Matrix Metalloproteinase-7 and Premalignant Host Responses in Helicobacter pylori–Infected Mice

Abstract

Helicobacter pylori-induced gastritis is the strongest singular risk factor for gastric adenocarcinoma. Matrix metalloproteinase-7 (MMP-7) is a proteolytic enzyme that can modify the intestinal microbial replicative niche as well as affect tumorigenesis, and H. pylori stimulates expression of MMP-7 in gastric epithelial cells in vitro.Utilizing a transgenic murine model of H. pylori-mediated injury, our experiments now show that gastric inflammation is increased within the context of MMP-7 deficiency, which involves both Th1-and Th17-mediated pathways. Enhanced gastritis in H. pylori-infected mmp-7 −/− mice is strongly linked to accelerated epithelial cellular turnover. However, more severe inflammation and heightened proliferation and apoptosis are not dependent on MMP-7-mediated bacterial eradication. Collectively, these studies indicate that H. pylorimediated induction of MMP-7 may serve to protect the gastric mucosa from pathophysiologic processes that promote carcinogenesis. Cancer Res; 70(1); 30-5. ©2010 AACR.

Matrix metalloproteinase 7 restrains Helicobacter pylori-induced gastric inflammation and premalignant lesions in the stomach by altering macrophage polarization

“…Our previous studies using a mouse model of H. pylori -induced gastritis demonstrated that MMP7 −/− C57BL/6 mice develop more severe inflammation in response to H. pylori infection than wild-type (WT) C57BL/6 mice 5 . To extend these findings and identify mechanisms that regulate this phenotype, WT C57BL/6 and MMP7 −/− C57BL/6 mice were challenged with broth alone as an uninfected control or the H. pylori strain PMSS1, and stomachs were harvested and analyzed 12 weeks post challenge.…”

“…One host response that augments the risk for gastric cancer is increased expression of the proinflammatory cytokine IL-1β, and individuals who harbor high-expression IL-1 β alleles are at increased risk for gastric cancer 4 . Another host factor linked to neoplasia within the intestinal tract is matrix metalloproteinase 7 (MMP7), a minimal-domain MMP secreted preferentially by epithelial cells 5–8 . Previously, we observed that C57BL/6 mice lacking MMP7 develop increased inflammation following H. pylori infection, although the specific mechanism regulating this phenotype was not identified 5 .…”

“…Another host factor linked to neoplasia within the intestinal tract is matrix metalloproteinase 7 (MMP7), a minimal-domain MMP secreted preferentially by epithelial cells 5–8 . Previously, we observed that C57BL/6 mice lacking MMP7 develop increased inflammation following H. pylori infection, although the specific mechanism regulating this phenotype was not identified 5 . One limitation of this model is that C57BL/6 mice rarely develop premalignant or malignant lesions of the stomach following H. pylori infection.…”

Pathogenesis of Helicobacter pylori Infection

“…Activated DCs are induced by CagA, but mainly by CagE, to release high amounts of IL-23 and IL-1 thus inducing the expansion of CD4+ Th17 T cells [54] which might exert an anti-inflammatory role [55] and a role in vaccine induced immunization [56]. Mast cells (MC) [57] and matrix metalloproteinase-7 (MMP-7) [58] were suggested to regulate Th17-dependent inflammatory response to H. pylori infection. Dotted lines represent inhibitory effects and continuous lines stimulatory effects.…”

Expression and significance of IGF-2, PCNA, MMP-7, and ?-actin in gastric carcinoma with Lauren classification

“…The matrix metalloproteinases (MMPs) family, which can degrade the extracellular matrix, is the most important group of proteolytic enzymes and is mostly produced by the interstitial cells. MMP-7 is relatively unique because it is mainly produced in epithelial cells (4). In the past, research about the relationship between MMP-7 expression and Lauren classification in gastric cancer has been quite inconsistent.…”