ROLE OF CELL-PROLIFERATION AT EARLY STAGES OF HEPATOCARCINOGENESIS

Hepatocarcinogenesis in rodents is characterized by the early appearan ce of foci of enzyme-altered (initiated) cells which are believed to r epresent precursors on the way to malignancy. Proliferation of cells w ithin enzyme-altered liver foci is generally increased as compared to surrounding normal hepatocytes. This may be mediated by changes in the rates of cell division and/or cell death (apoptosis). Cell proliferat ion is controlled by complex signaling networks and may be modulated b y xenobiotics. In mouse - but not rat or human - liver, mutation of th e Ha-ras gene appears to represent a critical genetic alteration which may confer a selective growth advantage to the mutated cells. Exogeno us tumor-promoting agents may stimulate cell division and depress apop tosis of preneoplastic hepatocytes, thereby increasing the probability of cancer. By means of histochemical methods, data on the frequencies of both cell division and cell death can be collected separately and utilized for estimation of promoter efficacy. In addition, quantitativ e stereology may be applied to the analysis of the size distribution o f enzyme-altered foci and used for modeling of hepatocarcinogenesis.