title: Mesenchymal stem cells utilize CXCR4-SDF-1 signaling for acute, but not chronic, trafficking to gastric mucosal inflammation.
abstract: BACKGROUND
  Helicobacter infection is the main risk factor in developing gastric cancer. Mesenchymal stem cells (MSCs) are non-hematopoietic stromal cells, which are able to differentiate into different cell lineages. MSC contribute to cancer development by forming the tumor directly, contributing to the microenvironment, or by promoting angiogenesis and metastasis. CXCR4/SDF-1 axis is used by MSC in trafficking, homing, and engraftment at chronic inflammation sites, and plays an important role in tumorigenesis.
  
  
  OBJECTIVE
  To determine if CXCR4 receptor has a role in MSC contribution to the development of Helicobacter-mediated gastric cancer.
  
  
  METHODS
  SDF-1 and CXCR4 expression in mouse gastric mucosa in the setting of acute and chronic inflammation was measured using RT-PCR. Mouse culture-adapted MSC express CXCR4. Wild-type C57BL/6 mice infected with Helicobacter felis for 6 months or controls were given IV injections of CXCR4 knock-down MSC. Animals were followed for another 4 months. Homing of MSC in the stomach was quantified using RT-PCR. MSC differentiation into gastric epithelia lineages was analyzed using immunohistochemistry and fluorescent in situ hybridization.
  
  
  RESULTS
  CXCR4 and SDF-1 are both upregulated in the settings of Helicobacter-induced chronic gastric inflammation. CXCR4 is fully required for homing of MSC to the stomach in acute gastric inflammation, but only partially in Helicobacter-induced gastric cancer. MSC lead to gastric intraepithelial neoplasia as early as 10 months of Helicobacter infection.
  
  
  CONCLUSIONS
  Our results show that MSC have a tumorigenic effect by promoting an accelerated form of gastric cancer in mice. The engraftment of MSC in chronic inflammation is only partially CXCR4-dependent.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01635, USA. calin.stoicov@umassmed.edu
authors.forename: Calin
authors.initials: C
authors.lastname: Stoicov
authors.forename: Hanchen
authors.initials: H
authors.lastname: Li
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Liu
authors.forename: JeanMarie
authors.initials: J
authors.lastname: Houghton
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004847:Epithelial Cells / Q000166:cytology; D000431:Ethanol; D005756:Gastritis / Q000150:complications / Q000378:metabolism* / Q000382:microbiology; D016481:Helicobacter Infections / Q000150:complications / Q000378:metabolism*; D044922:Helicobacter felis; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
chemical_list: C514936:CXCR4 protein, mouse; D019718:Receptors, CXCR4; D000431:Ethanol