Abstract PL05-01: Inflammatory mediators, tumor microenvironment, and progression of colorectal cancer

Abstract

Abstract Population studies and experimental observations indicate that chronic inflammation and diet are risk factors for colorectal cancer (CRC). The mechanisms by which these factors contribute to the development of cancer are poorly understood. A large body of work has shown that use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the relative risk for developing colorectal cancer (CRC) by up to 40-50%. NSAIDs exert some of their anti-inflammatory and anti-tumor effects by targeting cyclooxygenase enzymes (COX-1 and COX-2). Prostaglandin E2 (PGE2) is a pro-inflammatory mediator that promotes colorectal cancer progression. The aim of our present study was to determine the underlying mechanisms by which PGE2 affects progression of CRC. We have found a novel function of pro-inflammatory PGE2 in regulating DNA methylation in colorectal cancer. Our in vitro and in vivo studies demonstrated that PGE2 treatment silenced certain tumor suppressors and DNA repair genes such as CDKN2B (p15), CNR1, MGMT, and MLH1 by enhancing CpG island methylation of their promoter via inducing DNMT1 and DNMT3B expression. We also found that a demethylating agent inhibited the effect of PGE2 on promoting tumor growth in a mouse model of colorectal cancer, indicating that PGE2 accelerates tumor growth via regulating DNA methylation. Furthermore, combined treatment of Apcmin/+ mice with inhibitors of COX-2 and DNA methylation has more effectively anti-tumor effects than either single agent alone. To further determine the clinical relevance of our in vitro and in vivo results, we examine the relationship between COX-2 expression, PGE2 levels, DNMT1/3b expression, CpG island methylation status and expression of these tumor suppressors and DNA repair genes in human colorectal carcinomas. The levels of COX-2 and PGE2 positively correlated with DNMT1 and DNMT3B expression in these human colorectal cancer specimens. Importantly, the PGE2 levels as well as COX-2, DNMT1, and DNMT3B expression are also positively associated with the CpG island methylation in the promoters of these tumor suppressors and DNA repair genes. We also observed a specific type of immune cells (MDSCs) attracted to the tumor microenvironment by the presence of PGE2. Citation Format: Raymond N. DuBois. Inflammatory mediators, tumor microenvironment, and progression of colorectal cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr PL05-01.