Stromal cell-derived factor-1 overexpression induces gastric dysplasia through expansion of stromal myofibroblasts and epithelial progenitors
- Wataru Shibata1,
- Hiroshi Ariyama1,
- Christoph Benedikt Westphalen1,
- Daniel L Worthley1,
- Sureshkumar Muthupalani2,
- Samuel Asfaha1,
- Zinaida Dubeykovskaya1,
- Michael Quante3,
- James G Fox2,
- Timothy C Wang1
- 1Department of Medicine, Division of Digestive and Liver Disease, College of Physicians and Surgeons, Columbia University, New York, New York, USA
- 2Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- 3II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
- 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;
Contributors Study concept and design, obtained funding and study supervision: TCW. Acquisition of data: WS, HA. Analysis and interpretation of data: WS, HA, CBW, DW, JF, SM, SA, ZD, MQ, TCW. Drafting of manuscript: WS, HA, CBW, DW, MQ, TCW.
- Revised 4 January 2012
- Accepted 11 January 2012
- Published Online First 23 February 2012
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
- mesenchymal stem cells
- gastric cancer
- gastrointestinal cancer
- pancreatic cancer
- pancreatic tumours
- stem cells
- intestinal stem cell
- IBD models
- drug toxicity
- Barrett's oesophagus
- Helicobacter pylori—pathogenesis
- molecular mechanisms
- gastrointestinal immune response
- gastric neoplasia
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.