The Role of Urinary Proteases in Bladder Cancer

  • Paulo Bastos
  • Sandra Magalhães
  • Lúcio Lara Santos
  • Rita Ferreira
  • Rui VitorinoEmail author


Bladder cancer (BCa) is one of the most prevalent malignancies worldwide. Risk factors for BCa are well established and include smoking and infections, which can lead to immune system activation, altered gene expression patterns, proteolytic activity, tissue damage, and, ultimately, cancer development. Urine has become one of the most attractive diagnosis samples, and, notably, urine profiling by mass spectrometry allows the simultaneously analysis of multiple enzymes and their interactors, substrates, inhibitors, and regulators, providing an integrative view of enzymatic dynamics. Most BCa-associated enzymatic alterations take place at the level of proteases, being MMP-9, MMP-2, urokinase-type plasminogen activator, cathepsin D, and cathepsin G already related to BCa development and progression. Herein, we overview the role of proteases and the classes more studied in BCa pathogenesis, as well as the methodologies used for assessing protease amount and activity in urine samples, highlighting its advantages and limitations, and the value of urinary proteases as disease biomarkers.



This work was supported by the Portuguese Foundation for Science and Technology (FCT), European Union, QREN, FEDER, and COMPETE for funding the iBiMED, UnIC, QOPNA research units (project UID/BIM/04501/2013, UID/IC/00051/2013, UID/QUI/UI0062/2013), the Investigator Grant to RV (IF/00286/2015).


  1. 1.
    Ferlay J, Soerjomataram I, Ervik M et al (2014) GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012: IARC CancerBase No. 11. Int. Agency Res. CancerGoogle Scholar
  2. 2.
    Fajkovic H, Halpern JA, Cha EK et al (2011) Impact of gender on bladder cancer incidence, staging, and prognosis. World J Urol 29:457–463PubMedCrossRefGoogle Scholar
  3. 3.
    Madeb R, Messing EM (2004) Gender, racial and age differences in bladder cancer incidence and mortality. Urol Oncol Semin Orig Investig 22:86–92CrossRefGoogle Scholar
  4. 4.
    Bryan GT (1983) Pathogenesis of human urinary bladder cancer. Environ Health Perspect 49:201–207PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Lopez-Beltran A, Sauter G, Gasser T et al (2004) World Health Organization classification of tumours: pathology and genetics of tumours of the urinary system and male genital organs. Pathol Genet tumors Urin Syst Male Genit OrgansGoogle Scholar
  6. 6.
    WHO (2011) Environmental and occupational cancers. Fact sheet N°350Google Scholar
  7. 7.
    Bethesda (2016) PDQ adult treatment editorial board. bladder cancer treatment (PDQ®): health professional version. Natl Cancer InstGoogle Scholar
  8. 8.
    Yeung C, Dinh T, Lee J (2014) The health economics of bladder cancer: an updated review of the published literature. Pharmacoeconomics 32:1093–1104PubMedCrossRefGoogle Scholar
  9. 9.
    Johnson DC, Greene PS, Nielsen ME (2015) Surgical advances in bladder cancer: at what cost? Urol Clin North Am 42:235–252PubMedCrossRefGoogle Scholar
  10. 10.
    Mossanen M, Gore JL (2014) The burden of bladder cancer care: direct and indirect costs. Curr Opin Urol 24:487–491PubMedCrossRefGoogle Scholar
  11. 11.
    Svatek RS, Hollenbeck BK, Holmäng S et al (2014) The economics of bladder cancer: costs and considerations of caring for this disease. Eur Urol 66:253–262PubMedCrossRefGoogle Scholar
  12. 12.
    Rodrigues D, Jerónimo C, Henrique R et al (2016) Biomarkers in bladder cancer: a metabolomic approach using in vitro and ex vivo model systems. Int J Cancer n/a–n/aGoogle Scholar
  13. 13.
    Stenzl A, Cowan NC, De Santis M et al (2011) Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines. Eur Urol 59:1009–1018PubMedCrossRefGoogle Scholar
  14. 14.
    Kamat AM, Lamm DL (2004) Antitumor activity of common antibiotics against superficial bladder cancer. Urology 63:457–460PubMedCrossRefGoogle Scholar
  15. 15.
    Felix AS, Soliman AS, Khaled H et al (2008) The changing patterns of bladder cancer in Egypt over the past 26 years. Cancer Causes Control 19:421–429PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Heyns CF, van der Merwe A (2008) Bladder cancer in Africa. Can J Urol 15:3899–3908PubMedGoogle Scholar
  17. 17.
    Nagata M, Muto S, Horie S (2016) Molecular biomarkers in bladder cancer: novel potential indicators of prognosis and treatment outcomes. Dis Mark 2016:8205836Google Scholar
  18. 18.
    Kaufman DS, Shipley WU, Feldman AS (18AD) Bladder cancer. Lancet 374:239–249Google Scholar
  19. 19.
    Massari F, Ciccarese C, Santoni M et al (2016) Metabolic phenotype of bladder cancer. Cancer Treat Rev 45:46–57PubMedCrossRefGoogle Scholar
  20. 20.
    Lodillinsky C, Rodriguez V, Vauthay L et al (2009) Novel invasive orthotopic bladder cancer model with high cathepsin B activity resembling human bladder cancer. J Urol 182:749–755PubMedCrossRefGoogle Scholar
  21. 21.
    Gerhards S, Jung K, Koenig F et al (2001) Excretion of matrix metalloproteinases 2 and 9 in urine is associated with a high stage and grade of bladder carcinoma. Urology 57:675–679PubMedCrossRefGoogle Scholar
  22. 22.
    Rosser CJ, Chang M, Dai Y et al (2014) Urinary protein biomarker panel for the detection of recurrent bladder cancer. Cancer Epidemiol Biomark Prev 23:1340–1345CrossRefGoogle Scholar
  23. 23.
    Lam T, Nabi G (2007) Potential of urinary biomarkers in early bladder cancer diagnosis. Expert Rev Anticancer Ther 7:1105–1115PubMedCrossRefGoogle Scholar
  24. 24.
    Yang N, Feng S, Shedden K et al (2011) Urinary glycoprotein biomarker discovery for bladder cancer detection using LC/MS-MS and label-free quantification. Clin Cancer Res 17:3349–3359PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Urquidi V, Goodison S, Cai Y et al (2012) A candidate molecular biomarker panel for the detection of bladder cancer. Cancer Epidemiol Biomark Prev 21:2149–2158CrossRefGoogle Scholar
  26. 26.
    Ye F, Wang L, Castillo-Martin M et al (2014) Biomarkers for bladder cancer management: present and future. Am J Clin Exp Urol 2:1–14PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Burchardt M, Burchardt T, Shabsigh A et al (2000) Current concepts in biomarker technology for bladder cancers. Clin Chem 46:595–605PubMedGoogle Scholar
  28. 28.
    Twining SS (1994) Regulation of proteolytic activity in tissues. Crit Rev Biochem Mol Biol 29:315–383PubMedCrossRefGoogle Scholar
  29. 29.
    Li C, Li H, Zhang T et al (2014) Discovery of Apo-A1 as a potential bladder cancer biomarker by urine proteomics and analysis. Biochem Biophys Res Commun 446:1047–1052PubMedCrossRefGoogle Scholar
  30. 30.
    Roy R, Louis G, Loughlin KR et al (2008) Tumor-specific urinary matrix metalloproteinase fingerprinting: identification of high molecular weight urinary matrix metalloproteinase species. Clin Cancer Res 14:6610–6617PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Lei T, Zhao X, Jin S et al (2013) Discovery of potential bladder cancer biomarkers by comparative urine proteomics and analysis. Clin Genitourin Cancer 11:56–62PubMedCrossRefGoogle Scholar
  32. 32.
    Chen CL, Lai YF, Tang P et al (2012) Comparative and targeted proteomic analyses of urinary microparticles from bladder cancer and hernia patients. J Proteome Res 11:5611–5629PubMedCrossRefGoogle Scholar
  33. 33.
    Lindén M, Lind SB, Mayrhofer C et al (2012) Proteomic analysis of urinary biomarker candidates for nonmuscle invasive bladder cancer. Proteomics 12:135–144PubMedCrossRefGoogle Scholar
  34. 34.
    Tsui K-H, Tang P, Lin C-Y et al (2010) Bikunin loss in urine as useful marker for bladder carcinoma. J Urol 183:339–344PubMedCrossRefGoogle Scholar
  35. 35.
    Tan LB, Chen KT, Yuan YC et al (2010) Identification of urine PLK2 as a marker of bladder tumors by proteomic analysis. World J Urol 28:117–122PubMedCrossRefGoogle Scholar
  36. 36.
    Feldman AS, Banyard J, Wu C-L et al (2009) Cystatin B as a tissue and urinary biomarker of bladder cancer recurrence and disease progression. Clin Cancer Res 15:1024–1031PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Smalley DM, Sheman NE, Nelson K, Theodorescu D (2008) Isolation and identification of potential urinary microparticle biomarkers of bladder cancer. J Proteome Res 7:2088–2096PubMedCrossRefGoogle Scholar
  38. 38.
    Lin C-Y, Tsui K-H, Yu C-C et al (2006) Searching cell-secreted proteomes for potential urinary bladder tumor markers. Proteomics 6:4381–4389PubMedCrossRefGoogle Scholar
  39. 39.
    Staack A, Tolic D, Kristiansen G et al (2004) Expression of cathepsins B, H, and L and their inhibitors as markers of transitional cell carcinoma of the bladder. Urology 63:1089–1094PubMedCrossRefGoogle Scholar
  40. 40.
    Svatek RS, Karam J, Karakiewicz PI et al (2008) Role of urinary cathepsin B and L in the detection of bladder urothelial cell carcinoma. J Urol 179:478–484. (discussion 484)PubMedCrossRefGoogle Scholar
  41. 41.
    Ulrich F, Heisenberg CP (2009) Trafficking and cell migration. Traffic 10:811–818PubMedCrossRefGoogle Scholar
  42. 42.
    Malemud CJ (2006) Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci 11:1696PubMedCrossRefGoogle Scholar
  43. 43.
    Hadler-Olsen E, Fadnes B, Sylte I et al (2011) Regulation of matrix metalloproteinase activity in health and disease. FEBS J 278:28–45PubMedCrossRefGoogle Scholar
  44. 44.
    Chen C-L, Lin T-S, Tsai C-H et al (2013) Identification of potential bladder cancer markers in urine by abundant-protein depletion coupled with quantitative proteomics. J Proteomics 85:28–43PubMedCrossRefGoogle Scholar
  45. 45.
    Lee HJ, Nedelkov D, Corn RM (2006) Surface plasmon resonance imaging measurements of antibody arrays for the multiplexed detection of low molecular weight protein biomarkers. Anal Chem 78:6504–6510PubMedCrossRefGoogle Scholar
  46. 46.
    Ladd J, Taylor AD, Piliarik M et al (2009) Label-free detection of cancer biomarker candidates using surface plasmon resonance imaging. Anal Bioanal Chem 393:1157–1163PubMedCrossRefGoogle Scholar
  47. 47.
    Gorodkiewicz E, Guszcz T, Roszkowska-Jakimiec W, Kozłowski R (2014) Cathepsin D serum and urine concentration in superficial and invasive transitional bladder cancer as determined by surface plasmon resonance imaging. Oncol Lett 8:1323–1327PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Mohammed MA, Seleim MF, Abdalla MS et al (2013) Urinary high molecular weight matrix metalloproteinases as non-invasive biomarker for detection of bladder cancer. BMC Urol 13:25PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Õzdemir E, Kakehi Y, Okuno H, Yoshida O (1999) Role of matrix metalloproteinase-9 in the basement membrane destruction of superficial urothelial carcinomas. J Urol 161:1359–1363PubMedCrossRefGoogle Scholar
  50. 50.
    Eissa S, Ali-Labib R, Swellam M et al (2007) Noninvasive diagnosis of bladder cancer by detection of matrix metalloproteinases (MMP-2 and MMP-9) and their inhibitor (TIMP-2) in urine. Eur Urol 52:1388–1397PubMedCrossRefGoogle Scholar
  51. 51.
    Hattori S, Fujisaki H, Kiriyama T et al (2002) Real-time zymography and reverse zymography: a method for detecting activities of matrix metalloproteinases and their inhibitors using FITC-labeled collagen and casein as substrates. Anal Biochem 301:27–34PubMedCrossRefGoogle Scholar
  52. 52.
    Vandooren J, Geurts N, Martens E et al (2013) Zymography methods for visualizing hydrolytic enzymes. Nat Methods 10:211–220PubMedCrossRefGoogle Scholar
  53. 53.
    Moses MA, Wiederschain D, Loughlin KR et al (1998) Increased incidence of matrix metalloproteinases in urine of cancer patients. Cancer Res 58:1395–1399PubMedGoogle Scholar
  54. 54.
    Schönemeier B, Metzger J, Klein J, et al (2016) Urinary peptide analysis differentiates pancreatic cancer from chronic pancreatitis. Pancreas 45(7):1018–1026PubMedCrossRefGoogle Scholar
  55. 55.
    Theodorescu D, Wittke S, Ross MM et al (2006) Discovery and validation of new protein biomarkers for urothelial cancer: a prospective analysis. Lancet Oncol 7:230–240PubMedCrossRefGoogle Scholar
  56. 56.
    Jantos-Siwy J, Schiffer E, Brand K et al (2009) Quantitative urinary proteome analysis for biomarker evaluation in chronic kidney disease. J Proteome Res 8:268–281PubMedCrossRefGoogle Scholar
  57. 57.
    Frantzi M, Van Kessel KE, Zwarthoff EC et al (2016) Development and validation of urine-based peptide biomarker panels for detecting bladder cancer in a multi-center study. Clin Cancer Res 22(16):4077–4086PubMedCrossRefGoogle Scholar
  58. 58.
    Thongboonkerd V, Chutipongtanate S, Kanlaya R (2006) Systematic evaluation of sample preparation methods for gel-based human urinary proteomics: quantity, quality, and variability. J Proteome Res 5:183–191PubMedCrossRefGoogle Scholar
  59. 59.
    Sedic M, Gethings LA, Vissers JPC et al (2014) Label-free mass spectrometric profiling of urinary proteins and metabolites from paediatric idiopathic nephrotic syndrome. Biochem Biophys Res Commun 452:21–26PubMedCrossRefGoogle Scholar
  60. 60.
    Froehlich JW, Vaezzadeh AR, Kirchner M et al (2014) An in-depth comparison of the male pediatric and adult urinary proteomes. Biochim Biophys Acta 1844:1044–1050PubMedCrossRefGoogle Scholar
  61. 61.
    Valente MAE, Damman K, Dunselman PHJM et al (2012) Urinary proteins in heart failure. Prog Cardiovasc Dis 55:44–55PubMedCrossRefGoogle Scholar
  62. 62.
    Thongboonkerd V (2008) Urinary proteomics : towards biomarker discovery. Diagn Prognostics. 810–815Google Scholar
  63. 63.
    Lokeshwar VB, Habuchi T, Grossman HB et al (2005) Bladder tumor markers beyond cytology: international consensus panel on bladder tumor markers. Urology:35–63Google Scholar
  64. 64.
    Konety BR (2006) Molecular markers in bladder cancer: a critical appraisal. Urol Oncol 24:326–337PubMedCrossRefGoogle Scholar
  65. 65.
    Dancik GM (2015) An online tool for evaluating diagnostic and prognostic gene expression biomarkers in bladder cancer. BMC Urol 15Google Scholar
  66. 66.
    Lindgren D, Sjödahl G, Lauss M et al (2012) integrated genomic and gene expression profiling identifies two major genomic circuits in urothelial carcinoma. PLoS ONE 7:e38863PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Lindgren D, Frigyesi A, Gudjonsson S et al (2010) Combined gene expression and genomic profiling define two intrinsic molecular subtypes of urothelial carcinoma and gene signatures for molecular grading and outcome. Cancer Res 70:3463–3472PubMedCrossRefGoogle Scholar
  68. 68.
    Kim W-J, Kim E-J, Kim S-K et al (2010) Predictive value of progression-related gene classifier in primary non-muscle invasive bladder cancer. Mol Cancer 9:3PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Riester M, Taylor JM, Feifer A et al (2012) Combination of a novel gene expression signature with a clinical nomogram improves the prediction of survival in high-risk bladder cancer. Clin Cancer Res 18:1323–1333PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Blaveri E, Simko JP, Korkola JE et al (2005) Bladder cancer outcome and subtype classification by gene expression. Clin Cancer Res 11:4044–4055PubMedCrossRefGoogle Scholar
  71. 71.
    Dyrskjøt L, Zieger K, Real FX et al (2007) Gene expression signatures predict outcome in non–muscle-invasive bladder carcinoma: a multicenter validation study. Clin Cancer Res 13:3545–3551PubMedCrossRefGoogle Scholar
  72. 72.
    Dyrskjøt L, Kruhøffer M, Thykjaer T et al (2004) Gene expression in the urinary bladder: a common carcinoma in situ gene expression signature exists disregarding histopathological classification. Cancer Res 64:4040–4048PubMedCrossRefGoogle Scholar
  73. 73.
    Smith SC, Baras AS, Owens CR et al (2012) Transcriptional signatures of ral GTPase are associated with aggressive clinicopathologic characteristics in human cancer. Cancer Res 72:3480–3491PubMedCrossRefGoogle Scholar
  74. 74.
    Sanchez-Carbayo M, Socci ND, Lozano J et al (2006) Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol 24:778–789PubMedCrossRefGoogle Scholar
  75. 75.
    Choi W, Porten S, Kim S et al (2014) Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25:152–165PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Atapattu L, Lackmann M, Janes PW (2014) The role of proteases in regulating eph/ephrin signaling. Cell Adh Migr 8:294–307PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Serim S, Haedke U, Verhelst SHL (2012) Activity-based probes for the study of proteases: recent advances and developments. ChemMedChem 7:1146–1159PubMedCrossRefGoogle Scholar
  78. 78.
    López-Otín C, Bond JS (2008) Proteases: multifunctional enzymes in life and disease. J Biol Chem 283:30433–30437PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Felix K, Gaida MM (2016) Neutrophil-derived proteases in the microenvironment of pancreatic cancer -active players in tumor progression. Int J Biol Sci 12:302–313PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Pranjol MZI, Gutowski N, Hannemann M, Whatmore J (2015) The potential role of the proteases cathepsin D and cathepsin L in the progression and metastasis of epithelial ovarian cancer. Biomolecules 5:3260–3279PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Olson OC, Joyce JA (2015) Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response. Nat Rev Cancer 15:712–729PubMedCrossRefGoogle Scholar
  82. 82.
    Drag M, Salvesen GS (2010) Emerging principles in protease-based drug discovery. Nat Rev Drug Discov 9:690–701PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Turk B (2006) Targeting proteases : successes, failures and future prospects. Nat Rev Drug Discov 5(9):785–799PubMedCrossRefGoogle Scholar
  84. 84.
    Vandooren J, Opdenakker G, Loadman PM, Edwards DR (2016) Proteases in cancer drug delivery. Adv Drug Deliv Rev 97:144–155PubMedCrossRefGoogle Scholar
  85. 85.
    López-Otín C, Matrisian LM (2007) Emerging roles of proteases in tumour suppression. Nat Rev Cancer 7:800–808PubMedCrossRefGoogle Scholar
  86. 86.
    Gocheva V, Joyce JA (2007) Cysteine cathepsins and the cutting edge of cancer invasion. Cell Cycle 6:60–64CrossRefPubMedGoogle Scholar
  87. 87.
    Shi GP, Villadangos J a, Dranoff G et al (1999) Cathepsin S required for normal MHC class II peptide loading and germinal center development. Immunity 10:197–206PubMedCrossRefGoogle Scholar
  88. 88.
    Bania J, Gatti E, Lelouard H et al (2003) Human cathepsin S, but not cathepsin L, degrades efficiently MHC class II-associated invariant chain in nonprofessional APCs. Proc Natl Acad Sci U S A 100:6664–6669PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Stypmann J, Gläser K, Roth W et al (2002) Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L. Proc Natl Acad Sci U S A 99:6234–6239PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Gocheva V, Zeng W, Ke D et al (2006) Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes Dev 20:543–556PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Kuester D, Lippert H, Roessner A, Krueger S (2008) The cathepsin family and their role in colorectal cancer. Pathol Res Pract 204:491–500PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Stoeckle C, Sommandas V, Adamopoulou E et al (2009) Cathepsin G is differentially expressed in primary human antigen-presenting cells. Cell Immunol 255:41–45PubMedCrossRefGoogle Scholar
  93. 93.
    Kargi HA, Campbell EJ, Kuhn C 3rd (1990) Elastase and cathepsin G of human monocytes: heterogeneity and subcellular localization to peroxidase-positive granules. J Histochem Cytochem 38:1179–1186PubMedCrossRefGoogle Scholar
  94. 94.
    Shimoda N, Fukazawa N, Nonomura K, Fairchild RL (2007) Cathepsin g is required for sustained inflammation and tissue injury after reperfusion of ischemic kidneys. Am J Pathol 170:930–940PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Reeves EP, Lu H, Jacobs HL et al (2002) Killing activity of neutrophils is mediated through activation of proteases by K+flux. Nature 416:291–297PubMedCrossRefGoogle Scholar
  96. 96.
    Tkalcevic J, Novelli M, Phylactides M et al (2000) Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G. Immunity 12:201–210PubMedCrossRefGoogle Scholar
  97. 97.
    Owen CA, Campbell MA, Sannes PL et al (1995) Cell surface-bound elastase and cathepsin G on human neutrophils: a novel, non-oxidative mechanism by which neutrophils focus and preserve catalytic activity of serine proteinases. J Cell Biol 131:775–789PubMedCrossRefGoogle Scholar
  98. 98.
    Brinkmann V, Reichard U, Goosmann C et al (2004) Neutrophil extracellular traps kill bacteria. Science (80) 303:1532–1535Google Scholar
  99. 99.
    Polanowska J, Krokoszynska I, Czapinska H et al (1998) Specificity of human cathepsin G. Biochim Biophys Acta 1386:189–198PubMedCrossRefGoogle Scholar
  100. 100.
    Raymond WW, Trivedi NN, Makarova A et al (2010) How immune peptidases change specificity: cathepsin G gained tryptic function but lost efficiency during primate evolution. J Immunol 185:5360–5368PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Adkison AM, Raptis SZ, Kelley DG, Pham CTN (2002) Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. J Clin Invest 109:363–371PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Sambrano GR, Huang W, Faruqi T et al (2000) Cathepsin G activates protease-activated receptor-4 in human platelets. J Biol Chem 275:6819–6823PubMedCrossRefGoogle Scholar
  103. 103.
    Maison CM, Villiers CL, Colomb MG (1991) Proteolysis of C3 on U937 cell plasma membranes. Purif Cathepsin G. J Immunol 147:921–926Google Scholar
  104. 104.
    Drag B, Petersen LC (1994) Activation of pro-urokinase by cathepsin G in the presence of glucosaminoglycans. Fibrinolysis 8:192–199CrossRefGoogle Scholar
  105. 105.
    Reilly CF, Tewksbury DA, Schechter NM, Travis J (1982) Rapid conversion of angiotensin I to angiotensin II by neutrophil and mast cell proteinases. J Biol Chem 257:8619–8622PubMedGoogle Scholar
  106. 106.
    Klickstein LB, Kaempfer CE, Wintroub BU (1982) The granulocyte-angiotensin system. Angiotensin I-converting activity of cathepsin G. J Biol Chem 257:15042–15046PubMedGoogle Scholar
  107. 107.
    Shamamian P, Schwartz JD, Pocock BJZ et al (2001) Activation of progelatinase A (MMP-2) by neutrophil elastase, cathepsin G, and proteinase-3: a role for inflammatory cells in tumor invasion and angiogenesis. J Cell Physiol 189:197–206PubMedCrossRefGoogle Scholar
  108. 108.
    Benes P, Vetvicka V, Fusek M (2008) Cathepsin D-Many functions of one aspartic protease. Crit Rev Oncol Hematol 68:12–28PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Nicotra G, Castino R, Follo C et al (2010) The dilemma: Does tissue expression of cathepsin D reflect tumor malignancy? the question: does the assay truly mirror cathepsin D mis-function in the tumor? Cancer Biomarkers 7:47–64PubMedCrossRefGoogle Scholar
  110. 110.
    Hah YS, Noh HS, Ha JH et al (2012) Cathepsin D inhibits oxidative stress-induced cell death via activation of autophagy in cancer cells. Cancer Lett 323:208–214PubMedCrossRefGoogle Scholar
  111. 111.
    Dian D, Vrekoussis T, Shabani N et al (2012) Expression of cathepsin-D in primary breast cancer and corresponding local recurrence or metastasis: an immunohistochemical study. Anticancer Res 32:901–905PubMedGoogle Scholar
  112. 112.
    Lentari I, Segas I, Kandiloros D (2002) The importance of cathepsin’s-D tissular detection in laryngeal squamous cell carcinoma. Acta Otorhinolaryngol Belg 56:383–389PubMedGoogle Scholar
  113. 113.
    Paksoy M, Hardal U, Caglar C (2011) Expression of Cathepsin D and E-Cadherin in primary laryngeal cancers correlation with neck lymph node involvement. J Cancer Res Clin Oncol 137:1371–1377PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Dumartin L, Whiteman HJ, Weeks ME et al (2011) AGR2 is a novel surface antigen that promotes the dissemination of pancreatic cancer cells through regulation of cathepsins B and D. Cancer Res 71:7091–7102PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Lösch A, Schindl M, Kohlberger P et al (2004) Cathepsin D in ovarian cancer: prognostic value and correlation with p 53 expression and microvessel density. Gynecol Oncol 92:545–552PubMedCrossRefGoogle Scholar
  116. 116.
    González-Vela MC, Garijo MF, Fernández F et al (1999) Cathepsin D in host stromal cells is associated with more highly vascular and aggressive invasive breast carcinoma. Histopathology 34:35–42PubMedCrossRefGoogle Scholar
  117. 117.
    Ohri SS, Vashishta A, Proctor M et al (2008) The propeptide of cathepsin D increases proliferation, invasion and metastasis of breast cancer cells. Int J Oncol 32:491–498PubMedGoogle Scholar
  118. 118.
    Vashishta A, Ohri SS, Proctor M et al (2006) Role of activation peptide of procathepsin D in proliferation and invasion of lung cancer cells. Anticancer Res 26:4163–4170PubMedGoogle Scholar
  119. 119.
    Szajda SD, Darewicz B, Kudelski J et al (2005) Cancer procoagulant and cathepsin D activity in blood serum in patients with bladder cancer. Pol Merkur Lek 18:651–653Google Scholar
  120. 120.
    Tokyol C, Köken T, Demirbas M et al (2006) Expression of cathepsin D in bladder carcinoma: correlation with pathological features and serum cystatin C levels. Tumori 92:230–235PubMedCrossRefGoogle Scholar
  121. 121.
    Jean D, Rousselet N, Frade R (2006) Expression of cathepsin L in human tumor cells is under the control of distinct regulatory mechanisms. Oncogene 25:1474–1484PubMedCrossRefGoogle Scholar
  122. 122.
    Tan G-J, Peng Z-K, Lu J-P, Tang F-Q (2013) Cathepsins mediate tumor metastasis. World J Biol Chem 4:91–101PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8:221–233PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174CrossRefPubMedGoogle Scholar
  125. 125.
    Sun N, Zhao Q, Ye C et al (2014) Role of matrix metalloproteinase-1 (MMP-1)/protease-activated receptor-1 (PAR-1) signaling pathway in the cervical cancer invasion. J Reprod Contracept 25:18–25Google Scholar
  126. 126.
    Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463–516PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:52–67PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Vasala K, Turpeenniemi-Hujanen T (2007) Serum tissue inhibitor of metalloproteinase-2 (TIMP-2) and matrix metalloproteinase-2 in complex with the inhibitor (MMP-2:TIMP-2) as prognostic markers in bladder cancer. Clin Biochem 40:640–644PubMedCrossRefGoogle Scholar
  129. 129.
    Mitsiades N, Yu WH, Poulaki V et al (2001) Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity. Cancer Res 61:577–581PubMedPubMedCentralGoogle Scholar
  130. 130.
    Kleiner DE, Stetler-Stevenson WG (1999) Matrix metalloproteinases and metastasis. Cancer Chemother Pharmacol 43(Suppl):S42–S51PubMedCrossRefGoogle Scholar
  131. 131.
    Hanemaaijer R, Sier CFM, Visser H et al (1999) MMP-9 activity in urine from patients with various tumors, as measured by a novel MMP activity assay using modified urokinase as a substrate. Ann N Y Acad Sci:141–149PubMedCrossRefGoogle Scholar
  132. 132.
    Margulies IM, Hoyhtya M, Evans C et al (1992) Urinary type-IV collagenase—elevated levels are associated with bladder transitional cell-carcinoma. Cancer Epidemiol Biomark Prev 1:467–474Google Scholar
  133. 133.
    Cowden Dahl KD, Symowicz J, Ning Y et al (2008) Matrix metalloproteinase 9 is a mediator of epidermal growth factor-dependent E-cadherin loss in ovarian carcinoma cells. Cancer Res 68:4606–4613PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Maretzky T, Reiss K, Ludwig A et al (2005) ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation. Proc Natl Acad Sci U S A 102:9182–9187PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Massagué J (2008) TGF beta in Cancer. Cell 134:215–230PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14:163–176PubMedPubMedCentralGoogle Scholar
  137. 137.
    Waldhauer I, Goehlsdorf D, Gieseke F et al (2008) Tumor-associated MICA is shed by ADAM proteases. Cancer Res 68:6368–6376PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Le Maux Chansac B, Missé D, Richon C et al (2008) Potentiation of NK cell-mediated cytotoxicity in human lung adenocarcinoma: role of NKG2D-dependent pathway. Int Immunol 20:801–810CrossRefGoogle Scholar
  139. 139.
    Bergers G, Brekken R, McMahon G et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Olson MW, Bernardo MM, Pietila M et al (2000) Characterization of the monomeric and dimeric forms of latent and active matrix metalloproteinase-9: differential rates for activation by stromelysin 1. J Biol Chem 275:2661–2668PubMedCrossRefGoogle Scholar
  141. 141.
    Provatopoulou X, Gounaris A, Kalogera E et al (2009) Circulating levels of matrix metalloproteinase-9 (MMP-9), neutrophil gelatinase-associated lipocalin (NGAL) and their complex MMP-9/NGAL in breast cancer disease. BMC Cancer 9:390PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Yan L, Borregaard N, Kjeldsen L, Moses MA (2001) The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL): Modulation of MMP-9 activity by NGAL. J Biol Chem 276:37258–37265PubMedCrossRefGoogle Scholar
  143. 143.
    Aguirre Ghiso JA, Kovalski K, Ossowski L (1999) Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J Cell Biol 147:89–103PubMedCrossRefGoogle Scholar
  144. 144.
    Eissa S, Ahmed MI, Said H et al (2004) Cell cycle regulators in bladder cancer: relationship to schistosomiasis. IUBMB Life 56:557–564PubMedCrossRefGoogle Scholar
  145. 145.
    Di Cera E (2009) Serine Proteases. IUBMB Life 61:510–515. doi: 10.1002/iub.186CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Almonte AG, Sweatt JD (2011) Serine proteases, serine protease inhibitors, and protease-activated receptors: roles in synaptic function and behavior. Brain Res 1407:107–122PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Jin T, Bokarewa M, Tarkowski A (2005) Urokinase-type plasminogen activator, an endogenous antibiotic. J Infect Dis 192:429–437. doi: 10.1086/431600CrossRefPubMedGoogle Scholar
  148. 148.
    Gyetko MR, Libre EA, Fuller JA et al (1999) Urokinase is required for T lymphocyte proliferation and activation in vitro. J Lab Clin Med 133:274–288PubMedCrossRefGoogle Scholar
  149. 149.
    Vassalli JD (1985) A cellular binding site for the Mr 55,000 form of the human plasminogen activator, urokinase. J Cell Biol 100:86–92PubMedCrossRefGoogle Scholar
  150. 150.
    Uusitalo-Seppälä R, Huttunen R, Tarkka M et al (2012) Soluble urokinase-type plasminogen activator receptor in patients with suspected infection in the emergency room: a prospective cohort study. J Intern Med 272:247–256PubMedCrossRefGoogle Scholar
  151. 151.
    Jankun J, Skrzypczak-Jankun E (1999) Molecular basis of specific inhibition of urokinase plasminogen activator by amiloride. Cancer Biochem Biophys 17:109–123PubMedGoogle Scholar
  152. 152.
    Duffy MJ (2004) The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des 10:39–49PubMedCrossRefGoogle Scholar
  153. 153.
    Reuning U, Sperl S, Kopitz C et al Urokinase-type plasminogen activator (uPA) and its receptor (uPAR): development of antagonists of uPA/uPAR interaction and their effects in vitro and in vivo. Curr Pharm Des 9:1529–1543PubMedCrossRefGoogle Scholar
  154. 154.
    Andreasen PA, Kjøller L, Christensen L, Duffy MJ (1997) The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 72:1–22PubMedCrossRefGoogle Scholar
  155. 155.
    Gately S, Twardowski P, Stack MS et al (1996) Human prostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis inhibitor, angiostatin. Cancer Res 56:4887–4890PubMedGoogle Scholar
  156. 156.
    Rabbani S, Mazar A, Bernier S et al (1992) Structural requirements for the growth factor activity of the amino-terminal domain of urokinase. J Biol Chem 267:14151–14156PubMedGoogle Scholar
  157. 157.
    Mukhina S, Stepanova V, Traktouev D et al (2000) The chemotactic action of urokinase on smooth muscle cells is dependent on its kringle domain. Characterization of interactions and contribution to chemotaxis. J Biol Chem 275:16450–16458PubMedCrossRefGoogle Scholar
  158. 158.
    Hasui Y, Marutsuka K, Suzumiya J et al (1992) The content of urokinase-type plasminogen activator antigen as a prognostic factor in urinary bladder cancer. Int J Cancer 50:871–873CrossRefPubMedGoogle Scholar
  159. 159.
    McIntyre JO, Matrisian LM (2009) Optical proteolytic beacons for in vivo detection of matrix metalloproteinase activity. Methods Mol Biol 539:155–174PubMedCrossRefGoogle Scholar
  160. 160.
    Packard BZ, Artym VV, Komoriya A, Yamada KM (2009) Direct visualization of protease activity on cells migrating in three-dimensions. Matrix Biol 28:3–10PubMedCrossRefGoogle Scholar
  161. 161.
    Bremer C, Tung CH, Weissleder R (2001) In vivo molecular target assessment of matrix metalloproteinase inhibition. Nat Med 7:743–748PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Temma T, Sano K, Kuge Y et al (2009) Development of a radiolabeled probe for detecting membrane type-1 matrix metalloproteinase on malignant tumors. Biol Pharm Bull 32:1272–1277PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Furumoto S, Takashima K, Kubota K et al (2003) Tumor detection using 18F-labeled matrix metalloproteinase-2 inhibitor. Nucl Med Biol 30:119–125PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Smith SC, Theodorescu D (2009) The Ral GTPase pathway in metastatic bladder cancer: key mediator and therapeutic target. Urol Oncol Semin Orig Investig 27:42–47CrossRefGoogle Scholar
  165. 165.
    Oxford G, Theodorescu D (2003) The role of Ras superfamily proteins in bladder cancer progression. J Urol 170:1987–1993PubMedCrossRefGoogle Scholar
  166. 166.
    Chaudhary AK, Pandya S, Ghosh K, Nadkarni A (2013) Matrix metalloproteinase and its drug targets therapy in solid and hematological malignancies: an overview. Mutat Res—Rev Mutat Res 753:7–23CrossRefGoogle Scholar
  167. 167.
    Santoni M, Amantini C, Morelli MB et al (2013) Pazopanib and sunitinib trigger autophagic and non-autophagic death of bladder tumour cells. Br J Cancer 109:1040–1050PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Ishiguro H, Kawahara T, Zheng Y et al (2014) Differential regulation of bladder cancer growth by various glucocorticoids: corticosterone and prednisone inhibit cell invasion without promoting cell proliferation or reducing cisplatin cytotoxicity. Cancer Chemother Pharmacol 74:249–255PubMedCrossRefGoogle Scholar
  169. 169.
    Cheng DLW, Shu WP, Choi JCS et al (1994) Bacillus Calmette-Guerin interacts with the carboxyl-terminal heparin binding domain of fibronectin: implications for BCG-mediated antitumor activity. J Urol 152:1275–1280Google Scholar
  170. 170.
    Belotti D, Paganoni P, Manenti L et al (2003) Matrix metalloproteinases (MMP9 and MMP2) induce the release of vascular endothelial growth factor (VEGF) by ovarian carcinoma cells: implications for ascites formation. Cancer Res 63:5224–5229PubMedGoogle Scholar
  171. 171.
    Sandes E, Lodillinsky C, Cwirenbaum R et al (2007) Cathepsin B is involved in the apoptosis intrinsic pathway induced by Bacillus Calmette-Guerin in transitional cancer cell lines. Int J Mol Med 20:823–828PubMedGoogle Scholar
  172. 172.
    Dezutter-Dambuyant C, Durand I, Alberti L et al (2016) A novel regulation of PD-1 ligands on mesenchymal stromal cells through MMP-mediated proteolytic cleavage. Oncoimmunology 5:e1091146PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  • Paulo Bastos
    • 1
  • Sandra Magalhães
    • 1
    • 2
  • Lúcio Lara Santos
    • 3
  • Rita Ferreira
    • 2
  • Rui Vitorino
    • 1
    • 4
    Email author
  1. 1.iBiMED—Institute for Research in Biomedicine, Department of Medical SciencesUniversity of AveiroAveiroPortugal
  2. 2.QOPNA, Mass Spectrometry Center, Department of ChemistryUniversity of AveiroAveiroPortugal
  3. 3.Experimental Pathology and Therapeutics Group—Research CenterPortuguese Oncology Institute-Porto (IPO-Porto)PortoPortugal
  4. 4.Department of Physiology and Cardiothoracic Surgery, Faculty of MedicineUniversity of PortoPortoPortugal

Personalised recommendations