title: Matrix metalloproteinase-9 measured in urine from bladder cancer patients is an independent prognostic marker of poor survival.
abstract: BACKGROUND
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark. bvo@oncology.dk
authors.forename: Birgitte V
authors.initials: BV
authors.lastname: Offersen
authors.forename: Marianne M
authors.initials: MM
authors.lastname: Knap
authors.forename: Michael R
authors.initials: MR
authors.lastname: Horsman
authors.forename: Jan
authors.initials: J
authors.lastname: Verheijen
authors.forename: Roeland
authors.initials: R
authors.lastname: Hanemaaijer
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood / Q000652:urine*; D003404:Creatinine / Q000097:blood; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000652:urine*; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000652:urine; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000401:mortality* / Q000473:pathology / Q000652:urine
chemical_list: D014408:Biomarkers, Tumor; D019715:Tissue Inhibitor of Metalloproteinase-1; D003404:Creatinine; D020780:Matrix Metalloproteinase 9