Cancer and Metastasis Reviews

, Volume 25, Issue 1, pp 77–86 | Cite as

MT1-MMP: Universal or particular player in angiogenesis?

  • Laura Genís
  • Beatriz G. Gálvez
  • Pilar Gonzalo
  • Alicia G. Arroyo


Tumorigenesis involves not only tumor cells that become transformed but also the peritumoral stroma which reacts inducing inflammatory and angiogenic responses. Angiogenesis, the formation of new capillaries from preexisting vessels, is an absolute requirement for tumor growth and metastasis, and it can be induced and modulated by a wide variety of soluble factors. During angiogenesis, quiescent endothelial cells are activated and they initiate migration by degrading the basement membranes through the action of specific proteases, in particular of matrix metalloproteinases (MMPs). Among these, the membrane type 1-matrix metalloproteinase (MT1-MMP) has been identified as a key player during the angiogenic response. In this review, we will summarize the role of MT1-MMP in angiogenesis and the regulatory mechanisms of this protease in endothelial cells. Since our recent findings have suggested that MT1-MMP is not universally required for angiogenesis, we hypothesize that the regulation and participation of MT1-MMP in angiogenesis may depend on the nature of the angiogenic stimulus. Experiments aimed at testing this hypothesis have shown that similarly to the chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12, lipopolysaccharide (LPS) seems to induce the formation of capillary tubes by human or mouse endothelial cells (ECs) in an MT1-MMP-independent manner. The implications of these findings in the potential use of MT1-MMP inhibitors in cancer therapy are discussed.


Matrix metalloproteinases Angiogenesis Cancer Inflammation SDF-1/CXCL12 Lipopolysaccharide 


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  1. 1.
    Bergers G, Benjamin LE: Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3: 401–410, 2003PubMedCrossRefGoogle Scholar
  2. 2.
    Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A: Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380: 435–439, 1996PubMedCrossRefGoogle Scholar
  3. 3.
    Carmeliet P: VEGF as a key mediator of angiogenesis in cancer. Oncology 69(Suppl 3): 4–10, 2005PubMedCrossRefGoogle Scholar
  4. 4.
    Carmeliet P, Jain RK: Angiogenesis in cancer and other diseases. Nature 407: 249–257, 2000PubMedCrossRefGoogle Scholar
  5. 5.
    Carmeliet P: Angiogenesis in life, disease and medicine. Nature 438: 932–936, 2005PubMedCrossRefGoogle Scholar
  6. 6.
    Folgueras AR, Pendas AM, Sanchez LM, Lopez-Otin C: Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int J Dev Biol 48: 411–424, 2004PubMedCrossRefGoogle Scholar
  7. 7.
    Itoh T, Tanioka M, Yoshida H, Yoshioka T, Nishimoto H, Itohara S: Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res 58: 1048–1051, 1998PubMedGoogle Scholar
  8. 8.
    Lambert V, Wielockx B, Munaut C, Galopin C, Jost M, Itoh T, Werb Z, Baker A, Libert C, Krell HW, Foidart JM, Noel A, Rakic JM: MMP-2 and MMP-9 synergize in promoting choroidal neovascularization. Faseb J 17: 2290–2292, 2003PubMedGoogle Scholar
  9. 9.
    Vu TH, Shipley JM, Bergers G, Berger JE, Helms JA, Hanahan D, Shapiro SD, Senior RM, Werb Z: MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93: 411–422, 1998PubMedCrossRefGoogle Scholar
  10. 10.
    Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D: Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2: 737–744, 2000PubMedCrossRefGoogle Scholar
  11. 11.
    Plaisier M, Kapiteijn K, Koolwijk P, Fijten C, Hanemaaijer R, Grimbergen JM, Mulder-Stapel A, Quax PH, Helmerhorst FM, van Hinsbergh VW: Involvement of membrane-type matrix metalloproteinases (MT-MMPs) in capillary tube formation by human endometrial microvascular endothelial cells: Role of MT3-MMP. J Clin Endocrinol Metab 89: 5828–5836, 2004PubMedCrossRefGoogle Scholar
  12. 12.
    Hiraoka N, Allen E, Apel IJ, Gyetko MR, Weiss SJ: Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell 95: 365–377, 1998PubMedCrossRefGoogle Scholar
  13. 13.
    Holmbeck K, Bianco P, Caterina J, Yamada S, Kromer M, Kuznetsov SA, Mankani M, Robey PG, Poole AR, Pidoux I, Ward JM, Birkedal-Hansen H: MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99: 81–92, 1999PubMedCrossRefGoogle Scholar
  14. 14.
    Zhou Z, Apte SS, Soininen R, Cao R, Baaklini GY, Rauser RW, Wang J, Cao Y, Tryggvason K: Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc Natl Acad Sci USA 97: 4052–4057, 2000PubMedCrossRefGoogle Scholar
  15. 15.
    Galvez BG, Genis L, Matias-Roman S, Oblander SA, Tryggvason K, Apte SS, Arroyo AG: Membrane type 1-matrix metalloproteinase is regulated by chemokines monocyte-chemoattractant protein-1/ccl2 and interleukin-8/CXCL8 in endothelial cells during angiogenesis. J Biol Chem 280: 1292–1298, 2005PubMedCrossRefGoogle Scholar
  16. 16.
    Chun TH, Sabeh F, Ota I, Murphy H, McDonagh KT, Holmbeck K, Birkedal-Hansen H, Allen ED, Weiss SJ: MT1-MMP-dependent neovessel formation within the confines of the three-dimensional extracellular matrix. J Cell Biol 167: 757–767, 2004PubMedCrossRefGoogle Scholar
  17. 17.
    Oblander SA, Zhou Z, Galvez BG, Starcher B, Shannon JM, Durbeej M, Arroyo AG, Tryggvason K, Apte SS: Distinctive functions of membrane type 1 matrix-metalloprotease (MT1-MMP or MMP-14) in lung and submandibular gland development are independent of its role in pro-MMP-2 activation. Dev Biol 277: 255–269, 2005PubMedCrossRefGoogle Scholar
  18. 18.
    Lehti K, Allen E, Birkedal-Hansen H, Holmbeck K, Miyake Y, Chun TH, Weiss SJ: An MT1-MMP-PDGF receptor-beta axis regulates mural cell investment of the microvasculature. Genes Dev 19: 979–991, 2005PubMedCrossRefGoogle Scholar
  19. 19.
    Filippov S, Koenig GC, Chun TH, Hotary KB, Ota I, Bugge TH, Roberts JD, Fay WP, Birkedal-Hansen H, Holmbeck K, Sabeh F, Allen ED, Weiss SJ: MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells. J Exp Med 202: 663–671, 2005PubMedCrossRefGoogle Scholar
  20. 20.
    Galvez BG, Matias-Roman S, Albar JP, Sanchez-Madrid F, Arroyo AG: 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, 2001PubMedCrossRefGoogle Scholar
  21. 21.
    Galvez BG, Matias-Roman S, Yanez-Mo M, Sanchez-Madrid F, Arroyo AG: ECM regulates MT1-MMP localization with beta1 or alphavbeta3 integrins at distinct cell compartments modulating its internalization and activity on human endothelial cells. J Cell Biol 159: 509–521, 2002PubMedCrossRefGoogle Scholar
  22. 22.
    Langlois S, Gingras D, Beliveau R: Membrane type 1-matrix metalloproteinase (MT1-MMP) cooperates with sphingosine 1-phosphate to induce endothelial cell migration and morphogenic differentiation. Blood 103: 3020–3028, 2004PubMedCrossRefGoogle Scholar
  23. 23.
    Koshikawa N, Giannelli G, Cirulli V, Miyazaki K, Quaranta V: Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5. J Cell Biol 148: 615–624, 2000PubMedCrossRefGoogle Scholar
  24. 24.
    Robinet A, Fahem A, Cauchard JH, Huet E, Vincent L, Lorimier S, Antonicelli F, Soria C, Crepin M, Hornebeck W, Bellon G: Elastin-derived peptides enhance angiogenesis by promoting endothelial cell migration and tubulogenesis through upregulation of MT1-MMP. J Cell Sci 118: 343–356, 2005PubMedCrossRefGoogle Scholar
  25. 25.
    Betsholtz C: Biology of platelet-derived growth factors in development. Birth Defects Res C Embryo Today 69: 272–285, 2003PubMedCrossRefGoogle Scholar
  26. 26.
    Sounni NE, Roghi C, Chabottaux V, Janssen M, Munaut C, Maquoi E, Galvez BG, Gilles C, Frankenne F, Murphy G, Foidart JM, Noel A: Up-regulation of vascular endothelial growth factor-A by active membrane-type 1 matrix metalloproteinase through activation of Src-tyrosine kinases. J Biol Chem 279: 13564–13574, 2004PubMedCrossRefGoogle Scholar
  27. 27.
    Hotary KB, Allen ED, Brooks PC, Datta NS, Long MW, Weiss SJ: Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell 114: 33–45, 2003PubMedCrossRefGoogle Scholar
  28. 28.
    Golubkov VS, Boyd S, Savinov AY, Chekanov AV, Osterman AL, Remacle A, Rozanov DV, Doxsey SJ, Strongin AY: Membrane type-1 matrix metalloproteinase (MT1-MMP) exhibits an important intracellular cleavage function and causes chromosome instability. J Biol Chem 280: 25079–25086, 2005PubMedCrossRefGoogle Scholar
  29. 29.
    Golubkov VS, Chekanov AV, Doxsey SJ, Strongin AY: Centrosomal pericentrin is a direct cleavage target of membrane type-1 matrix metalloproteinase in humans but not in mice: Potential implications for tumorigenesis. J Biol Chem 280: 42237–42241, 2005PubMedCrossRefGoogle Scholar
  30. 30.
    Langlois S, Di Tomasso G, Boivin D, Roghi C, Murphy G, Gingras D, Beliveau R: Membrane type 1-matrix metalloproteinase induces endothelial cell morphogenic differentiation by a caspase-dependent mechanism. Exp Cell Res 307: 452–464, 2005PubMedCrossRefGoogle Scholar
  31. 31.
    Haas TL, Davis SJ, Madri JA: Three-dimensional type I collagen lattices induce coordinate expression of matrix metalloproteinases MT1-MMP and MMP-2 in microvascular endothelial cells. J Biol Chem 273: 3604–3610, 1998PubMedCrossRefGoogle Scholar
  32. 32.
    Alfonso-Jaume MA, Mahimkar R, Lovett DH: Co-operative interactions between NFAT (nuclear factor of activated T cells) c1 and the zinc finger transcription factors Sp1/Sp3 and Egr-1 regulate MT1-MMP (membrane type 1 matrix metalloproteinase) transcription by glomerular mesangial cells. Biochem J 380: 735–747, 2004PubMedCrossRefGoogle Scholar
  33. 33.
    Mori H, Tomari T, Koshikawa N, Kajita M, Itoh Y, Sato H, Tojo H, Yana I, Seiki M: CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain. Embo J 21: 3949–3959, 2002PubMedCrossRefGoogle Scholar
  34. 34.
    Galvez BG, Matias-Roman S, Yanez-Mo M, Vicente-Manzanares M, Sanchez-Madrid F, Arroyo AG: Caveolae are a novel pathway for membrane-type 1 matrix metalloproteinase traffic in human endothelial cells. Mol Biol Cell 15: 678–687, 2004PubMedCrossRefGoogle Scholar
  35. 35.
    Labrecque L, Nyalendo C, Langlois S, Durocher Y, Roghi C, Murphy G, Gingras D, Beliveau R: Src-mediated tyrosine phosphorylation of caveolin-1 induces its association with membrane type 1 matrix metalloproteinase. J Biol Chem 279: 52132–52140, 2004PubMedCrossRefGoogle Scholar
  36. 36.
    Jiang A, Lehti K, Wang X, Weiss SJ, Keski-Oja J, Pei D: Regulation of membrane-type matrix metalloproteinase 1 activity by dynamin-mediated endocytosis. Proc Natl Acad Sci USA 98: 13693–13698, 2001PubMedCrossRefGoogle Scholar
  37. 37.
    Uekita T, Itoh Y, Yana I, Ohno H, Seiki M: Cytoplasmic tail-dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity. J Cell Biol 155: 1345–1356, 2001PubMedCrossRefGoogle Scholar
  38. 38.
    Remacle A, Murphy G, Roghi C: Membrane type I-matrix metalloproteinase (MT1-MMP) is internalised by two different pathways and is recycled to the cell surface. J Cell Sci 116: 3905–3916, 2003PubMedCrossRefGoogle Scholar
  39. 39.
    Remacle AG, Rozanov DV, Baciu PC, Chekanov AV, Golubkov VS, Strongin AY: The transmembrane domain is essential for the microtubular trafficking of membrane type-1 matrix metalloproteinase (MT1-MMP). J Cell Sci 118: 4975–4984, 2005PubMedCrossRefGoogle Scholar
  40. 40.
    Wang X, Ma D, Keski-Oja J, Pei D: Co-recycling of MT1-MMP and MT3-MMP through the trans-Golgi network. Identification of DKV582 as a recycling signal. J Biol Chem 279: 9331–9336, 2004PubMedCrossRefGoogle Scholar
  41. 41.
    Wang P, Wang X, Pei D: Mint-3 regulates the retrieval of the internalized membrane-type matrix metalloproteinase, MT5-MMP, to the plasma membrane by binding to its carboxyl end motif EWV. J Biol Chem 279: 20461–20470, 2004PubMedCrossRefGoogle Scholar
  42. 42.
    Takino T, Miyamori H, Kawaguchi N, Uekita T, Seiki M, Sato H: Tetraspanin CD63 promotes targeting and lysosomal proteolysis of membrane-type 1 matrix metalloproteinase. Biochem Biophys Res Commun 304: 160–166, 2003PubMedCrossRefGoogle Scholar
  43. 43.
    Rozanov DV, Deryugina EI, Monosov EZ, Marchenko ND, Strongin AY: Aberrant, persistent inclusion into lipid rafts limits the tumorigenic function of membrane type-1 matrix metalloproteinase in malignant cells. Exp Cell Res 293: 81–95, 2004PubMedCrossRefGoogle Scholar
  44. 44.
    Itoh Y, Takamura A, Ito N, Maru Y, Sato H, Suenaga N, Aoki T, Seiki M: Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion. Embo J 20: 4782–4793, 2001PubMedCrossRefGoogle Scholar
  45. 45.
    Rozanov DV, Deryugina EI, Ratnikov BI, Monosov EZ, Marchenko GN, Quigley JP, Strongin AY: Mutation analysis of membrane type-1 matrix metalloproteinase (MT1-MMP). The role of the cytoplasmic tail Cys(574), the active site Glu(240), and furin cleavage motifs in oligomerization, processing, and self-proteolysis of MT1-MMP expressed in breast carcinoma cells. J Biol Chem 276: 25705–25714, 2001PubMedCrossRefGoogle Scholar
  46. 46.
    Lehti K, Lohi J, Juntunen MM, Pei D, Keski-Oja J: Oligomerization through hemopexin and cytoplasmic domains regulates the activity and turnover of membrane-type 1 matrix metalloproteinase. J Biol Chem 277: 8440–8448, 2002PubMedCrossRefGoogle Scholar
  47. 47.
    Uekita T, Gotoh I, Kinoshita T, Itoh Y, Sato H, Shiomi T, Okada Y, Seiki M: Membrane-type 1 matrix metalloproteinase cytoplasmic tail-binding protein-1 is a new member of the Cupin superfamily. A possible multifunctional protein acting as an invasion suppressor down-regulated in tumors. J Biol Chem 279: 12734–12743, 2004PubMedCrossRefGoogle Scholar
  48. 48.
    Toth M, Hernandez-Barrantes S, Osenkowski P, Bernardo MM, Gervasi DC, Shimura Y, Meroueh O, Kotra LP, Galvez BG, Arroyo AG, Mobashery S, Fridman R: Complex pattern of membrane type 1 matrix metalloproteinase shedding. Regulation by autocatalytic cells surface inactivation of active enzyme. J Biol Chem 277: 26340–26350, 2002PubMedCrossRefGoogle Scholar
  49. 49.
    Toth M, Osenkowski P, Hesek D, Brown S, Meroueh S, Sakr W, Mobashery S, Fridman R: Cleavage at the stem region releases an active ectodomain of the membrane type 1 matrix metalloproteinase. Biochem J 387: 497–506, 2005PubMedCrossRefGoogle Scholar
  50. 50.
    Wu YI, Munshi HG, Sen R, Snipas SJ, Salvesen GS, Fridman R, Stack MS: Glycosylation broadens the substrate profile of membrane type 1 matrix metalloproteinase. J Biol Chem 279: 8278–8289, 2004PubMedCrossRefGoogle Scholar
  51. 51.
    Anilkumar N, Uekita T, Couchman JR, Nagase H, Seiki M, Itoh Y: Palmitoylation at Cys574 is essential for MT1-MMP to promote cell migration. Faseb J 19: 1326–1328, 2005PubMedGoogle Scholar
  52. 52.
    McQuibban GA, Butler GS, Gong JH, Bendall L, Power C, Clark-Lewis I, Overall CM: Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J Biol Chem 276: 43503–43508, 2001PubMedCrossRefGoogle Scholar
  53. 53.
    Bartolome RA, Galvez BG, Longo N, Baleux F, Van Muijen GN, Sanchez-Mateos P, Arroyo AG, Teixido J: Stromal cell-derived factor-1alpha promotes melanoma cell invasion across basement membranes involving stimulation of membrane-type 1 matrix metalloproteinase and Rho GTPase activities. Cancer Res 64: 2534–2543, 2004PubMedCrossRefGoogle Scholar
  54. 54.
    Murakami T, Maki W, Cardones AR, Fang H, Tun Kyi A, Nestle FO, Hwang ST: Expression of CXC chemokine receptor-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells. Cancer Res 62: 7328–7334, 2002PubMedGoogle Scholar
  55. 55.
    Pollet I, Opina CJ, Zimmerman C, Leong KG, Wong F, Karsan A: Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-kappaB and c-Jun N-terminal kinase. Blood 102: 1740–1742, 2003PubMedCrossRefGoogle Scholar
  56. 56.
    Dauphinee SM, Karsan A: Lipopolysaccharide signaling in endothelial cells. Lab Invest 86: 9–22, 2006PubMedCrossRefGoogle Scholar
  57. 57.
    Harmey JH, Bucana CD, Lu W, Byrne AM, McDonnell S, Lynch C, Bouchier-Hayes D, Dong Z: Lipopolysaccharide-induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion. Int J Cancer 101: 415–422, 2002PubMedCrossRefGoogle Scholar
  58. 58.
    De Bono JS, Dalgleish AG, Carmichael J, Diffley J, Lofts FJ, Fyffe D, Ellard S, Gordon RJ, Brindley CJ, Evans TR: Phase I study of ONO-4007, a synthetic analogue of the lipid A moiety of bacterial lipopolysaccharide. Clin Cancer Res 6: 397–405, 2000PubMedGoogle Scholar
  59. 59.
    Hotary KB, Yana I, Sabeh F, Li XY, Holmbeck K, Birkedal-Hansen H, Allen ED, Hiraoka N, Weiss SJ: Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and -independent processes. J Exp Med 195: 295–308, 2002PubMedCrossRefGoogle Scholar
  60. 60.
    Nisato RE, Hosseini G, Sirrenberg C, Butler GS, Crabbe T, Docherty AJ, Wiesner M, Murphy G, Overall CM, Goodman SL, Pepper MS: Dissecting the role of matrix metalloproteinases (MMP) and integrin alpha(v)beta3 in angiogenesis in vitro: Absence of hemopexin C domain bioactivity, but membrane-Type 1-MMP and alpha(v)beta3 are critical. Cancer Res 65: 9377–9387, 2005PubMedCrossRefGoogle Scholar
  61. 61.
    Kheradmand F, Rishi K, Werb Z: Signaling through the EGF receptor controls lung morphogenesis in part by regulating MT1-MMP-mediated activation of gelatinase A/MMP2. J Cell Sci 115: 839–848, 2002PubMedGoogle Scholar
  62. 62.
    Shankavaram UT, Lai WC, Netzel-Arnett S, Mangan PR, Ardans JA, Caterina N, Stetler-Stevenson WG, Birkedal-Hansen H, Wahl LM: Monocyte membrane type 1-matrix metalloproteinase. Prostaglandin-dependent regulation and role in metalloproteinase-2 activation. J Biol Chem 276: 19027–19032, 2001PubMedCrossRefGoogle Scholar
  63. 63.
    Parmo-Cabanas M, Molina-Ortiz I, Matias-Roman S, Garcia-Bernal D, Carvajal-Vergara X, Valle I, Pandiella A, Arroyo AG, Teixido J: Role of metalloproteinases MMP-9 and MT1-MMP in CXCL12-promoted myeloma cell invasion across basement membranes. J Pathol 208: 108–118, 2006PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Laura Genís
    • 1
  • Beatriz G. Gálvez
    • 1
  • Pilar Gonzalo
    • 1
  • Alicia G. Arroyo
    • 1
  1. 1.Matrix Metalloproteinase UnitCentro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain

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