Abstract
Putative preneoplastic foci (islands) of altered hepatocytes were induced by single doses of initiating hepatocarcinogens and identified by various histochemical and morphological markers. DNA synthesis, measured by 3H-thymidine and autoradiography, as well as mitotic activity were found to be higher in the foci than in normal hepatocytes. Without promotion this proliferative advantage is partially counterbalanced by reversion of altered cells to the normal phenotype and/or increased incidence of cell death by apoptosis, so that the islands show little growth. Prolonged administration of promoters such as phenobarbital, hexachlorocyclohexane etc. resulted in the appearance of more and larger foci, which exhibited steady growth. Island enlargement was due to an upsurge of cell proliferation (in the initial stage only) and to interference of the promoter with phenotypic reversion and/or apoptosis of island cells. Island multiplication during promotion was essentially due to induction of the histochemical marker (γ-GT) in “latent” islands. Promoter withdrawal led to rapid reductions in size and number of foci suggesting that the effect of promoters on the phenotype of island cells is reversible under the conditions employed. Finally we offer the hypothesis that non-mutagenic compounds may produce liver tumors in experimental animals by promotion of “spontaneous” preneoplastic lesions.