Phenotypic Cellular Changes in Multistage Carcinogenesis

Abstract

The concept that carcinogenesis is a multistage process comprising initiation, promotion and progression has mainly been inferred from experiments in which certain operational steps were used to induce tumors of the skin, liver or other tissues (Pitot, 1988). However, an unequivocal explanation of initiation, promotion and progression in biological terms has not been reached by this experimental approach. The more recent discovery of characteristic sequential cellular changes during neoplastic development in different organs, especially in the liver, has opened a new approach for the distinction of stages of carcinogenesis which can now be defined by biological rather than operational criteria (Bannasch, 1988). In many tissues, preneoplastic foci composed of phenotypically altered cells emerging weeks and months before benign or malignant tumors appear have been described (Carter, 1984; IARC, 1986). The diagnosis of foci implies that the altered cell populations are perfectly integrated into the normal architecture of the respective tissue and do not show any expansive growth. At the histological level, preneoplasia may be defined as a phenotypically altered cell population which has no obvious neoplastic nature but has a high probability of progressing to a benign or malignant neoplasm (Bannasch, 1986). Frequently, the transition from preneoplastic foci into benign or malignant tumors is associated with additional changes of the cellular phenotype. A precise knowledge of the sequence of phenotypic cellular changes during carcinogenesis is not only a prerequisite for the elucidation of the mechanism of oncogenesis but is also of increasing importance in the assessment of the carcinogenic risk caused by chemicals. In the past few years, preneoplastic lesions have been used with advantage as end points in carcinogenicity testing in a number of laboratories. Sequential cellular changes induced with chemicals in the liver and kidney of rodents will be presented as examples for modulations of the cellular phenotype during carcinogenesis which may help to unravel a general principle underlying the phenotypic diversity of preneoplastic and neoplastic cells, and may improve the evaluation of bioassays for carcinogenicity.