Abstract
BackgroundMembers 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.MethodsCorresponding 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.ResultsAntigen 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).ConclusionsHigh levels of uPA and uPAR in tumour tissue extracts are associated with a significantly shorter DSS of ccRCC patients without distant metastases.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-974) contains supplementary material, which is available to authorized users.
Highlights
Members of the urokinase-type plasminogen activator system including uPA, its receptor uPA 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
Reduced antigen levels of uPA were observed in the tumour tissue specimens compared to the corresponding non-malignant tissues (P = 0.002), whereas PAI-1 antigen levels were significantly increased in tumour tissue specimens (P < 0.001)
For clear cell renal cell carcinoma (ccRCC) patients with either high uPA (HR = 2.86; 95% confidence interval (CI) 1.07-7.67; P = 0.037) or uPAR antigen levels (HR = 4.70; 95% CI 1.5114.6; P = 0.008) we observed a significantly increased risk of cancer-related death compared with those patients who displayed low uPA or uPAR antigen levels in ccRCC tissue (Table 3)
Summary
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. Clear cell RCC (ccRCC) is the most common and the most aggressive subtype of this disease [3]. Since the disease progression of RCC is still not sufficiently predictable by clinical and histopathological parameters, there is an urgent need for additional powerful biological prognostic factors that may help to refine individual risk stratification of RCC patients. Several clinicopathological parameters and molecular biomarkers or their combination have been described to be prognostically useful for RCC [7,8,9]. Further research and validation of these molecular markers for diagnostic and prognostic purposes in RCC patients are still necessary
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