High levels of MMP-2, MMP-9, MT1-MMP and TIMP-2 mRNA correlate with poor survival in ovarian carcinoma

The object of this study was to analyze the potential association between t he expression of MMP-2, MMP-9, MT1-MMP and TIMP-2, and disease outcome in a dvanced-stage ovarian carcinomas. Sections from 70 paraffin-embedded blocks (36 primary ovarian carcinomas and 34 metastatic lesions) from 45 patients diagnosed with advanced stage ovarian carcinomas (FIGO stages III-IV) were studied using mRNA in situ hybridization (ISH) technique. Patients were di vided retrospectively in two groups based on disease outcome. Long-term sur vivors (21 patients) and short-term survivors (24 patients) were defined us ing a double cut-off of 36 months for disease-free survival (DFS) and 60 mo nths for overall survival (OS). Mean follow-up period for patients that wer e diagnosed with advanced-stage carcinoma was 70 months. The mean values fo r DFS and OS were 109 and 125 months for long-term survivors, as compared t o 3 and 21 months for short-term survivors, respectively. Intense mRNA sign als were detected more frequently in tumor cells of short-term survivors wi th use of all four probes. Comparable findings were observed in peritumoral stromal cells with ISH for MMP-2, MMP-9 and TIMP-2 mRNA. Notably, primary tumors with intense mRNA signal for TIMP-2 (No = 14) were uniformly associa ted with a fatal outcome. In univariate analysis of primary tumors, mRNA le vels of TIMP-2 in stromal cells (P=0.0002), as well as for MMP-9 (P=0.012) and TIMP-2 (P=0.02) in tumor cells, correlated with poor outcome. In univar iate analysis of metastatic lesions, mRNA levels of TIMP-2 in stromal cells (P=0.031), as well as for MMP-2 (P=0.027) and MT1-MMP (P=0.008) in tumor c ells, correlated with poor outcome. Interestingly, the presence of MT1-MMP in stromal cells correlated with longer survival (P=0.025). In a multivaria te analysis of ISH results for primary tumors, TIMP-2 levels in stromal cel ls (P=0.006) and MMP-9 levels in tumor cells (P=0.011) retained their predi ctive value. We conclude that MMP-2, MMP-9, MT1-MMP and TIMP-2 are valid ma rkers of poor survival in advanced-stage ovarian carcinoma.