Potential significance of phenotypic heterogeneity of focal lesions at different stages in hepatocarcinogenesis

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Abstract
In this study we used morphometric methods to investigate the number, size and phenotype of foci of altered hepatocytes in male rats after limited (7 weeks) oral administration of N-nitrosomorpholine (stop-model). We found a chronological sequence from clear and eosinophilic cell foci (CCF and ECF) of early appearance followed by intermediate and mixed (MCF) and basophilic cell foci (BCF). Eventually, neoplastic nodules (NN) and hepatocellular carcinomas (HC) developed. The animals killed first (7 weeks) showed a large number of CCF and ECF and virtually no MCF and BCF. During the following weeks, we observed a temporary increase in the number of MCF and a progressive decrease in the number of CCF and ECF. A few BCF appeared for the first time 5 weeks after cessation of treatment. Subsequently there was an increase in the number of BCF and a decrease in the number of MCF, the latter starting 20 weeks after withdrawal of the carcinogen. MCF were found most frequently in animals with a high incidence of CCF. BCF and tumours were found most frequently in animals with a high incidence of MCF. The increase in the number of CCF was due to the appearance of small foci of this phenotype. However, the increase in the number of MCF and BCF was not related to an increase in number of small foci of these phenotypes. On the contrary, while the total number of MCF and BCF increased, there was a decrease in the incidence of small foci, but an increase in the incidence of large foci of these phenotypes. From these results, we concluded that phenotypically different foci essentially reflect different stages in the process of hepatocarcinogenesis. Moreover, the lack of small MCF and BCF suggests that the transition from CCF and ECF to MCF and finally to BCF is the result of a conversion of large cell populations within foci from ''early'' to ''late'' phenotypes rather than the consequence of a repeated clonal selection.

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