PHENOTYPIC DIVERSITY AS AN EARLY PROPERTY OF PUTATIVE PRENEOPLASTIC HEPATOCYTE POPULATIONS IN LIVER CARCINOGENESIS

  • 1 January 1980
    • journal article
    • research article
    • Vol. 40  (3) , 725-733
Abstract
Whether the phenotypic diversity characteristic of hepatocellular carcinomas is acquired early in carcinogenesis or late in the process was studied. A new model for the sequential analysis of hepatocarcinogenesis was used. This model utilizes a single initiating dose of a carcinogen, such as diethylnitrosamine, followed by the selective stimulation of the rare, initiated hepatocyte to proliferate under conditions in which the proliferation of the majority of uninitiated hepatocytes is inhibited. Under these conditions, discrete early foci of altered hepatocytes and hyperplastic foci and nodules are quite well-synchronized for about 10-12 cell cycles, after which the synchrony is progressively lost. As phenotypic expressions, cell proliferation and the activities of 4 enzyme markers, 2 positive ones, .gamma.-glutamyltranspeptidase and DT-diaphorase, and 2 negative ones, glucose-6-phosphatase and adenosine triphosphatase, were used. At the earliest time of observation, 7 days, and at subsequent time points thereafter, all histologically recognizable foci and nodules showed variable degrees of staining for each enzyme activity. Prior to selection, .gamma.-glutamyltranspeptidase activity was much more consistent than was that of the others; however, during and after the selection, the 4 markers showed almost the same consistency among developing lesions. During the period of selection, 80-90% of hepatocytes in the proliferating nodules were labeled with [3H]thymidine, while only an occasional labeled hepatocyte was seen in the foci prior to selection and in the nodules following selection. In the postselection period, the majority of nodules acquired the histochemical and architectural properties of normal liver, while a minority persisted as typical hyperplastic nodules. Phenotypes of carcinogen-altered hepatocytes are variable, but the cause of this diversity is not understood.