Abstract 1519: Peroxisome Proliferator-Activated Receptor ≤ Promotes Colonic Inflammation and Inflammation-Associated Tumorigenesis

Abstract Although epidemiologic and experimental evidence strongly indicates chronic inflammation as a risk factor for cancer, it remains unclear how chronic inflammation contributes carcinogenesis. Peroxisome proliferator-activated receptor ≤ (PPARδ) is one member of PPAR family that belongs to the nuclear hormone receptor superfamily and is also ligand-dependent transcription factor. Although PPARδ has been shown to be involved in chronic inflammation and the progression of hereditary and sporadic CRC, its role in inflammation-induced carcinogenesis is not defined. The aim of our present study was to determine whether PPARδ contributes to the pathogenesis of colonic inflammation and inflammation-associated carcinogenesis. Here we present genetic evidence demonstrating that deletion of PPARδ diminishes colonic inflammation accompanied with reducing infiltration of immune cells and the expression of pro-inflammatory chemokines and cytokines in a mouse model of colitis. These PPARδ-dependent chemokines are responsible for recruitment of leukocytes from the circulation to local inflammatory sites and the tumor microenvironment. Our results further reveal that activation of PPARδ induces COX-2 expression in colonic epithelial cells. Importantly, COX-2-derived PGE2 stimulates macrophages to produce pro-inflammatory chemokines and cytokines. More intriguingly, loss of PPARδ attenuated colonic chronic inflammation and colitis-associated adenoma growth via PGE2 signaling in two mouse models of colitis-associated tumorigenesis. Collectively, our results demonstrate that PPARδ promotes colonic chronic inflammation and colitis-associated tumor growth via a PGE2 signaling which mediates the crosstalk between tumor epithelial cells and macrophages. Our data further supports the notion that the existence of crosstalk between PPARδ and COX-2 signaling in CRC progression. These findings indicate that PPARδ plays a pivotal role in connecting colonic inflammation to cancer progression and may represent a potential therapeutic target for prevention or treatment of colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1519. doi:1538-7445.AM2012-1519