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Further Understanding of Urokinase Plasminogen Activator Overexpression in Urothelial Bladder Cancer Progression, Clinical Outcomes and Potential Therapeutic Targets

Authors Grossmann NC, Schuettfort VM, Pradere B, Moschini M, Quhal F, Mostafaei H, Soria F, Katayama S, Laukhtina E, Mori K, Sari Motlagh R, Poyet C, Abufaraj M, Karakiewicz PI, Shariat SF, D’Andrea D

Received 1 December 2020

Accepted for publication 29 December 2020

Published 13 January 2021 Volume 2021:14 Pages 315—324

DOI https://doi.org/10.2147/OTT.S242248

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Gaetano Romano


Nico C Grossmann,1,2 Victor M Schuettfort,1,3 Benjamin Pradere,1,4 Marco Moschini,5 Fahad Quhal,1,6 Hadi Mostafaei,1,7 Francesco Soria,8 Satoshi Katayama,1,9 Ekaterina Laukhtina,1,10 Keiichiro Mori,1,11 Reza Sari Motlagh,1,12 Cédric Poyet,2 Mohammad Abufaraj,1,13 Pierre I Karakiewicz,14 Shahrokh F Shariat,1,10,15– 19 David D’Andrea1

1Department of Urology, Comprehensive Cancer Center, Vienna General Hospital, Medical University of Vienna, Vienna, Austria; 2Department of Urology, University Hospital Zurich, Zurich, Switzerland; 3Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4Department of Urology, University Hospital of Tours, Tours, France; 5Department of Urology, Luzerner Kantonsspital, Luzern, Switzerland; 6Department of Urology, King Fahad Specialist Hospital, Dammam, Saudi Arabia; 7Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; 8Department of Urology, Molinette Hospital, University of Turin, Turin, Italy; 9Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 10Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; 11Department of Urology, The Jikei University School of Medicine, Tokyo, Japan; 12Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 13Division of Urology, Department of Special Surgery, Jordan University Hospital, The University of Jordan, Amman, Jordan; 14Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Canada; 15Department of Urology, Weill Cornell Medical College, New York, NY, USA; 16Department of Urology, University of Texas Southwestern, Dallas, TX, USA; 17Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; 18Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria; 19European Association of Urology Research Foundation, Arnhem, Netherlands

Correspondence: Shahrokh F Shariat
Department of Urology, Comprehensive Cancer Center, Vienna General Hospital, Medical University of Vienna, Währinger Gürtel 18-20, Vienna 1090, Austria
Tel +4314040026150
Fax +4314040023320
Email shahrokh.shariat@meduniwien.ac.at

Purpose: The Plasminogen Activation System (PAS) plays a role in tumor growth, invasion and metastasis and has been associated with oncological outcomes in urinary bladder carcinoma (UBC). The use of the different components of this system as molecular markers could improve our understanding of the heterogeneous behavior of UBC and might enable earlier disease detection, individual risk stratification, more accurate outcome prediction and be a rationale for new targeted therapies.
Methods: A comprehensive literature search including relevant articles up to October 2020 was performed using the MEDLINE/PubMed database.
Results: The components of the PAS axis are involved in tumor progression through their signaling processes during angiogenesis, cell migration, metastasis and adhesion. The body of evidence shows an association of PAS component overexpression with adverse pathological features and clinical outcome in UBC. Overexpressed PAS components correlate with a higher pathological tumor grade and advanced tumor stage. In non-muscle-invasive bladder cancer (NMIBC), the PAS components were associated with disease outcome while in muscle-invasive bladder cancer (MIBC), it was associated with disease outcome and pathological features. Possible therapeutic approaches in the PAS for the treatment of UBC have only been sparsely investigated in in vitro and in vivo studies. Intravesical plasminogen activator inhibitor 1 (PAI-1) instillation in animal models yielded interesting results and warrant further exploration in Phase II studies.
Conclusion: The overexpression of PAS components in UBC tumor tissue is associated with adverse pathological features and worse oncological outcomes. These findings are mainly based on preclinical studies and retrospective series, which requires further prospective studies to translate the PAS into clinically useful biomarkers and therapeutic targets.

Keywords: urothelial cancer, uPA, uPAR, PAI, therapy, review

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