title: Mast cell-derived prostaglandin D2 inhibits colitis and colitis-associated colon cancer in mice.
abstract: Compared with prostaglandin E2, which has an established role in cancer, the role of the COX metabolite prostaglandin D2 (PGD2) in chronic inflammation leading to tumorigenesis is uncertain. In this study, we investigated the role of PGD2 in colitis and colitis-associated colon cancer (CAC) using genetically modified mice and an established model of inflammatory colon carcinogenesis. Systemic genetic deficiency in hematopoietic PGD synthase (H-PGDS) aggravated colitis and accelerated tumor formation in a manner associated with increased TNFα expression. Treatment with a TNFα receptor antagonist attenuated colitis regardless of genotype. Histologic analysis revealed that infiltrated mast cells strongly expressed H-PGDS in inflamed colons. Mast cell-specific H-PGDS deficiency also aggravated colitis and accelerated CAC. In contrast, treatment with a PGD2 receptor agonist inhibited colitis and CAC. Together, our results identified mast cell-derived PGD2 as an inhibitor of colitis and CAC, with implications for its potential use in preventing or treating colon cancer.
authors.affiliation: Authors' Affiliations: Departments of Animal Radiology and Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo; and Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Iwanaga
authors.affiliation: Authors' Affiliations: Departments of Animal Radiology and Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo; and Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Authors' Affiliations: Departments of Animal Radiology and Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo; and Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Authors' Affiliations: Departments of Animal Radiology and Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo; and Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Aritake
authors.affiliation: Authors' Affiliations: Departments of Animal Radiology and Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo; and Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.affiliation: Authors' Affiliations: Departments of Animal Radiology and Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo; and Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.affiliation: Authors' Affiliations: Departments of Animal Radiology and Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo; and Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
authors.affiliation: Authors' Affiliations: Departments of Animal Radiology and Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo; and Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan amurata@mail.ecc.u-tokyo.ac.jp.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Murata
mesh_terms: D000818:Animals; D003092:Colitis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005838:Genotype; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015230:Prostaglandin D2 / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D054834:Lipocalins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D014409:Tumor Necrosis Factor-alpha; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor