title: Altered growth regulation and loss of response to retinoic acid accompany tumorigenic transformation of prostatic cells.
abstract: In vitro models of human prostatic carcinogenesis are increasingly available and include representatives of normal, immortal, tumorigenic and metastatic phenotypes. In this study, growth regulation of immortal, but non-tumorigenic, human papillomavirus-transformed prostatic epithelial cells was compared to that of their tumorigenic variants. These variants were created either by exposure to a carcinogen or by passage through mice. In all cases, tumorigenic cells retained responsiveness to a potent mitogen, epidermal growth factor, and to a potent growth inhibitory factor, 1,25-dihydroxyvitamin D3. Responses to other growth regulatory factors were altered. One set of transformants, CA-HPV-10 and its tumorigenic variants 5019 and 5019IIc, lost their requirement for insulin-like growth factor. Another set, RWPE-1 and its tumorigenic variant 129Nu5002-1 Tu, became unresponsive to growth inhibition by transforming growth factor-beta. The only alteration uniquely correlated with the tumorigenic phenotype was loss of response to retinoic acid. This factor, which inhibits growth of normal and immortal but non-tumorigenic prostatic epithelial cells, had no effect on tumorigenic 129Nu5002-1 Tu cells. We previously reported that conversion of an SV40-immortalized prostatic epithelial cell line to tumorigenicity by introduction of the ras oncogene also resulted in loss of responsiveness to growth inhibitory activity of retinoic acid. 129Nu5002-1 Tu cells, which do not have an altered ras gene, gained the same phenotype. This suggests that loss of inhibition by retinoic acid may be a critical element in the tumorigenic conversion of prostatic epithelial cells.
authors.affiliation: Department of Urology, Stanford University School of Medicine, CA 94305, USA. dpeehl@leland.stanford.edu
authors.forename: D M
authors.initials: DM
authors.lastname: Peehl
authors.forename: R G
authors.initials: RG
authors.lastname: Sellers
authors.forename: P
authors.initials: P
authors.lastname: Arnstein
authors.forename: H F
authors.initials: HF
authors.lastname: Kung
authors.forename: J S
authors.initials: JS
authors.lastname: Rhim
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008934:Mitogens / Q000494:pharmacology; D027383:Papillomaviridae / Q000378:metabolism; D011003:Ploidies; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D006131:Growth Inhibitors; D007527:Isoenzymes; D008934:Mitogens; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D002117:Calcitriol