Cellular biochemistry of the stepwise development of cancer with chemicals: G. H. A. Clowes memorial lecture.

The sequence of possible cellular, tissue, biochemical, and molecular changes that are important during the development of experimental liver cancer with chemicals is reviewed from the viewpoint of the author's experience in carcinogenesis over the past 25 years. The development of a new model for the analysis of liver carcinogenesis, the resistant hepatocyte model, is briefly described, as are the known steps between exposure to an initiating dose of a chemical carcinogen to the appearance of hepatocellular carcinoma. These steps include: (a) the interactions with DNA; (b) the dependence on a round of cell proliferation for initiation; (c) one type of initiated hepatocyte, a resistant hepatocyte; (d) the selection of these new hepatocytes, probably by clonal expansion, to form synchronously the first type of hepatocyte nodules, early nodules; (e) the election of the majority of these nodules to undergo remodeling to normal-appearing liver by differentiation ("redifferentiation"); (f) the election of a minority of early nodules to persist; (g) the slow growth of the few persistent nodules; and (h) the precursor role of persistent nodules in the development of hepatocellular carcinoma. The evidence for such a precursor role includes: (a) the common occurrence in persistent nodules of a subsequent precancerous step, "nodules in nodules"; (b) the occurrence of metastasizing cancer inside nodules without cancer elsewhere in the liver; and (c) the high rate of evolution to cancer of persistent nodules, but not of early nodules, when transplanted to the spleen. Based on the common architecture, organization, blood supply, and biochemical pattern of properties relating to the metabolism of xenobiotics in hepatocyte nodules in six different models of liver carcinogenesis and on the common occurrence of a highly programmed redifferentiation pattern of carcinogen-induced hepatocyte nodules, it is concluded that heterogeneity and diversity seen in many phenotypic properties of cancers, including liver cancers, is preceded by a precursor population that is unusually homogeneous and uniform in phenotype. Thus, the heterogeneity and diversity of cancers are probably late manifestations in carcinogenesis. The available evidence is very suggestive that the hepatocyte nodules are an expression of physiological adaptation to exposure to hazardous xenobiotics and not a form of aberration or mutation. The data also suggest that hepatocyte nodules are an additional pattern of liver differentiation and that liver cancer, to be understood, should be compared with this precursor new state rather than the conventional adult, fetal, or embryonic states.(ABSTRACT TRUNCATED AT 400 WORDS)