Abstract 654: Impact of epithelial cell-specific deletion of mPGES-1 on colon carcinogenesis

Abstract

Abstract Activation of the COX-2/mPGES-1/PGE2 signaling axis is a hallmark of many cancers, including colorectal cancer (CRC), prompting the implementation of cancer prevention strategies targeting COX-2 activity. We have shown that targeting the downstream terminal PGE2 synthase, mPGES-1, specifically reduces inducible PGE2 formation without disrupting synthesis of other essential prostanoids. Additionally, global deletion of mPGES-1 (gKO) confers dramatic protection against intestinal cancer development in several mouse models, including the AOM+DSS inflammation-associated colon cancer model. Understanding the role of PGE2 under inflammatory conditions, however, is complicated by the diverse cellular sources and context-dependence of inducible PGE2. To clarify the relative contribution of inducible PGE2 synthesis within distinct cell compartments in colon, we have recently created an mPGES-1 conditional knockout mouse (cKO), where exon 3 of the mPGES-1 gene (mPtges) is floxed for tissue-specific Cre-mediated deletion. To test the role of epithelial-derived PGE2 synthesis on inflammation-associated cancer, we crossed the cKO mice with carbonic anhydrase 1 (Car1)-controlled Cre mice (cKO:Car1), thereby inactivating mPGES-1 function specifically within colonic epithelial cells. Based on our recent observation that global inactivation mPGES-1 sensitizes the colonic mucosa to direct environmental injury, we first examined the sensitivity of the cKO:Car1 mice to DSS-induced acute colitis. Two days after a five-day treatment with 0, 0.5 or 1% DSS, clinical signs of colitis, including the extent of colonic ulceration were determined. Both cKO:Car1 and cKO:WT control mice showed a comparable extent of colonic ulceration, covering ∼60% of the epithelial surface. We next examined the impact of epithelial-specific deletion of mPGES-1 on DSS-induced colon carcinogenesis. KO:Car1 and cKO:WT control mice were treated with a single injection of AOM (10 mg/kg bw) followed by five days of 0, 0.5 or 1% DSS, and colons were examined five weeks after the end of DSS treatment. Surprisingly, epithelial deletion of mPGES-1 in the cKO:Car1 mice failed to provide against cancer development in comparison to the cKO:WT mice. This is the first study to show that genetic inactivation of inducible PGE2 formation within a specific cell lineage (e.g. epithelial cells) does not affect both the extent of acute colonic inflammation nor subsequent inflammation-associated carcinogenesis. Citation Format: Masako Nakanishi, Daniel W. Rosenberg. Impact of epithelial cell-specific deletion of mPGES-1 on colon carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 654.