CELL-PROLIFERATION AND APOPTOSIS IN NORMAL LIVER AND PRENEOPLASTIC FOCI

The growth rate of tissues including tumors is determined by the difference between cell replication and cell death. Among different types of cell death, apoptosis, a form of programmed cell death, is of particular importance. Nongenotoxic carcinogens exert their carcinogenic effects not only via stimulation of cell replication but also by modulating the incidence of apoptosis. This can be seen at different stages of carcinogenesis: a) After initiation in the liver, many initiated cells may undergo apoptosis and never develop into preneoplastic foci, as suggested by both biological and mathematical studies. Thus, apoptosis appears to determine the efficiency of initiation. b) In the promotion stage, early preneoplastic hepatic foci originate either from treatment with a genotoxic carcinogen or spontaneously exhibit much higher rates of cell replication than normal cells, but nevertheless show little preferential growth. This is due to enhanced rates of apoptosis. Some tumor promoters were found to inhibit apoptosis and thereby accelerate foci growth and carcinogenesis. c) In neoplastic nodules and tumors, apoptosis has been shown to be an important growth determinant and to be regulated by growth regulatory hormones, which thereby may decrease or accelerate tumor growth. Studies on the regulation of apoptosis revealed that in the liver, transforming growth factor TGF-beta(1) is involved in the initiation of apoptosis. This was based on three lines of evidence: TGF-beta(1) induced apoptosis in isolated hepatocytes, b) in vivo hepatocytes undergoing apoptosis showed positive immunostaining with antibodies against a precursor of TGF-beta(1). This staining response was not seen in normal or necrotic hepatocytes, c) injection of TGF-beta 1 into intact animals induced apoptosis in the liver in vivo.