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

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Abstract

The object of this study was to analyze the potential association between the expression of MMP-2, MMP-9, MT1-MMP and TIMP-2, and disease outcome in advanced-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 divided retrospectively in two groups based on disease outcome. Long-term survivors (21 patients) and short-term survivors (24 patients) were defined using a double cut-off of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Mean follow-up period for patients that were diagnosed with advanced-stage carcinoma was 70 months. The mean values for DFS and OS were 109 and 125 months for long-term survivors, as compared to 3 and 21 months for short-term survivors, respectively. Intense mRNA signals were detected more frequently in tumor cells of short-term survivors with 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 associated with a fatal outcome. In univariate analysis of primary tumors, mRNA levels 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 univariate 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 cells, correlated with poor outcome. Interestingly, the presence of MT1-MMP in stromal cells correlated with longer survival (P = 0.025). In a multivariate analysis of ISH results for primary tumors, TIMP-2 levels in stromal cells (P = 0.006) and MMP-9 levels in tumor cells (P = 0.011) retained their predictive value. We conclude that MMP-2, MMP-9, MT1-MMP and TIMP-2 are valid markers of poor survival in advanced-stage ovarian carcinoma.

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Authors and Affiliations

  1. Department of Pathology, The Norwegian Radium Hospital, affiliated with the University of Oslo, Montebello, Oslo, Norway

    Ben Davidson, Jahn M. Nesland, Aasmund Berner & Magne Bryne

  2. Department of Pharmacology, Faculty of Medicine, Hebrew University, Jerusalem, Israel

    Reuven Reich

  3. Department of Pathology, Sheba Medical Center, affiliated with Sackler School of Medicine, Tel-Aviv University, Israel, Tel-Hashomer, Israel

    Iris Goldberg & Juri Kopolovic

  4. Division of Gynecologic Oncology, Sheba Medical Center, affiliated with Sackler School of Medicine, Tel-Aviv University, Israel, Tel-Hashomer, Israel

    Walter H. Gotlieb & Gilad Ben-Baruch

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  1. Ben Davidson
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Davidson, B., Goldberg, I., Gotlieb, W.H. et al. High levels of MMP-2, MMP-9, MT1-MMP and TIMP-2 mRNA correlate with poor survival in ovarian carcinoma. Clin Exp Metastasis 17, 799–808 (1999). https://doi.org/10.1023/A:1006723011835

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