Oncogenic potential in fibroblasts from individuals genetically predisposed to cancer

Abstract

There is now considerable evidence to suggest that genetic factors can influence the incidence of cancer. Although expression of this susceptibility to cancer appears to be tissue-specific, the normal skin fibroblasts from individuals predisposed to cancer (predisposed fibroblasts) have also been shown to express the risk of the target cell in the development of cancer. In the context of the 2-stage theory of chemical carcinogenesis predisposed fibroblasts may, therefore, exist in a pre-neoplastic or initiated state. The purpose of the present study was to determine whether predisposed fibroblasts would be oncogenically transformed in vitro by the tumor promoter 12- O-tetradecanoylphorbol-13-acetate (TPA) alone. TPA treatment induced similar changes in cellular morphology, cytoskeleton, and epidermal growth-factor binding, in predisposed and normal cells. None of these cell lines acquired anchorage-independent growth or an unlimited growth potential in culture after chronic application of TPA. Fluorescent microscopy with an F-actin probe, in the absence of TPA, showed a disorganization of the microfilament and intermediate filament network in skin fibroblasts from individuals with familial polyposis coli, hereditary and sporadic retinoblastoma, basal cell nevus syndrome, and Gardner's syndrome, as compared to normal skin fibroblasts. Single and 2-dimensional electrophoresis also indicated that the incorporation of 35S-methionine into actin in predisposed fibroblasts was 2-fold greater than in normal fibroblasts, and the turnover rate of actin in predisposed fibroblasts was less than 5 h, compared to 48 h in normal fibroblasts. These observations clearly suggest that predisposed fibroblasts may not exist in a pre-neoplastic or initiated state, and that the mechanism of genetic susceptibility to cancer may be different from that of chemical carcinogenesis. In contrast, the results of this study indicate that genetic susceptibility to a variety of cancers may be associated with a rapid turnover of actin and a disorganization of the microfilament and intermediate filament networks.