Matrix metalloproteinase-9 measured in urine from bladder cancer patients is an independent prognostic marker of poor survival

Acta Oncol. 2010 Nov;49(8):1283-7. doi: 10.3109/0284186X.2010.509109. Epub 2010 Sep 15.

Abstract

Introduction: Matrix metalloproteinase 9 (MMP-9) is an endopeptidase involved in various cellular processes, such as tumour development and metastatic spread. In biological samples, MMP-9 can occur as pro-MMP-9 and active MMP-9, or these factors complexed with the inhibitor TIMP-1. An assay, which can measure active and total MMP-9 in biological samples, has been used on the urine from bladder cancer patients and demonstrated a significant correlation between MMP-9 and clinical parameters. The prognostic value of these measurements has never been investigated. Using this assay we have investigated the prognostic influence of total and active MMP-9 in urine from bladder cancer patients.

Material and methods: Fresh voided urines from 188 consecutive patients diagnosed with bladder cancer were collected and frozen at diagnosis. After 15 years follow-up 13 patients were still alive, and 175 patients had died. MMP-9 was measured with an immunocapture activity assay.

Results: Median MMP-9(total) was 173.7 units/10 g creatinine (range 0-34 792), and median MMP-9(active) was 14 units/10g creatinine (range, 0-294 757). The two factors were correlated (Spearman´s rho 0.74, p<0.0001). High MMP-9(total) and MMP-9(active) were significantly correlated with large tumour size and poor malignancy grade. Increasing tertiles of MMP-9(total) and MMP-9(active) were associated with poor overall survival (p<0.0001 and p=0.003, respectively). A Cox multivariate analysis using death as endpoint identified high tertiles of MMP-9(total) as independent prognostic markers with a relative risk 2.25 (95% confidence interval, 1.53-3.30).

Conclusion: MMP-9 measured in urine from bladder cancer patients was a strong independent prognostic marker of poor survival. This is the first time high levels of MMP-9 measured in urine from bladder cancer patients have been linked to poor prognosis. This may reflect MMP-9 playing a role in tumour invasion and metastasis. It may be possible to non-invasively measure tumour response to therapy and identify possible tumour recurrence in an early phase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / urine*
  • Creatinine / blood
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Matrix Metalloproteinase 9 / urine*
  • Middle Aged
  • Neoplasm Staging
  • Predictive Value of Tests
  • Prognosis
  • Proportional Hazards Models
  • Risk Assessment
  • Risk Factors
  • Survival Analysis
  • Tissue Inhibitor of Metalloproteinase-1 / urine
  • Urinary Bladder Neoplasms / enzymology*
  • Urinary Bladder Neoplasms / mortality*
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / urine

Substances

  • Biomarkers, Tumor
  • Tissue Inhibitor of Metalloproteinase-1
  • Creatinine
  • Matrix Metalloproteinase 9