Cell phenotype instability in preneoplastic foci of rat liver.

Carcinogenesis is a multi-step process in which genetic--phenotypic instability and sequential selection of preneoplastic cells for increased growth capacity and other neoplastic characteristics are essential phenomena. During chemical carcinogenesis in rat liver, the development of enzyme-deficient foci, their clonal origin and their relationship to tumour formation are known. We report the results of four carcinogenesis protocols consisting of one or two cycles of diethylnitrosamine and phenobarbital. Histochemistry of three enzymes on serial sections has revealed seven different kinds of homogeneous liver foci, resulting from simple and combined enzyme deficiencies, and also heterogeneous foci showing smaller foci inside. We consider such secondary foci as subclones originating from cells already modified that have developed an additional phenotypic change. Some of such foci develop after the first cycle if the promotion phase is as long as 57 weeks. Comparing the number of foci per surface area of liver section with the number of secondary foci per surface area of focus section, it seems clear that cells already modified are less stable than other hepatocytes, showing a higher tendency to develop secondary changes.