Evaluation of MMP‑2, MMP‑9, TIMP‑1, TIMP‑2, NGAL and MMP‑9/NGAL complex in urine and sera from patients with bladder cancer

Ricci,Serena; Bruzzese,Dario; Di Carlo,Angelina

doi:10.3892/ol.2015.3558

Evaluation of MMP‑2, MMP‑9, TIMP‑1, TIMP‑2, NGAL and MMP‑9/NGAL complex in urine and sera from patients with bladder cancer

Authors:
- Serena Ricci
- Dario Bruzzese
- Angelina Di Carlo
View Affiliations

Affiliations: Department of Translational Medical Science, University of Naples ‘Federico II’, Naples 80131, Italy, Department of Public Health, University of Naples ‘Federico II’, Naples 80131, Italy, Department of Medico‑Surgical Sciences and Biotechnologies, ‘Sapienza’ University of Rome, Latina 04100, Italy
Published online on: August 3, 2015 https://doi.org/10.3892/ol.2015.3558
Pages: 2527-2532

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The identification of biomarkers in urine or serum samples from patients with bladder cancer is urgently required for the development of non‑invasive methods for the diagnosis of bladder carcinoma and to facilitate follow‑up surveillance, to combat the high progression and recurrence rates of this type of cancer. The current study measured the content of matrix metalloproteinase (MMP)‑2 and ‑9, as well as tissue inhibitor of metalloproteinase (TIMP)‑1 and ‑2 in the urine and sera of 41 patients with bladder cancer by ELISA. The association between levels of MMP‑2 and ‑9 and TIMP‑1 and ‑2, and tumor grade and stage were investigated to verify whether these molecules are involved in tumor differentiation. Statistical analysis of the data revealed that urinary TIMP‑1 levels were significantly higher in the high grade group compared with those of the low grade samples (P=0.022). The results also revealed a significantly differing distribution of TIMP-1 expression between Ta and T1 stage specimens (P=0.040). The corresponding area under the curves (AUCs) were 0.72, with a sensitivity of 0.70 and specificity of 0.75. In addition, neutrophil gelatinase‑associated lipocalin (NGAL) and MMP‑9/NGAL complex levels in the sera were measured. All molecules evaluated were detected in the sera of the patients studied. In particular, tumors staged as non-muscle invasive (Ta and T1), demonstrated significantly higher NGAL levels compared with those of muscle invasive (>T1) bladder cancer (32.8 ng/ml vs. 16.2 ng/ml; P=0.029). The discriminatory ability of NGAL expression was confirmed by receiver operating characteristic curve analysis that revealed an AUC of 0.75, a sensitivity of 0.88 and a specificity of 0.67. These data indicated that urinary TIMP‑1 and serum NGAL may be useful non‑invasive biomarkers to provide clinical information for bladder cancer disease management. Multicenter, prospective studies are required to confirm these preliminary results.

View Figures

View References

1	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: GLOBOCAN 2008, Cancer incidence and mortality worldwide: IARC CancerBase No. 10. Lyon, France. International Agency for Research on Cancer. 2010.PubMed/NCBI
2	Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A and Abnet CC: Association between smoking and risk of bladder cancer among men and women. JAMA. 306:737–745. 2011. View Article : Google Scholar : PubMed/NCBI
3	Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, Kassouf W, Kiemeney LA, La Vecchia C, Shariat S and Lotan Y: Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 63:234–241. 2013. View Article : Google Scholar : PubMed/NCBI
4	Wu XR: Urothelial tumorigenesis: A tale of divergent pathways. Nat Rev Cancer. 5:713–725. 2005. View Article : Google Scholar : PubMed/NCBI
5	Montie JE, Bahnson RR, Cohen SM, Drucker B, Eisenberger MA, El-Galley R, Herr HW, Hudes GR, Kuzel TM, Lange PH, et al: National Comprehensive Cancer Network: Bladder cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 1:19–34. 2005.
6	Carlo A, Terracciano D, Mariano A, Oliva A, D'Armiento M and Macchia V: Role of cytokeratins, nuclear matrix proteins, Lewis antigen and epidermal growth factor receptor in human bladder tumors. Int J Oncol. 23:757–762. 2003.PubMed/NCBI
7	Vrooman OP and Witjes JA: Urinary marker in bladder cancer. Eur Urol. 53:909–916. 2008. View Article : Google Scholar : PubMed/NCBI
8	VanTilborg AA, Bangma CH and Zwarthoff EC: Bladder cancer biomarkers and their role in surveillance and screening. Int J Urol. 16:23–30. 2009. View Article : Google Scholar : PubMed/NCBI
9	Shariat SF, Passoni N, Bagrodia A, Rachakonda V, Xylinas E, Robinson B, Kapur P, Sagalowsky AI and Lotan Y: Prospective evaluation of a preoperative biomarker panel for prediction of upstaging at radical cystectomy. BJU Int. 113:70–76. 2014. View Article : Google Scholar : PubMed/NCBI
10	Brinckerhoff CE and Matrisian LM: Matrix metalloproteinases: A tail of a frog that became a prince. Nat Rev Mol Cell Biol. 3:207–214. 2002. View Article : Google Scholar : PubMed/NCBI
11	DiCarlo A, Mariano A, Terracciano D, Mazzarella C, Galzerano S, Cicalese M, Cecere C and Macchia V: Gelatinolytic activities (matrix metalloproteinase-2 and-9) and soluble extracellular domain of Her-2/neu in pleural effusions. Oncol Rep. 18:425–431. 2007.PubMed/NCBI
12	Nagase H, Visse R and Murphy G: Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 69:562–573. 2006. View Article : Google Scholar : PubMed/NCBI
13	DiCarlo A, Terracciano D, Mariano A and Macchia V: Urinary gelatinase activities (matrix metalloproteinases 2 and 9) in human bladder tumors. Oncol Rep. 15:1321–1326. 2006.PubMed/NCBI
14	Roy R, Louis G, Loughlin KR, Wiederschain D, Kilroy SM, Lamb CC, Zurakowski D and Moses MA: Tumor-specific urinary matrix metalloproteinase fingerprinting: Identification of high molecular weight urinary matrix metalloproteinase species. Clin Cancer Res. 14:6610–6617. 2008. View Article : Google Scholar : PubMed/NCBI
15	Chakrabotory S, Kaur S, Guha S and Batra SK: The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochem Biophys Acta. 1826:129–169. 2012.PubMed/NCBI
16	DiCarlo A: Evaluation of neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase-9 (MMP-9) and their complex MMP-9/NGAL in sera and urine of patients with kidney tumors. Oncol Lett. 5:1677–1681. 2013.PubMed/NCBI
17	Volpe V, Raia Z, Sanguigno L, Somma D, Mastrovito P, Moscato F, Mellone S, Leonardi A and Pacifico F: NGAL controls the metastatic potential of anaplastic thyroid carcinoma cells. J Endocrinol Metab. 98:228–235. 2013. View Article : Google Scholar
18	Bouchet S and Bauvois B: Neutrophil gelatinase-associated lipocalin (NGAL), pro-matrix metalloproteinase-9 (pro-MMP-9) and their complex Pro-MMP-9/NGAL in leukemias. Cancers (Basel). 6:796–812. 2014. View Article : Google Scholar : PubMed/NCBI
19	Hoboken NJ: Urological tumoursTNM Classification of Malignant Tumors. Sobin LH, Gospodariwicz M and Wittekind C: 7th. Wiley-Blackwell; London: pp. 262–265. 2009
20	Shariat SF, Palapattu GS, Karakiewicz PI, Roger CG, Vazina A, Bastian PJ, Schoenberg MP, Lerner SP, Sagalowsky AI and Lotan Y: Discrepancy between clinical and pathological stage: Impact on prognosis after radical cystectomy. Eur Urol. 51:137–149. 2007. View Article : Google Scholar : PubMed/NCBI
21	Szarvas T, vom Dorp F, Ergün S and Rübben H: Matrix metalloproteinases and their clinical relevance in urinary bladder cancer. Nat Rev Urol. 8:241–254. 2011. View Article : Google Scholar : PubMed/NCBI
22	Gomez DE, Alonso DF, Yoshiji H and Thorgeirsson UP: Tissue inhibitors of metalloproteinases: Structure, regulation and biological functions. Eur J Cell Biol. 74:111–122. 1997.PubMed/NCBI
23	Hayakawa T: Tissue inhibitors of metalloproteinases and their cell growth-promoting activity. Cell Struct Funct. 19:109–114. 1994. View Article : Google Scholar : PubMed/NCBI
24	Miyata Y, Kanda S, Nomata K, Hayashida Y and Kanetake H: Expression of metalloproteinase-2, metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in transitional cell carcinoma of upper urinary tract: Correlation with tumor stage and survival. Urology. 63:602–608. 2004. View Article : Google Scholar : PubMed/NCBI
25	Durkan GC, Nutt JE, Rajjayabun PH, Neal DE, Lunec J and Mellon JK: Prognostic significance of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in voided urine samples from patients with transitional cell carcinoma of the bladder. Clinical Cancer Res. 7:3450–3456. 2001.
26	Monier F, Mollier S, Guillot M, Rambeaud JJ, Morel F and Zaoui P: Urinary release of 72 and 92 kDa gelatinases, TIMPs, N-GAL and conventional prognostic factors in urothelial carcinomas. Eur Urol. 42:356–363. 2002. View Article : Google Scholar : PubMed/NCBI
27	Candido S, Maestro R, Polesel J, Catania A, Maira F, Signorelli SS, McCubrey JA and Libra M: Role of neutrophil gelatinase-associated lipocalin (NGAL) in human cancer. Oncotarget. 5:1576–1594. 2014.PubMed/NCBI