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.

Gastrin Is an Essential Cofactor for Helicobacter-Associated Gastric Corpus Carcinogenesis in C57BL/6 Mice

“…Gastrin has been reported to have a growth factor-like effect on gastric cells, and we have previously reported that Reg I, amphiregulin, and some of MMP family members, such as MMP-7, -9, -10, and -13 were up-regulated in INS-GAS mice of FVB/N background. 23,26,27 In the current study, we confirmed up-regulation of these genes except MMP-7 and -10 as shown in Figure 6, A-C. Previously we have reported that H. felis or H. pylori infection of INS-GAS male mice in an FVB/N background rapidly leads to corpus gastric cancer at 7 to 8 MPI.…”

Transmucosal Gastric Leak Induced by Proton Pump Inhibitors

“…Similarly, pertinent changes in epithelialmesenchymal signaling have been linked to increases in gastrin expression, another effect of PPI therapy [28]. Although we cannot definitively ascribe the leak we observed to the tight junction per se, the above actions could negatively impinge on barrier elements.…”

A Digest on the Role of the Tumor Microenvironment in Gastrointestinal Cancers

“…The different cell types in the microenvironment become stimulated by cancer cell-produced factors such as TGF-β, EGF, TGF-α, PDGFs, FGFs, IGFs, shh and MMPs [69,72,[75][76][77][78][79]. In turn, stromal cells respond by producing growth factors (e.g.…”