Tumor Biology

, Volume 37, Issue 7, pp 9855–9863 | Cite as

Diagnostic value of neutrophil gelatinase-associated lipocalin/matrix metalloproteinase-9 pathway in transitional cell carcinoma of the bladder

  • Saverio Candido
  • Matteo Di Maso
  • Diego Serraino
  • James A. McCubrey
  • Roberto Bortolus
  • Martina Zanin
  • Monica Battiston
  • Rossella Salemi
  • Massimo Libra
  • Jerry Polesel
Original Article


Neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase (MMP)-9, and NGAL/MMP-9 complex have been evaluated as diagnostic markers of several cancers, but results for bladder cancer are scanty. We evaluated these proteins in urine and serum of 89 patients with histologically confirmed bladder cancer and 119 cancer-free controls from a case-control study. Urinary concentrations were standardized on creatinine level. The performance of these proteins as cancer biomarkers was evaluated through the receiver operating characteristic (ROC) analysis. Urinary level of NGAL, MMP-9, and NGAL/MMP-9 complex was higher in current smokers, whereas no impact of dietary habits was observed. After adjusting for tobacco smoking, urinary concentration of MMP-9 was independently associated with cancer invasiveness, grading, and histological subtype, with elevated concentrations among T2–T4 and non-papillary bladder cancers. Conversely, NGAL and NGAL/MMP-9 complex were significantly higher in non-papillary than in papillary subtype. The pattern was less clear in serum, but correlation between urinary and serum concentration was poor, especially for Ta/is–T1 tumors. The ROC analysis confirmed that MMP-9 was the best marker (area under the ROC curve (AUC) = 0.68). Performances were much greater for muscle-invasive bladder cancers (AUC = 0.90), with elevated negative predictive values (97 %). The present study suggests that NGAL/MMP-9 pathway is associated with an aggressive phenotype of bladder cancer. The elevated negative predictive value of MMP-9 and NGAL/MMP-9 complex makes them candidate markers of exclusion test for bladder cancer. These proteins may be integrated in the surveillance of bladder cancer, thus diminishing patients’ discomfort and improving compliance.


Neutrophil gelatinase-associated lipocalin (NGAL) Matrix metalloproteinase (MMP) Bladder cancer Diagnosis 



The authors wish to thank Dr. R. Talamini for the design of the original case-control study on bladder cancer, Mrs O. Volpato for coordination of data collection, Dr. L. Falzone for technical assistance, and Mrs. L. Mei for editorial assistance.

Compliance with ethical standards


This work was supported by a grant from Fondazione Umberto Veronesi entitled “Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinases (MMPs) as biomarkers of bladder cancer development and progression” and by the Lega Italiana per la Lotta contro i Tumori (LILT).

Conflicts of interest


Supplementary material

13277_2016_4872_MOESM1_ESM.pdf (103 kb)
ESM 1 (PDF 103 kb)


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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Saverio Candido
    • 1
  • Matteo Di Maso
    • 2
  • Diego Serraino
    • 2
  • James A. McCubrey
    • 3
  • Roberto Bortolus
    • 4
  • Martina Zanin
    • 5
  • Monica Battiston
    • 6
  • Rossella Salemi
    • 1
  • Massimo Libra
    • 1
  • Jerry Polesel
    • 2
  1. 1.Department of Biomedical and Biotechnological Sciences, Laboratory of Translational Oncology & Functional Genomics, Section of General & Clinical Pathology and OncologyUniversity of CataniaCataniaItaly
  2. 2.Epidemiology and Biostatistics UnitCRO Aviano National Cancer InstituteAvianoItaly
  3. 3.Department of Microbiology and Immunology, Brody School of MedicineEast Carolina UniversityGreenvilleUSA
  4. 4.Division of Radiation OncologyCRO Aviano National Cancer InstituteAvianoItaly
  5. 5.Division of UrologyAzienda Ospedaliera S. Maria degli AngeliPordenoneItaly
  6. 6.Unit of Stem Cells and Cellular TherapyCRO Aviano National Cancer InstituteAvianoItaly

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