Transformation of primate cells by chemicals and oncogenes: requirements for multiple factors

Although several chemical carcinogenes have been shown to induce malignant transformation in human cells in culture, the molecular events involved in conversion of normal cells to malignant cells remain unknown at present. Normal human cells seem to be resistant to transformation by a single oncogene unless these cells have been immortalized by chemical carcinogens or DNA tumor virus genes. In some human cell systems, malignant phenotype is expressed after activation of protooncogenes probably through the mechanism of point mutations. Our results represent the first induction of KRAS gene rearrangement in cells of patients with familiar polyposis coli (FPC) treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and 12-0-tetradecanoyl-phorbol-13-acetate (TPA). Whether or not KRAS rearrangement is a prerequisite for transformation in these cells is unknown. The contrast between the response of the FPC cells following treatment with these chemicals compared with that of normal fibroblasts suggests that KRAS gene rearrangement in FPC cells may be considered as a genetic marker for the disease. Studies of transformation with chemicals and oncogenes extended to nonhuman primate--marmoset cells have shown that two viral oncogenes, v-src and v-sis, converted marmoset cells to altered morphology, anchorage independence and immortality in cell culture. The transformed cells, however, lacked tumorigenicity in allogeneic and xenogeneic hosts. In v-src transformed cells additional changes associated with mutations of transforming virus and chromosome rearrangements were necessary for induction of tumorigenicity in allogeneic marmosets. Transformation of marmoset cells by chemical carcinogens depended on the type of target cells. Skin fibroblasts treated with MNNG acquired transformed morphology, anchorage independence and random chromosome aberrations. Kidney cells treated with the same carcinogen remained untransformed, but attained the same characteristics of transformation when exposed to TPA. Neither skin nor kidney transformed cells showed true tumorigenic potential in nude mice.