title: Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response.
abstract: OBJECTIVE
  To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation.
  
  
  METHODS
  C57BL/6 male mice were infected with H felis and placed on a high-fat diet (45% calories from fat). Study animals were analysed for gastric and adipose pathology, inflammatory markers in serum, stomach and adipose tissue, and immune responses in blood, spleen, stomach and adipose tissue.
  
  
  RESULTS
  H felis-induced gastric carcinogenesis was accelerated in diet-induced obese mice compared with lean controls. Obesity increased bone marrow-derived immature myeloid cells in blood and gastric tissue of H felis-infected mice. Obesity also led to elevations in CD4 T cells, IL-17A, granulocyte macrophage colony-stimulating factor, phosphorylated STAT3 and prosurvival gene expression in gastric tissue of H felis-infected mice. Conversely, in adipose tissue of obese mice, H felis infection increased macrophage accumulation and expression of IL-6, C-C motif ligand 7 (CCL7) and leptin. Finally, the combination of obesity and gastric inflammation synergistically increased serum proinflammatory cytokines, including IL-6.
  
  
  CONCLUSIONS
  Here, we have established a model to study the molecular mechanism by which obesity predisposes individuals to gastric cancer. In H felis-infected mice, obesity increased proinflammatory immune responses and accelerated gastric carcinogenesis. Interestingly, gastric inflammation augmented obesity-induced adipose inflammation and production of adipose-derived factors in obese, but not lean, mice. Our findings suggest that obesity accelerates Helicobacter-associated gastric cancer through cytokine-mediated cross-talk between inflamed gastric and adipose tissues, augmenting immune responses at both tissue sites, and thereby contributing to a protumorigenic gastric microenvironment.
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research, , Singapore, Singapore.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Ericksen
authors.forename: Shannon
authors.initials: S
authors.lastname: Rose
authors.forename: Christoph Benedikt
authors.initials: CB
authors.lastname: Westphalen
authors.forename: Wataru
authors.initials: W
authors.lastname: Shibata
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.forename: Yagnesh
authors.initials: Y
authors.lastname: Tailor
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friedman
authors.forename: Weiping
authors.initials: W
authors.lastname: Han
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Ferrante
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D005434:Flow Cytometry; D005756:Gastritis / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism / Q000382:microbiology; D016481:Helicobacter Infections / Q000150:complications* / Q000276:immunology; D044922:Helicobacter felis; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023461:Myeloid Progenitor Cells / Q000502:physiology*; D009765:Obesity / Q000150:complications* / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013274:Stomach Neoplasms / Q000209:etiology* / Q000276:immunology / Q000382:microbiology; D058504:Th17 Cells / Q000502:physiology*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse
keywords: Gastric Cancer; Helicobacter Felis; Helicobacter Pylori; Inflammation; Obesity