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

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.

[1]  妹尾 浩.  Cyclooxygenase 2- and prostaglandin E2 receptor EP2-dependent angiogenesis in ApcΔ716 mouse intestinal polyps , 2002 .

[2]  L. Zon,et al.  Genetic Interaction of PGE2 and Wnt Signaling Regulates Developmental Specification of Stem Cells and Regeneration , 2009, Cell.

[3]  M. Karin,et al.  IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. , 2009, Cancer cell.

[4]  S. Narumiya,et al.  Cyclooxygenase 2- and prostaglandin E2 receptor EP2-dependent angiogenesis in ApcΔ716 mouse intestinal polyps , 2002 .

[5]  T. Taniguchi,et al.  Myeloid Differentiation Factor 88 Signaling in Bone Marrow–Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment , 2016, Cancer Prevention Research.

[6]  T. Mak,et al.  Modulation of oxidative stress as an anticancer strategy , 2013, Nature Reviews Drug Discovery.

[7]  G. Mor,et al.  TLR2 enhances ovarian cancer stem cell self-renewal and promotes tumor repair and recurrence , 2013, Cell cycle.

[8]  J. Pollard,et al.  Immune cell promotion of metastasis , 2015, Nature Reviews Immunology.

[9]  M. Thun,et al.  Aspirin use and reduced risk of fatal colon cancer. , 1991, The New England journal of medicine.

[10]  S. Dey,et al.  Prostaglandin E2 promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferator-activated receptor δ , 2004 .

[11]  V. Dixit,et al.  Signaling in innate immunity and inflammation. , 2012, Cold Spring Harbor perspectives in biology.

[12]  R. Langenbach,et al.  Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice. , 2000, Cancer research.

[13]  Ozge Canli,et al.  gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. , 2009, Cancer cell.

[14]  E. El-Omar,et al.  Interplay of the Gastric Pathogen Helicobacter pylori with Toll-Like Receptors , 2015, BioMed research international.

[15]  Jilly F. Evans,et al.  Chemoprevention of intestinal polyposis in the APCΔ716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor , 2000, American Journal of Gastroenterology.

[16]  M. Karin,et al.  Immunity, Inflammation, and Cancer , 2010, Cell.

[17]  D. Sahoo,et al.  A cell-intrinsic role for TLR2–MYD88 in intestinal and breast epithelia and oncogenesis , 2014, Nature Cell Biology.

[18]  R. DuBois,et al.  The role of COX-2 in intestinal inflammation and colorectal cancer , 2010, Oncogene.

[19]  A. Ochiai,et al.  High Mobility Group Box1 (HMGB1) released from cancer cells induces the expression of pro‐inflammatory cytokines in peritoneal fibroblasts , 2014, Pathology international.

[20]  T. Nheu,et al.  Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-β signaling , 2005, Nature Medicine.

[21]  T. Tsukamoto,et al.  Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and prostaglandin E2 pathway. , 2006, Gastroenterology.

[22]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.

[23]  R. DuBois,et al.  Prostaglandin E2 Promotes Colorectal Cancer Stem Cell Expansion and Metastasis in Mice. , 2015, Gastroenterology.

[24]  Chemoprevention of intestinal polyposis in the APCΔ716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor , 2000 .

[25]  K. McGrath,et al.  Prostaglandin E2 Increases Hematopoietic Stem Cell Survival and Accelerates Hematopoietic Recovery After Radiation Injury , 2013, Stem cells.

[26]  D. Graham,et al.  Helicobacter pylori Infection Introduces DNA Double-Strand Breaks in Host Cells , 2014, Infection and Immunity.

[27]  Michael Karin,et al.  References and Notes Supporting Online Material Materials and Methods Som Text Figs. S1 to S6 Tables S1 to S4 Gender Disparity in Liver Cancer Due to Sex Differences in Myd88-dependent Il-6 Production , 2022 .

[28]  Y. Yamaoka,et al.  Aggregatibacter actinomycetemcomitans infection causes DNA double‐strand breaks in host cells , 2018, Genes to cells : devoted to molecular & cellular mechanisms.

[29]  D. Carbone,et al.  Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. , 2008, Cancer cell.

[30]  H. Herfarth,et al.  Modulation of the Intestinal Microbiota Alters Colitis-Associated Colorectal Cancer Susceptibility , 2009, PloS one.

[31]  H. Clevers,et al.  Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties , 2013, Cell.

[32]  C. Buskens,et al.  Cyclooxygenase‐2 and gastric carcinogenesis , 2003, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[33]  M. Taketo,et al.  COX selectivity and animal models for colon cancer. , 2002, Current pharmaceutical design.

[34]  Jongdae Lee,et al.  ERK activation drives intestinal tumorigenesis in Apcmin/+ mice , 2010, Nature Medicine.

[35]  R. Schwabe,et al.  The Yin and Yang of Toll-like receptors in cancer , 2014, Oncogene.

[36]  Michael Karin,et al.  IKKβ Links Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer , 2004, Cell.

[37]  H. Kotani,et al.  Mouse gastric tumor models with prostaglandin E2 pathway activation show similar gene expression profiles to intestinal-type human gastric cancer , 2009, BMC Genomics.

[38]  L. Yu,et al.  Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis , 2014, Oncogene.

[39]  H. Saya,et al.  TNF-α/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells , 2014, Oncogene.

[40]  Ho-Jun Song.  Car cinogenesis in Mouse Stomach by Simultaneous Activation of the Wnt Signaling and Prostaglandin $E_2$ Pathway. , 2007 .

[41]  R. Medzhitov,et al.  Toll-like receptors and cancer , 2009, Nature Reviews Cancer.

[42]  Jason G. Jin,et al.  Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes , 2015, Nature Medicine.

[43]  K. Block,et al.  Aiding and abetting roles of NOX oxidases in cellular transformation , 2012, Nature Reviews Cancer.

[44]  M. Thun,et al.  The role of aspirin in cancer prevention , 2012, Nature Reviews Clinical Oncology.

[45]  M. Neurath,et al.  Tumor development in murine ulcerative colitis depends on MyD88 signaling of colonic F4/80+CD11b(high)Gr1(low) macrophages. , 2011, The Journal of clinical investigation.

[46]  Laura Conti,et al.  The noninflammatory role of high mobility group box 1/toll‐like receptor 2 axis in the self‐renewal of mammary cancer stem cells , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[47]  M. Plummer,et al.  Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. , 2012, The Lancet. Oncology.

[48]  D. Bowtell,et al.  A dynamic inflammatory cytokine network in the human ovarian cancer microenvironment. , 2012, Cancer research.

[49]  R. Medzhitov,et al.  Regulation of Spontaneous Intestinal Tumorigenesis Through the Adaptor Protein MyD88 , 2007, Science.

[50]  O. Sieber,et al.  Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. , 2013, Cancer cell.

[51]  園下 将大.  Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc[Δ716] knockout mice , 2004 .

[52]  Gabriela Kalna,et al.  ROS Production and NF-κB Activation Triggered by RAC1 Facilitate WNT-Driven Intestinal Stem Cell Proliferation and Colorectal Cancer Initiation , 2013, Cell stem cell.

[53]  M. Ohmura,et al.  CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth. , 2011, Cancer cell.

[54]  A. Bothwell,et al.  IL-17F deficiency inhibits small intestinal tumorigenesis in ApcMin/+ mice. , 2011, Biochemical and biophysical research communications.

[55]  M. Oshima,et al.  Prostaglandin E2, Wnt, and BMP in gastric tumor mouse models , 2009, Cancer science.

[56]  M. Hatakeyama.  Helicobacter pylori CagA and gastric cancer: a paradigm for hit-and-run carcinogenesis. , 2014, Cell host & microbe.

[57]  Sun-Hee Kim,et al.  Prostaglandin E2 promotes intestinal tumor growth via DNA methylation , 2011, Nature Medicine.

[58]  Wenhui Liu,et al.  Nox1 is over‐expressed in human colon cancers and correlates with activating mutations in K‐Ras , 2008, International journal of cancer.

[59]  J. Pollard.  Tumour-educated macrophages promote tumour progression and metastasis , 2004, Nature Reviews Cancer.

[60]  Ruslan Medzhitov,et al.  Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis , 2004, Cell.

[61]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of gastric adenocarcinoma , 2014, Nature.

[62]  Bruno C. Hancock,et al.  Suppression of Intestinal Polyposis in Apc Δ716 Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2) , 1996, Cell.

[63]  A. Parker,et al.  STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. , 2012, Cancer cell.

[64]  S. Dey,et al.  CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis. , 2013, Cancer cell.

[65]  F. Akiyama,et al.  Clinicopathological significance of ‘atypical ductal proliferation’ in core needle biopsy of the breast , 2014, Pathology international.

[66]  C. Yabe-Nishimura,et al.  ROS‐generating oxidases Nox1 and Nox4 contribute to oncogenic Ras‐induced premature senescence , 2013, Genes to cells : devoted to molecular & cellular mechanisms.

[67]  M. Karin,et al.  Tumor-Elicited Inflammation and Colorectal Cancer. , 2015, Advances in cancer research.

[68]  D. Parkin,et al.  The global health burden of infection‐associated cancers in the year 2002 , 2006, International journal of cancer.

[69]  Hiroko Oshima,et al.  The interleukin-6 family cytokine interleukin-11 regulates homeostatic epithelial cell turnover and promotes gastric tumor development. , 2009, Gastroenterology.

[70]  Hans Clevers,et al.  Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. , 2010, Cell stem cell.

[71]  T. Ishikawa,et al.  Prostaglandin E₂ signaling and bacterial infection recruit tumor-promoting macrophages to mouse gastric tumors. , 2011, Gastroenterology.

[72]  C. Datz,et al.  Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth , 2012, Nature.

[73]  Wan-Wan Lin,et al.  Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis , 2009, Nature.

[74]  Hiroko Oshima,et al.  Hyperplastic gastric tumors induced by activated macrophages in COX‐2/mPGES‐1 transgenic mice , 2004, The EMBO journal.

[75]  F. Chan,et al.  Cyclooxygenase-2 expression in Helicobacter pylori-associated premalignant and malignant gastric lesions. , 2000, The American journal of pathology.

[76]  T. Evans.  Fishing for a WNT-PGE2 link: beta-catenin is caught in the stem cell net-work. , 2009, Cell stem cell.

[77]  S. Akira,et al.  Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis , 2008, Proceedings of the National Academy of Sciences.