Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Matrix metalloproteinases and their clinical relevance in urinary bladder cancer

Nature Reviews Urology volume 8, pages 241–254 (2011)Cite this article

Subjects

Abstract

Matrix metalloproteinases (MMPs) have important roles in several cancer-supporting cellular processes, such as extracellular matrix (ECM) remodeling, angiogenesis, apoptosis, epithelial-to-mesenchymal transition and cell proliferation. This broad range of activity has led to considerable interest in the use of MMPs in the clinical setting as diagnostic or prognostic biomarkers and as therapeutic targets. Levels of the different MMPs can be measured in several sample types, including paraffin-embedded or fresh frozen tissue, serum, plasma and urine, and by various analytical methodologies, such as immunohistochemistry, real-time PCR, western and northern blot analyses, enzyme-linked immunosorbent assay and zymography. Several MMPs have been identified as having potential diagnostic or prognostic utility, whether alone or in combination with currently available diagnostic tests or imaging modalities. Although the early broad-spectrum anti-MMP agents showed a lack of efficacy, our continually improving understanding of the complex physiologic and pathologic roles of MMPs might enable the development of new MMP-specific and tumor-specific therapies. Accordingly, MMPs will continue to be the subjects of intensive research in bladder cancer.

Key Points

  • Matrix metalloproteinases (MMPs) are zinc-dependent endogenous proteases with distinct but partly overlapping substrate specificities and structural similarities

  • The proteolytic activity of MMPs is regulated by transcription factors, endogenous inhibitors, and proteases that are able to remove the pro-domains of MMPs from their inactive, latent form

  • MMPs are involved in several physiological and tumor-supporting cellular processes, including loss of cell adhesion, tumor angiogenesis, cell proliferation, epithelial-to-mesenchymal transition and apoptosis

  • MMP levels can be assessed in various sample types (tissue, serum, plasma and urine) using several methods (immunohistochemistry, real-time PCR, western and northern blot analyses, enzyme-linked immunosorbent assay and zymography)

  • MMPs have been extensively analyzed in bladder cancer, which has revealed potential roles for some MMPs as diagnostic markers and prognostic factors at different stages of the disease course

  • Although broad-spectrum anti-MMP agents provided disappointing results, MMPs remain promising targets for tumor therapy; tissue-specific and/or selective MMP inhibition combined with novel imaging techniques might allow development of effective new anti-MMP therapies

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: MMP-induced cellular processes relevant to tumor growth and progression.

Similar content being viewed by others

References

  1. Aitken, K. J. & Bägli, D. J. The bladder extracellular matrix. Part I: architecture, development and disease. Nat. Rev. Urol. 6, 596–611 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2, 563–572 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Deryugina, E. I. & Quigley, J. P. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 25, 9–34 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Page-McCaw, A., Ewald, A. J. & Werb, Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat. Rev. Mol. Cell Biol. 8, 221–233 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Haas, T. L. Matrix metalloproteinase activity is required for activity-induced angiogenesis in rat skeletal muscle. Am. J. Physiol. Heart Circ. Physiol. 279, 1540–1547 (2000).

    Article  Google Scholar 

  6. Fata, J. E., Ho, A. T., Leco, K. J., Moorehead, R. A. & Khokha, R. Cellular turnover and extracellular matrix remodeling in female reproductive tissues: functions of metalloproteinases and their inhibitors. Cell. Mol. Life Sci. 57, 77–95 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Burrage, P. S., Mix, K. S. & Brinckerhoff, C. E. Matrix metalloproteinases: role in arthritis. Front. Biosci. 11, 529–543 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Liu, P., Sun, M. & Sader, S. Matrix metalloproteinases in cardiovascular disease. Can. J. Cardiol. 22, 25–30 (2006).

    Article  Google Scholar 

  9. Westermarck, J. & Kähäri, V. M. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J. 13, 781–792 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer 2, 161–174 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Nagase, H. & Woessner, J. F. Jr. Matrix metalloproteinases. J. Biol. Chem. 274, 21491–21494 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Bode, W. & Maskos, K. Structural studies on MMPs and TIMPs. Methods Mol. Biol. 151, 45–77 (2001).

    CAS  PubMed  Google Scholar 

  13. Yan, C. & Boyd, D. D. Regulation of matrix metalloproteinase gene expression. J. Cell Physiol. 211, 19–26 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Fanjul-Fernández, M., Folgueras, A. R., Cabrera, S. & López-Otín, C. Matrix metalloproteinases: evolution, gene regulation and functional analysis in mouse models. Biochim. Biophys. Acta 1803, 3–19 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Chicoine, E. et al. Evidence for the role of promoter methylation in the regulation of MMP-9 gene expression. Biochem. Biophys. Res. Commun. 297, 765–772 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Shukeir, N., Pakneshan, P., Chen, G., Szyf, M. & Rabbani, S. A. Alteration of the methylation status of tumor-promoting genes decreases prostate cancer cell invasiveness and tumorigenesis in vitro and in vivo. Cancer Res. 66, 9202–9210 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Hadler-Olsen, E., Fadnes, B., Sylte, I., Uhlin-Hansen, L. & Winberg, J. O. Regulation of matrix metalloproteinase activity in health and disease. FEBS J. 278, 28–45 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Kähäri, V. M. & Saarialho-Kere, U. Matrix metalloproteinases and their inhibitors in tumour growth and invasion. Ann. Med. 31, 34–45 (1999).

    Article  PubMed  Google Scholar 

  19. Cruz-Munoz, W. & Khokha, R. The role of tissue inhibitors of metalloproteinases in tumorigenesis and metastasis. Crit. Rev. Clin. Lab. Sci. 45, 291–338 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Thomas, P., Khokha, R., Shepherd, F. A., Feld, R. & Tsao, M. S. Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer. J. Pathol. 190, 150–156 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. de Vicente, J. C., Fresno, M. F., Villalain, L., Vega, J. A. & López, Arranz, J. S. Immunoexpression and prognostic significance of TIMP-1 and -2 in oral squamous cell carcinoma. Oral Oncol. 41, 568–579 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Rhee, J. S., Diaz, R., Korets, L., Hodgson, J. G. & Coussens, L. M. TIMP-1 alters susceptibility to carcinogenesis. Cancer Res. 64, 952–961 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Kong, Y. et al. Matrix metalloproteinase activity modulates tumor size, cell motility, and cell invasiveness in murine aggressive fibromatosis. Cancer Res. 64, 5795–5803 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Baker, A. H., Edwards, D. R. & Murphy, G. Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J. Cell Sci. 115, 3719–3727 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Aparicio, T., Kermorgant, S., Dessirier, V., Lewin, M. J. & Lehy, T. Matrix metalloproteinase inhibition prevents colon cancer peritoneal carcinomatosis development and prolongs survival in rats. Carcinogenesis 20, 1445–1451 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Haq, M., Shafii, A., Zervos, E. E. & Rosemurgy, A. S. Addition of matrix metalloproteinase inhibition to conventional cytotoxic therapy reduces tumor implantation and prolongs survival in a murine model of human pancreatic cancer. Cancer Res. 60, 3207–3211 (2000).

    CAS  PubMed  Google Scholar 

  27. Nelson, A. R., Fingleton, B. & Rothenberg, M. L. Matrisian, L. M. Matrix metalloproteinases: biologic activity and clinical implications. J. Clin. Oncol. 18, 1135–1149 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Itoh, T. et al. Experimental metastasis is suppressed in MMP-9-deficient mice. Clin. Exp. Metastasis 17, 177–181 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Szabova, L., Chrysovergis, K., Yamada, S. S. & Holmbeck, K. MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease. Oncogene 27, 3274–3281 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Itoh, T. et al. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res. 58, 1048–1051 (1998).

    CAS  PubMed  Google Scholar 

  31. Kupferman, M. E. et al. Matrix metalloproteinase 9 promoter activity is induced coincident with invasion during tumor progression. Am. J. Pathol. 157, 1777–1783 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lochter, A. et al. Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J. Cell Biol. 139, 1861–1872 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Vihinen, P. & Kähäri, V. M. Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets. Int. J. Cancer 99, 157–166 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Roy, R., Yang, J. & Moses, M. A. Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J. Clin. Oncol. 27, 5287–5297 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sier, C. F. et al. Endothelium specific matrilysin (MMP-7) expression in human cancers. Matrix Biol. 27, 267–271 (2008).

    CAS  PubMed  Google Scholar 

  36. Harper, J. & Moses, M. A. Molecular regulation of tumor angiogenesis: mechanisms and therapeutic implications. EXS 96, 223–268 (2006).

    CAS  Google Scholar 

  37. Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2, 737–744 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lee, S., Jilani, S. M., Nikolova, G. V., Carpizo, D. & Iruela-Arispe, M. L. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors J. Cell. Biol. 169, 681–691 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Whitelock, J. M., Murdoch A. D., Iozzo, R. V. & Underwood, P. A. The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases. J. Biol. Chem. 271, 10079–10086 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Du, R. et al. HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Heljasvaara, R. et al. Generation of biologically active endostatin fragments from human collagen XVIII by distinct matrix metalloproteases. Exp. Cell Res. 307, 292–304 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Chang, J. H., Javier, J. A., Chang, G. Y., Oliveira, H. B. & Azar, D. T. Functional characterization of neostatins, the MMP-derived, enzymatic cleavage products of type XVIII collagen. FEBS Lett. 579, 3601–3606 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Mitsiades, N., Yu, W. H., Poulaki, V., Tsokos, M. & Stamenkovic, I. Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity. Cancer Res. 61, 577–581 (2001).

    CAS  PubMed  Google Scholar 

  44. Almendro, V. et al. The role of MMP7 and its cross-talk with the FAS/FASL system during the acquisition of chemoresistance to oxaliplatin. PLoS ONE 4, 4728 (2009).

    Article  CAS  Google Scholar 

  45. Vargo-Gogola, T., Fingleton, B., Crawford, H. C. & Matrisian, L. M. Matrilysin (matrix metalloproteinase-7) selects for apoptosis-resistant mammary cells in vivo. Cancer Res. 62, 5559–5563 (2002).

    CAS  PubMed  Google Scholar 

  46. Liu, H. et al. Predictive value of MMP-7 expression for response to chemotherapy and survival in patients with non-small cell lung cancer. Cancer Sci. 99, 2185–2192 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Noë, V. et al. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J. Cell Sci. 114, 111–118 (2001).

    PubMed  Google Scholar 

  48. Cowden Dahl, K. D. et al. Matrix metalloproteinase 9 is a mediator of epidermal growth factor-dependent e-cadherin loss in ovarian carcinoma cells. Cancer Res. 68, 4606–4613 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Radisky, D. C. et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436, 123–127 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Suzuki, M., Raab, G., Moses, M. A., Fernandez, C. A. & Klagsbrun, M. Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specific juxtamembrane site. J. Biol. Chem. 272, 31730–31737 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Kivisaari, A. K. et al. Matrix metalloproteinase-7 activates heparin-binding epidermal growth factor-like growth factor in cutaneous squamous cell carcinoma. Br. J. Dermatol. 163, 726–735 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Nakamura, M. et al. Matrix metalloproteinase-7 degrades all insulin-like growth factor binding proteins and facilitates insulin-like growth factor bioavailability. Biochem. Biophys. Res. Commun. 333, 1011–1016 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Mañes, S. et al. Identification of insulin-like growth factor-binding protein-1 as a potential physiological substrate for human stromelysin-3. J. Biol. Chem. 272, 25706–25712 (1997).

    Article  PubMed  Google Scholar 

  54. Dormán, G. et al. Matrix metalloproteinase inhibitors: a critical appraisal of design principles and proposed therapeutic utility. Drugs 70, 949–964 (2010).

    Article  PubMed  Google Scholar 

  55. Verheijen, J. H. et al. Modified proenzymes as artificial substrates for proteolytic enzymes: colorimetric assay of bacterial collagenase and matrix metalloproteinase activity using modified pro-urokinase. Biochem. J. 323, 603–609 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Scherer, R. L. & McIntyre, J. O. Matrisian LM. Imaging matrix metalloproteinases in cancer. Cancer Metastasis Rev. 27, 679–690 (2008).

    Article  PubMed  Google Scholar 

  57. Jung, K., Klotzek, S., Stephan, C., Mannello, F. & Lein, M. Impact of blood sampling on the circulating matrix metalloproteinases 1, 2, 3, 7, 8, and 9. Clin. Chem. 54, 772–773 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Mannello, F., Tonti, G. A., Tanus-Santos, J. E. & Gerlach, R. F. Silicate increases the release of MMP-9 forms in peripheral blood: why gelatin zymography differs significantly in citrate plasma and serum obtained with or without clot activators. Clin. Chem. 53, 1981–1982 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Smith, E. R., Zurakowski, D., Saad, A., Scott, R. M. & Moses, M. A. Urinary biomarkers predict brain tumor presence and response to therapy. Clin. Cancer Res. 14, 2378–2386 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Ozdemir, E., Kakehi, Y., Okuno, H. & Yoshida, O. Role of matrix metalloproteinase-9 in the basement membrane destruction of superficial urothelial carcinomas. J. Urol. 161, 1359–1363 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. Nakopoulou, L. et al. MMP-3 mRNA and MMP-3 and MMP-1 proteins in bladder cancer: a comparison with clinicopathologic features and survival. Appl. Immunohistochem. Mol. Morphol. 9, 130–137 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Choi, Y. D. et al. Matrix metalloproteinase expression in the recurrence of superficial low grade bladder transitional cell carcinoma. J. Urol. 177, 1174–1178 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Durkan, G. C. et al. 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. Clin. Cancer Res. 7, 3450–3456 (2001).

    CAS  PubMed  Google Scholar 

  64. Staack, A., Badendieck, S., Schnorr, D., Loening, S. A. & Jung, K. Combined determination of plasma MMP2, MMP9, and TIMP1 improves the non-invasive detection of transitional cell carcinoma of the bladder. BMC Urol. 6, 19 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Svatek, R. S. et al. A multiplexed, particle-based flow cytometric assay identified plasma matrix metalloproteinase-7 to be associated with cancer-related death among patients with bladder cancer. Cancer 116, 4513–4519 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Nutt, J. E., Mellon, J. K., Qureshi, K. & Lunec, J. Matrix metalloproteinase-1 is induced by epidermal growth factor in human bladder tumour cell lines and is detectable in urine of patients with bladder tumours. Br. J. Cancer 78, 215–220 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Itoh, M. et al. Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells. Oncogene 25, 1195–1204 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Davies, B. et al. Levels of matrix metalloproteases in bladder cancer correlate with tumor grade and invasion. Cancer Res. 53, 5365–5369 (1993).

    CAS  PubMed  Google Scholar 

  69. Mohammad, M. A., Ismael, N. R., Shaarawy, S. M. & El-Merzabani, M. M. Prognostic value of membrane type 1 and 2 matrix metalloproteinase expression and gelatinase A activity in bladder cancer. Int. J. Biol. Markers 25, 69–74 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Wallard, M. J. et al. Comprehensive profiling and localisation of the matrix metalloproteinases in urothelial carcinoma. Br. J. Cancer 94, 569–577 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Grignon, D. J. et al. High levels of tissue inhibitor of metalloproteinase-2 (TIMP-2) expression are associated with poor outcome in invasive bladder cancer. Cancer Res. 56, 1654–1659 (1996).

    CAS  PubMed  Google Scholar 

  72. Vasala, K., Pääkkö, P. & Turpeenniemi-Hujanen, T. Matrix metalloproteinase-2 immunoreactive protein as a prognostic marker in bladder cancer. Urology 62, 952–957 (2003).

    Article  PubMed  Google Scholar 

  73. Kanayama, H. et al. Prognostic values of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression in bladder cancer. Cancer 82, 1359–1366 (1998).

    Article  CAS  PubMed  Google Scholar 

  74. Hara, I., Miyake, H., Hara, S., Arakawa, S. & Kamidono, S. Significance of matrix metalloproteinases and tissue inhibitors of metalloproteinase expression in the recurrence of superficial transitional cell carcinoma of the bladder. J. Urol. 165, 1769–1772 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Gohji, K. et al. Elevation of serum levels of matrix metalloproteinase-2 and -3 as new predictors of recurrence in patients with urothelial carcinoma. Cancer 78, 2379–2387 (1996).

    Article  CAS  PubMed  Google Scholar 

  76. Vasala, K. & Turpeenniemi-Hujanen, T. 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, 640–644 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Vasala, K., Kuvaja, P. & Turpeenniemi-Hujanen, T. Low circulating levels of ProMMP-2 are associated with adverse prognosis in bladder cancer. Tumour Biol. 29, 279–286 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Sier, C. F. et al. Enhanced urinary gelatinase activities (matrix metalloproteinases 2 and 9) are associated with early-stage bladder carcinoma: a comparison with clinically used tumor markers. Clin. Cancer Res. 6, 2333–2340 (2000).

    CAS  PubMed  Google Scholar 

  79. Gerhards, S. et al. Excretion of matrix metalloproteinases 2 and 9 in urine is associated with a high stage and grade of bladder carcinoma. Urology 57, 675–679 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Eissa, S. et al. 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, 1388–1396 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Miyake, H. et al. Basic fibroblast growth factor regulates matrix metalloproteinases production and in vitro invasiveness in human bladder cancer cell lines. J. Urol. 157, 2351–2355 (1997).

    Article  CAS  PubMed  Google Scholar 

  82. Nutt, J. E., Durkan, G. C., Mellon, J. K. & Lunec, J. Matrix metalloproteinases (MMPs) in bladder cancer: the induction of MMP9 by epidermal growth factor and its detection in urine. BJU Int. 91, 99–104 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Shin, K. Y. et al. Effects of tumor necrosis factor-α and interferon-γ on expressions of matrix metalloproteinase-2 and -9 in human bladder cancer cells. Cancer Lett. 159, 127–134 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Dehnavi, E., Soheili, Z. S., Samiei, S., Ataei, Z. & Aryan, H. The effect of TGF-β2 on MMP-2 production and activity in highly metastatic human bladder carcinoma cell line 5637. Cancer Invest. 27, 568–574 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Lee, S. J., Park, S. S., Lee, U. S., Kim, W. J. & Moon, S. K. Signaling pathway for TNF-α-induced MMP-9 expression: mediation through p38 MAP kinase, and inhibition by anti-cancer molecule magnolol in human urinary bladder cancer 5637 cells. Int. Immunopharmacol. 8, 1821–1826 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Chang, H. R. et al. The suppressive effect of Rho kinase inhibitor, Y-27632, on oncogenic Ras/RhoA induced invasion/migration of human bladder cancer TSGH cells. Chem. Biol. Interact. 183, 172–180 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Kumar, B. et al. p38 mitogen-activated protein kinase-driven MAPKAPK2 regulates invasion of bladder cancer by modulation of MMP-2 and MMP-9 activity. Cancer Res. 70, 832–841 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Lynch, C. C. et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 7, 485–496 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Maurel, J. et al. Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients. Int. J. Cancer 121, 1066–1071 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Ramankulov, A. et al. Plasma matrix metalloproteinase-7 as a metastatic marker and survival predictor in patients with renal cell carcinomas. Cancer Sci. 99, 1188–1194 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Szarvas, T. et al. Elevated serum matrix metalloproteinase 7 levels predict poor prognosis after radical prostatectomy. Int. J. Cancer 128, 1486–1492 (2010).

    Article  CAS  Google Scholar 

  92. Szarvas, T. et al. Matrix metalloproteinase-7 as a marker of metastasis and predictor of poor survival in bladder cancer. Cancer Sci. 101, 1300–1308 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Szarvas, T. et al. Urinary matrix metalloproteinase-7 level is associated with the presence of metastasis in bladder cancer. BJU Int. doi: 10.1111/j.1464-410X.2010.09625.x.

  94. Szarvas, T. et al. Validation of circulating MMP-7 level as an independent prognostic marker of poor survival in urinary bladder cancer. Pathol. Oncol. Res. doi: 10.1007/s12253-010-9320-4.

  95. Guan, K. P., Ye, H. Y., Yan, Z., Wang, Y. & Hou, S. K. Serum levels of endostatin and matrix metalloproteinase-9 associated with high stage and grade primary transitional cell carcinoma of the bladder. Urology 61, 719–723 (2003).

    Article  PubMed  Google Scholar 

  96. Durkan, G. C. et al. Alteration in urinary matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio predicts recurrence in nonmuscle-invasive bladder cancer. Clin. Cancer Res. 9, 2576–2582 (2003).

    CAS  PubMed  Google Scholar 

  97. Vasala, K., Pääkko, P. & Turpeenniemi-Hujanen, T. Matrix metalloproteinase-9 (MMP-9) immunoreactive protein in urinary bladder cancer: a marker of favorable prognosis. Anticancer Res. 28, 1757–1761 (2008).

    PubMed  Google Scholar 

  98. Donmez, G. et al. Vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and thrombospondin-1 (TSP-1) expression in urothelial carcinomas. Pathol. Res. Pract. 205, 854–857 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Slaton, J. W. et al. Correlation of metastasis related gene expression and relapse-free survival in patients with locally advanced bladder cancer treated with cystectomy and chemotherapy. J. Urol. 171, 570–574 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Bianco, F. J. Jr et al. Matrix metalloproteinase-9 expression in bladder washes from bladder cancer patients predicts pathological stage and grade. Clin. Cancer Res. 4, 3011–3016 (1998).

    PubMed  Google Scholar 

  101. Offersen, B. V. et al. Matrix metalloproteinase-9 measured in urine from bladder cancer patients is an independent prognostic marker of poor survival. Acta Oncol. 49, 1283–1287 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Moses, M. A. et al. Increased incidence of matrix metalloproteinases in urine of cancer patients. Cancer Res. 58, 1395–1399 (1998).

    CAS  PubMed  Google Scholar 

  103. Roy, R. et al. Tumor-specific urinary matrix metalloproteinase fingerprinting: identification of high molecular weight urinary matrix metalloproteinase species. Clin. Cancer Res. 14, 6610–6617 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ongusaha, P. P. et al. HB-EGF is a potent inducer of tumor growth and angiogenesis. Cancer Res. 64, 5283–5290 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Lee, S. J. et al. Activation of matrix metalloproteinase-9 by TNF-α in human urinary bladder cancer HT1376 cells: the role of MAP kinase signaling pathways. Oncol. Rep. 19, 1007–1013 (2008).

    CAS  PubMed  Google Scholar 

  106. Inoue, K. et al. Interleukin 8 expression regulates tumorigenicity and metastasis in human bladder cancer. Cancer Res. 60, 2290–2299 (2000).

    CAS  PubMed  Google Scholar 

  107. Chang, C. C. et al. Oct-3/4 expression reflects tumor progression and regulates motility of bladder cancer cells. Cancer Res. 68, 6281–6291 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Xue, Y. J., Lu, Q. & Sun, Z. X. CD147 overexpression is a prognostic factor and a potential therapeutic target in bladder cancer. Med. Oncol. doi: 10.1007/s12032-010-9582-4.

  109. Saeb-Parsy, K. et al. MT1-MMP regulates urothelial cell invasion via transcriptional regulation of Dickkopf-3. Br. J. Cancer 99, 663–669 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Seargent, J. M. et al. Expression of matrix metalloproteinase-10 in human bladder transitional cell carcinoma. Urology 65, 815–820 (2005).

    Article  PubMed  Google Scholar 

  111. Mueller, J., Steiner, C. & Höfler, H. Stromelysin-3 expression in noninvasive and invasive neoplasms of the urinary bladder. Hum. Pathol. 31, 860–865 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Rodríguez Faba, O. et al. Significance of collagenase 3 (matrix metalloproteinase 13) in invasive bladder cancer: correlation with pathological parameters. Urol. Int. 78, 140–144 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Naruo, S. et al. Serum levels of a tissue inhibitor of metalloproteinases-1 (TIMP-1) in bladder cancer patients. Int. J. Urol. 1, 228–231 (1994).

    Article  CAS  PubMed  Google Scholar 

  114. Gakiopoulou, H. et al. Tissue inhibitor of metalloproteinase-2 as a multifunctional molecule of which the expression is associated with adverse prognosis of patients with urothelial bladder carcinomas. Clin. Cancer Res. 9, 5573–5581 (2003).

    CAS  PubMed  Google Scholar 

  115. Hayakawa, T., Yamashita, K., Ohuchi, E. & Shinagawa, A. Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2). J. Cell Sci. 107, 2373–2379 (1994).

    CAS  PubMed  Google Scholar 

  116. Nicholson, B. E. et al. Profiling the evolution of human metastatic bladder cancer. Cancer Res. 64, 7813–7821 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Chaffer, C. L. et al. Upregulated MT1-MMP/TIMP-2 axis in the TSU-Pr1-B1/B2 model of metastatic progression in transitional cell carcinoma of the bladder. Clin. Exp. Metastasis 22, 115–125 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Eissa, S., Shabayek, M. I., Ismail, M. F., El-Allawy, R. M. & Hamdy, M. A. Diagnostic evaluation of apoptosis inhibitory gene and tissue inhibitor matrix metalloproteinase-2 in patients with bladder cancer. IUBMB Life 62, 394–399 (2010).

    CAS  PubMed  Google Scholar 

  119. Kader, A. K. et al. Matrix metalloproteinase polymorphisms and bladder cancer risk. Cancer Res. 66, 11644–11648 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Kader, A. K. et al. Matrix metalloproteinase polymorphisms are associated with bladder cancer invasiveness. Clin. Cancer Res. 13, 2614–2620 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Tasci, A. I. et al. A single-nucleotide polymorphism in the matrix metalloproteinase-1 promoter enhances bladder cancer susceptibility. BJU Int. 101, 503–507 (2008).

    CAS  PubMed  Google Scholar 

  122. Srivastava, P., Mandhani, A., Kapoor, R. & Mittal, R. D. Role of MMP-3 and MMP-9 and their haplotypes in risk of bladder cancer in North Indian cohort. Ann. Surg. Oncol. 17, 3068–3075 (2010).

    Article  PubMed  Google Scholar 

  123. Srivastava, P., Gangwar, R., Kapoor, R. & Mittal, R. D. Bladder cancer risk associated with genotypic polymorphism of the matrix metalloproteinase-1 and 7 in North Indian population. Dis. Markers 29, 37–46 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Mitra, A. P. & Cote, R. J. Molecular screening for bladder cancer: progress and potential. Nat. Rev. Urol. 7, 11–20 (2010).

    Article  CAS  PubMed  Google Scholar 

  125. Fernández, C. A. et al. A novel approach to using matrix metalloproteinases for bladder cancer. J. Urol. 182, 2188–2194 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Leissner, J. et al. Extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective multicenter study. J. Urol. 171, 139–144 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Shariat, S. F. et al. Multiple biomarkers improve prediction of bladder cancer recurrence and mortality in patients undergoing cystectomy. Cancer 112, 315–325 (2008).

    Article  PubMed  Google Scholar 

  128. Nemunaitis, J. et al. Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer-term studies. Clin. Cancer Res. 4, 1101–1109 (1998).

    CAS  Google Scholar 

  129. Pavlaki, M. & Zucker, S. Matrix metalloproteinase inhibitors (MMPIs): the beginning of phase I or the termination of phase III clinical trials. Cancer Metastasis Rev. 22, 177–203 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Coussens, L. M., Fingleton, B. & Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295, 2387–2392 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Urology, University Hospital Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany

    Tibor Szarvas, Frank vom Dorp & Herbert Rübben

  2.  Institute of Anatomy, University Hospital of Essen, Hufelandstrasse 55, 45122, Essen, Germany

    Süleyman Ergün

Authors
  1. Tibor Szarvas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frank vom Dorp
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Süleyman Ergün
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Herbert Rübben
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T. Szarvas researched data for the article. All authors made substantial contributions to the discussion of content. T. Szarvas and S. Ergün wrote the article. F. vom Dorp, S. Ergün and H. Rübben performed review/editing of the manuscript before submission.

Corresponding author

Correspondence to Tibor Szarvas.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Szarvas, T., vom Dorp, F., Ergün, S. et al. Matrix metalloproteinases and their clinical relevance in urinary bladder cancer. Nat Rev Urol 8, 241–254 (2011). https://doi.org/10.1038/nrurol.2011.44

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrurol.2011.44

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing