Matrilysin (MMP-7) promotes invasion of ovarian cancer cells by activation of progelatinase

Abstract

Although matrilysin (MMP-7) is overexpressed in various malignancies, few studies have evaluated its role in epithelial ovarian cancer (EOC) invasion and metastasis. We report that the secretion of MMP-7 in EOC is stimulated significantly by vascular endothelial growth factor (VEGF) and interlukin-8 (IL-8). We also examined the in vivo expression of MMP-7 in EOC and its effects on the in vitro invasion and progelatinase activation. We report that MMP-7 is overexpressed in ovarian cancer cell lines and EOC surgical specimens. DOV13 cells incubated with active rhMMP-7 significantly increased cellular invasion and proMMP-2 activation. RhMMP-7 also showed the ability to activate proMMP-2 and proMMP-9 in immortalized ovarian epithelial cell (IOSE-29) conditioned medium. In addition, rhMMP-7 was able to activate progelatinase in a concentration-dependent manner in vitro. TIMP-2 or the generic MMP inhibitor-GM6001 inhibited both the activation of proMMP-2 and the increased invasion of DOV13 cells promoted by rhMMP-7. By incubation of MMP2-TIMP-2 complex with equal molar rhMMP-7, MMP-2 was dissociated from the complex and activated in a time-dependent manner, suggesting that TIMP-2 helps to keep the latency of MMP-2. TIMP-2 also showed inhibitory effects on the MMP-7 induced increase of gelatinolytic activity in DOV13 and IOSE-29 conditioned media. Epithelial ovarian cancer (EOC) has the highest mortality of all gynecological malignancies and is the 5th most common cancer in women in the United States. This year approximately 25,000 women will be newly diagnosed with ovarian cancer and 14,000 will die from this disease. 1,2 Unfortunately, at initial diagnosis 70 -75% of women with EOC present with widespread intraabdominal carcinomatosis, with the resultant 5-year survival approximating 15%. The diffuse spread of tumor cells throughout the peritoneal cavity and ultimate resistance to chemotherapy are responsible for the poor clinical outcome. 1,3 To provide urgently needed insights that may lead to early detection, prevention and effective intervention, it is important to understand the molecular events that support the survival and implantation of metastatic malignant ovarian epithelium. Protease activation and extracellular matrix (ECM) degradation are regarded as important steps that facilitate EOC invasion and metastasis. 4 Matrix metalloproteinases (MMPs) are a family of structurally related zinc-dependent endopeptidases that are frequently elevated in the tumor microenvironment and capable of degrading essentially all components of the ECM. 5,6 With the ability to degrade ECM proteins, MMPs expose cryptic sites within the matrix molecules that may facilitate tumor invasion and metastasis through the complicated interactions with other proteases, growth factors and cytokines. Matrix metalloproteinases are usually secreted in a latent (pro) form and are activated by the proteolytic removal of the NH 2 -terminal propeptide. Pro-MMP activation can be physically achieved by proteases belonging to the MMP family as well...

S1P induced changes in epithelial ovarian cancer proteolysis, invasion, and attachment are mediated by Gi and Rac

“…Invasion assays were performed using Matrigel coated invasion chambers (Bedford, MA) as previously described [20] with several modifications. Cells were pretreated with vehicle or S1P with or without 25µM Rac inhibitor for the 6 hours in most experiments, detached, and counted.…”

“…Cell migration and invasion are coordinated active processes involving ECM degradation by proteases such as MMPs [19,20]. At baseline we studied the effects of S1P on MMP expression and activity.…”

“…Plasmin directly degrades various ECM components as well as activating matrix metalloproteinases (MMP's), a family of zinc-dependent endopeptidases capable of degrading virtually all ECM components and correlated with cellular invasiveness [7,[18][19][20]. uPA activity is upregulated by LPA in DOV 13 cells [21]; however, the effect of S1P on uPA activity is unknown.…”

Active matrix metalloproteinase-7 is associated with invasion in buccal squamous cell carcinoma

“…Two mechanisms may be responsible for the enhancement of cancer invasion and metastasis by MMP-7: direct effects of MMP-7 proteinase activity and indirect effects of MMP-7, such as activation of MMP-2 and MMP-9. 38,40 Previous studies that did not use antibodies specific for active MMP-7 have produced conflicting results. For example, Sillanpaa et al 41 and Leinonen et al 42 found that high MMP-7 expression indicated less aggressive tumor behavior and better survival in ovarian and non-small-cell lung cancer.…”

Role of matrix metalloproteinase 7 in ovarian cancer (review of literature)

“…Так, F. Wang и соавт. продемонстрировали, что ММП-7 индуциру-ет инвазию раковых клеток линии DOV 13 и активи-рует предшественник ММП-2 [16].…”