title: Stromal cell-derived factor-1 overexpression induces gastric dysplasia through expansion of stromal myofibroblasts and epithelial progenitors.
abstract: OBJECTIVE
  Stromal cell-derived factor-1 (SDF-1/CXCL12), the main ligand for CXCR4, is overexpressed in human cancer. This study addressed the precise contribution of SDF-1 to gastric carcinogenesis.
  
  
  METHODS
  SDF-1 transgenic mice were created and a Helicobacter-induced gastric cancer model was used in combination with H/K-ATPase-IL-1β mice. Gastric tissue was analysed by histopathology and cells isolated from the stomach were analysed by molecular biological methods.
  
  
  RESULTS
  Analysis of the H/K-ATPase/SDF-1 transgenic (SDF-Tg) mice showed that SDF-1 overexpression results in significant gastric epithelial hyperproliferation, mucous neck cell hyperplasia and spontaneous gastric dysplasia (wild-type mice 0/15 (0%) vs SDF-Tg mice 4/14 (28.6%), p=0.042, Fisher exact test) but has minimal effects on inflammation. SDF-Tg mice also showed a dramatic expansion of α-smooth muscle actin-positive myofibroblasts and CXCR4-expressing gastric epithelial cells in the progenitor zone, both of which preceded the development of significant gastritis or dysplasia. Gremlin 1-expressing mesenchymal stem cells, the putative precursors of myofibroblasts, were also increased within the dysplastic stomachs of SDF-Tg mice and showed chemotaxis in response to SDF-1 stimulation. SDF-1 overexpression alone resulted in minimal recruitment of haematopoietic cells to the gastric mucosa, although macrophages were increased late in the disease. When SDF-Tg mice were crossed with H/K-ATPase-IL-1β mice or infected with Helicobacter felis, however, there were dramatic synergistic effects on recruitment of bone marrow-derived cells and progression to preneoplasia.
  
  
  CONCLUSIONS
  Activation of the SDF-1/CXCR4 axis can contribute to early stages of carcinogenesis primarily through recruitment of stromal cells and modulation of the progenitor niche.
authors.affiliation: Department of Medicine, Division of Digestive and Liver Disease, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shibata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ariyama
authors.forename: Christoph Benedikt
authors.initials: CB
authors.lastname: Westphalen
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Worthley
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.forename: Samuel
authors.initials: S
authors.lastname: Asfaha
authors.forename: Zinaida
authors.initials: Z
authors.lastname: Dubeykovskaya
authors.forename: Michael
authors.initials: M
authors.lastname: Quante
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000235:genetics*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005753:Gastric Mucosa / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology*; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology*; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D016207:Cytokines
chemical_list: D054377:Chemokine CXCL12; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D019718:Receptors, CXCR4; C113178:Grem1 protein, mouse; D016207:Cytokines