HEPATOCARCINOGENESIS IN RODENTS AND HUMANS

In hepatocarcinogenesis in rodents, induction of foci and nodules comp rising clonally proliferated initiated cells is considered to be essen tial for the future development of carcinomas. Nodules in human cirrho tic liver, though known to be associated with a high hepatocellular ca rcinoma risk, have generally been regarded as regenerative in nature, and not the result of clonal or neoplastic cell proliferation, on a mo rphological basis. However, when we analyzed 83 cirrhotic nodules from 11 HBV carrier patients, utilizing hepatitis B virus (KBV) integratio n as a marker for clonal proliferation, we found the existence of clon al populations of more than 10(5) hepatocytes in 26 (31.3%) of them. A lthough such clonal cell populations are morphologically not discernib le from neighboring hepatocytes, they may have particular histogenetic significance in human hepatocarcinogenesis and clearly deserve furthe r investigation. Allelotype analysis of mouse hepatocellular carcinoma s (HCC), induced by a single dose of diethyl nitrosaminine in C3H/MSM F-1 hybrids, revealed no remarkable alterations in the original tumors when microsatellite probes were used, but loss of heterozygosity of c hromosome 4 at extremely high frequency (95%) in cultured cell lines d erived from these HCC. The shortest common region was about 10 cM dist al to the interferon alpha gene, in which the p16 gene is located. The results indicated that loss of gene function, most probably including that of the p16 gene, may be essential for immortalization of culture d hepatocytes but that it may not play any role in initiation or early events in mouse hepatocarcinogenesis in vivo. The mouse HCC used for analysis in this study may be comparable with human HCC at an early st age, for which only very limited genetic alterations have so far been identified.