Role of inflammation and inflammatory mediators in colorectal cancer.

Chronic inflammation is a risk factor for several different cancers including colorectal cancer (CRC). However, the mechanisms underlying the contribution of inflammation to cancer remain elusive. Pro-inflammatory mediators such as cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2) contribute to cancer progression. Here, we show that COX-2 is an immediate-early response gene induced by growth factors and pro-inflammatory cytokines and its levels are elevated in human CRCs. Furthermore, we show that COX-2-derived PGE2 promotes colonic tumor growth via silencing certain tumor suppressors and DNA repair genes by DNA methylation in colonic epithelial tumor cells. We also report that C-X-C motif chemokine receptor 2 accelerates colonic inflammation and colitis-associated tumorigenesis by mediating myeloid-derived suppressor cell recruitment to the tumor microenvironment. These findings not only support a rationale to target these pro-inflammatory pathways for cancer prevention and treatment but also provide support for developing new therapeutic approaches to subvert chronic inflammation- and tumor-induced immunosuppression.