Is liver cancer a stem cell—derived disease?



In transgenic mice bearing the Simian Virus 40 large T antigen under the control of the human anti-thrombin III regulatory sequences, a step-wise progression toward hepatocellular carcinoma is observed. We have used two monoclonal antibodies (A6 and G7) developed against a surface antigen expressed in oval cells from dipin-treated mice, to analyze the emergence of such preneoplastic populations in the livers of anti-thrombin III Simian Virus 40 T transgenic mice. We show that a unique population of small heterogenous epithelial cells, which probably corresponds to oval and/or transitional cells according to their morphological features, consistently appears at approximately the 10th week after birth and proliferates thereafter. This oval cell-like population stained positively for A6 and G7 monoclonal antibodies. Furthermore, different subpopulations usually recognized as possible precursors of carcinoma cells including hyperplastic foci and neoplastic nodules as well as carcinoma cells, were also positive for A6 but not G7 monoclonal antibodies. Stimulation of cell proliferation by partial hepatectomy performed at the time of emergence of the oval-like cells resulted in a rapid 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 the oval/transitional cells and the development of neoplastic hepatocytes in this transgenic model.