Development and growth of early preneoplastic lesions induced in the liver by chemical carcinogens.

Proliferative events are significant at all stages of malignant transformation in the liver (Rabes 1979). Hepatocytes at a rather limited stage of the cell cycle, i.e. the late G1 and early S phase, are a preferred target for the initiating action of chemical carcinogens in spite of an increased rapid repair activity during S phase. Fixation of promutagenic lesions by subsequent DNA synthesis might belong to the critical events of initiation. During preneoplastic development of the initiated cell clone, proliferative processes appear to be decisive for further progression into malignancy. Several cycles of replication not only increase the size of the preneoplastic clone, but may represent an intrinsic prerequisite for the ultimate expression of the malignant phenotype in a possibly very small fraction or even in a single hepatocyte from the progeny of the initiated cell. It remains an open problem whether evolution from a single initiated hepatocyte into a malignant subclone involves any additional mutations (Armitage and Doll 1954; Knudson 1977; Emmelot and Scherer 1980) or is rather due to an increased genetic instability (Cairns 1981; Klein 1981) of the particular preneoplastic population. It is tempting to speculate about the possibility that, in analogy to human cancer-prone diseases, it is a reduced DNA repair capacity (xeroderma pigmentosum) and/or chromosomal instability (Bloom's syndrome) that renders an enzyme-aberrant preneoplastic hepatocellular clone a high-risk population for malignant progression. Experiments in progress will test the validity of these concepts.