title: Myeloid Differentiation Factor 88 Signaling in Bone Marrow-Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment.
abstract: It has been established that COX-2 and downstream signaling by prostaglandin E2 (PGE2) play a key role in tumorigenesis through generation of inflammatory microenvironment. Toll-like receptor (TLR) signaling through myeloid differentiation factor 88 (MyD88) also regulates inflammatory responses in tumors. However, the relationship between these distinct pathways in tumorigenesis is not yet fully understood. We herein investigated the role of MyD88 in gastric tumorigenesis using Gan mice, which develop inflammation-associated gastric tumors due to the simultaneous activation of the COX-2/PGE2 pathway and Wnt signaling. Notably, the disruption of Myd88 in Gan mice resulted in the significant suppression of gastric tumorigenesis with the inhibition of inflammatory responses, even though COX-2/PGE2 pathway is constitutively activated. Moreover, Myd88 disruption in bone marrow-derived cells (BMDCs) in Gan mice also suppressed inflammation and tumorigenesis, indicating that MyD88 signaling in BMDCs regulates the inflammatory microenvironment. We also found that expression of Tlr2 and its coreceptor Cd14 was induced in tumor epithelial cells in Gan mice, which was suppressed by the disruption of Myd88. It has already been shown that TLR2/CD14 signaling is important for stemness of intestinal epithelial cells. These results indicate that MyD88 in BMDCs, together with COX-2/PGE2 pathway, plays an essential role in the generation of the inflammatory microenvironment, which may promote tumorigenesis through induction of TLR2/CD14 pathway in tumor epithelial cells. These results suggest that inhibition of TLR/MyD88 signaling together with COX-2/PGE2 pathway will be an effective preventive strategy for gastric cancer.
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. Research Fellow of Japan Society for the Promotion of Science (JSPS), 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: Kanae
authors.initials: K
authors.lastname: Echizen
authors.affiliation: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Oshima
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, Clayton, Australia.
authors.forename: Liang
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.
authors.forename: Natthiya
authors.initials: N
authors.lastname: Sakulsak
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: Faculty of Electrical and Computer Engineering, Institute of Science and Engineering, Kanazawa University, Kanazawa, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, Clayton, Australia.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. AMED-CREST, AMED, Japan Agency for Medical Research and Development, Tokyo, Japan. oshimam@staff.kanazawa-u.ac.jp.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oshima
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D011230:Precancerous Conditions / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D047368:Tumor Burden; D014407:Tumor Cells, Cultured
chemical_list: D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D051546:Cyclooxygenase 2; D015232:Dinoprostone