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1 Physiology, School of Biomedical Sciences, University of Liverpool, Liverpool, United Kingdom
2 Gastroenterology, School of Clinical Sciences, University of Liverpool, Liverpoool, United Kingdom
3 Medicine, Columbia University, New York, New York, United States
* To whom correspondence should be addressed. E-mail: avarro{at}liv.ac.uk.
Background & aims: Chronic hypergastrinemia is associated with enterochromaffin-like (ECL) cell hyperplasia which may progress to gastric carcinoid tumors. The latter consist of epithelial cells and stroma and both compartments usually regress after normalization of hypergastrinemia. We previously showed that MMP-7 in gastric epithelial cells was upregulated by H.pylori and described MMP-7 dependent reciprocal signaling between epithelium and a key stromal cell type, the myofibroblast. Here we describe regulation of gastric MMP-7 by gastrin and the potential significance for recruiting and maintaining myofibroblast populations. Methods: Biopsies of gastric corpus and ECL cell carcinoid tumors were obtained from hypergastrinemic patients. Western blotting, ELISA, immunohistochemistry, and promoter-luciferase reporter assays were used to study MMP-7 expression. Gastric myofibroblasts were identified by 
-smooth muscle actin (SMA) expression and the effects of MMP-7 on myofibroblast proliferation were investigated. Results: In hypergastrinemic patients there was increased abundance of MMP-7 and -SMA in gastric corpus biopsies and ECL cell carcinoid tumors. In the latter, MMP-7 was localized to ECL- but not stromal cells which were nevertheless well represented. Gastrin stimulated MMP-7-luc expression both in AGS-GR and primary human gastric epithelial cells. Conditioned medium from gastrin-treated human gastric glands stimulated myofibroblast proliferation that was inhibited by neutralising antibodies to MMP-7. MMP-7 increased proliferation of myofibroblasts via the MAPkinase and PI-3-kinase pathways. Conclusion: Stimulation of gastric MMP-7 by elevated plasma gastrin may activate epithelial-mesenchymal signaling pathways regulating myofibroblast function via the MAPkinase and PI-3-kinase pathways and contributing to stromal deposition in ECL cell carcinoid tumors.
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