Tumour promoter alone induces neoplastic transformation of fibroblasts from humans genetically predisposed to cancer

Abstract

Neoplastic transformation is a multi-phase process apparently caused by carcinogens and subject to the influence of promoters^1–4. The naturally occurring phorbol esters^4–6 such as 12-O-tetradecanoyl phorbol-13-acetate (TPA) are potent tumour promoting agents. Through the use of phorbol esters a two-stage process of malignant transformation has been demonstrated in the mouse skin model^4–7 and, more recently, in cell culture systems^8–10. Studies in vitro suggest that TPA reversibly inhibits terminal differentiation in most¹⁰, but not all model systems, and that its function is presumably to increase the probability of expression of the malignant phenotype¹⁰. We have studied the effects of TPA on mutant human fibroblast cell strains derived from individuals with hereditary adenomatosis of the colon and rectum (ACR), an autosomal dominant trait¹¹. We have previously demonstrated in these fibroblasts abnormal phenotypic expressions which often appear in transformed cells^12–17. In these studies, we have assumed that the ACR cell exists in an ‘initiated state’ due to a dominant mutation and that expression of the malignant state might only require treatment with a promoting agent^18,19. This simple experimental protocol provided a novel system for the study of cancer promotion in vitro^20,21. We have now demonstrated, for the first time, the growth in vivo of human mutant cells exposed to TPA alone.