toward hepatocellular carcinoma is observed. We have u sed two monoclonal antibodies (A6 and G7) developed against a surface antigen expressed in oval cells from dipin-treated mice, to analyze th e emergence of such preneoplastic populations in the livers of antithr ombin III Simian Virus 40 T transgenic mice. We show that a unique pop ulation of small heterogenous epithelial cells, which probably corresp onds to oval and/or transitional cells according to their morphologica l features, consistently appears at approximately the 10th week after birth and proliferates thereafter. This oval cell-like population stai ned positively for A6 and G7 monoclonal antibodies. Furthermore, diffe rent subpopulations usually recognized as possible precursors of carci noma cells including hyperplastic foci and neoplastic nodules as well as carcinoma cells, were also positive for A6 but not G7 monoclonal an tibodies. Stimulation of cell proliferation by partial hepatectomy per formed at the time of emergence of the oval-Uke cells resulted in a ra pid increase in the number of oval/transitional A6-positive cells. Our findings support the view that a common mechanism may be involved in the development of carcinomas that are induced by chemical carcinogens and in transgenic mice expressing a potent oncogene under the control of a hepatic specific promoter. In addition, our findings demonstrate a specific precursor-product relationship between the appearance of t he oval/transitional cells and the development of neoplastic hepatocyt es in this transgenic model.