Sequential phenotypic changes in hyperplastic areas during hepatocarcinogenesis in the rat

Sequential phenotypic changes in hyperplastic areas of rat liver during N-2-fluorenylacetamide feeding were studied by enzyme and immunohistochemical methods combined with radioautography. Hyperplastic area showed a marked deficiency of beta-glucuronidase and serine dehydratase during their developing phase, the 6th through the 9th experimental weeks, and were fairly specifically labeled by injections of tritiated thymidine after partial hepatectomy performed at the 9th week. A sequential observation on these labeled hyperplastic areas revealed a considerable elevation of the levels of these marker enzymes in the majority of the labeled areas in 3 to 18 weeks after labeling. On the other hand, there was a small group of hyperplastic areas in which the enzyme deficiency persisted during the observation period. This type of lesion was generally larger than those showing enzymic maturation. Labeled cells were not detectable either in distinct hyperplastic nodules at late phase or in carcinomas. The metabolic regulation in the cells comprising hyperplastic areas was studied by checking the induction and repression of serine dehydratase after dietary stimuli. Serine dehydratase was not inducible in hyperplastic areas during the developing phase or in areas with persistent enzyme deficiency, but it was clearly induced and repressed in areas where there was an elevation of the endogenous enzyme level. The areas of hyperplasia with persistent enzyme deficiency and growth appeared to be more important than the ones of phenotypic maturation in relation to the later development of carcinoma. The phenotypic maturation in hyperplastic areas might represent reversion of altered cells towards normalcy from the condition related with neoplastic transformation.