Inflammation in gastric cancer: Interplay of the COX‐2/prostaglandin E₂ and Toll‐like receptor/MyD88 pathways

Abstract

Cyclooxygenase‐2 (COX‐2) and its downstream product prostaglandin E2 (PGE2) 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/PGE2 pathway through nuclear factor‐κB activation. A pathway analysis of human gastric cancer shows that both the COX‐2 pathway and Wnt/β‐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/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, and Sox9, which are induced in both gastritis and gastric tumors through a COX‐2/PGE2‐dependent mechanism. In contrast, disruption of Myd88 results in suppression of the 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 maintenance of stemness, could be an effective preventive or therapeutic strategy for gastric cancer.

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

“…Besides, the upregulation of IL‐6 after the coincubation of fibroblasts with H. pylori (cagA+vacA+), we have observed a reciprocal increase in the expression of SDF‐1 mRNA. Both, IL‐6 and SDF‐1 mRNA signals have been shown to potentiate each other, thus accelerating the cytokine network in tumor tissues 64. Consistently, we have observed an increase in mRNAs for IL‐8 suggesting that both, IL‐8 and SDF‐1 could contribute to phenotypic changes observed in myofibroblasts cocultured with H. pylori .…”

“…Consistently, we have observed an increase in mRNAs for IL‐8 suggesting that both, IL‐8 and SDF‐1 could contribute to phenotypic changes observed in myofibroblasts cocultured with H. pylori . SDF‐1 and IL‐8 can synergistically increase endothelial cell proliferation and migration, boosting the angiogenic pathway with IL‐8, predominantly induced in gastric cancer 35, 38, 64. The secretion of IL‐6, FAP, and IL‐8 by CAFs plays pivotal role in macrophage differentiation or M2 polarization resulting in an immunosuppressive microenvironment 36…”

Conformational dynamics of cancer-associated MyD88-TIR domain mutant L252P (L265P) allosterically tilts the landscape toward homo-dimerization

“…Disruption of MyD88 results in suppression of the inflammatory microenvironment in gastric tumors, and TLR2/MyD88 signaling plays a role in maintenance of stemness in normal stem cells as well as in gastric tumor cells (Echizen et al, 2016). MyD88 is a frequently altered gene in many studies (Xia et al, 2015;Cani et al, 2016), with potentially clinically relevant hot spot gain-of-function mutations identified in 71% of diffuse large B-cell lymphomas and 25% of marginal zone lymphomas (Cani et al, 2016).…”

Murine Models of Gastric Corpus Preneoplasia

“…Activated β-catenin activity, but not mutations in APC, is observed in 51% of human intestinal-type gastric cancers 115 . K19-promoter–expressing cells driving Wnt1 expression caused suppression of normal gastric epithelial cell differentiation that was accompanied with increased proliferation and TFF2-positive cells.…”