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

Abstract

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.

Esophageal Cancer Development: Crucial Clues Arising from the Extracellular Matrix

“…MMPs are also biologically relevant for esophageal carcinogenesis. It has been previously shown that MMPs function as potential biomarkers, and distinct MMP subtypes, including MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9, have been associated with EC diagnosis and/or prognosis [74][75][76][77][78][79]. In this way, among the nearly 30 distinct MMPs subtypes, MMP-2 and MMP-9 are the most strongly associated with esophageal carcinogenesis [74].…”

“…Oppositely, the study performed by Garalla and colleagues showed that the blockage of the MAPK pathway was not able to interfere in MMP-7 expression [78], although MMP-7 aberrant levels had been previously related to EC progression [79,81]. Nonetheless, in the same study, the authors demonstrated that PI3K blockage, by using the chemical inhibitor LY294002, was able to strongly abolish MMP-7 secretion by EAC cells [78]. Additionally, the increase in MMP-7 levels could also be triggered through the modulation of other pathways, and, by using a panel of ESCC malignant cell lines, it was shown that the upregulation of AP-1 induced by activin A culminated with an increase in MMP-7 levels [82].…”

“…In addition, the involvement of MAPK members in MMP-2 and MMP-9 expression control is likely to be also indirectly regulated by DNA damage events, because DNA polymerase iota, which acts in translesion DNA repair, is able to increase the expression of both MMPs by inducing the activation of the JNK/activator protein 1 (AP-1) axis in ESCC cells [77]. Oppositely, the study performed by Garalla and colleagues showed that the blockage of the MAPK pathway was not able to interfere in MMP-7 expression [78], although MMP-7 aberrant levels had been previously related to EC progression [79,81]. Nonetheless, in the same study, the authors demonstrated that PI3K blockage, by using the chemical inhibitor LY294002, was able to strongly abolish MMP-7 secretion by EAC cells [78].…”

<p>Esophageal Microenvironment: From Precursor Microenvironment to Premetastatic Niche</p>

“…Previous studies have shown that MMP-7 in BE epithelial cells could stimulate stromal cell migration and invasion and remodel the microenvironment under the regulation of PI3-K kinases. 30 In addition, MMP9 and MMP13 are also up-regulated in BE. 31 It is noteworthy that MMP13 is more highly expressed in BE, while MMP-9 is more highly expressed in EAC.…”

Impact of Deoxycholic Acid on Oesophageal Adenocarcinoma Invasion: Effect on Matrix Metalloproteinases

“…The matrix metalloproteinases (MMPs) are a family of enzymes that digest components of the extracellular matrix (ECM) and are involved in cancer spreading and invasion [ 18 , 19 , 20 ]. Increases in MMP-1, MMP-2, MMP-7, MMP-9 and MMP-10 expression have all been linked to progression of normal oesophageal tissue to OAC [ 21 , 22 , 23 , 24 , 25 , 26 ] but the mechanism underlying what causes the increase in expression is currently unknown. It has been previously shown that BAs can promote MMPs that in turn enhance colon cancer invasion and metastasis [ 27 ].…”