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Matrix Metalloproteinases in Tumor Progression

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Cell Motility in Cancer Invasion and Metastasis

Part of the book series: Cancer Metastasis - Biology and Treatment ((CMBT,volume 8))

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Abstract

The matrix metalloproteinases (MMPs) are well established as mediators of tumor invasion and metastasis. The classic view that these enzymes simply provide a mechanism for the breakdown of connective tissue barriers led to development of synthetic MMP inhibitors for cancer therapy. The lack of understanding of the complex roles of MMPs in cancer accounts for the failure of this strategy to significantly impact cancer therapy. It is now recognized that members of the MMP family function at all stages of cancer development to both promote and inhibit tumor progression. This overview summarizes recent evidence to support the emerging roles for MMP in all aspects of cancer progression, including tumor cell growth, programmed cell death, and tumor angiogenesis in addition to their classic role in cell invasion and metastasis. The MMP-dependent stimulation of tumor cell growth, stimulation of cell migration, and generation of cryptic sites and signals from within the extracellular matrix (ECM) are reviewed.

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References

  1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000, 100: 57–70.

    Article  PubMed  CAS  Google Scholar 

  2. Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 2002, 295: 2387–92.

    Article  PubMed  CAS  Google Scholar 

  3. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer 2002, 2: 161–74.

    Article  PubMed  CAS  Google Scholar 

  4. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 2003, 92: 827–39.

    Article  PubMed  CAS  Google Scholar 

  5. Overall CM, Lopez-Otin C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nature Reviews. Cancer 2002, 2: 657–72.

    PubMed  CAS  Google Scholar 

  6. Bode, W. Structural basis of matrix metalloproteinase function. Biochemical Society Symposia 2003, 1–14.

    Google Scholar 

  7. Crocker SJ, Pagenstecher A, Campbell LL. The TIMPs tango with MMPs and more in the central nervous system. J. Neurosci. Res. 2004, 75: 1–11.

    Article  PubMed  CAS  Google Scholar 

  8. Brew K, Dinakarpandian D, Nagase H. Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim. Biophys. Acta. 2000, 1477: 267–83.

    PubMed  CAS  Google Scholar 

  9. Lambert E, et al. TIMPs as multifacial proteins. Critical Reviews in Oncology Hematology 2004, 49: 187–198.

    Article  Google Scholar 

  10. Takahashi C, et al. Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. Proc. Natl. Acad. Sci. USA 1998, 95: 13221–6.

    Article  PubMed  CAS  Google Scholar 

  11. Oh J, et al. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell 2001, 107: 789–800.

    Article  PubMed  CAS  Google Scholar 

  12. Hoegy SE, et al. Tissue inhibitor of metalloproteinases-2 (TIMP-2) suppresses TKRgrowth factor signaling independent of metalloproteinase inhibition. J. Biol. Chem. 2001, 276: 3203–14.

    Article  PubMed  CAS  Google Scholar 

  13. Seo DW, et al. TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 2003, 114: 171–80.

    Article  PubMed  CAS  Google Scholar 

  14. Fedarko NS, et al. Three small integrin binding ligand N-linked glycoproteins (SIBLINGs) bind and activate specific matrix metalloproteinases. FASEB Journal 2004, 18: 734–6.

    PubMed  CAS  Google Scholar 

  15. Liotta LA, et al. Preferential digestion of basement membrane collagen by an enzyme derived from a metastatic murine tumor. Proc. Natl. Acad. Sci. USA 1979, 76: 2268–72.

    Article  PubMed  CAS  Google Scholar 

  16. Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 1991, 64: 327–36.

    Article  PubMed  CAS  Google Scholar 

  17. Polette M, et al. Tumour invasion and matrix metalloproteinases. Critical Reviews in Oncology-Hematology 2004, 49: 179–86.

    Article  Google Scholar 

  18. Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annual Review of Cell & Developmental Biology 2001, 17: 463–516.

    Article  CAS  Google Scholar 

  19. Toole BP, Emmprin (CD147), a cell surface regulator of matrix metalloproteinase production and function. Current Topics in Developmental Biology 2003, 54: 371–89.

    PubMed  CAS  Google Scholar 

  20. Monteagudo C, et al. Immunohistochemical distribution of type IV collagenase in normal, benign, and malignant breast tissue. Am. J. Pathol. 1990, 136: 585–92.

    PubMed  CAS  Google Scholar 

  21. Gururajan R, et al. Duplication of a genomic region containing the Cdc2L1-2 and MMP21-22 genes on human chromosome 1p36.3 and their linkage to D1Z2. Genome Research 1998, 8: 929–39.

    PubMed  CAS  Google Scholar 

  22. Gururajan R, et al. Isolation and characterization of two novel metalloproteinase genes linked to the Cdc2L locus on human chromosome 1p36.3. Genomics 1998, 52: 101–6.

    Article  PubMed  CAS  Google Scholar 

  23. Llano E, et al. Identification and characterization of human MT5-MMP, a new membrane-bound activator of progelatinase a overexpressed in brain tumors. Cancer Res. 1999, 59: 2570–6.

    PubMed  CAS  Google Scholar 

  24. Rutter JL, et al. A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates an Ets binding site and augments transcription. Cancer Res. 1998, 58: 5321–5.

    PubMed  CAS  Google Scholar 

  25. Tower GB, et al. Erk 1/2 differentially regulates the expression from the 1G/2G single nucleotide polymorphism in the MMP-1 promoter in melanoma cells. Biochimica et Biophysica Acta 2002, 1586: 265–74.

    PubMed  CAS  Google Scholar 

  26. Tower GB, Coon CI, Brinckerhoff CE. The 2G single nucleotide polymorphism (SNP) in the MMP-1 promoter contributes to high levels of MMP-1 transcription in MCF-7/ADR breast cancer cells. Breast Cancer Res. Treat. 2003, 82: 75–82.

    Article  PubMed  CAS  Google Scholar 

  27. Tower GB, et al. Fra-1 targets the AP-1 site/2G single nucleotide polymorphism (ETS site) in the MMP-1 promoter. Eur. J. Biochem. 2003, 270: 4216–25.

    Article  PubMed  CAS  Google Scholar 

  28. Martignetti JA, et al. Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome. Nat. Genet. 2001, 28: 261–5.

    Article  PubMed  CAS  Google Scholar 

  29. Zhou Y, et al. Substantial reduction in risk of breast cancer associated with genetic polymorphisms in the promoters of the matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 genes. Carcinogenesis 2004, 25: 399–404.

    Article  PubMed  CAS  Google Scholar 

  30. Sternlicht MD, et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 1999, 98: 137–46.

    Article  PubMed  CAS  Google Scholar 

  31. Sternlicht MD, Bissell MJ, Werb Z. The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter. Oncogene 2000, 19: 1102–13.

    Article  PubMed  CAS  Google Scholar 

  32. Wilson CL, et al. Intertinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. Proc. Natl. Acad. Sci. USA 1997, 94: 1402–1407.

    Article  PubMed  CAS  Google Scholar 

  33. Crawford HC, et al. The metalloproteinase matrilysin is a target of β-catenin transactivation in intestinal tumors. Oncogene 1999, 18: 2883–2891.

    Article  PubMed  CAS  Google Scholar 

  34. George SJ, Dwivedi A. MMPs, Cadherins, and Cell Proliferation. Trends in Cardiovascular Medicine 2004, 14: 100–105.

    Article  PubMed  CAS  Google Scholar 

  35. Noe V, et al. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J. Cell Science 2001, 114: 111–118.

    PubMed  CAS  Google Scholar 

  36. Bergers G, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biology 2000, 2: 737–744.

    Article  PubMed  CAS  Google Scholar 

  37. Whitelock JM, et al. 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. 1996, 271: 10079–10086.

    Article  PubMed  CAS  Google Scholar 

  38. Manes S, et al. The matrix metalloproteinase-9 regulates the insulin-like growth factor-triggered autocrine response in DU-145 carcinoma cells. J. Biol. Chem. 1999, 274: 6935–45.

    Article  PubMed  CAS  Google Scholar 

  39. Manes S, et al. Identification of insulin-like growth factor-binding protein-1 as a potential physiological substrate for human stromelysin-3. J. Biol. Chem. 1997, 272: 25706–12.

    Article  PubMed  CAS  Google Scholar 

  40. Mu D, et al. The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J. Cell Biol. 2002, 157: 493–507.

    Article  PubMed  CAS  Google Scholar 

  41. Yu Q, Stamenkovic I. Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes. Dev. 1999, 13: 35–48.

    PubMed  CAS  Google Scholar 

  42. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes & Development 2000, 14: 163–76.

    Google Scholar 

  43. Dallas SL, et al. Proteolysis of latent transforming growth factor-beta (TGF-beta)-binding protein-1 by osteoclasts. A cellular mechanism for release of TGF-beta from bone matrix. J. Biol. Chem. 2002, 277: 21352–60.

    Article  PubMed  CAS  Google Scholar 

  44. Lauffenburger DA, Horowitz AF. Cell Migration: A Physically Integrated Molecular Process. Cell 1996, 84: 359–369.

    Article  PubMed  CAS  Google Scholar 

  45. Gumbiner BM. Cell Adhesion: The Molecular Basis of Tissue Architecture and Morphogenesis. Cell 1996, 84: 345–357.

    Article  PubMed  CAS  Google Scholar 

  46. Mitchison TJ, Cramer LP. Actin-Base Cell Motility and Cell Locomotion. Cell 1996, 84: 371–379.

    Article  PubMed  CAS  Google Scholar 

  47. Tapon N, Hall A. Rho, Rac and Cdc42 GTPases regulate the organization of the actin cytoskeleton. Curr. Opin. Cell Biol. 1997, 9: 86–92.

    Article  PubMed  CAS  Google Scholar 

  48. Felsenfeld DP, et al. Selective regulation of integrin—cytoskeleton interactions by the tyrosine kinase Src. Nat. Cell Biol. 1999, 1: 200–6.

    Article  PubMed  CAS  Google Scholar 

  49. Choquet D, Felsenfeld DP, Sheetz MP. Extracellular matrix rigidity causes strengthening of integrin-cytoskeleton linkages. Cell 1997, 88: 39–48.

    Article  PubMed  CAS  Google Scholar 

  50. Sheetz MP, Felsenfeld DP, Galbraith CG. Cell migration: regulation of force on extracellular-matrix-integrin complexes. Trends Cell Biol. 1998, 8: 51–4.

    Article  PubMed  CAS  Google Scholar 

  51. Brooks PC, et al. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 1996, 85: 683–693.

    Article  PubMed  CAS  Google Scholar 

  52. Brooks PC, et al. Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell 1998, 92: 391–400.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  54. Wolf K, et al. Compensation mechanism in tumor cell migration: mesenchymalamoeboid transition after blocking of pericellular proteolysis. J. Cell Biol. 2003, 160: 267–77.

    Article  PubMed  CAS  Google Scholar 

  55. Friedl P, Wolf K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nature Reviews. Cancer 2003, 3: 362–74.

    Article  PubMed  CAS  Google Scholar 

  56. Hiraoka N, et al. Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell 1998, 95: 365–377.

    Article  PubMed  CAS  Google Scholar 

  57. Hotary KB, et al. Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and-independent processes. Journal of Experimental Medicine 2002, 195: 295–308.

    Article  PubMed  CAS  Google Scholar 

  58. Hotary KB, et al. Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell 2003, 114: 33–45.

    Article  PubMed  CAS  Google Scholar 

  59. Sabeh F, et al. Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP. J. Cell Biol. 2004, 167: 769–781.

    Article  PubMed  CAS  Google Scholar 

  60. Giannelli G, et al. Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 1997, 277: 225–8.

    Article  PubMed  CAS  Google Scholar 

  61. Hangai M, et al. Matrix metalloproteinase-9-dependent exposure of a cryptic migratory control site in collagen is required before retinal angiogenesis. Am. J. Pathol. 2002, 161: 1429–37.

    PubMed  CAS  Google Scholar 

  62. Xu J, et al. Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo. J. Cell Biol. 2001, 154: 1069–79.

    Article  PubMed  CAS  Google Scholar 

  63. O’Reilly MS, et al. Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance. J. Biol. Chem. 1999, 274: 29568–71.

    Article  PubMed  CAS  Google Scholar 

  64. Dong ZY, et al. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 1997, 88: 801–810.

    Article  PubMed  CAS  Google Scholar 

  65. Cornelius LA, et al. Matrix metalloproteinases generate angiostatin: Effects on neovascularization. Journal of Immunology 1998, 161: 6845–6852.

    CAS  Google Scholar 

  66. Hamano Y, et al. Physiological levels of tumstatin, a fragment of collagen IV alpha 3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alpha V beta 3 integrin. Cancer Cell 2003, 3: 589–601.

    Article  PubMed  CAS  Google Scholar 

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Stetler-Stevenson, W.G., Seo, DW. (2006). Matrix Metalloproteinases in Tumor Progression. In: Wells, A. (eds) Cell Motility in Cancer Invasion and Metastasis. Cancer Metastasis - Biology and Treatment, vol 8. Springer, Dordrecht. https://doi.org/10.1007/1-4020-4009-1_7

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