Cell Proliferation and Apoptosis in Normal Liver and Preneoplastic Foci

Abstract

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-01 is involved in the initiation of apoptosis. This was based on three lines of evidence: TGF-fi1 induced apoptosis in isolated hepatocytes, b) in vivo hepatocytes undergoing apoptosis showed positive immunostaining with antibodies against a precursor of TGF-i1. This staining response was not seen in normal or necrotic hepatocytes, c) injection of TGF-I1 into intact animals induced apoptosis in the liver in vivo.

Hepatocyte death in hepatocarcinogenesis

“…These include TCDD, 68 phenobarbital, and cyproterone acetate. 69 In addition, several other hepatic promoting agents have been shown to inhibit apoptosis in normal hepatocytes both in vivo 70 and in vitro. 71,72 Furthermore, withdrawal of a promoting agent during rat hepatocarcinogenesis may cause a dramatic increase in apoptosis of hepatocytes and preneoplastic foci.…”

NF-κB protects rat ARL-6 hepatocellular carcinoma cells against hydrogen peroxide-induced apoptosis

“…1,2 During regeneration, it is the predominant cell death pathway to counteract mitosis so that a balance is maintained between cell growth and cell death. 3,4 Many cancer tissues exhibit high rates of apoptosis, both before and after chemotherapy. 5,6 In hepatocellular carcinoma (HCC), the balance between cell growth and cell death is the principal determinant of malignant cell expansion and thus of tissue mass.…”

Extraction and purification of TGFβ and its effect on the induction of apoptosis of hepatocytes

“…Apoptosis is a genetically and highly conserved process. Regulation of the balance between cell proliferation and apoptosis is essential for development and maintenance of multicellular organisms [73][74][75][76][77] . Previous studies suggest that TGF β is able to induce evidently apoptosis of hepatocytes and hepatoma cells in vitro.…”