Role of cell proliferation at early stages of hepatocarcinogenesis

Hepatocarcinogenesis in rodents is characterized by the early appearance of foci of enzyme-altered (initiated) cells which are believed to represent precursors on the way to malignancy. Proliferation of cells within 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 proliferation is controlled by complex signaling networks and may be modulated by xenobiotics. In mouse--but not rat or human--liver, mutation of the Ha-ras gene appears to represent a critical genetic alteration which may confer a selective growth advantage to the mutated cells. Exogenous tumor-promoting agents may stimulate cell division and depress apoptosis 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, quantitative stereology may be applied to the analysis of the size distribution of enzyme-altered foci and used for modeling of hepatocarcinogenesis.