Journal of Cancer Research and Clinical Oncology

, Volume 139, Issue 8, pp 1373–1382 | Cite as

Expression of MMP-1, MMP-9 and TIMP-2 in prostate carcinoma and their influence on prognosis and survival

  • Ferhat Ozden
  • Caner Saygin
  • Didem Uzunaslan
  • Bulent Onal
  • Haydar Durak
  • Hilal AkiEmail author
Original Paper



Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) participate in tumorigenesis, and their association with disease outcome is highly controversial. The present study investigates the influence of MMP-1, MMP-9 and TIMP-2 on different clinicopathologic variables and disease-free survival (DFS) of patients with prostate carcinoma.


Hundred and forty-five cases are included in the study, and levels of MMP/TIMP expressions are assessed in three tissue compartments (i.e., tumor, stroma and normal glands) with immunohistochemistry.


Matrix metalloproteinase-1 expression in tumor cells was associated with lower Gleason scores, pretreatment prostate-specific antigen levels and lower incidence of vascular, perineural and extracapsular invasions. Moreover, MMP-9 positivity and TIMP-2 expression in normal glands were correlated with lower Gleason patterns and early stage at presentation. Expression of MMP in tumor cells and the presence of TIMP-2 in normal glands were associated with better DFS.


Variability of MMP/TIMP expressions from case to case makes it difficult to evaluate their impact on clinical outcome. However, these proteins might be new and promising targets for prostate cancer therapy in the future.


Matrix metalloproteinases Tissue inhibitors of metalloproteinase Prostate carcinoma Prognosis Survival 


Conflict of interest



  1. Alonso DF, Skilton G, DeLorenzo MS, Scursoni AM, Yoshiji H, Gomez DE (1998) Histopathologic findings in a highly invasive mouse mammary carcinoma transfected with human tissue inhibitor of metalloproteinase-1. Oncol Rep 5:1083–1087PubMedGoogle Scholar
  2. Baker AH, Edwards DR, Murphy G (2002) Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 115:3719–3727PubMedCrossRefGoogle Scholar
  3. Bendardaf R, Lamlum H, Vihinen P, Ristamaki R, Laine J, Pyrhonen S (2003) Low collagenase-1 (MMP-1) and MT1-MMP expression levels are favourable survival markers in advanced colorectal carcinoma. Oncology 65:337–346PubMedCrossRefGoogle Scholar
  4. Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 1477:267–283PubMedCrossRefGoogle Scholar
  5. Cardillo MR, Di Silverio F, Gentile V (2006) Quantitative immunohistochemical and in situ hybridization analysis of metalloproteinases in prostate cancer. Anticancer Res 26:973–982PubMedGoogle Scholar
  6. Cheng S, Tada M, Hida Y, Asano T, Kuramae T, Takemoto N, Hamada J, Miyamoto M, Hirano S, Kondo S, Moriuchi T (2008) High MMP-1 mRNA expression is a risk factor for disease-free and overall survivals in patients with invasive breast carcinoma. J Surg Res 146:104–109PubMedCrossRefGoogle Scholar
  7. Davidsen ML, Würtz S, Romer MU, Sørensen NM, Johansen SK, Christensen IJ, Larsen JK, Offenberg H, Brünner N, Lademann U (2006) TIMP-1 gene deficiency increases tumour cell sensitivity to chemotherapy-induced apoptosis. Br J Cancer 95:1114–1120PubMedCrossRefGoogle Scholar
  8. DeClerck YA, Alvarez O, Shimada H, Taylor SM, Langley KE (1994) Tissue inhibitors of metalloproteinases: role in tumor progression. Contrib Nephrol 107:108–115Google Scholar
  9. Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174PubMedCrossRefGoogle Scholar
  10. Escaff S, Fernández JM, González LO, Suárez A, González-Reyes S, González JM, Vizoso FJ (2010) Study of matrix metalloproteinases and their inhibitors in prostate cancer. Br J Cancer 102:922–929PubMedCrossRefGoogle Scholar
  11. Giannelli G, Fransvea E, Marinosci F, Bergamini C, Daniele A, Colucci S, Paradiso A, Quaranta M, Antonaci S (2002) Gelatinase levels in male and female breast cancer. Biochem Biophys Res Commun 292:161–166PubMedCrossRefGoogle Scholar
  12. Gil Ugarteburu R, Rivas del Fresno M, González Rodríguez I, González Arriaga P, López Cima F, Fernández Samoano A, Fernández García I, Benito García P, Muruamendiaraz Fernández V, Tardón A (2010) Matrix metalloproteinase-9 polymorphisms in the diagnosis of prostate cancer. A preliminary experience. Arch Esp Urol 63:125–132PubMedCrossRefGoogle Scholar
  13. Gonzalez Rodriguez I, Rivas del Fresno M, Gil Ugarteburu R, Gonzalez Arriaga P, Lopez Cima F, Fernandez Samoano A, Muruamendiaraz Fernandez V, Fernandez Garcia I, Perez-Carral JR, Tardon A (2010) Expression of matrix metalloproteinase-9 in prostate cancer. Preliminary experience. Arch Esp Urol 63:119–124PubMedCrossRefGoogle Scholar
  14. Grignon DJ, Sakr W, Toth M, Ravery V, Angulo J, Shamsa F, Pontes JE, Crissman JC, Fridman R (1996) High levels of tissue inhibitors metalloproteinase-2 (TIMP-2) expression are associated with poor outcome in invasive bladder cancer. Cancer Res 56:1654–1659PubMedGoogle Scholar
  15. Hilska M, Roberts PJ, Collan YU, Laine VJ, Kössi J, Hirsimäki P, Rahkonen O, Laato M (2007) Prognostic significance of matrix metalloproteinases-1, -2, -7 and -13 and tissue inhibitors of metalloproteinases-1, -2, -3 and -4 in colorectal cancer. Int J Cancer 121:714–723PubMedCrossRefGoogle Scholar
  16. Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:52–67PubMedCrossRefGoogle Scholar
  17. Kugler A, Hemmerlein B, Thelen P, Kallerhoff M, Radzun H-J, Ringert R-H (1998) Expression of metalloproteinase 2 and 9 and their inhibitors in renal cell carcinoma. J Urol 160:1914–1918PubMedCrossRefGoogle Scholar
  18. Kuniyasu H, Troncoso P, Johnston D, Bucana CD, Tahara E, Fidler IJ, Peltaway CA (2000) Relative expression of type IV collagenase, E-cadherin, and vascular endothelial growth factor/vascular permeability factor in prostatectomy specimens distinguishes organ-confined from pathologically advanced prostate cancers. Clin Cancer Res 6:2295–2308PubMedGoogle Scholar
  19. Laack E, Kohler A, Kugler C, Dierlamm T, Knuffmann C, Vohwinkel G, Niestroy A, Dahlmann N, Peters A, Berger J, Fiedler W, Hossfeld DK (2002) Pretreatment serum levels of matrix metalloproteinase-9 and vascular endothelial growth factor in non-small-cell lung cancer. Ann Oncol 13:1550–1557PubMedCrossRefGoogle Scholar
  20. Lia NG, Shib ZH, Tang YP, Duan JA (2009) Selective matrix metalloproteinase inhibitors for cancer. Curr Med Chem 16:3805–3827PubMedCrossRefGoogle Scholar
  21. Liabakk NB, Talbot I, Smith RA, Wilkinson K, Balkwill F (1996) Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res 56:190–196PubMedGoogle Scholar
  22. MacDougall JR, Bani MR, Lin Y, Muschel RJ, Kerbel RS (1999) Proteolytic switching: opposite patterns of regulation of gelatinase B and its inhibitor TIMP-1 during human melanoma progression and consequences of gelatinase B overexpression. Br J Cancer 80:504–512PubMedCrossRefGoogle Scholar
  23. Miyake H, Muramaki M, Kurahashi T, Takenaka A, Fujisawa M (2008) Expression of potential molecular markers in prostate cancer: correlation with clinicopathological outcomes in patients undergoing radical prostatectomy. Urol Oncol 28:145–151PubMedGoogle Scholar
  24. Morgia G, Falsaperla M, Malaponte G, Madonia M, Indelicato M, Travali S, Mazzarino MC (2005) Matrix metalloproteases as diagnostic (MMP-13) and prognostic (MMP-2, MMP-9) markers of prostate cancer. Urol Res 33:44–50PubMedCrossRefGoogle Scholar
  25. Murashige M, Miyahara M, Shiraishi N, Saito T, Kohno K, Kobayashi M (1996) Enhanced expression of tissue inhibitors of metalloproteinases in human colorectal tumors. Jpn J Clin Oncol 26:303–309PubMedCrossRefGoogle Scholar
  26. Nakopoulou L, Gakiopoulou H, Zervas A, Giannopoulou I, Constantinides C, Lazaris AC, Liapis H, Kyriakou G, Dimopoulos C (2001) MMP-3 mRNA and MMP-3 and MMP-1 proteins in bladder cancer: a comparison with clinicopathologic features and survival. Appl Immunohistochem Mol Morphol 9:130–137PubMedCrossRefGoogle Scholar
  27. Ohbayashi H (2002) Matrix metalloproteinases in lung diseases. Curr Protein Pept Sci 3:409–421PubMedCrossRefGoogle Scholar
  28. Overall CM, Kleifeld O (2006) Tumour microenvironment-opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 6:227–239PubMedCrossRefGoogle Scholar
  29. Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8:221–233PubMedCrossRefGoogle Scholar
  30. Pajouh MS, Nagle RB, Breathnach R, Finch JS, Brawer MK, Bowden GT (1991) Expression of metalloproteinase genes in human prostate cancer. J Cancer Res Clin Oncol 117:144–150PubMedCrossRefGoogle Scholar
  31. Pulukuri SM, Rao JS (2008) Matrix metalloproteinase-1 promotes prostate tumor growth and metastasis. Int J Oncol 32:757–765PubMedGoogle Scholar
  32. Ree AH, Florenes VA, Berg JP, Malandsmo GM, Nesland JM, Fodstad O (1997) High levels of messenger RNAs for tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-2) in primary breast carcinomas are associated with development of distant metastasis. Clin Cancer Res 3:1623–1628PubMedGoogle Scholar
  33. Reis ST, Pontes-Junior J, Antunes AA, de Sousa-Canavez JM, Dall’Oglio MF, Passerotti CC, Abe DK, Crippa A, da Cruz JA, Timoszczuk LM, Srougi M, Leite KR (2011) MMP-9 over expression due to TIMP-1 and RECK under expression is associated with prognosis in prostate cancer. Int J Biol Markers 26:255–261PubMedGoogle Scholar
  34. Remacle AG, Noël A, Duggan C, McDermott E, O’Higgins N, Foidart JM, Duffy MJ (1998) Assay of matrix metalloproteinases types 1, 2, 3 and 9 in breast cancer. Br J Cancer 77:926–931PubMedCrossRefGoogle Scholar
  35. Ross JS, Kaur P, Sheehan CE, Fisher HA, Kaufman RA, Kallakury BV (2003) Prognostic significance of matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 expression in prostate cancer. Mod Pathol 16:198–205PubMedCrossRefGoogle Scholar
  36. Salminen EK, Kallioinen MJ, Ala-Houhala MA, Vihinen PP, Tiitinen SL, Varpula M, Vahlberg TJ (2006) Survival markers related to bone metastases in prostate cancer. Anticancer Res 26:4879–4884PubMedGoogle Scholar
  37. Sauer CG, Kappeler A, Späth M, Kaden JJ, Michel MS, Mayer D, Bleyl U, Grobholz R (2004) Expression and activity of matrix metalloproteinases-2 and -9 in serum, core needle biopsies and tissue specimens of prostate cancer patients. Virchows Arch 444:518–526PubMedCrossRefGoogle Scholar
  38. Scorilas A, Karameris A, Arnogiannaki N, Ardavanis A, Bassilopoulos P, Trangas T, Talieri M (2001) Overexpression of matrix-metalloproteinase-9 in human breast cancer: a potential favourable indicator in node-negative patients. Br J Cancer 84:1488–1496PubMedCrossRefGoogle Scholar
  39. Seitz C, Djavan B (2006) Biological markers of prostate cancer. Ann Urol 40:329–335CrossRefGoogle Scholar
  40. Stratton M, Dalkin B, Nagle R, Ranger-Moore J, Ahmann F, Bowden G (2006) Matrix metalloproteinase-7 in prostatic fluid versus serum PSA for diagnosis of prostate cancer. In: Prostate cancer symposium general poster session A, ASCO, 24–26 February 2006Google Scholar
  41. Trudel D, Fradet Y, Meyer F, Harel F, Têtu B (2008) Membrane-type-1 matrix metalloproteinase, matrix metalloproteinase 2, and tissue inhibitor of matrix proteinase 2 in prostate cancer: identification of patients with poor prognosis by immunohistochemistry. Hum Pathol 39:731–739PubMedCrossRefGoogle Scholar
  42. Trudel D, Fradet Y, Meyer F, Têtu B (2010) Matrix metalloproteinase 9 is associated with Gleason score in prostate cancer but not with prognosis. Hum Pathol 41:1694–1701PubMedCrossRefGoogle Scholar
  43. Turpeenniemi-Hujanen T (2005) Gelatinases (MMP-2 and-9) and their natural inhibitors as prognostic indicators in solid cancers. Biochimie 87:287–297PubMedCrossRefGoogle Scholar
  44. Wilson MJ, Jiang A, Wiehr C, Wang X, Sinha AA, Pei D (2004) Limited processing of pro-matrix metalloprotease-2 (gelatinase A) over expressed by transfection in PC-3 human prostate tumor cells: association with restricted cell surface localization of membrane-type matrix metalloproteinase-1. J Androl 25:274–285PubMedGoogle Scholar
  45. Woessner JF (1991) Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 5:2145–2154PubMedGoogle Scholar
  46. Yang SF, Hsieh YS, Lin CL, Hsu NY, Chiou HL, Chou FP, Chu SC (2005) Increased plasma levels of urokinase plasminogen activator and matrix metalloproteinase-9 in nonsmall cell lung cancer patients. Clin Chim Acta 354:91–99PubMedCrossRefGoogle Scholar
  47. Yoon JH, Choi YJ, Lee SG (2012) Ginsenoside Rh1 suppresses matrix metalloproteinase-1 expression through inhibition of activator protein-1 and mitogen-activated protein kinase signaling pathway in human hepatocellular carcinoma cells. Eur J Pharmacol 679:24–33PubMedCrossRefGoogle Scholar
  48. Zhong WD, Han ZD, He HC, Bi XC, Dai QS, Zhu G, Ye YK, Liang YX, Qin WJ, Zhang Z, Zeng GH, Chen ZN (2008) CD147, MMP-1, MMP-2 and MMP-9 protein expression as significant prognostic factors in human prostate cancer. Oncology 75:230–236PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Ferhat Ozden
    • 1
  • Caner Saygin
    • 2
  • Didem Uzunaslan
    • 2
  • Bulent Onal
    • 3
  • Haydar Durak
    • 1
  • Hilal Aki
    • 1
    Email author
  1. 1.Department of PathologyIstanbul University Cerrahpasa Medical SchoolKocamustafapasa/IstanbulTurkey
  2. 2.Istanbul University Cerrahpasa Medical SchoolKocamustafapasa/IstanbulTurkey
  3. 3.Department of UrologyIstanbul University Cerrahpasa Medical SchoolKocamustafapasa/IstanbulTurkey

Personalised recommendations