KINETICS OF PHENOTYPIC MATURATION OF REMODELING OF HYPERPLASTIC NODULES DURING LIVER CARCINOGENESIS

Abstract

Hyperplastic nodules appearing during the preneoplastic phase of liver carcinogenesis were divided into 2 types, persistent and remodeling, according to the pattern of staining for .gamma.-glutamyltransferase. In a resistant [rat] cell model of liver carcinogenesis, hyperplastic nodules, uniformly stained for .gamma.-glutamyltransferase, rapidly emerge by 4 wk after a single injection of diethylnitrosamine and brief selection by dietary 2-acetylaminofluorene plus partial hepatectomy. By 6 wk, a majority of nodules (.apprx. 75%) show an obvious irregularity and loss of uniformity in staining for .gamma.-glutamyltransferase while the remaining nodules continue to be uniformly stained. The number of irregularly stained nodules increases over the next 18 wk until > 95% of nodules show the nonuniform loss of enzyme activity. The progressive loss of enzyme activity is accompanied by architectural remodeling to normal-appearing liver. This is associated with the increasing disappearance of many obvious nodules from the liver as the remodeling ones blend imperceptibly with the surrounding liver. The uniformly stained nodules show the persistence of hepatocyte arrangements in plates 2 or more cells thick and in acini and of cytoplasmic hypertrophy characteristic of persistent hyperplastic nodules. Labeling indices are much higher in hepatocytes of the persistent uniformly stained nodules than in the remodeling ones. The possibility of exploiting this phase of the model further for in-depth analysis of the nodule-to-carcinoma sequence is discussed.