Cellular and molecular mechanisms of carcinogenesis in lining epithelia.
Lining epithelia are the major target sites for cancer in man. The induction of carcinomas on mouse skin following the application of chemical agents is the prototype model for cancer development in a lining epithelium. In this tissue, the earliest carcinogen-induced lesion, initiation, results in an epidermal cell with an altered program of terminal differentiation. Such "initiated" cells can be selected in culture since normal cells can be induced to terminally differentiate by Ca2+ or phorbol ester tumor promoters and will be lost from the cultured population. In situ, the growth of initiated cells is suppressed by surrounding normal cells. The differentiation-inducing effects of tumor promoters on normal cells, therefore, are essential in providing a selective growth advantage which results in the clonal selection of initiated cells and the evolution of a papilloma. This benign tumor is the pathological manifestation of the initiated phenotype. The c-rasH gene appears to be one target for initiating carcinogens, as a mutated and activated form of this gene is frequently isolated from chemically induced papillomas. Furthermore, the introduction of an activated rasH gene into cultured normal keratinocytes produces papillomas when the cells are transplanted as a skin graft in vivo. After a long latency period, some papillomas convert to carcinomas. Since the conversion process can be accelerated and the frequency enhanced by mutagens, it is presumed that genetic damage in papilloma cells plays an important role in malignant conversion. In papilloma cells lacking an activated rasH oncogene, introduction of an exogenous rasH oncogene leads to malignant progression. Thus, mutation and activation of this gene can contribute to early or late events in skin carcinogenesis. In either case it appears that the rasH oncogene must cooperate with other genetic changes to contribute to the malignant phenotype.
Yuspa
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Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892.
D000818:Animals; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004847:Epithelial Cells
D002273:Carcinogens