title: Combined determination of plasma MMP2, MMP9, and TIMP1 improves the non-invasive detection of transitional cell carcinoma of the bladder.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play a major role in the maintenance of extracellular matrix homeostasis and are involved in the process of tumour invasion and metastasis in several malignant tumour entities. The goal of this study is to evaluate the diagnostic value of various circulating MMPs and TIMPs in blood plasma for a non-invasive detection of transitional cell carcinoma of the bladder (TCC).
  
  
  METHODS
  In this study the concentrations of MMP1, MMP2, MMP3, MMP9, their inhibitors TIMP1, TIMP2, and the MMP1/TIMP1-complex (MTC1) were quantified in blood plasma with the sandwich enzyme-linked immunosorbent assay (ELISA). Blood plasma samples were investigated from 68 patients (non-metastasized, n = 57 and metastasized, n = 11) with TCC of the bladder and from 79 healthy controls. The mROC program was used to calculate the best two- and three- marker combinations. The diagnostic values for all single markers and the marker combinations were estimated both by the overall diagnostic performance index area under the ROC curve (AUC) and the sensitivity and specificity at cutoff limits with the highest diagnostic accuracy and at the 90% and 95% limits of sensitivity and specificity, respectively.
  
  
  RESULTS
  The median MMP2 concentration was elevated in blood plasma in all patient groups with TCC in comparison to the controls (p < 0.001). The concentrations of TIMP1, TIMP2, and MTC1 in plasma probes were significantly lower from patients with non-metastasized TCC compared to the controls. MMP2 tested alone reached the highest sensitivity and specificity at 75%, respectively. The sensitivity and specificity increased when tested in combination with MMP9 and TIMP1 (97%, 94%, respectively). The combination of MMP9 and TIMP1 also showed an improved sensitivity (80%) and specificity (99%) than tested alone.
  
  
  CONCLUSIONS
  MMP2 is a statistically significant marker in blood plasma for bladder cancer detection with an increased diagnostic value in combination with MMP9 and TIMP1. This study showed that the highest sensitivities and specificities are not obtained by testing each marker alone. As shown by the best two-marker combination, which includes MMP9 and TIMP1, the optimized combination does not always include the best single markers.
authors.affiliation: Department of Urology, University Hospital Charité, CCM, Humboldt University, Berlin, Germany. andrea.staack@charite.de
authors.forename: Andrea
authors.initials: A
authors.lastname: Staack
authors.forename: Steffen
authors.initials: S
authors.lastname: Badendieck
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schnorr
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Loening
authors.forename: Klaus
authors.initials: K
authors.lastname: Jung
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D002295:Carcinoma, Transitional Cell / Q000097:blood / Q000175:diagnosis / Q000201:enzymology*; D005260:Female; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood*; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D012680:Sensitivity and Specificity; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D001749:Urinary Bladder Neoplasms / Q000097:blood / Q000175:diagnosis / Q000201:enzymology*
chemical_list: D014408:Biomarkers, Tumor; D019715:Tissue Inhibitor of Metalloproteinase-1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9