Advertisement

Matrix Metalloproteinases and Tumor Progression

  • José M. P. Freije
  • Milagros Balbín
  • Alberto M. Pendás
  • Luis M. Sánchez
  • Xose S. Puente
  • Carlos López-Otín
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 532)

Abstract

The matrix metalloproteinases (MMPs) are a family of more than 20 distinct enzymes that are frequently overexpressed in human tumors. Functional studies have shown that MMPs play an important role in the proteolytic destruction of extracellular matrix and basement membranes, thereby facilitating tumor invasion and metastasis. In addition, these enzymes may also be important in other steps of tumor evolution including neoplastic cell proliferation and angiogenesis stimulation. On the basis of the relevance of MMPs in tumor progression, a number of different strategies aimed to block the unwanted activity of these enzymes in cancer have been developed. Unfortunately, most clinical trials with the first series of MMP inhibitors have failed to show clear benefit in patients with advanced cancer. Explanations for this lack of success include the failure to recognize the role of these enzymes in early stages of the disease as well as inadequacy of either the employed inhibitors or the proteases to be targeted.

The introduction of novel concepts such as tumor degradome, and global approaches to protease analysis, may facilitate the identification of the relevant MMPs that must be targeted in each individual cancer patient. On the other hand, the finding that MMPs are enzymes whose effects on biologically active substrates can have profound consequences on cell behaviour, suggests that selective inhibition of a limited set of MMPs at early stages of tumor evolution might be much more effective than using wide-spectrum inhibitors active against most family members, and administered to patients at late stages of the disease. Further studies directed to elucidate these questions will be necessary to clarify whether any of the multiple strategies of MMP inhibition may be part of future therapeutic approaches to control tumor progression.

Keywords

Matrix Metalloproteinase Matrix Metalloproteinase Inhibitor Cell BioI Future Therapeutic Approach proMMP Activation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Chambers, A. F., Groom, A.C., and MacDonald, I.C. Dissemination and growth of cancer cells in metastatic sites.Nature Rev Cancer2, 563–572 (2002)CrossRefGoogle Scholar
  2. 2.
    López-Otín, C. and Overall, C. M. Protease degradomics, a challenge for proteomics.Nature Rev. Mol. Cell Biol. 3509–519 (2002)CrossRefGoogle Scholar
  3. 3.
    Brinckerhoff, C. E. and Matrisian, L. M. Matrix metalloproteinases: a tail of a frog that became a prince.Nature Rev. Mol. Cell Biol. 3,207–214 (2002).CrossRefGoogle Scholar
  4. 4.
    Egeblad, M. and Werb, Z. New functions for the matrix metalloproteinases in cancer progression.Nature Rev. Cancer 2,163–175 (2002).CrossRefGoogle Scholar
  5. 5.
    Overall, C. M. and López-Otín, C Strategies for MMP inhibition in cancer: innovations for the post-trial era.Nature Rev. Cancer. 2657–672 (2002)CrossRefGoogle Scholar
  6. 6.
    Urfa, J. A. and López-Otín, C. Matrilysin-2, a new matrix metalloproteinase expressed in human tumors and showing the minimal domain organization required for secretion, latency, and activity.Cancer Res. 60,4745–4751 (2000).Google Scholar
  7. 7.
    Velasco, G.et al.Cloning and characterization of human MMP-23, a new matrix metalloproteinase predominantly expressed in reproductive tissues and lacking conserved domains in other family members.J. Biol. Chem. 274,4570–4576 (1999).PubMedCrossRefGoogle Scholar
  8. 8.
    Sternlicht, M. D.et al.The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis.Cell 98,137–146 (1999).PubMedCrossRefGoogle Scholar
  9. 9.
    Sternlicht, M. D. and Werb, Z. How matrix metalloproteinases regulate cell behavior.Annu. Rev. Cell Dev. Biol. 17,463–516 (2001)PubMedCrossRefGoogle Scholar
  10. 10.
    Rifkin, D. B., Mazzieri, R., Munger, J. S., Noguera, 1. and Sung, J. Proteolytic control of growth factor availability.APMIS 107,80–85 (1999).Google Scholar
  11. 11.
    Mañes, S.et al.The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells.J Biol. Chem. 274,6935–6945 (1999).PubMedCrossRefGoogle Scholar
  12. 12.
    Noe, V.et al.Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1.J. Cell Sci. 114,111–118 (2001).PubMedGoogle Scholar
  13. 13.
    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).PubMedCrossRefGoogle Scholar
  14. 14.
    Ho, A. T., Voura, E. B., Soloway, P. D., Watson, K. L. and Khokha, R. MMP inhibitors augment fibroblast adhesion through stabilization of focal adhesion contacts and up-regulation of cadherin function.J. Biol.Chem. 276,40215–40224 (2001).PubMedGoogle Scholar
  15. 15.
    McQuibban, G. A.et al.Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3.Science 289,1202–1206 (2000).PubMedCrossRefGoogle Scholar
  16. 16.
    Fingleton, B., Vargo-Gogola, T., Crawford, H. C. and Matrisian, L. M. Matrilysin (MMP-7) expression selects for cells with reduced sensitivity to apoptosis.Neoplasia 3,459–468 (2001).PubMedCrossRefGoogle Scholar
  17. 17.
    Yu, Q. and Stamenkovic, I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-ß and promotes tumor invasion and angiogenesis.Genes Dev. 14,163–176 (2000).PubMedGoogle Scholar
  18. 18.
    Stetler-Stevenson, W. G. Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention.J. Clin. Invest. 103,1237–1241 (1999).PubMedCrossRefGoogle Scholar
  19. 19.
    Dong, Z., Kumar, R., Yang, X. and Fidler, I. J. Macrophage-derived metalIoelastase is responsible for the generation of angiostatin in Lewis lung carcinoma.Cell 88,801–810 (1997).PubMedCrossRefGoogle Scholar
  20. 20.
    Cornelius, L. A.et al.Matrix metalloproteinases generate angiostatin: effects on neovascularization.J. Immunol. 161,6845–6852 (1998).PubMedGoogle Scholar
  21. 21.
    Ferreras, M., Felbor, U., Lenhard, T., Olsen, B. R. and Delaisse, J. Generation and degradation of human endostatin proteins by various proteinases.FEBS Lett. 486,247–251 (2000).PubMedCrossRefGoogle Scholar
  22. 22.
    Kheradmand, F., Werner, E., Tremble, P., Symons, M. and Werb, Z. Role of Racl and oxygen radicals in collagenase-1 expression induced by cell shape change.Science 280,898–902 (1998).PubMedCrossRefGoogle Scholar
  23. 23.
    Overall, C. M., Wrana, J. L. and Sodek, J. Independent regulation of collagenase, 72–10a progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-ß.J. Biol. Chem. 264,1860–1869 (1989).PubMedGoogle Scholar
  24. 24.
    Guérin, E., Ludwig, M. G., Basset, P. and Anglard, P. Stromelysin-3 induction and interstitial collagenase repression by retinoic acid: therapeutical implication of receptor-selective retinoids dissociating transactivation and AP-1-mediated transrepression.J. Biol. Chem. 272,11088–11095 (1997).PubMedCrossRefGoogle Scholar
  25. 25.
    Urfa, J. A., Jiménez, M. G., Balbín, M., Freije, J. M. P. and López-Otín, C. Differential effects of transforming growth factor-(3 on the expression of collagenase-1 and collagenase-3 in human fibroblasts.J. Biol. Chem. 273,9769–9777 (1998).CrossRefGoogle Scholar
  26. 26.
    Jiménez, M. J.et al.A regulatory cascade involving retinoic acid, Cbfal, and matrix metalloproteinases is coupled to the development of a process of perichondrial invasion and osteogenic differentiation during bone formation.J Cell Biol. 155,1333–1344 (2001).PubMedCrossRefGoogle Scholar
  27. 27.
    Simon, C., Goepfert, H. and Boyd, D. Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion.Cancer Res.58, 1135–1139 (1998).PubMedGoogle Scholar
  28. 28.
    Johansson, N.et al.Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase.J. Cell Sci.113, 227–235 (2000).PubMedGoogle Scholar
  29. 29.
    Pendás, A. M., Balbin, M., Llano, E., Jimenez, M. G. and López-Otín, C. Structural analysis and promoter characterization of the human collagenase-3 gene (MMP13).Genomics40, 222–233 (1997).PubMedCrossRefGoogle Scholar
  30. 30.
    Gutman, A. and Wasylyk, B. The collagenase gene promoter contains a TPA and oncogeneresponsive unit encompassing the PEA3 and AP-1 binding sites.EMBO J.9, 2241–2246 (1990).PubMedGoogle Scholar
  31. 31.
    Bond, M., Fabunmi, R. P., Baker, A. H. and Newby, A. C. Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF-kappa B.FEBS Lett.435, 29–34 (1998).PubMedCrossRefGoogle Scholar
  32. 32.
    Rutter, J. L.et al.A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription.Cancer Res.58, 5321–5325 (1998).PubMedGoogle Scholar
  33. 33.
    Biondi, M. L.et al.MMP1 and MMP3 polymorphisms in promoter regions and cancer.Clin. Chem.46, 2023–2024 (2000).PubMedGoogle Scholar
  34. 34.
    Springman, E. B., Angleton, E. L., Birkedal-Hansen, H. and Van Wart, H.E. Multiple modes of activation of latent human fibroblast collagenase: evidence for the role of a Cys73 active-site zinc complex in latency and a “cysteine switch” mechanism for activation.Proc. Natl Acad. Sci. USA87, 364–368 (1990).PubMedCrossRefGoogle Scholar
  35. 35.
    Bannikov, G. A., Karelina, T. V., Collier, I. E., Marmer, B. L. and Goldberg, G. I. Substrate binding of gelatinase B induces its enzymatic activity in the presence of intact propeptide. J.Biol. Chem.277, 1 6022–16027 (2002).Google Scholar
  36. 36.
    Knauper, V.et al.Cellular mechanisms for human collagenase-3 (MMP-13) activation: evidence that MT1-MMP (MMP-14) and gelatinase A (MMP-2) are able to generate active enzyme.J Biol. Chem.271, 17124–17131 (1996).PubMedCrossRefGoogle Scholar
  37. 37.
    Sato, H.et al.A matrix metalloproteinase expressed on the surface of invasive tumour cells.Nature370, 61–65 (1994).PubMedCrossRefGoogle Scholar
  38. 38.
    Strongin, A. Y.et al.Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. JBiol. Chem.270, 5331–5338 (1995).PubMedCrossRefGoogle Scholar
  39. 39.
    Overall, C. M.et al.Identification of the tissue inhibitor of metalloproteinases-2 (TIMP-2) binding site on the hemopexin carboxyl domain of human gelatinase A by site-directed mutagenesis. The hierarchical role in binding TIMP-2 of the unique cationic clusters of hemopexin modules III and IV.J. Biol. Chem.274, 4421–4429 (1999).PubMedCrossRefGoogle Scholar
  40. 40.
    Pei, D. and Weiss, S. J. Furin-dependent intracellular activation of the human stromelysin-3 zymogen.Nature375, 244–247 (1995).PubMedCrossRefGoogle Scholar
  41. 41.
    Yana, I. and Weiss, S. J. Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases.Mol. Biol. Ce!!11, 2387–2401 (2000).Google Scholar
  42. 42.
    Lohi, J., Wilson, C. L., Roby, J. D. and Parks, W. C. Epilysin, a novel human matrix metalloproteinase (MMP-28) expressed in testis and keratinocytes and in response to injury.J Biol. Chem.276, 10134–10144 (2001).PubMedCrossRefGoogle Scholar
  43. 43.
    Velasco, G.et al.Human MT6-matrix metalloproteinase: identification, progelatinase A activation, and expression in brain tumors.Cancer Res.60, 877–882 (2000).PubMedGoogle Scholar
  44. 44.
    Nagase, H., Itoh, Y. and Binner, S. Interaction of alpha 2-macroglobulin with matrix metalloproteinases and its use for identification of their active forms.Ann. N. Y. Acad. Sci.732, 294302 (1994).Google Scholar
  45. 45.
    Brew, K.. Dinakarpandian, D. and Nagase, H. Tissue inhibitors of metalloproteinases: evolution, structure and function.Biochim Biophys Acta1477, 267–283 (2000).PubMedCrossRefGoogle Scholar
  46. 46.
    Amour, A.et al.The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3.FEES Lett.473, 275–279 (2000).CrossRefGoogle Scholar
  47. 47.
    Kashiwagi, M., Tortorella, M., Nagase, H. and Brew, K. TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). JBiot. Chem.276, 12501–12504 (2001).CrossRefGoogle Scholar
  48. 48.
    Khokha, R.et al.Antisense RNA-induced reduction in murine TIMP levels confers oncogenicity on Swiss 3T3 cells.Science243, 947–950 (1989).PubMedCrossRefGoogle Scholar
  49. 49.
    Corcoran, M. L. and Stetler-Stevenson, W. G. Tissue inhibitor of metalloproteinase-2 stimulates fibroblast proliferation via a cAMP-dependent mechanism.J. Biol. Chem.270, 13453–13459 (1995).PubMedCrossRefGoogle Scholar
  50. 50.
    Jiang, Y., Goldberg, I. D. and Shi, Y. E. Complex roles of tissue inhibitors of metalloproteinases in cancer.Oncogene21, 2245–2252 (2002).PubMedCrossRefGoogle Scholar
  51. 51.
    Oh, J.et al.The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis.Cell107, 789–800 (2001).PubMedCrossRefGoogle Scholar
  52. 52.
    Herman, M. P.et al.Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis.J Clin. Invest.107, 1117–1126 (2001).PubMedCrossRefGoogle Scholar
  53. 53.
    Mott, J. D.et al.Post-translational proteolytic processing of procollagen C-terminal proteinase enhancer releases a metalloproteinase inhibitor.J. Biol. Chem.275, 1384–1390 (2000).PubMedCrossRefGoogle Scholar
  54. 54.
    Petitclerc, E.et al.New functions for non-collagenous domains of human collagen type IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo.J. Biot. Chem.275, 8051–8061 (2000).CrossRefGoogle Scholar
  55. 55.
    Stetefeld, J.et al.The laminin-binding domain of agrin is structurally related to N-TIMP-1.Nat. Struct. Biol. 8, 705–709 (2001)PubMedCrossRefGoogle Scholar
  56. 56.
    Westermarck, J. and Kähäri, V. M. Regulation of matrix metalloproteinase expression in tumor invasion.FASEBJ.13, 781–792 (1999).Google Scholar
  57. 57.
    Hua, J. and Muschel, R. J. Inhibition of matrix metalloproteinase 9 expression by a ribozyme blocks metastasis in a rat sarcoma model system.Cancer Res.56, 5279–5284 (1996).PubMedGoogle Scholar
  58. 58.
    Kondraganti, S.et al.Selective suppression of matrix metalloproteinase-9 in human glioblastoma cells by antisense gene transfer impairs glioblastoma cell invasion.Cancer Res.60, 6851–6855 (2000).PubMedGoogle Scholar
  59. 59.
    Nagavarapu, U., Relloma, K. and Herron, G. S. Membrane type 1 matrix metalloproteinase regulates cellular invasiveness and survival in cutaneous epidermal cells.J. Invest. Dermatol.118, 573–581 (2002).PubMedCrossRefGoogle Scholar
  60. 60.
    Slaton, J. W.et al.Treatment with low-dose interferon-alpha restores the balance between matrix metalloproteinase-9 and E-cadherin expression in human transitional cell carcinoma of the bladder.Clin. Cancer Res.7, 2840–2853 (2001).PubMedGoogle Scholar
  61. 61.
    Ala-aho, R.et al.Inhibition of collagenase-3 (MMP-13) expression in transformed human keratinocytes by interferon-gamma is associated with activation of extracellular signal-regulated kinase-1,2 and STAT1.Oncogene.19, 248–257 (2000).PubMedCrossRefGoogle Scholar
  62. 62.
    Ma, Z., Qin, H. and Benveniste, E. N. Transcriptional suppression of matrix metalloproteinase-9 gene expression by IFN-y and IFN-(3: critical role of STAT-lce.J. Immunol.167, 5150–5159 (2001).PubMedGoogle Scholar
  63. 63.
    Mengshol, J. A., Mix, K. S. and Brinckerhoff, C. E. Matrix metalloproteinases as therapeutic targets in arthritic diseases: bull’s-eye or missing the mark?Arthritis Rheum.46, 13–20 (2002).PubMedCrossRefGoogle Scholar
  64. 64.
    Futamura, M.et al.Malolactomycin D, a potent inhibitor of transcription controlled by the Ras responsive element, inhibit Ras-mediated transformation activity with suppression of MMP-1 and MMP-9 in NIH3T3 cells.Oncogene20, 6724–6730 (2001).PubMedCrossRefGoogle Scholar
  65. 65.
    Zhang, Y.et al.Hyaluronan-CD44s signaling regulates matrix metalloproteinase-2 secretion in a human lung carcinoma cell line QG90.Cancer Res.62, 3962–3965 (2002).PubMedGoogle Scholar
  66. 66.
    McGaha, T. L., Phelps, R. G., Spiera, H. and Bona, C. Halofuginone, an inhibitor of type-I collagen synthesis and skin sclerosis, blocks transforming-growth-factor-beta-mediated Smad3 activation in fibroblasts.J. Invest. Dermatol.118, 461–470 (2002).PubMedCrossRefGoogle Scholar
  67. 67.
    Elkin M, Reich R, Nagler A, Aingorn E, Pines M, de-Groot N, Hochberg A, Vlodaysky I. Inhibition of matrix metalloproteinase-2 expression and bladder carcinoma metastasis by halofuginone.Clin. Cancer Res.5, 1982–1988 (1999).PubMedGoogle Scholar
  68. 68.
    Karin, M. and Chang, L. AP-1-glucocorticoid receptor crosstalk taken to a higher level.J. Endocrinol. 169447–451 (2001).PubMedCrossRefGoogle Scholar
  69. 69.
    Sato, T.et al.Inhibition of activator protein-1 binding activity and phosphatidylinositol 3-kinase pathway by nobiletin, a polymethoxy flavonoid, results in augmentation of tissue inhibitor of metalloproteinases-1 production and suppression of production of matrix metalloproteinases-1 and —9 in human fibrosarcoma HT-1080 cells.Cancer Res.62, 1025–1029 (2002).PubMedGoogle Scholar
  70. 70.
    Mohan, R.et al.Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B.J. Biol. Chem.275, 1040510412 (2000).Google Scholar
  71. 71.
    Adams, J.et al.Proteasome inhibitors: a novel class of potent and effective antitumor agents.Cancer Res.59, 2615–2622 (1999).PubMedGoogle Scholar
  72. 72.
    Tan, C. and Waldmann, T. A. Proteasome inhibitor PS-341, a potential therapeutic agent for adult T-cell leukemia.Cancer Res.62, 1083–1086 (2002).PubMedGoogle Scholar
  73. 73.
    Barille, S.et al.Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of proMMP-2, and induction of MMP-1 by myeloma cells.Blood90, 16491655 (1997).Google Scholar
  74. 74.
    Jimenez, M. J.et al.Collagenase 3 is a target of Cbfal, a transcription factor of the runt gene family involved in bone formation.Mol. Cell Biol.19, 4431–4442 (1999).PubMedGoogle Scholar
  75. 75.
    Yang J. et al. Prostate cancer cells induce osteoblast differentiation through a Cbfal-dependent pathway. Cancer Res.61, 5652–5659 (2001).PubMedGoogle Scholar
  76. 76.
    Sun Y. et al. Wild type and mutant p53 differentially regulate the gene expression of human collagenase-3 (hMMP-13). J. Biol. Chem.275, 11327–11332 (2000).PubMedCrossRefGoogle Scholar
  77. 77.
    Koul, D.et al.Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN.Oncogene20, 6669–6678 (2001).PubMedCrossRefGoogle Scholar
  78. 78.
    Fenrick, R.et al.TEL, a putative tumor suppressor, modulates cell growth and cell morphology of ras-transformed cells while repressing the transcription of stromelysin-1.Mol. Cell Biol.20, 58285839 (2000).Google Scholar
  79. 79.
    Galvez, B. G., Matias-Roman, S., Albar, J. P., Sanchez-Madrid, F. and Arroyo, A. G. Membrane type 1-matrix metalloproteinase is activated during migration of human endothelial cells and modulates endothelial motility and matrix remodeling.J. Biol. Chem.276, 37491–37500 (2001).PubMedCrossRefGoogle Scholar
  80. 80.
    Annabi, B.et al.Green tea polyphenol (-)-epigallocatechin 3-gallate inhibits MMP-2 secretion and MTI-MMP-driven migration in glioblastoma cells.Biochim. Biophys. Acta.1542, 209–220 (2002).PubMedCrossRefGoogle Scholar
  81. 81.
    Bassi, D. E.et al.Furin inhibition results in absent or decreased invasiveness and tumorigenicity of human cancer cells.Proc. Natl. Acad. Sci. USA98, 10326–10331 (2001).PubMedCrossRefGoogle Scholar
  82. 82.
    Rodriguez-Manzaneque, J. C.et al.Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor.Proc. Natl Acad. Sci. USA98, 12485–12490 (2001).PubMedCrossRefGoogle Scholar
  83. 83.
    Yang, Z., Strickland, D. K. and Bornstein, P. Extracellular matrix metalloproteinase 2 levels are regulated by the low density lipoprotein-related scavenger receptor and thrombospondin 2.1 Biol.Chem.276, 8403–8408 (2001).CrossRefGoogle Scholar
  84. 84.
    Kim, Y. M.et al.Endostatin inhibits endothelial and tumor cellular invasion by blocking the activation and catalytic activity of matrix metalloproteinase.Cancer Res.60, 5410–5413 (2000).PubMedGoogle Scholar
  85. 85.
    Nakada, M.et al.Suppression of membrane-type 1 matrix metalloproteinase (MMP)-mediated MMP-2 activation and tumor invasion by testican 3 and its splicing variant gene product, N-tes.Cancer Res.61, 8896–8902 (2001).PubMedGoogle Scholar
  86. 86.
    Sgadari, C.et al.HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma.Nature Med.8, 225–232 (2002).PubMedCrossRefGoogle Scholar
  87. 87.
    Kruger, A., Fata, J. E. and Khokha, R. Altered tumor growth and metastasis of a T-cell lymphoma in Timp-1 transgenic mice.Blood90, 1993–2000 (1997).PubMedGoogle Scholar
  88. 88.
    Martin, D. C.et al.Transgenic TIMP-1 inhibits simian virus 40 T antigen-induced hepatocarcinogenesis by impairment of hepatocellular proliferation and tumor angiogenesis.Lab. Invest.79, 225–234 (1999).PubMedGoogle Scholar
  89. 89.
    Brown, P. D. Clinical studies with matrix metalloproteinase inhibitors.APMIS107, 174–180 (1999).PubMedCrossRefGoogle Scholar
  90. 90.
    Duivenvoorden, W. C.et al.Doxycycline decreases tumor burden in a bone metastasis model of human breast cancer.Cancer Res.62, 1588–1591 (2002).PubMedGoogle Scholar
  91. 91.
    Cianfrocca, M.et al.Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi’s sarcoma: a phase I AIDS malignancy consortium study.J Clin. Oncol.20, 153–159 (2002).PubMedCrossRefGoogle Scholar
  92. 92.
    Boissier, S.et al.Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases.Cancer Res.60, 2949–2954 (2000).PubMedGoogle Scholar
  93. 93.
    Coussens, L. M., Fingleton, B. and Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations.Science295, 2387–2392 (2002).PubMedCrossRefGoogle Scholar
  94. 94.
    Bramhall, S.R.et al.Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial.Br. J. Cancer.86, 1864–1870 (2002).PubMedCrossRefGoogle Scholar
  95. 95.
    Bramhall, S. R., Rosemurgy, A., Brown, P. D., Bowry, C. and Buckels, J. A. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial.J. Clin. Oncol.19, 3447–3455 (2001).PubMedGoogle Scholar
  96. 96.
    Groves, M. D.et al.Phase II trial of temozolomide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and progressive glioblastoma multiforme.J Clin. Oncol20, 1383–1388 (2002).PubMedCrossRefGoogle Scholar
  97. 97.
    Zucker, S., Cao, J. and Chen, W. T. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment.Oncogene19, 6642–6650 (2000).PubMedCrossRefGoogle Scholar
  98. 98.
    Bergers, G., Javaherian, K., Lo, K. M., Folkman, J. and Hanahan, D. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice.Science284, 808–812 (1999).PubMedCrossRefGoogle Scholar
  99. 99.
    Fingleton, B. M., Heppner Goss, K. J., Crawford, H. C. and Matrisian, L. M. Matrilysin in early stage intestinal tumorigenesis.APMIS107, 102–110 (1999).PubMedCrossRefGoogle Scholar
  100. 100.
    Pozzi, A.et al.Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization.Proc. Natl Acad Sci. USA97, 2202–2207 (2000).PubMedCrossRefGoogle Scholar
  101. 101.
    Pozzi, A., LeVine, W. F. and Gardner, H. A. Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis.Oncogene 22,272–281 (2002).CrossRefGoogle Scholar
  102. 102.
    Vazquez, F.et al.METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity.J. Biol. Chem. 274,23349–23357 (1999).PubMedCrossRefGoogle Scholar
  103. 103.
    Cal, S.et al.Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains.Gene 283,49–62 (2002)PubMedCrossRefGoogle Scholar
  104. 104.
    Gomis-Ruth, F. X.et al.Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1.Nature 389,77–81 (1997).PubMedCrossRefGoogle Scholar
  105. 105.
    Bode, W.et al.Structural properties of matrix metalloproteinases.Cell Mol. Life Sci. 55,639–652 (1999).PubMedCrossRefGoogle Scholar
  106. 106.
    Morgunova, E., Tuuttila, A., Bergmann, U. and Tryggvason, K. Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2.Proc. Natl. Acad. Sci. USA. 99,7414–7419 (2002).PubMedCrossRefGoogle Scholar
  107. 107.
    Koivunen, E.et al.Tumor targeting with a selective gelatinase inhibitor.Nat. Biotechnol. 17,768–774 (1999).PubMedCrossRefGoogle Scholar
  108. 108.
    Bernardo, M. M., Brown, S., Li, Z. H., Fridman, R. and Mobashery, S. Design, synthesis, and characterization of potent, slow-binding inhibitors that are selective for gelatinases.J. Biol. Chem.277, 11201–11207 (2002).PubMedCrossRefGoogle Scholar
  109. 109.
    Garbisa, S.et al.Tumor gelatinases and invasion inhibited by the green tea flavanol epigallocatechin3-gallate.Cancer 91,822–832 (2001).PubMedCrossRefGoogle Scholar
  110. 110.
    Falardeau, P., Champagne, P., Poyet, P., Hariton, C. and Dupont, E. Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials.Semin. Oncol. 28,620–625 (2001).PubMedCrossRefGoogle Scholar
  111. 111.
    Nielsen, B. S.et al.Collagenase-3 expression in breast myofibroblasts as a molecular marker of transition of ductal carcinoma in situ lesions to invasive ductal carcinomas.Cancer Res.61, 70917100 (2001).Google Scholar
  112. 112.
    Bissell, M. J. and Radisky, D. Putting tumours in context.Nature Rev.Cancer1, 46–54 (2001).CrossRefGoogle Scholar
  113. 113.
    Silletti, S., Kessler, T., Goldberg, J., Boger, D. L. and Cheresh, D. A. Disruption of matrix metalloproteinase 2 binding to integrin ctv133 by an organic molecule inhibits angiogenesis and tumor growth in vivo.Proc. Natl Acad. Sci. USA98, 119–124 (2001).PubMedGoogle Scholar
  114. 114.
    Overall, C. M. Matrix metalloproteinase substrate binding domains, modules, and exosites: overview and experimental strategies.Methods Mol. Biol.151, 73–114 (2001).Google Scholar
  115. 115.
    Liu, S., Netzel-Arnett, S., Birkedal-Hansen, H. and Leppla, S. H. Tumor cell-selective cytotoxicity of matrix metalloproteinase-activated anthrax toxin.Cancer Res.60, 6061–6067 (2000).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • José M. P. Freije
    • 1
  • Milagros Balbín
    • 1
  • Alberto M. Pendás
    • 1
  • Luis M. Sánchez
    • 1
  • Xose S. Puente
    • 1
  • Carlos López-Otín
    • 2
  1. 1.Departamento de Bioquímica, Instituto Universitario de OncologíaUniversidad de OviedoSpain
  2. 2.Departamento de Bioquímica y Biología Molecular Facultad de Medicina/Edificio S. GascónUniversidad de OviedoSpain

Personalised recommendations