Dubois Raymond N
Trans Am Clin Climatol Assoc. 2014;125:358-72; discussion 372-3.
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.
慢性炎症是包括结直肠癌（CRC）在内的几种不同癌症的危险因素。然而，炎症促进癌症发生的潜在机制仍不清楚。环氧化酶2（COX-2）和前列腺素E2（PGE2）等促炎介质有助于癌症进展。在此，我们表明COX-2是一种由生长因子和促炎细胞因子诱导的早期反应基因，其水平在人类结直肠癌中升高。此外，我们表明COX-2衍生的PGE2通过结肠上皮肿瘤细胞中的DNA甲基化沉默某些肿瘤抑制因子和DNA修复基因来促进结肠肿瘤生长。我们还报告称，C-X-C基序趋化因子受体2通过介导骨髓来源的抑制性细胞募集到肿瘤微环境中，加速结肠炎症和结肠炎相关的肿瘤发生。这些发现不仅支持了针对这些促炎途径进行癌症预防和治疗的基本原理，也为开发新的治疗方法以颠覆慢性炎症和肿瘤诱导的免疫抑制提供了支持。
