Inflammation in gastric cancer: Interplay of the COX-2/prostaglandin E sub(2) and Toll-like receptor/MyD88 pathways

Cyclooxygenase-2 (COX-2) and its downstream product prostaglandin E sub(2) (PGE sub(2)) play a key role in generation of the 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/PGE sub(2) pathway through nuclear factor- Kappa B activation. A pathway analysis of human gastric cancer shows that both the COX-2 pathway and Wnt/ beta -catenin signaling are significantly activated in tubular-type gastric cancer, and basal levels of these pathways are also increased in other types of gastric cancer. Expression of interleukin-11, chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and CXCL5, which play tumor-promoting roles through a variety of mechanisms, is induced in a COX-2/PGE sub(2) pathway-dependent manner in both human and mouse gastric tumors. Moreover, the COX-2/PGE sub(2) pathway plays an important role in the maintenance of stemness with expression of stem cell markers, including CD44, Prom1, and Sox9, which are induced in both gastritis and gastric tumors through a COX-2/PGE sub(2)-dependent mechanism. In contrast, disruption of Myd88 results in suppression of the inflammatory microenvironment in gastric tumors even when the COX-2/PGE sub(2) pathway is activated, indicating that the interplay of the COX-2/PGE sub(2) 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/PGE sub(2) pathway together with TLR/MyD88 signaling, which would suppress the inflammatory microenvironment and maintenance of stemness, could be an effective preventive or therapeutic strategy for gastric cancer. Chronic inflammation plays an tumor-promoting role in gastric cancer development. We review the latest understanding about the roles of COX-2/PGE sub(2)-associated inflammation in gastric tumorigenesis and its connection to TLR/MyD88-related innate immune responses.