The research proposed in this application is designed to study aspects of the process of hepatocarcinogenesis. Studies will be carried out with one experimental model not involving the use of chemical carcinogens, that of induction of hepatocellular carcinomas in rats solely fed a choline-devoid diet. In this model, tumor development is preceded by an abnormal, chronic state of high proliferative activity of liver cells, which persists for much of the adult life of the animals. It seems possible therefore, if not likely, that the genesis of the tumors resides in either the chronicity of such a state, or new alteration(s) arising in the processes of division, growth and/or differentiation of adult liver cells, facilitated by it. The chronic state has episodic features similar to those seen, acutely, in the adult liver regeneration that follows a partial hepatectomy. During the latter, a transient increase in the expression of certain proto-oncogenes. Experiments will be performed to investigate whether feeding a choline-devoid diet to rats results in an increased expression of liver cell proto-oncogene(s); whether such an increase, if induced, persists only for as long as there is an active proliferation of liver cells; and whether tumor development may be linked to activation of proto-oncogenes. Similar studies are proposed using rats treated with chemical carcinogens, to explore whether the action of the latter involve alteration(s) in proto-oncogene expression. Finally, experiments are proposed, to confirm and extend initial findings indicating that occurrence of more than one genomic alteration may be required for induction of liver tumors by chemical carcinogens.
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