Cell proliferation and the aetiology of hepatocellular carcinoma

doi:10.1016/S0168-8278(88)80002-3

Journal of Hepatology

Volume 7, Issue 3, 1988, Pages 305-309

https://doi.org/10.1016/S0168-8278(88)80002-3 Get rights and content

Summary

The liver is, under normal conditions, mitotically inactive and relatively resistant to chemical carcinogenesis. When rat or mouse hepatocytes are stimulated to divide, however, the liver becomes exquisitely sensitive to carcinogenesis. The heightened sensitivity of dividing liver cells to carcinogens is one of the most dramatic phenomena in the field of experimental chemical carcinogenesis and is reproducible with a wide variety of chemical agents and experimental conditions. This same phenomenon seems to apply to humans, as circumstances that produce a sustained hepatocellular proliferation in man are associated with an increased risk of hepatocellular carcinoma (HCC). These include inborn errors of metabolism (e.g., haemochromatosis, Wilson's disease, hereditary tyrosinaemia) as well as alcoholism. A recent editorial in this Journal suggested that any condition resulting in cirrhosis is also associated with an increased risk of HCC, and this may in turn be due to regenerative hyperplasia always present in cirrhotic liver (^[1]; Johnson PJ, Williams R. J Hepatol 1987; 4: 140–147). In the case of HCC associated with hepatitis B virus (HBV) infection, the possibility must be entertained that chronic HBV infection serves to produce a sustained hepatonecrosis with concurrent (regenerative) hyperplasia. This proliferative state would in theory serve to increase the liver's susceptibility to environmental dietary carcinogens and may tend to increase the risk of HCC by this indirect mechanism. Until a molecular mechanism is demonstrated whereby HBV produces a defined cellular lesion that endows hepatocytes with a malignant phenotype, it should not be assumed that HBV is a direct cause of HCC.

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This chapter discusses the molecular biology of hepatitis B virus (HBV)-associated hepatocellular carcinoma. On the basis of epidemiological studies, there is an unequivocal causal relationship between chronic hepatitis B virus infection and the subsequent development of hepatocellular carcinoma (HCC). This relationship can be shown in the presence of a firm clinical diagnosis of HCC together with the detection of the hepatitis B surface antigen (HBsAg) in serum. The chapter discusses the mechanism of the association at a molecular level, and the interaction of HBV with other known etiological factors to cause HCC. HBV is a member of the hepadnaviridae family, a group of small DNA viruses characterized by an unusual replication strategy that requires reverse transcription of RNA pregenome. Hepatotoxic agents generate a selection pressure that results in the emergence of resistant clones that are the first step in carcinogenesis. The virus mutants develop in many patients during the course of chronic HBV infection. Some of these result in the loss of detectable HBV surface and core antigens that are the targets of immune-mediated cytotoxicity, thereby giving hepatocytes harboring these mutations a distinct growth advantage.
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A histological method utilizing the optical dissector principle has been developed for determining the absolute numbers of rat hepatocytes in the liver after treatment with phenobarbital (PB). The optical dissector is a technique derived from the “new stereology” used to measure the number of features, in this case hepatocyte nuclear profiles, that are present in a reference volume of tissue. The method has been applied to distinguish between the hepatomegaly that commonly occurs in rodents after treatment with chemicals, due to an increase in the number of cells caused by cell division (hyperplasia), rather than the size of cells (hypertrophy). In the case of PB treatment, the hepatomegaly was found to be partly due to hypertrophy and partly to hyperplasia after 2 weeks of treatment. While the increase in the absolute number of hepatocytes was not significant after 2 weeks, after 12 weeks of treatment with PB the number of hepatocytes was significantly increased, compared to the controls at that time point. PCNA labeling index measurements of liver hepatocytes confirmed that there was a significant increase in the growth fraction of hepatocytes during PB treatment. The induction of hyperplasia can be associated with an increased risk of eventual liver tumor formation, and the distinction of hyperplasia from hypertrophy, using a purely histological method, for the determination of increases in absolute hepatocyte cell numbers, will be useful in assessing whether treatment-related sustained hyperplasia is occurring in the liver, although this methodology could be applied to any organ.
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Conclusions: We conclude that the hepatotrophic activity of the serum is not significantly different in patients with cirrhosis with or without hepatocellular carcinoma. These results suggest that the increased DNA synthesis in hepatocytes of cirrhotic liver with hepatocellular carcinoma might be due to prolfierative factor(s) acting by paracrine or autocrine pathways.
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Research PaperCell proliferation and the aetiology of hepatocellular carcinoma

Summary

J Hepatol

Exp Cell Res

Chem-Biol Interact

Arch Oral Biol

Cancer Lett

Chem-Biol Interact

Life span of liver cells

Arch Intern Med

The normal hepatocyte in division: regeneration of the mammalian liver

Experimental pathology of liver. I. Restoration of liver of white rat following partial surgical removal

Arch Pathol

Exerimental aspects of hepatic regeneration

N Engl J Med

Experimental aspects of hepatic regeneration (concluded)

N Engl J Med

Liver carcinomas induced in rats by single administration of dimethylnitrosamine after partial hepatectomy

J Natl Cancer Inst

Induction of liver cell adenomata in the rat by a single treatment of N-methyl-N-nitrosourea given at various times after partial hepatectomy

Br J Cancer

Liver regeneration and induction of hepatomas in B6AF/B6AF mice by urethan

Cancer Res

Enhancement of urethan induction of hepatomas in mice by prior partial hepatectomy

J Natl Cancer Inst

Rapid emergence of carcinogen-induced initiated hepatocytes in liver carcinogenesis

Am J Pathol

Initiation of liver carcinogenesis requires cell proliferation

Nature

Cytochemical and ultrastructural alterations associated with confluent growth in cell cultures of epithelial-like cells from rat liver

Lab Invest

Cell cycle-specific mutagenesis at the hypoxanthine phosphoribosyltransferase locus in adult rat liver epithelial cells

Cell cycle dependency of oncogenic transformation induced by N-methyl-N′-nitro-N-nitroguanidine in culture

Cancer Res

Cell cycle dependence of chemically induced malignant transformation in vitro

Cancer Res

Hycanthone-induced hepatic changes in mice infected with Schistosoma mansoni

J Pharmacol Exp Ther

Research Paper
Cell proliferation and the aetiology of hepatocellular carcinoma