Some conclusions derived from a liver model for carcinogenesis.

Abstract

A new model of liver cancer development with chemicals is described. This model was based on the hypothesis that chemical carcinogens induced as a first step altered hepatocytes that are resistant to the inhibitory effect of a carcinogen, such as N-2-fluorenylacetamide, on cell proliferation. After the administration of a single initiating dose of a carcinogen, the rare resistant hepatocyte is selected by the creation of a special selection pressure, consisting of a stimulus for cell proliferation in the presence of an environment that inhibits normal hepatocyte proliferation. The latter is created by brief exposure to dietary N-2-fluorenylacetamide. With this approach, initiated hepatocytes and large hyperplastic liver nodules can be rapidly induced in a synchronized fashion. A direct material continuity between resistant hepatocytes, foci, and nodules of such cells (hyperplastic nodules) and hepatocellular carcinoma was established with diethylnitrosamine as the initiating carcinogen. The use of the resistant cell model has shown that initiation consisted of at least two steps, the second of which is a compulsory round of cell proliferation. With this model, three mechanisms of promotion in the liver are suggested: differential inhibition, differential stimulation, and differential recovery. The relationship of these early changes to liver cancer development is discussed.