Tumor formation in a mouse model of colitis-associated colon cancer does not require COX-1 or COX-2 expression.
Cyclooxygenase-2 (COX-2), a key enzyme of prostanoid biosynthesis, plays an important role in both hereditary and spontaneous colon cancer. Individuals with ulcerative colitis are also at high risk for colorectal cancer. To investigate the role of Cox-2 in colitis-associated colon cancer, we subjected Cox-2 luciferase-knock-in mice and Cox-2-knockout mice to a well-known mouse model of colitis-associated cancer in which animals are treated with a single-azoxymethane (AOM) injection followed by dextran sulfate sodium (DSS) administration. Tumors induced by AOM and DSS expressed significantly higher Cox-2 levels when compared with surrounding areas of colon, as detected both by luciferase reporter gene expression driven from the endogenous Cox-2 promoter and by western blotting of COX-2 protein in Cox-2 luciferase heterozygous knock-in mice. Immunofluorescence revealed that tumor stromal fibroblasts, macrophages and endothelial cells express COX-2 protein. In contrast, little COX-2 expression was observed in myofibroblasts or epithelial cells. Despite a significant elevation of COX-2 expression in AOM/DSS-induced colon tumors in wild-type mice, similar tumors developed in AOM/DSS-treated Cox-2(-/-)- and Cox-1(-/-)-knockout mice. These results indicate that cyclooxygenase-derived prostanoids are not major players in colitis-associated cancer. In contrast, tumor formation induced by multiple injections of AOM (with no DSS-induced colitis) did not occur in Cox-2(-/-)-knockout mice. Our data suggest that the mechanism of colorectal tumor promotion in colitis-associated cancer differs from the mechanism of tumor promotion for hereditary and sporadic colorectal cancer.
Ishikawa
Tomo-O
TO
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
Herschman
Harvey R
HR
D000818:Animals; D001397:Azoxymethane; D003092:Colitis / Q000150:complications*; D003110:Colonic Neoplasms / Q000209:etiology*; D051545:Cyclooxygenase 1 / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D016264:Dextran Sulfate; D017491:Genes, APC / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology
D008565:Membrane Proteins; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016264:Dextran Sulfate; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D001397:Azoxymethane