Expression of urokinase-type plasminogen activator system in non-metastatic prostate cancer

  • Shoji Kimura
  • David D’Andrea
  • Takehiro Iwata
  • Beat Foerster
  • Florian Janisch
  • Mehdi Kardoust Parizi
  • Marco Moschini
  • Alberto Briganti
  • Marko Babjuk
  • Piotr Chlosta
  • Pierre I. Karakiewicz
  • Dmitry Enikeev
  • Leonid M. Rapoport
  • Veronica Seebacher
  • Shin Egawa
  • Mohammad Abufaraj
  • Shahrokh F. ShariatEmail author
Original Article



To investigate the prognostic role of expression of urokinase-type plasminogen activator system members, such as urokinase-type activator (uPA), uPA-receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1), in patients treated with radical prostatectomy (RP) for prostate cancer (PCa).


Immunohistochemical staining for uPA system was performed on a tissue microarray of specimens from 3121 patients who underwent RP. Cox regression analyses were performed to investigate the association of overexpression of these markers alone or in combination with biochemical recurrence (BCR). Decision curve analysis was used to assess the clinical impact of these markers.


uPA, uPAR, and PAI-1 were overexpressed in 1012 (32.4%), 1271 (40.7%), and 1311 (42%) patients, respectively. uPA overexpression was associated with all clinicopathologic characteristics of biologically aggressive PCa. On multivariable analysis, uPA, uPAR, and PAI-1 overexpression were all three associated with BCR (HR: 1.75, p < 0.01, HR: 1.22, p = 0.01 and HR: 1.20, p = 0.03, respectively). Moreover, the probability of BCR increased incrementally with increasing cumulative number of overexpressed markers. Decision curve analysis showed that addition of uPA, uPAR, and PAI-1 resulted in a net benefit compared to a base model comparing standard clinicopathologic features across the entire threshold probability range. In subgroup analyses, overexpression of all three markers remained associated with BCR in patients with favorable pathologic characteristics.


Overexpression of uPA, uPAR, and PAI-1 in PCa tissue were each associated with worse BCR. Additionally, overexpression of all three markers is informative even in patients with favorable pathologic characteristics potentially helping clinical decision-making regarding adjuvant therapy and/or intensified follow-up.


Biochemical recurrence Prostate cancer Radical prostatectomy Urokinase-type plasminogen activator 


Author contributions

SK: protocol/project development, data collection, data analysis, and manuscript writing/editing. DD: data collection and data analysis. TI: manuscript writing/editing. BF: data collection, data analysis, and manuscript writing/editing. FJ: data collection and manuscript writing/editing. MKP: data collection and manuscript writing/editing. MM: data collection and manuscript writing/editing. AB: manuscript writing/editing. MB: manuscript writing/editing. PC: manuscript writing/editing. PIK: data collection and manuscript writing/editing. DE: data collection and manuscript writing/editing. LMR: data collection and manuscript writing/editing. VS: manuscript writing/editing. SE: protocol/project development. MA: data collection, data analysis, and manuscript writing/editing. SFS: protocol/project development and manuscript writing/editing.

Compliance with conflict of interest

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving Human participants and/or animals

This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

345_2019_3038_MOESM1_ESM.docx (123 kb)
Supplementary file1 Supplementary Figure1. Calibration plots with 1000 bootstrap resample for the nomogram including uPA, uPAR, and PAI-1 predicting biochemical recurrence-free survival at 6 months, 1, 3, and 5years in 3121 patients treated with radical prostatectomy for non-metastatic prostate cancer. PAI-1: plasminogen activator inhibitor-type1, uPA: urokinase-type plasminogen activator, uPAR: urokinase-type plasminogen activator receptor (DOCX 122 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Shoji Kimura
    • 1
    • 2
  • David D’Andrea
    • 1
  • Takehiro Iwata
    • 1
    • 3
  • Beat Foerster
    • 1
    • 4
  • Florian Janisch
    • 1
    • 5
  • Mehdi Kardoust Parizi
    • 1
    • 6
  • Marco Moschini
    • 1
    • 7
    • 8
  • Alberto Briganti
    • 8
  • Marko Babjuk
    • 9
  • Piotr Chlosta
    • 10
  • Pierre I. Karakiewicz
    • 11
  • Dmitry Enikeev
    • 12
  • Leonid M. Rapoport
    • 12
  • Veronica Seebacher
    • 13
  • Shin Egawa
    • 2
  • Mohammad Abufaraj
    • 1
    • 14
  • Shahrokh F. Shariat
    • 1
    • 12
    • 15
    • 16
    • 17
    Email author
  1. 1.Department of Urology and Comprehensive Cancer Center, Vienna General HospitalMedical University of ViennaViennaAustria
  2. 2.Department of UrologyJikei University School of MedicineTokyoJapan
  3. 3.Department of UrologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  4. 4.Department of UrologyKantonsspital WinterthurWinterthurSwitzerland
  5. 5.Department of UrologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  6. 6.Department of Urology, Shariati HospitalTehran University of Medical SciencesTeheranIran
  7. 7.Klinik für UrologieLuzerner KantonsspitalLucerneSwitzerland
  8. 8.Urological Research Institute, San Raffaele Scientific InstituteVita-Salute San Raffaele UniversityMilanItaly
  9. 9.Department of Urology, Hospital Motol, Second Faculty of MedicineCharles UniversityPragueCzech Republic
  10. 10.Department of UrologyJagiellonian UniversityKrakówPoland
  11. 11.Division of UrologyUniversity of Montreal Health CenterMontrealCanada
  12. 12.Institute for Urology and Reproductive HealthSechenov UniversityMoscowRussia
  13. 13.Department of Gynecology and Gynecologic OncologyMedical University of ViennaViennaAustria
  14. 14.Division of Urology, Department of Special Surgery, Jordan University HospitalThe University of JordanAmmanJordan
  15. 15.Department of UrologyWeill Cornell Medical CollegeNew YorkUSA
  16. 16.Department of UrologyUniversity of Texas Southwestern Medical CenterDallasUSA
  17. 17.Karl Landsteiner Institute of Urology and AndrologyViennaAustria

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