Specific growth response of ras-transformed embryo fibroblasts to tumour promoters

Chemical carcinogenesis is a process involving multiple steps, as shown in several in vivo experimental systems¹. Two early steps have been well characterized: initiation, achieved by a single, subthreshold dose of a carcinogen, and promotion, induced by repetitive treatments with a non-carcinogenic tumour promoter. At the cellular level, establishment of the transformed phenotype is also a multi-step process and activation of several, independent genes appears to be required^2-4. Here we show that, like initiated cells, primary rat embryo fibroblasts (REFs) containing a ras but not a myc oncogene, are strongly and specifically stimulated to grow by tumour promoters. In the presence of these promoters, ras-containing REFs acquire the ability to overgrow normal cells in the monolayer and to form foci with 100% efficiency. Similar to the in vivo situation, promoter effects can be blocked by the concomitant application of retinoic acid.