DIFFERENTIAL RESPONSE OF PREMALIGNANT EPITHELIAL-CELL CLASSES TO PHORBOL ESTER TUMOR PROMOTERS AND TO DEOXYCHOLIC-ACID

Abstract

The effects of 2 agents, 12-O-tetradecanoylphorbol-13-acetate (TPA) and deoxycholic acid (DOC), which act as tumor promoters in the gastrointestinal epithelium of experimental animals, were compared using primary cultures of human premalignant colonic epithelial cells at different stages in tumor progression. DOC and TPA enhanced the size of the proliferative fraction in colonies of early-stage premalignant cells, with DOC providing more stimulation. TPA-treated intermediate- and late-stage premalignant cells elongated and then disrupted the monolayer by forming rills several cells in thickness and then multicellular clusters. This multilayering was reminiscent of the areas of carcinoma found within adenomas. DOC had no such effects on morphology. Cell clustering was concomitant with secretion of a protease with characteristics of a plasminogen activator. Premalignant cells secreted several-fold higher levels of protease in response to TPA than did TPA-treated primary cultures of colonic adenocarcinomas or established colon carcinoma cell lines. DOC and TPA seem to act sequentially during tumor promotion. Cell clustering and protease release may be associated with the transition of premalignant epithelial cells to colonic carcinoma.