Inflammation in gastric cancer: Interplay of the COX-2/PGE2 and TLR/MyD88 pathways

Abstract

Cyclooxygenase 2 (COX-2) and its downstream product prostaglandin E₂ (PGE₂) play a key role in generation of inflammatory microenvironment in tumor tissues. Gastric cancer is closely associated with Helicobacter pylori infection, which stimulates innate immune responses through Toll-like receptors (TLRs), inducing COX-2/PGE₂ pathway through NF-κB activation. A pathway analysis of human gastric cancer shows that both COX-2 pathway and Wnt/β-catenin signaling are significantly activated in tubular-type gastric cancer, while basal levels of these pathways are also increased in other types of gastric cancer. Expression of IL-11, CXCL1, CXCL2 and CXCL5, which play tumor-promoting roles through a variety of mechanisms, is induced in a COX-2/PGE₂ pathway-dependent manner in both human and mouse gastric tumors. Moreover, the COX-2/PGE₂ pathway plays an important role in the maintenance of stemness with expression of stem cell markers, including CD44, Prom1, Cxcr4, and Noxo1, which are induced in both gastritis and gastric tumors via a COX-2/PGE₂-dependent mechanism. In contrast, disruption of Myd88 results in suppression of inflammatory microenvironment in gastric tumors even when the COX-2/PGE₂ pathway is activated, indicating that the interplay of the COX-2/PGE₂ and TLR/MyD88 pathways is needed for inflammatory response in tumor tissues. Furthermore, TLR2/MyD88 signaling plays a role in maintenance of stemness in normal stem cells as well as gastric tumor cells. Accordingly, these results suggest that targeting the COX-2/PGE₂ pathway together with TLR/MyD88 signaling, which would suppress the inflammatory microenvironment and maintain stemness, could be an effective preventive or therapeutic strategy for gastric cancer.

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