title: 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.
authors.affiliation: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.|AMED-CREST, AMED, Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Echizen
authors.affiliation: Faculty of Electrical and Computer Engineering, Institute of Science and Engineering, Kanazawa University, Kanazawa, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Hirose
authors.affiliation: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.|Division of Gene Regulation, Institute for Advanced Medical Research, Keio University, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.|AMED-CREST, AMED, Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oshima
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000235:genetics* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D009363:Neoplasm Proteins; D051195:Toll-Like Receptor 2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone
keywords: Gastric cancer; inflammation; innate immunity; microenvironment; stemness