Matrix metalloproteinase (MMP)-7 in Barrett's esophagus and esophageal adenocarcinoma: expression, metabolism, and functional significance.

Matrix metalloproteinase (MMP)-7, unlike many MMPs, is typically expressed in epithelial cells. It has been linked to epithelial responses to infection, injury, and tissue remodeling including the progression of a number of cancers. We have now examined how MMP-7 expression changes in the progression to esophageal adenocarcinoma (EAC), and have studied mechanisms regulating its expression and its functional significance. Immunohistochemistry revealed that MMP-7 was weakly expressed in normal squamous epithelium adjacent to EAC but was abundant in epithelial cells in both preneoplastic lesions of Barrett's esophagus and EAC particularly at the invasive front. In the stroma, putative myofibroblasts expressing MMP-7 were abundant at the invasive front but were scarce or absent in adjacent tissue. Western blot and ELISA revealed high constitutive secretion of proMMP-7 in an EAC cell line (OE33) that was inhibited by the phosphatidylinositol (PI) 3-kinase inhibitor LY294002 but not by inhibitors of protein kinase C, or MAP kinase activation. There was detectable proMMP-7 in cultured esophageal myofibroblasts but it was undetectable in media. Possible metabolism of MMP-7 by myofibroblasts studied by proteomic analysis indicated degradation via extensive endopeptidase, followed by amino- and carboxpeptidase, cleavages. Myofibroblasts exhibited increased migration and invasion in response to conditioned media from OE33 cells that was reduced by MMP-7 knockdown and immunoneutralization. Thus, MMP-7 expression increases at the invasive front in EAC which may be partly attributable to activation of PI 3-kinase. Secreted MMP-7 may modify the tumor microenvironment by stimulating stromal cell migration and invasion.

Increased prevalence of gallstone disease and impaired gallbladder motility in patients with Barrett's esophagus.

The prevalence of gallstones in patients with Barrett's esophagus (BE) and their gallbladder motility relative to that of healthy volunteers and GERD patients without BE were investigated. Of the 707 patients reviewed, 203 (125 males and 78 females) had BE. The prevalence of gallstones was significantly higher in the patients with BE than in those without BE (34 vs. 20%, respectively). The gallbladder functions of 22 patients with GERD, 27 patients with BE and 21 healthy volunteers were assessed by ultrasonography before and after a test meal. The patients with BE had significantly higher fasting volume and residual volume, but lower ejection volume, ejection fraction and ejection rate values than those of the healthy controls. None of the ultrasonographic parameters of patients without BE were significantly different from those of the controls. Patients with BE have a more complex gastrointestinal motility disorder that involves the gallbladder, and this makes this subset of patients with GERD more prone to gallstone disease.