Transgenic cyclooxygenase-2 overexpression sensitizes mouse skin for carcinogenesis.
Genetic and pharmacological evidence suggests that overexpression of cyclooxygenase-2 (COX-2) is critical for epithelial carcinogenesis and provides a major target for cancer chemoprevention by nonsteroidal antiinflammatory drugs. Transgenic mouse lines with keratin 5 promoter-driven COX-2 overexpression in basal epidermal cells exhibit a preneoplastic skin phenotype. As shown here, this phenotype depends on the level of COX-2 expression and COX-2-mediated prostaglandin accumulation. The transgenics did not develop skin tumors spontaneously but did so after a single application of an initiating dose of the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Long-term treatment with the tumor promoter phorbol 12-myristate 13-acetate, as required for tumorigenesis in wild-type mice, was not necessary for transgenics. The ratios of squamous cell carcinomas to papillomas and of sebaceous gland adenomas to papillomas plus squamous cell carcinomas were increased markedly in transgenic mice treated with DMBA alone compared with DMBA/phorbol 12-myristate 13-acetate-treated transgenic and wild-type mice. Thus, COX-2 overexpression, which leads to high levels of epidermal prostaglandin E(2), prostaglandin F(2alpha), and 15-deoxy(delta12,14)-PGJ(2), is insufficient for tumor induction but transforms epidermis into an "autopromoted" state, i.e., dramatically sensitizes the tissue for genotoxic carcinogens.
Muller-Decker
Karin
K
Research Program Tumor Cell Regulation, Deutsches Krebsforschungszentrum, and Department of Pathology, Ruprecht-Karls-University, 69120 Heidelberg, Germany. K.Mueller-Decker@DKFZ-Heidelberg.de
Neufang
Gitta
G
Berger
Irina
I
Neumann
Melanie
M
Marks
Friedrich
F
Furstenberger
Gerhard
G
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000236:Adenoma / Q000209:etiology; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000209:etiology; D000068579:Celecoxib; D003043:Cocarcinogenesis; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010212:Papilloma / Q000209:etiology; D010641:Phenotype; D011230:Precancerous Conditions / Q000209:etiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis; D011720:Pyrazoles; D012867:Skin / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D012878:Skin Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D002273:Carcinogens; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011453:Prostaglandins; D011720:Pyrazoles; D013449:Sulfonamides; D015127:9,10-Dimethyl-1,2-benzanthracene; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D013755:Tetradecanoylphorbol Acetate