Gastroenterology

Gastroenterology

Volume 130, Issue 6, May 2006, Pages 1754-1763
Gastroenterology

Basic–alimentary tract
The Role of Matrix Metalloproteinase-7 in Redefining the Gastric Microenvironment in Response to Helicobacter pylori

https://doi.org/10.1053/j.gastro.2006.02.031Get rights and content

Background & Aims: Interactions between epithelial and stromal cells are important determinants of mucosal organization, but the signaling mechanisms are understood incompletely. Matrix metalloproteinase (MMP)-7 is produced uniquely in epithelia, may act on growth factors and matrix proteins, and in the stomach is increased with Helicobacter pylori infection. We have studied the role of MMP-7 in signaling between epithelial cells and a key stromal cell type, the myofibroblast. Methods: Immunohistochemistry and Western blotting were applied to gastric corpus biopsy specimens; primary cultures of human gastric glands and myofibroblasts were used to study the role of MMP-7 in regulating proliferation and migration of the latter, and MMP-7 substrates were identified by proteomic methods. Results: Increased abundance of the myofibroblast marker α-smooth muscle actin was identified in H pylori–positive biopsy specimens. Media from H pylori–infected gastric epithelial cultures stimulated proliferation and migration of primary human gastric myofibroblasts and antisense oligonucleotide treatment indicated a role for MMP-7. Proteomic methods identified insulin-like growth factor binding protein (IGFBP)-5 as a substrate for MMP-7 in medium from gastric myofibroblasts. Knockdown of IGFBP-5 by small interfering RNA or immunoneutralization of IGF-II, abolished myofibroblast responses to MMP-7. Proliferation of gastric epithelial cells also was stimulated by MMP-7–treated myofibroblasts via IGF-II. Conclusions: MMP-7 acts as an epithelial-derived signal increasing the bioavailability of IGF-II released from myofibroblasts. Because IGF-II acts on both stromal and epithelial cells, the findings suggest that increased MMP-7 expression contributes to redefining the niche occupied by dividing cells and leading to hyperproliferation in H pylori infection.

Section snippets

Cells and Drugs

Human gastric glands and myofibroblasts were prepared as described later. Human recombinant MMP-7, MMP-7 antisense oligonucleotides, control oligonucleotides, MMP-7 fluorogenic substrate, and human collagen IV were obtained from Calbiochem (Nottingham, UK). Human recombinant IGFBP-5, IGF-II, and neutralizing IGF-II antibody were obtained from R&D Systems (Abingdon, Oxon, UK). All other chemicals were obtained from Sigma (Poole, Dorset, UK).

Patients

Endoscopic pinch biopsy specimens of gastric corpus

Increased Abundance of α-SMA in Human and Mouse Stomach With Helicobacter Infection

In initial studies we asked whether there is an increased abundance of the myofibroblast marker α-SMA in the corpus of Helicobacter-infected stomachs. In samples from H pylori–infected patients, densitometric analysis of Western blots revealed a significant increase in the abundance of α-SMA (Figure 1A and B). Immunohistochemistry for α-SMA in infected gastric corpus mucosa indicated the presence of myofibroblasts at all levels including around the neck region of the gastric glands, whereas

Discussion

The present study shows that in Helicobacter pylori infection there is increased abundance of the myofibroblast marker α-SMA in the gastric mucosa. We identify a role for MMP-7 derived from gastric epithelial cells as a myofibroblast growth factor acting via cleavage of IGFBP-5 to liberate IGF-II. MMP-7 does not (on its own) stimulate epithelial cell proliferation. However, IGF-II stimulates gastric epithelial cell proliferation, and medium from MMP-7–treated myofibroblasts stimulates

References (40)

  • R.M. Peek et al.

    Helicobacter pylori and gastrointestinal tract adenocarcinomas

    Nat Rev Cancer

    (2002)
  • P. Correa et al.

    Gastric cancer

    Cancer Surv

    (1994)
  • M. Egeblad et al.

    New functions for the matrix metalloproteinases in cancer progression

    Nat Rev Cancer

    (2002)
  • Y.S. Lopez-Boado et al.

    Bacterial exposure induces and activates matrilysin in mucosal epithelial cells

    J Cell Biol

    (2000)
  • L.E. Wroblewski et al.

    Stimulation of MMP-7 (matrilysin) by Helicobacter pylori in human gastric epithelial cellsrole in epithelial cell migration

    J Cell Sci

    (2003)
  • J.R. Bebb et al.

    Helicobacter pylori upregulates matrilysin (MMP-7) in epithelial cells in vivo and in vitro in a Cag dependent manner

    Gut

    (2003)
  • H. Haro et al.

    Matrix metalloproteinase-7-dependent release of tumor necrosis factor-alpha in a model of herniated disc resorption

    J Clin Invest

    (2000)
  • W.H. Yu et al.

    CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling

    Genes Dev

    (2002)
  • E. Hemers et al.

    Insulin-like growth factor binding protein-5 is a target of matrix metalloproteinase-7implications for epithelial-mesenchymal signaling

    Cancer Res

    (2005)
  • K.C. Wu et al.

    Phenotypic and functional characterisation of myofibroblasts, macrophages, and lymphocytes migrating out of the human gastric lamina propria following the loss of epithelial cells

    Gut

    (1999)
  • Cited by (93)

    • Helicobacter pylori infection induces stem cell-like properties in Correa cascade of gastric cancer

      2022, Cancer Letters
      Citation Excerpt :

      Increased MMP-3 expression facilitates genomic instability and functional CagA, which leads to transcriptional activation of EMT markers, such as vimentin, Snail, and ZEB1, and CD44 in GC cells [108]. In gastric epithelial cells, CagA + H. pylori upregulates MMP-7, which promotes EMT by cleaving E-cadherin [109]. Collectively, H. pylori infection may increase MMP levels to cause ECM remodeling [110], impairing host defense, degrading the matrix, or damaging the basement membrane, thereby promoting bacterial persistence, chronic gastritis progression, and GC metastasis.

    • Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in kidney disease

      2021, Advances in Clinical Chemistry
      Citation Excerpt :

      In DKD, an enhanced IGFBP degradation liberates the locally available renal IGF-1 protein, resulting in an increase in ECM and mesangium expansion [139]. The known ability of matrilysin, MMP-7, to cleave IGFBP-3 and IGFBP-5 [96,188] potentiates the liberation of IGF-II [189]. Additionally, the ability of MMP-7 to degrade decorin, an ECM protein that binds TGF-β1, increases the TGF-β1 caused accentuation of kidney fibrotic changes in diabetic nephropathy [190].

    • Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors

      2020, Cellular and Molecular Gastroenterology and Hepatology
    View all citing articles on Scopus

    Supported by North West Cancer Research Fund, the Medical Research Council, and the Wellcome Trust.

    View full text