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. The naturally occurring phorbol esters 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 and, more recently, in cell culture systems. Studies in vitro suggest that TPA reversibly inhibits terminal differentiation in most, but not all model systems, and that its function is presumably to increase the probability of expression of the malignant phenotype. 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 trait. We have previously demonstrated in these fibroblasts abnormal phenotypic expressions which often appear in transformed cells. 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. This single experimental protocol provided a novel system for the study of cancer promotion in vitro. We have now demonstrated, for the first time, the growth in vivo of human mutant cells exposed to TPA alone.