Liver tumour promotion by chemicals: models and mechanisms.

DS Sarma, PM Rao, S Rajalakshmi - Cancer surveys, 1986 - europepmc.org
DS Sarma, PM Rao, S Rajalakshmi
Cancer surveys, 1986europepmc.org
Tumour promotion is defined as the process whereby a carcinogen initiated organ develops
focal proliferations such as nodules, polyps or papillomas, one or more of which become
precursors for subsequent steps in the carcinogenic process. The available models for a
sequential analysis of carcinogenesis in liver have been examined within the framework of
this operational definition with respect to the models themselves as well as the promoted
hepatocytes. Using initiation-promotion protocols, several promoters which differ in the …
Tumour promotion is defined as the process whereby a carcinogen initiated organ develops focal proliferations such as nodules, polyps or papillomas, one or more of which become precursors for subsequent steps in the carcinogenic process. The available models for a sequential analysis of carcinogenesis in liver have been examined within the framework of this operational definition with respect to the models themselves as well as the promoted hepatocytes. Using initiation-promotion protocols, several promoters which differ in the biological responses they elicit have been identified. The key issue in promotion pertains to the mechanisms involved in the focal proliferation of the initiated hepatocytes. The resistant hepatocyte model and perhaps the phenobarbital model suggest that focal proliferation of the initiated hepatocyte is induced by exerting a selective mitoinhibitory effect on the surrounding cells while permitting the initiated hepatocyte to respond to the proliferative stimulus, whether it is exogenous or endogenous. The promoter orotic acid, on the other hand, is a natural precursor of pyrimidine nucleotide biosynthesis and is neither an inducer nor an inhibitor of liver cell proliferation but it creates an imbalance in cellular nucleotide pools. Since nucleotides are intermediates in DNA synthesis as well as in the glycosylation of proteins and lipids including that of membranes, it has been postulated that the promotional effect of orotic acid is mediated through this imbalance affecting both DNA and membranes. There is some experimental evidence for this. The importance of this hypothesis is that it raises the possibility of achieving promotion in several organs by disturbing the normal nucleotide pool patterns. Indeed orotic acid has also been found to promote duodenal cancer. The finding that hepatic nodules, regardless of how they have been promoted, exhibit a common biochemical pattern with resistance to several agents has raised some important issues. For example, what is the basis for the resistant phenotype and how is it related to cancer development? Are all initiated hepatocytes identical? If not, do all promoters exert their effect on the same population of initiated hepatocytes? Is the heterogeneity of the initiated hepatocyte population generated by the carcinogen due to the induction of more than one critical lesion: a primary lesion responsible for initiation and secondary lesions in which different types of initiated cells are selected by different promoters?(ABSTRACT TRUNCATED AT 250 WORDS)
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