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.

Fig. 1

Immunohistochemical expression pattern of MMP-2, MMP-9, and MT1-MMP in epithelial ovarian carcinoma. Expression of MMP-2, MMP-9, and MT1-MMP was detected in both tumor epithelial cells (T) and stromal cells (S). A–C, negative, weak, and strong expression of MMP-2. D–F, negative, weak, and strong expression of MMP-9. G–I, negative, weak, and strong expression of MT1-MMP. Original magnification, ×200.

Fig. 2

Kaplan-Meier survival curves for epithelial (left) and stromal (right) expression of MMP-2 (A and B), MMP-9 (C and D), and MT1-MMP (E and F). In all categories other than epithelial MMP-2 and MMP-9, high (OS = 2 or 3) MMP expression was significantly associated with shorter DSS (P < 0.01). For epithelial MMP-2 and MMP-9, 97% and 100% of the samples, respectively, had high expression. For these two variables, patients with moderate or less (OS ≤ 2) expression were compared with those with strong (OS = 3) expression.

Fig. 3

A, survival regression tree for all 90 patients with invasive epithelial ovarian carcinoma. The study group was divided into two distinct populations based on epithelial MT1-MMP expression. All samples had either moderate (OS = 2) or strong (OS = 3) epithelial MT1-MMP expression. Within the group with moderate MT1-MMP expression, low (OS = 0 or 1) or high (OS = 2 or 3) stromal MMP-9 expression further stratifies the group. B, Kaplan-Meier survival curves for each node of the survival tree. Patients with strong expression of epithelial MT1-MMP had the shortest DSS, whereas those with moderate expression of epithelial MT1-MMP and low expression of stromal MMP-9 had the best outcome. The difference between the three groups was highly significant by log-rank test (P < 0.01).