Mast Cell-Produced Prostaglandin D2 prevents Colitis and Colitis-Related Colon Cancer in Mice

Introduction & Aim: Colorectal cancer is the cause of death for 600 million people per year in the world and patient numbers are still increasing. Inherited factors and/or daily habits such as smoking or alcohol consumption, as well as bacterial/viral infections, cause bowel inflammation, the prolongation of which leads to tumorigenesis. PGD2 is one PG produced by activation of COX and PGD synthase. Mast cells, macrophages, and helper T (TH)2-type lymphocytes are reported to express hematopoietic PGD synthase (H-PGDS) and potentially produce PGD2. 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. Results: 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. Conclusion: 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.