Dissociation of mitogenesis and late-stage promotion of tumor cell phenotype by phorbol esters: mitogen-resistant variants are sensitive to promotion.
The JB-6 mouse epidermal cell line has been used as a model system for studying the mechanism of late-stage promoter-dependent preneoplastic progression. The studies reported here are concerned with determining whether there is a requirement for mitogenic stimulation in promotion of anchorage independence and tumorigenicity in JB-6 cells. Such a requirement would predict that variants selected for 12-O-tetradecanoylphorbol 13-acetate (TPA) mitogen resistance would also be promotion resistant. Promotion-responsive cell lines have been selected for resistance to TPA-induced mitogenic stimulation at plateau density by cotreatment with colchicine and removal of mitogen-responsive colchicine-detached cells. The selected TPA-resistant population of cells showed a mitogenic response that was diminished by a factor of four but showed no diminution in the promotion-of-anchorage-independence response to TPA. Mitogen-resistant clonal lines derived from the selected population fell into three phenotypic classes when assayed in soft agar: (i) anchorage-independent transformants; (ii) variants resistant to promotion of anchorage independence by TPA; and (iii) variants sensitive to promotion by TPA. The existence of the latter class (i.e., the mitogen-resistant promotable variants) indicates a lack of obligatory causal relationship between TPa-induced mitogenesis and late-stage promotion and, thereby suggests that the two events can be dissociated.
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells; D003078:Colchicine / Q000494:pharmacology; D004351:Drug Resistance; D014644:Genetic Variation; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D010641:Phenotype; D010704:Phorbols / Q000494:pharmacology*; D012867:Skin; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D008934:Mitogens; D010704:Phorbols; D013755:Tetradecanoylphorbol Acetate; D003078:Colchicine