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

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Abstract

Purpose

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).

Methods

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.

Results

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.

Conclusion

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.

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Author information

Authors and Affiliations

  1. Department of Urology and Comprehensive Cancer Center, Vienna General Hospital, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria

    Shoji Kimura, David D’Andrea, Takehiro Iwata, Beat Foerster, Florian Janisch, Mehdi Kardoust Parizi, Marco Moschini, Mohammad Abufaraj & Shahrokh F. Shariat

  2. Department of Urology, Jikei University School of Medicine, Tokyo, Japan

    Shoji Kimura & Shin Egawa

  3. Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Takehiro Iwata

  4. Department of Urology, Kantonsspital Winterthur, Winterthur, Switzerland

    Beat Foerster

  5. Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Florian Janisch

  6. Department of Urology, Shariati Hospital, Tehran University of Medical Sciences, Teheran, Iran

    Mehdi Kardoust Parizi

  7. Klinik für Urologie, Luzerner Kantonsspital, Lucerne, Switzerland

    Marco Moschini

  8. Urological Research Institute, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

    Marco Moschini & Alberto Briganti

  9. Department of Urology, Hospital Motol, Second Faculty of Medicine, Charles University, Prague, Czech Republic

    Marko Babjuk

  10. Department of Urology, Jagiellonian University, Kraków, Poland

    Piotr Chlosta

  11. Division of Urology, University of Montreal Health Center, Montreal, QC, Canada

    Pierre I. Karakiewicz

  12. Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia

    Dmitry Enikeev, Leonid M. Rapoport & Shahrokh F. Shariat

  13. Department of Gynecology and Gynecologic Oncology, Medical University of Vienna, Vienna, Austria

    Veronica Seebacher

  14. Division of Urology, Department of Special Surgery, Jordan University Hospital, The University of Jordan, Amman, Jordan

    Mohammad Abufaraj

  15. Department of Urology, Weill Cornell Medical College, New York, NY, USA

    Shahrokh F. Shariat

  16. Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Shahrokh F. Shariat

  17. Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria

    Shahrokh F. Shariat

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  1. Shoji Kimura
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  2. David D’Andrea
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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.

Corresponding author

Correspondence to Shahrokh F. Shariat.

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345_2019_3038_MOESM1_ESM.docx

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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Kimura, S., D’Andrea, D., Iwata, T. et al. Expression of urokinase-type plasminogen activator system in non-metastatic prostate cancer. World J Urol 38, 2501–2511 (2020). https://doi.org/10.1007/s00345-019-03038-5

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