title: The role of matrix metalloproteinase MMP-9 and TIMP-2 tissue inhibitor of metalloproteinases as serum markers of bladder cancer.
abstract: BACKGROUND
  The diagnosis and molecular staging of bladder cancer based on the detection of gelatinases mRNA (MMP-2 and MMP-9) in peripheral blood circulating and mononuclear cells have shown promising results. We analyze if the determination of the corresponding protein synthesis products makes it possible to diagnose and characterize patients with bladder cancer.
  
  
  METHODS
  Quantification of the serum levels of MMP-2, MMP-9 and TIMP-2 in a series of 42 individuals (31 patients with bladder cancer in different stages and 11 healthy controls) using the ELISA technique was carried out. The determinations were compared between cases and controls (Mann-Whitney U) and between different groups of tumors (Mann-Whitney U or Kruskal-Wallis), according to the clinical-pathological characteristics (age, gender, T category, M category or grade). Diagnostic yield of these markers was evaluated by analysis of the ROC curves.
  
  
  RESULTS
  There is a correlation between the determinations of MMP-2 and TIMP-2 (R=.699; P>.0001) and MMP-9 and TIMP-2 (R=.305; P=.049). Patients with bladder cancer have higher levels of MMP-9 (p<0.0001) and TIMP-2 (P=.047) than the controls. Furthermore, the MMP-9/TIMP-2 ratio is also superior in cancer patients (P<.001). Differences were not detected between cancer and controls regarding age (P=.64) or gender (P=.64). Differences were also not detected regarding MMP-2 (P=.35) or MMP-2/TIMP-2 rate (P=.45). Within the cancer patient population, the MMP-2 and MMP-9 values differ according to T category (P=.022 and P=.038, respectively) and those of the TIMP-2 according to M category (P=.036). ROC curve analysis showed that both MMP-9 and the MMP-9/TIMP-2 ratio discriminate patients with cancer and controls, with equivalent diagnostic accuracy (ABC 0.953) and cut offs of 3.93 ng/mL (S 90%; Sp 81%) and 0.053 ng/mL (S 96%; Sp 84%), respectively.
  
  
  CONCLUSIONS
  The results obtained suggest that both serum MMP-9 and TIMP-2 would have an application in the prediction of the development and progression of bladder cancer, and a potential utility as clinical markers of the disease. Multicenter, prospective studies that confirm their preliminary results are necessary.
authors.affiliation: Servicio de Urología, Hospital Universitario de Getafe, Fundación para la Investigación Biomédica, Universidad Europea de Madrid, Madrid, España. Electronic address: frfata@hotmail.com.
authors.forename: F
authors.initials: F
authors.lastname: Ramón de Fata
authors.forename: A
authors.initials: A
authors.lastname: Ferruelo
authors.forename: G
authors.initials: G
authors.lastname: Andrés
authors.forename: H
authors.initials: H
authors.lastname: Gimbernat
authors.forename: M
authors.initials: M
authors.lastname: Sánchez-Chapado
authors.forename: J C
authors.initials: JC
authors.lastname: Angulo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000097:blood*; D001749:Urinary Bladder Neoplasms / Q000097:blood* / Q000175:diagnosis*
chemical_list: D014408:Biomarkers, Tumor; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; D020780:Matrix Metalloproteinase 9
keywords: Ensayo por inmunoabsorción ligado a enzimas; Enzyme-Linked ImmunoSorbent Assay; Inhibidor Tisular de Metaloproteinasa-2; Metalloproteinase-2; Metalloproteinase-9; Metaloproteinasa-2; Metaloproteinasa-9; Tisular Inhibitor of Metalloproteinase-2