The Clinical Relevance of Stromal Matrix Metalloproteinase Expression in Ovarian Cancer

Abstract

Purpose: Matrix metalloproteinases (MMP) are proteolytic enzymes implicated in cancer progression and metastasis. We sought to determine the role of epithelial (tumor cell^derived) and stromal (host-derived) expression of MMPs in predicting the clinical outcome of patients with epithelial ovarian cancer (EOC). Experimental Design: MMP-2, MMP-9, and membrane type 1 (MT1)-MMP expression was evaluated using immunohistochemistry in 90 invasive EOCs, and samples were scored for epithelial and stromal staining. Results were correlated with clinicopathologic characteristics using univariate and multivariate analyses. Results: High expression of MMP-2, MMP-9, and MT1-MMP in tumor epithelium was detected in 54%, 97%, and 100% of cases, and in stromal compartments, in 38%, 70%, and 38% of cases, respectively. High stromal expression of MMP-2, MMP-9, and MT1-MMP was significantly associated with aggressive features such as high stage, high grade ascites, and positive lymph node status. Kaplan-Meier analysis showed that high epithelial and stromal expression of MMP-2, MMP-9, and MT1-MMP were each significantly associated with shorter disease-specific survival (DSS; P < 0.01). On tree-structured survival analysis, patients with strong epithelial MT1-MMP expression had the shortest DSS, whereas patients with moderate epithelial MT1-MMP and low stromal MMP-9 expression had the longest DSS (P < 0.01). On multivariate analysis, high stromal expression of MMP-9 (P = 0.01) and MT1-MMP (P = 0.04), strong epithelial MT1-MMP (P = 0.01) and high stage (P = 0.04) were independent predictors of poor DSS. Conclusions: Overexpression of stromal MMP-9 and MT1-MMP is independently associated with shorter DSS in EOC. Thus, host-derived MMPs are valuable predictors of clinical outcome in EOC.

PEA3 Is Necessary for Optimal Epidermal Growth Factor Receptor–Stimulated Matrix Metalloproteinase Expression and Invasion of Ovarian Tumor Cells

“…MMP-14 is expressed in borderline and malignant, but not benign ovarian tumors, suggesting that MMP-14 is associated with more advanced disease (47). Our findings of PEA3-dependent regulation of MMP-9 and MMP-14 in ovarian tumor cells may reflect an important biological role for PEA3 overexpression in ovarian cancer based on the observations that epithelial expression of MMP-9 or MMP-14 correlate with decreased patient survival (44)(45)(46). Understanding oncogenic signaling cascades that culminate in the expression of metastatic genes will be critical to understanding the etiology of ovarian cancer, and in identifying new potential therapeutic targets.…”

“…PEA3-dependent regulation of these MMPs may have significant consequences for metastatic progression in ovarian cancer. MMP-9 expression in either ovarian epithelial tumor cells or the adjacent malignant stroma was indicative of poor prognosis (44)(45)(46). MMP-14 is expressed in borderline and malignant, but not benign ovarian tumors, suggesting that MMP-14 is associated with more advanced disease (47).…”

A biochemical mechanism for resistance of intervertebral discs to metastatic cancer: Fas ligand produced by disc cells induces apoptotic cell death of cancer cells

“…Another explanation is that the abundant collagen content and high intradiscal pressure of the discs act as mechanical barriers against tumor invasion. However, metastatic cancer cells secrete matrix metalloproteinases, such as collagenase, that can destroy extracellular matrix components of the discs during metastasis or progression [5,11,17,23]. Therefore, these findings suggest that there may be a mechanism other than the disc's anatomic characteristics that confer its resistance to metastases.…”

Differential Associations of MMP-2 and MMP-14 with Stromal Amounts and T lymphocyte Presence in Ovarian Cancer

“…It is possible that chemotactic signals in the micro-environment of the tumor could be more important than the arrangement of the collagen fibers [29,33]. The negative association of MMP-14 on T-lymphocyte influx is in accordance with the negative effect of MMP-14 expression and survival [16]. This negative correlation that we have found would favor the use of MMP-14 inhibitors, which have been, however, already been reported to be ineffective in advanced ovarian cancer [36].…”

“…The scoring system according to Kamat et al used for MMP-14 and MMP-2 incorporated intensity (0 = absent, 1 = weak, 2 = moderate, 3 = strong staining) and percentage of positive tumor cells (0 = 0%, 1 = 1-25%, 2 = 26-50%, 3 = 51-75%, 4 = 76-100% of cells) [16]. Two investigators scored all slides (MCV, EB).…”