BERKELEY, CA (UroToday.com) - Prostate cancer (PCa), as the second most frequently diagnosed malignancy and the sixth leading cause of cancer-related death in men worldwide,[1] is still a serious problem, especially since castration-resistant PCa patients have only a limited therapeutic window. Although several biomarkers for PCa have been described, measured either in tumor tissue or urine,[2, 3] there is still an urgent need for the characterization and validation of novel biomarkers for diagnostic, prognostic, and predictive purposes in PCa patients.
We studied the urokinase plasminogen activator (uPA) system – i.e., its members urokinase plasminogen activator (uPA), its receptor (uPAR) and the inhibitor (PAI-1) – on the mRNA level in tumor tissue and on the protein level in serum of PCa patients to test the hypothesis that their mRNA/antigen levels could be used as diagnostic and/or prognostic biomarkers. It is worth mentioning that uPA and its inhibitor PAI-1 have been extensively validated in preclinical/clinical studies and have been shown to be relevant cancer biomarkers in different solid malignant tumors, reaching the highest level of evidence (LOE-1) as a tumor-associated biomarker in breast cancer.[4] Prostate cancer is a hormone-driven tumor like breast cancer, and therefore studying the uPA system in PCa may have clinical relevance as well.
We showed that elevated uPA mRNA expression in PCa (N=132) was significantly associated with higher Gleason score (P = 0.001; Fisher’s exact test), suggesting that uPA mRNA transcript has tumor biological relevance in PCa. Next, we studied serum of PCa patients (N=81) for antigen levels of the three uPA system members. We found that an increased concentration of soluble uPAR (suPAR) in serum ( > 66% percentile) was significantly associated with a poor overall survival of PCa patients (P = 0.022; log rank test). PCa patients with high suPAR levels have a significantly higher risk of death (HR = 7.12, P = 0.027; multivariate Cox’s regression analysis). In the literature, there are two reports studying uPAR antigen levels in serum in combination with survival analysis. Miyake et al. found in PCa patients (with a high proportion of metastatic patients) an association of an increased co-expression of uPAR/uPA with poor prognosis.[5] Almasi and coworkers reported for 131 metastatic PCa patients a significant association of elevated pretreatment levels of suPAR (full length and cleaved forms) in serum with shorter overall survival.[6] Our results in a non-selected PCa cohort support their findings and add knowledge for PCa patients in general.
Altogether, we suggest that the association of high suPAR levels in the serum with poor survival of PCa patients has prognostic impact for PCa patients. Although this finding has to be validated in prospective long-term studies, it may show that the uPA system can provide a useful biomarker that can be easily and non-invasively measured in the blood of PCa patients.
References:
- Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893-917.
- Miyake H, Fujisawa M. Prognostic prediction following radical prostatectomy for prostate cancer using conventional as well as molecular biological approaches. Int J Urol. 2013;20:301-11.
- Truong M, Yang B, Jarrard DF. Toward the detection of prostate cancer in urine: a critical analysis. J Urol. 2013;189:422-9.
- Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC Jr; American Society of Clinical Oncology. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J. Clin. Oncol. 2007;25: 5287–5312.
- Miyake H, Hara I, Yamanaka K, Gohji K, Arakawa S, Kamidono S. Elevation of serum levels of urokinase-type plasminogen activator and its receptor is associated with disease progression and prognosis in patients with prostate cancer. Prostate. 1999;39:123-9.
- Almasi CE, Brasso K, Iversen P, Pappot H, Høyer-Hansen G, Danø K, Christensen IJ. Prognostic and predictive value of intact and cleaved forms of the urokinase plasminogen activator receptor in metastatic prostate cancer. Prostate 2011;71:899-907.
Written by:
Helge Taubert, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Urologische Klinik, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, 91052 Erlangen, Germany