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

Clin Exp Metastasis. 1999;17(10):799-808. doi: 10.1023/a:1006723011835.


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.

Publication types

  • Evaluation Study

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / metabolism*
  • Carcinoma / metabolism
  • Carcinoma / mortality
  • Carcinoma / secondary
  • Female
  • Humans
  • In Situ Hybridization / methods
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase 9 / metabolism*
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / metabolism*
  • Middle Aged
  • Multivariate Analysis
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / mortality*
  • Ovarian Neoplasms / secondary
  • Predictive Value of Tests
  • RNA, Messenger / metabolism
  • Retrospective Studies
  • Survival Rate
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism*


  • Biomarkers, Tumor
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-2
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9