Mast Cell-Derived Prostaglandin D2 Inhibits Colitis and Colitis-Associated Colon Cancer in Mice

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-06, Vol.74 (11), p.3011-3019
• Main Authors: IWANAGA, Koichi, NAKAMURA, Tatsuro, MAEDA, Shingo, ARITAKE, Kosuke, HORI, Masatoshi, URADE, Yoshihiro, OZAKI, Hiroshi, MURATA, Takahisa
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Colitis - drug therapy; Colitis - genetics; Colitis - metabolism; Colitis - pathology; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Gastroenterology. Liver. Pancreas. Abdomen; Genotype; Intramolecular Oxidoreductases - deficiency; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; Lipocalins - genetics; Lipocalins - metabolism; Mast Cells - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pharmacology. Drug treatments; Prostaglandin D2 - genetics; Prostaglandin D2 - metabolism; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Receptors, Prostaglandin - genetics; Receptors, Prostaglandin - metabolism; Signal Transduction; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-13-2792

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.