APOPTOSIS AND MULTISTAGE CARCINOGENESIS IN RAT-LIVER

Apoptosis is a type of active cell death. It is involved in the homeos tasis of cell number in tissues and is controlled by the growth regula tory network in the organism. It is also involved in the active remova l of damaged cells. We have studied the role of apoptosis in cancer pr e-stages and overt cancer in vivo, using rat liver as our main model s ystem. Quantitative determination of apoptosis in histological specime ns revealed that the rate of apoptosis tends to increase from normal t o (pre)neoplastic to malignant cells. Thereby active cell death largel y counterbalances the increasing replicative activity in developing ma lignancy. Tumor promoters shift the balance in favor of cell replicati on, whereas promoter withdrawal, fasting or TGF-beta 1 favor apoptosis (anti-promotion). Preneoplastic cells are more susceptible than norma l liver cells to stimulation of both cell replication or cell death. C onsequentially (pre)neoplastic tissue may preferentially grow or die d uring the appropriate treatment. Regimens that favor apoptosis and low er cell replication are shown to result in the elimination of preneopl astic cell clones from the liver (anti-initiation) and to reduce the c ancer risk of the animal.