In vitro studies of the possible mechanisms whereby tumour promoters mediate their responses

Carcinogenesis is commonly considered to be a multi-step process, comprising "initiation" and "promotion" events. Skin fibroblasts from patients with hereditary retinoblastoma (RB) and familial polyposis coli (FPC) were chosen for study since their predisposition to the tumour may be due to an inherited "initiation" event which is present in every somatic cell. Thus, one might predict that skin fibroblasts from these patients might exhibit an increased susceptibility to in vitro transformation, by either tumour promoters alone or by the complete carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). In the case of skin fibroblasts from RB patients, transformation as measured by the ability of cells to grow in semi-solid medium and their migration in collagen gels, did not occur with either class of agent. However, experiments involving skin fibroblasts from FPC patients, showed these cells to grow in semi-solid medium following treatment with the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) alone, although their pattern of migration in collagen gels was unchanged and they were non-tumorigenic in nude mice. The clones which grew in semi-solid medium were also unaltered in terms of their migration in collagen gels and tumorigenicity in nude mice and were considered not to be completely transformed. These results are discussed in relation to theories that tumour promoters are only involved in cell selection and clonal expansion of initiated cells a second "mutational" event being required for complete transformation.