Non-cell autonomous effects of targeting inducible PGE2 synthesis during inflammation-associated colon carcinogenesis

Microsomal PGE(2) synthase-1 (mPGES-1), the terminal enzyme in the formation of inducible PGE(2), represents a potential target for cancer chemoprevention. We have previously shown that genetic abrogation of mPGES-1 significantly suppresses tumorigenesis in two preclinical models of intestinal cancer. In this study, we examined the role of mPGES-1 during colon tumorigenesis in the presence of dextran sulfate sodium (DSS)-induced inflammatory microenvironment. Using Apc(Delta 14/+) in which the mPGES-1 gene is either wild-type (D14: WT) or deleted (D14: KO), we report that mPGES-1 deficiency enhances sensitivity to acute mucosal injury. As a result of the increased epithelial damage, protection against adenoma formation is unexpectedly compromised in the D14: KO mice. Examining the DSS-induced acute injury, cryptal structures are formed within inflamed areas of colonic mucosa of both genotypes that display the hallmarks of early neoplasia. When acute epithelial injury is balanced by titration of DSS exposures, however, these small cryptal lesions progress rapidly to adenomas in the D14: WT mice. Given that mPGES-1 is highly expressed within the intestinal stroma under the inflammatory conditions of DSS-induced ulceration, we propose a complex and dual role for inducible PGE(2) synthesis within the colonic mucosa. Our data suggest that inducible PGE(2)Z is critical for the maintenance of an intact colonic epithelial barrier, while promoting epithelial regeneration. This function is exploited during neoplastic transformation in Apc(Delta 14/+) mice as PGE(2) contributes to the growth and expansion of the early initiated cryptal structures. Taken together, inducible PGE(2) plays a complex role in inflammation-associated cancers that requires further analysis. Inducible PGE(2) production by mPGES-1 is critical for the colonic mucosal homeostasis. This function is exploited in the presence of the neoplastic transformation in Apc(Delta 14/+) mice as PGE(2) contributes to the growth and expansion of the early cryptal structures.