The Prognostic Value of the Urokinase Plasminogen Activator (uPA) Pathway Proteins in Non-Muscle Invasive Bladder Cancer Patients - Expert Commentary

Non-muscle invasive bladder cancer (NMIBC) has a high recurrence rate. Understanding the risk factors for recurrence is essential.

The Urokinase Plasminogen Activator (uPA) pathway consists of uPA, its receptor (uPAR), and its inhibitor type 1 (PAI-1). The expression of these genes is associated with tumor aggressiveness in various cancers. A recent article published by Iwata et al. in Urologic Oncology evaluated the expression of these proteins as markers for NMIBC recurrence. The investigators performed immunohistochemical staining of uPA, uPAR, and PAI-1 on tissue from 827 NMIBC patients who underwent transurethral resection of the bladder. The investigators defined overexpression as 30% for uPA, 50% for uPAR, and 30% PAI-1. They also performed Cox proportional hazard analyses.

uPA overexpression was identified in 37.7% (312), uPAR overexpression in 44.7% (370) and PAI-1 overexpression in 44.6% (369) of patients. A positive correlation between high tumor grade and overexpression of uPA, uPAR, and PAI-1 was found. The investigators reported an association between recurrence-free survival (RFS) and uPA (hazard ratio [HR]: 1.40; P = 0.006), uPAR (HR: 1.70; P < 0.001), PAI-1 (HR: 1.35; P = 0.014), and the combination of all three markers (HR: 3.38; P < 0.001). They also found an association between progression-free survival (PFS) and uPA (HR: 1.68; P = 0.035) and the combination of all three markers (HR: 8.79; P = 0.005). The addition of the uPA system to a base model improved the discrimination by 1.3% for RFS and 2.1% for PFS.

This study highlights the importance of identifying new prognostic and predictive biomarkers for NMIBC. Understanding the mechanistic role of these proteins in NMIBC progression and using robust techniques for quantifying their quantification are the next steps towards clinical translation.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York


1. Iwata, Takehiro, Shoji Kimura, Mohammad Abufaraj, Florian Janisch, Mehdi Kardoust Parizi, Andrea Haitel, Micheal Rink et al. "Prognostic role of the urokinase plasminogen activator (uPA) system in patients with nonmuscle invasive bladder cancer." In Urologic Oncology: Seminars and Original Investigations. Elsevier, 2019.

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