Stromal cell-derived factor-1 overexpression induces gastric dysplasia through expansion of stromal myofibroblasts and epithelial progenitors

Wataru Shibata, Hiroshi Ariyama, Christoph Benedikt Westphalen, Daniel L. Worthley, Sureshkumar Muthupalani, Samuel Asfaha, Zinaida Dubeykovskaya, Michael Quante, James G. Fox, Timothy C. Wang

Research output: Contribution to journalArticle

48 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)192-200
Number of pages9
JournalGut
Volume62
Issue number2
DOIs
Publication statusPublished - Feb 2013

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Fingerprint Dive into the research topics of 'Stromal cell-derived factor-1 overexpression induces gastric dysplasia through expansion of stromal myofibroblasts and epithelial progenitors'. Together they form a unique fingerprint.

  • Cite this

    Shibata, W., Ariyama, H., Westphalen, C. B., Worthley, D. L., Muthupalani, S., Asfaha, S., Dubeykovskaya, Z., Quante, M., Fox, J. G., & Wang, T. C. (2013). Stromal cell-derived factor-1 overexpression induces gastric dysplasia through expansion of stromal myofibroblasts and epithelial progenitors. Gut, 62(2), 192-200. https://doi.org/10.1136/gutjnl-2011-301824