Article Text

other Versions

PDF
Original article
Stromal cell-derived factor-1 overexpression induces gastric dysplasia through expansion of stromal myofibroblasts and epithelial progenitors
  1. Wataru Shibata1,
  2. Hiroshi Ariyama1,
  3. Christoph Benedikt Westphalen1,
  4. Daniel L Worthley1,
  5. Sureshkumar Muthupalani2,
  6. Samuel Asfaha1,
  7. Zinaida Dubeykovskaya1,
  8. Michael Quante3,
  9. James G Fox2,
  10. Timothy C Wang1
  1. 1Department of Medicine, Division of Digestive and Liver Disease, College of Physicians and Surgeons, Columbia University, New York, New York, USA
  2. 2Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
  3. 3II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
  1. Correspondence to Dr Professor Timothy C Wang, Chief, Division of Digestive and Liver Diseases, Silberberg Professor of Medicine, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, 1130 Street Nicholas Avenue, Room #925, New York, NY 10032-3802, USA; tcw21{at}columbia.edu

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.

Design 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.

Conclusion 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.

  • Stromal derived factor-1
  • CXCR4
  • myofibroblasts
  • mesenchymal stem cells
  • carcinogenesis
  • gastric cancer
  • interleukin-1beta
  • gastrointestinal cancer
  • cancer
  • pancreatic cancer
  • pancreatic tumours
  • pancreatitis
  • stem cells
  • intestinal stem cell
  • inflammation
  • hepatitis
  • IBD models
  • drug toxicity
  • Barrett's oesophagus
  • Helicobacter pylori—pathogenesis
  • molecular mechanisms
  • gastrointestinal immune response
  • gastric neoplasia

Statistics from Altmetric.com

Footnotes

  • Funding This research was supported by grants from the National Institute of Health grants 5R01CA093405-08 (TCW). WS was supported by the Japan Society for the Promotion of Science. MQ is supported by the Deutsche Krebshilfe.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.