Noninvasive Diagnosis of Bladder Cancer by Detection of Matrix Metalloproteinases (MMP-2 and MMP-9) and Their Inhibitor (TIMP-2) in Urine

Eur Urol. 2007 Nov;52(5):1388-96. doi: 10.1016/j.eururo.2007.04.006. Epub 2007 Apr 10.


Objectives: TIMPs control the activity of MMPs, one of the key molecules for tumor invasion and metastasis. The aim of this study was to assess the usefulness of MMP-2 and MMP-9 in relation to their inhibitor (TIMP2) as noninvasive diagnostic tests for bilharzial bladder cancer.

Material and methods: Voided urine samples were provided from 244 subjects (154 bladder cancer [136 bilharzial]; 60 benign urologic disorders; 30 healthy volunteers). Urine sediment was used for cytology, and the supernatant for estimation of MMPs and TIMP-2 by ELISA and gelatin zymography.

Results: The best cut-off values for the investigated markers were determined by ROC curve. Positivity rates and median levels for MMP-2, MMP-9, TIMP-2, MMP-2/TIMP-2, and MMP-9/TIMP-2 showed significant difference among the three investigated groups (p<0.001). MMP-9 and MMP-2/TIMP-2 were related to pathologic type, MMP-2/TIMP-2 was inversely related to the grade, and MMP-9/TIMP-2 was related to bilharziasis (p<0.05). MMP zymography results were comparable to those from ELISA.

Conclusion: The sensitivity and specificity of MMP zymography, MMP-9/TIMP-2 ratio, and MMP-2/TIMP2 ratio were superior among all investigated parameters; furthermore, combined testing of cytology with them improves the sensitivity even in superficial and low-grade tumors.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / urine
  • Carcinoma, Squamous Cell / diagnosis*
  • Carcinoma, Squamous Cell / enzymology
  • Carcinoma, Transitional Cell / diagnosis*
  • Carcinoma, Transitional Cell / enzymology
  • Disease Progression
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Matrix Metalloproteinase 2 / urine*
  • Matrix Metalloproteinase 9 / urine*
  • Middle Aged
  • Prognosis
  • Prospective Studies
  • ROC Curve
  • Severity of Illness Index
  • Tissue Inhibitor of Metalloproteinase-2 / urine*
  • Urinary Bladder Neoplasms / diagnosis*
  • Urinary Bladder Neoplasms / enzymology


  • Biomarkers, Tumor
  • Tissue Inhibitor of Metalloproteinase-2
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9