title: Gastritis promotes an activated bone marrow-derived mesenchymal stem cell with a phenotype reminiscent of a cancer-promoting cell.
abstract: BACKGROUND
  Bone marrow-derived mesenchymal stem cells (BM-MSCs) promote gastric cancer in response to gastritis. In culture, BM-MSCs are prone to mutation with continued passage but it is unknown whether a similar process occurs in vivo in response to gastritis.
  
  
  OBJECTIVE
  The purpose of this study was to identify the role of chronic gastritis in the transformation of BM-MSCs leading to an activated cancer-promoting phenotype.
  
  
  METHODS
  Age matched C57BL/6 (BL/6) and gastrin deficient (GKO) mice were used for isolation of stomach, serum and mesenchymal stem cells (MSCs) at 3 and 6 months of age. MSC activation was assessed by growth curve analysis, fluorescence-activated cell sorting and xenograft assays. To allow for the isolation of bone marrow-derived stromal cells and assay in response to chronic gastritis, IRG/Vav-1(Cre) mice that expressed both enhanced green fluorescent protein-expressing hematopoietic cells and red fluorescent protein-expressing stromal cells were generated. In a parabiosis experiment, IRG/Vav-1(Cre) mice were paired to either an uninfected Vav-1(Cre) littermate or a BL/6 mouse inoculated with Helicobacter pylori.
  
  
  RESULTS
  GKO mice displayed severe atrophic gastritis accompanied by elevated gastric tissue and circulating transforming growth factor beta (TGFβ) by 3 months of age. Compared to BM-MSCs isolated from uninflamed BL/6 mice, BM-MSCs isolated from GKO mice displayed an increased proliferative rate and elevated phosphorylated-Smad3 suggesting active TGFβ signaling. In xenograft assays, mice injected with BM-MSCs from 6-month-old GKO animals displayed tumor growth. RFP+ stromal cells were rapidly recruited to the gastric mucosa of H. pylori parabionts and exhibited changes in gene expression.
  
  
  CONCLUSIONS
  Gastritis promotes the in vivo activation of BM-MSCs to a phenotype reminiscent of a cancer-promoting cell.
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert B. Sabin Way, Room 4255 MSB, Cincinnati, OH, 45267-0576, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Donnelly
authors.forename: Amy C
authors.initials: AC
authors.lastname: Engevik
authors.forename: Melinda
authors.initials: M
authors.lastname: Engevik
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schumacher
authors.forename: Chang
authors.initials: C
authors.lastname: Xiao
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Roger T
authors.initials: RT
authors.lastname: Worrell
authors.forename: Yana
authors.initials: Y
authors.lastname: Zavros
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D005755:Gastrins / Q000172:deficiency; D005757:Gastritis, Atrophic / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D053823:Hedgehog Proteins / Q000378:metabolism; D016481:Helicobacter Infections / Q000473:pathology; D016480:Helicobacter pylori; D015151:Immunoblotting; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010227:Parabiosis; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015415:Biomarkers; D005755:Gastrins; D053823:Hedgehog Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta