Tohoku J. Exp. Med., 2020 November, 252(3)

Urine Lactoferrin as a Potential Biomarker Reflecting the Degree of Malignancy in Urothelial Carcinoma of the Bladder

EIRI MATSUMURA,¹ NORITAKE KOSUGE,² SHOTARO NAKANISHI,¹ TETSUJI SUDA,¹ AI SUGAWA,¹ TSUTOMU FUJIMURA,³ RYOTA MIYAGI,¹ NAOKI YOSHIMI² and SEIICHI SAITO¹

¹Department of Urology, University of the Ryukyus Graduate School of Medicine, Nakagami-gun, Okinawa, Japan
²Department of Tumor Pathology, University of the Ryukyus Graduate School of Medicine, Nakagami-gun, Okinawa, Japan
³Laboratory of Bioanalytical Chemistry, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan

Urothelial carcinoma of the bladder (UCB) is potentially life-threatening; therefore, we aimed to discover a novel urine biomarker for diagnosis and prognostication of UCB. This is a retrospective case-control study. Exploration of a new biomarker using urine from 20 UCB patients in the present study revealed that urinary level of lactoferrin (LF), a multifunctional glycoprotein released from neutrophils, was higher in 11 of 15 with invasive/high-grade UCB than 5 with non-invasive one, and 2 healthy adults. We therefore focused on LF and assessed the value of urine LF normalized by urine creatinine concentration (LF/Cr) using an enzyme-linked immunosorbent assay. Diagnostic performance of urine LF/Cr was examined using urine from 92 patients with primary (newly diagnosed) untreated UCB and 166 controls without UCB, including 62 patients with pyuria, and 104 subjects without pyuria consisting of 84 patients and 20 healthy adults. However, the diagnostic accuracies were accompanied by the risk of bias. In 92 primary UCB patients, both pyuria and tumor-infiltrating neutrophils (TINs) were independent predictors for urine LF/Cr. In contrast, TINs or urine LF/Cr were independent predictors for invasive histology, whereas pyuria was not. In terms of prognostication, urine LF/Cr and nodal metastasis were independent predictors of disease-specific survival in 22 patients with muscle-invasive bladder cancer, characterized by a high mortality rate, in the Cox proportional hazards model. In conclusion, urine LF/Cr linked to TINs was a predictor of both invasive histology and prognosis in UCB. Urine LF/Cr is a potential biomarker reflecting the degree of malignancy in UCB.

Keywords —— degree of malignancy; lactoferrin; tumor-infiltrating neutrophils; urine biomarker; urothelial carcinoma of the bladder

© 2020 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2020 252, 225-244.

Correspondence: Seiichi Saito, M.D., Ph.D., Department of Urology, University of the Ryukyus Graduate School of Medicine, 207 Uehara, Nishihara, Nakagami-gun, Okinawa 903-0215, Japan.

e-mail: ssaito@med.u-ryukyu.ac.jp

*These authors contributed equally to this work.