Prognostic impact of urokinase-type plasminogen activator system components in clear cell renal cell carcinoma patients without distant metastasis

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.

Transforming growth factor-β promotes aggressiveness and invasion of clear cell renal cell carcinoma

“…One earlier study on ccRCC using immunohistochemistry also reported that PAI-1 was associated with tumor stage and disease progression [31], which is in line with our findings. Furthermore, we found that high PAI-1 mRNA as well as PAI-1 protein levels were associated with poor survival of the patients, confirming the independent survival information previously reported [29, 30]. The association between PAI-1 and tumor progression might be due to the regulation of angiogenesis by PAI-1 [30].…”

“…In breast cancer, it has a pivotal role in tumor vascular remodeling and neovascularization [25]. Expression of PAI-1 promotes cancer progression and high levels of PAI-1 proteins are associated with poor survival in some malignancies [26–29]. In ccRCC, high PAI-1 expression is correlated with a high nuclear grade, an advanced stage, distant metastasis, and shortened disease-free survival [30, 31].…”

Diagnostic and prognostic biomarker potential of kallikrein family genes in different cancer types

“…Our analysis differed and found that KLK1 , KLK2 , KLK3 , KLK4 and KLK15 are highly upregulated in chromophobe renal cell carcinoma. We hypothesize that the increase in these five kallikreins may cause increased expression of uPA and the destruction of the ECM, which has been shown to be active in renal carcinoma [ 37 – 39 ]. KLK5 and KLK6 are decreased in all three types of the renal carcinomas.…”

Tumor Associated Macrophages in Kidney Cancer

“…The level of uPA receptor expression correlated with the density of blood vessels in tumors and poor prognosis of the disease [28, 29]. In renal cancer, high levels of uPA and uPAR in tumor tissue extracts are associated with a significantly shorter survival of ccRCC patients though without distant metastases [30]. These data indicate the importance of uPA regulated by tumor associated macrophages in the reorganization of the vascular system of the tumor.…”