title: Increased gastric expression of MMP-7 in hypergastrinemia and significance for epithelial-mesenchymal signaling.
abstract: Chronic hypergastrinemia is associated with enterochromaffin-like (ECL) cell hyperplasia, which may progress to gastric carcinoid tumors. The latter consists of epithelial cells and stroma, and both compartments usually regress after normalization of hypergastrinemia. We previously showed that matrix metalloproteinase (MMP)-7 in gastric epithelial cells was upregulated by Helicobacter pylori and described MMP-7-dependent reciprocal signaling between the epithelium and a key stromal cell type, the myofibroblast. Here, we describe the regulation of gastric MMP-7 by gastrin and the potential significance for recruiting and maintaining myofibroblast populations. Biopsies of the gastric corpus and ECL cell carcinoid tumors were obtained from hypergastrinemic patients. Western blot analysis, ELISA, immunohistochemistry, and promoter-luciferase (luc) reporter assays were used to study MMP-7 expression. Gastric myofibroblasts were identified by alpha-smooth muscle actin (alpha-SMA) expression, and the effects of MMP-7 on myofibroblast proliferation were investigated. In hypergastrinemic patients, there was an increased abundance of MMP-7 and alpha-SMA in gastric corpus biopsies and ECL cell carcinoid tumors. In the latter, MMP-7 was localized to ECL cells but not stromal cells, which were nevertheless well represented. Gastrin stimulated MMP-7-luc expression in both AGS-G(R) and primary human gastric epithelial cells. Conditioned medium from gastrin-treated human gastric glands stimulated myofibroblast proliferation, which was inhibited by neutralizing antibodies to MMP-7. MMP-7 increased the proliferation of myofibroblasts via the MAPK and phosphatidylinositol 3-kinase (PI3K) pathways. In conclusion, stimulation of gastric MMP-7 by elevated plasma gastrin may activate epithelial-mesenchymal signaling pathways regulating myofibroblast function via MAPK and PI3K pathways and contribute to stromal deposition in ECL cell carcinoid tumors.
authors.affiliation: Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown St., Liverpool L69 3BX, UK. avarro@liverpool.ac.uk
authors.forename: Andrea
authors.initials: A
authors.lastname: Varro
authors.forename: Susan
authors.initials: S
authors.lastname: Kenny
authors.forename: Elaine
authors.initials: E
authors.lastname: Hemers
authors.forename: Catherine
authors.initials: C
authors.lastname: McCaig
authors.forename: Sabine
authors.initials: S
authors.lastname: Przemeck
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.forename: Keith
authors.initials: K
authors.lastname: Bodger
authors.forename: D Mark
authors.initials: DM
authors.lastname: Pritchard
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002276:Carcinoid Tumor / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019861:Enterochromaffin-like Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism*; D005755:Gastrins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018761:Multiple Endocrine Neoplasia Type 1 / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D013270:Stomach / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013274:Stomach Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D046509:Tissue Culture Techniques; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D000199:Actins; D017077:Culture Media, Conditioned; D005755:Gastrins; D019869:Phosphatidylinositol 3-Kinases; D020783:Matrix Metalloproteinase 7