title: Prognostic impact of urokinase-type plasminogen activator system components in clear cell renal cell carcinoma patients without distant metastasis.
abstract: BACKGROUND
  Members of the urokinase-type plasminogen activator (uPA) system including uPA, its receptor uPAR and the plasminogen activator inhibitor 1 (PAI-1) play an important role in tumour invasion and progression in a variety of tumour types. Since the majority of clear cell renal cell carcinoma (ccRCC) shows distant metastasis at time of diagnosis or later, the interplay of uPA, uPAR and PAI-1 might be of importance in this process determining the patients' outcome.
  
  
  METHODS
  Corresponding pairs of malignant and non-malignant renal tissue specimens were obtained from 112 ccRCC patients without distant metastasis who underwent tumour nephrectomy. Tissue extracts prepared from fresh-frozen tissue samples by detergent extraction were used for the determination of antigen levels of uPA, uPAR and PAI-1 by ELISA. Antigen levels were normalised to protein concentrations and expressed as ng per mg of total protein.
  
  
  RESULTS
  Antigen levels of uPA, uPAR, and PAI-1 correlated with each other in the malignant tissue specimens (rs=0.51-0.65; all P<0.001). Antigen levels of uPA system components were significantly higher in tissue extracts of non-organ confined tumours (pT3+4) compared to organ-confined tumours (pT1+2; all P<0.05). Significantly elevated levels of uPAR and PAI-1 were also observed in high grade ccRCC. When using median antigen levels as cut-off points, all three uPA system factors were significant predictors for disease-specific survival (DSS) in univariate Cox's regression analyses. High levels of uPA and uPAR remained independent predictors for DSS with HR=2.86 (95% CI 1.07-7.67, P=0.037) and HR=4.70 (95% CI 1.51-14.6, P=0.008), respectively, in multivariate Cox's regression analyses. A combination of high antigen levels of uPA and/or uPAR further improved the prediction of DSS in multivariate analysis (HR=14.5, 95% CI 1.88-111.1, P=0.010). Moreover, high uPA and/or uPAR levels defined a patient subgroup of high risk for tumour-related death in ccRCC patients with organ-confined disease (pT1+2) (HR=9.83, 95% CI 1.21-79.6, P=0.032).
  
  
  CONCLUSIONS
  High levels of uPA and uPAR in tumour tissue extracts are associated with a significantly shorter DSS of ccRCC patients without distant metastases.
authors.affiliation: Department of Urology, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany. susanne.fuessel@uniklinikum-dresden.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Fuessel
authors.forename: Kati
authors.initials: K
authors.lastname: Erdmann
authors.forename: Helge
authors.initials: H
authors.lastname: Taubert
authors.forename: Andrea
authors.initials: A
authors.lastname: Lohse-Fischer
authors.forename: Stefan
authors.initials: S
authors.lastname: Zastrow
authors.forename: Matthias
authors.initials: M
authors.lastname: Meinhardt
authors.forename: Karen
authors.initials: K
authors.lastname: Bluemke
authors.forename: Lorenz
authors.initials: L
authors.lastname: Hofbauer
authors.forename: Paolo
authors.initials: P
authors.lastname: Fornara
authors.forename: Bernd
authors.initials: B
authors.lastname: Wullich
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baretton
authors.forename: Viktor
authors.initials: V
authors.lastname: Magdolen
authors.forename: Manfred P
authors.initials: MP
authors.lastname: Wirth
authors.forename: Matthias
authors.initials: M
authors.lastname: Kotzsch
mesh_terms: D000368:Aged; D000941:Antigens / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000737:chemistry* / Q000401:mortality; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007668:Kidney / Q000737:chemistry; D007680:Kidney Neoplasms / Q000737:chemistry* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis* / Q000276:immunology; D011237:Predictive Value of Tests; D011379:Prognosis; D055293:Receptors, Urokinase Plasminogen Activator / Q000032:analysis* / Q000276:immunology; D015996:Survival Rate; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis* / Q000276:immunology
chemical_list: D000941:Antigens; D017395:Plasminogen Activator Inhibitor 1; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator