Semin Thromb Hemost 2004; 30(1): 71-82
DOI: 10.1055/s-2004-822972
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

The Fibrinolytic System and Matrix Metalloproteinases in Angiogenesis and Tumor Progression

Marten A. Engelse1 , Roeland Hanemaaijer1 , Pieter Koolwijk1 , Victor W. M. van Hinsbergh1 , 2
  • 1Gaubius Laboratory TNO-PG, Leiden, The Netherlands
  • 2Professor, Laboratory for Physiology, Institute for Cardiovascular Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands
Further Information

Publication History

Publication Date:
22 March 2004 (online)

Angiogenesis is the formation of new microvessels from existing vasculature. It is a crucial component of normal embryogenic development and of some physiological processes in adulthood. Pathological conditions such as tumor growth and metastasis, which involve tissue remodeling and inflammation, are usually associated with vascular leakage and subsequent angiogenesis. Tumor angiogenesis often augments tumor survival, progression, and metastasis, thus enhancing the malignant characteristics of the disease. Proteolytic degradation of the extracellular matrix that surrounds both the capillary sprouts and the migrating tumor cells is an essential part of tumor angiogenesis and tumor growth. In particular, proteases of the fibrinolytic system and the matrix metalloproteinase family play a role in these processes. In addition to proangiogenic effects, proteases also can negatively regulate angiogenesis. Protein fragments that result from proteolytic degradation of extracellular matrix components and other proteins can exhibit potent antiangiogenic properties. A thorough understanding of tumor-associated proteolytic processes is required to identify specific targets that are suitable for protease-based tumor therapy.

REFERENCES

  • 1 Risau W. Mechanisms of angiogenesis.  Nature. 1997;  386 671-674
  • 2 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease.  Nat Med. 1995;  1 27-31
  • 3 Carmeliet P, Jain R K. Angiogenesis in cancer and other diseases.  Nature. 2000;  407 249-257
  • 4 Dvorak H F, Brown L F, Detmar M, Dvorak A M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.  Am J Pathol. 1995;  146 1029-1039
  • 5 van Hinsbergh V W, Koolwijk P, Hanemaaijer R. Role of fibrin and plasminogen activators in repair-associated angiogenesis: in vitro studies with human endothelial cells. In: Goldberg ID, Rosen E Regulation of Angiogenesis. Experientia Supplementa. Vol. 79 Basel, Switzerland; Birkhäuser 1997: 391-411
  • 6 Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.  Cell. 1996;  86 353-364
  • 7 Weidner N, Semple J P, Welch W R, Folkman J. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma.  N Engl J Med. 1991;  324 1-8
  • 8 Weidner N. Angiogenesis as a predictor of clinical outcome in cancer patients.  Hum Pathol. 2000;  31 403-405
  • 9 Vermeulen P B, Gasparini G, Fox S B et al.. Second international consensus on the methodology and criteria of evaluation of angiogenesis quantification in solid human tumours.  Eur J Cancer. 2002;  38 1564-1579
  • 10 Carmeliet P, Moons L, Dewerchin M et al.. Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system.  Ann N Y Acad Sci. 1997;  811 191-206
  • 11 Saaristo A, Karpanen T, Alitalo K. Mechanisms of angiogenesis and their use in the inhibition of tumor growth and metastasis.  Oncogene. 2000;  19 6122-6129
  • 12 Marti H H, Risau W. Angiogenesis in ischemic disease.  Thromb Haemost. 1999;  82(suppl 1) 44-52
  • 13 Pepper M S. Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis.  Arterioscler Thromb Vasc Biol. 2001;  21 1104-1117
  • 14 Giatromanolaki A, Harris A L. Tumour hypoxia, hypoxia signaling pathways and hypoxia inducible factor expression in human cancer.  Anticancer Res. 2001;  21 4317-4324
  • 15 Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression.  Nat Rev Cancer. 2002;  2 161-174
  • 16 Zetter B R. Angiogenesis and tumor metastasis.  Annu Rev Med. 1998;  49 407-424
  • 17 Relf M, LeJeune S, Scott P A et al.. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis.  Cancer Res. 1997;  57 963-969
  • 18 Carmeliet P, Dor Y, Herbert J M et al.. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis.  Nature. 1998;  394 485-490
  • 19 Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.  Nature. 1992;  359 843-845
  • 20 Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease.  Cancer Cell. 2002;  1 219-227
  • 21 Stacker S A, Achen M G, Jussila L, Baldwin M E, Alitalo K. Lymphangiogenesis and cancer metastasis.  Nat Rev Cancer. 2002;  2 573-583
  • 22 Ferrara N, Alitalo K. Clinical applications of angiogenic growth factors and their inhibitors.  Nat Med. 1999;  5 1359-1364
  • 23 Senger D R. Molecular framework for angiogenesis: a complex web of interactions between extravasated plasma proteins and endothelial cell proteins induced by angiogenic cytokines.  Am J Pathol. 1996;  149 1-7
  • 24 Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors.  Nat Rev Cancer. 2002;  2 727-739
  • 25 Luttun A, Tjwa M, Moons L et al.. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1.  Nat Med. 2002;  8 831-840
  • 26 Leibovich S J, Polverini P J, Shepard H M, Wiseman D M, Shively V, Nuseir N. Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha.  Nature. 1987;  329 630-632
  • 27 Polverini P J. Role of the macrophage in angiogenesis-dependent diseases. In: Goldberg ID, Rosen E Regulation of Angiogenesis. Experientia Supplementa. Vol. 79 Basel, Switzerland; Birkhäuser 1997: 11-28
  • 28 Koolwijk P, van Erck M G, de Vree W J et al.. Cooperative effect of TNF-alpha, bFGF, and VEGF on the formation of tubular structures of human microvascular endothelial cells in a fibrin matrix. Role of urokinase activity.  J Cell Biol. 1996;  132 1177-1188
  • 29 Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors.  Cancer Res. 2000;  60 203-212
  • 30 Young M R, Kolesiak K, Wright M A, Gabrilovich D I. Chemoattraction of femoral CD34+ progenitor cells by tumor-derived vascular endothelial cell growth factor.  Clin Exp Metastasis. 1999;  17 881-888
  • 31 Bellamy W T, Richter L, Sirjani D et al.. Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes.  Blood. 2001;  97 1427-1434
  • 32 van Hinsbergh V W, Collen A, Koolwijk P. Role of fibrin matrix in angiogenesis.  Ann N Y Acad Sci. 2001;  936 426-437
  • 33 Dvorak H F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.  N Engl J Med. 1986;  315 1650-1659
  • 34 Graeber T G, Osmanian C, Jacks T et al.. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours.  Nature. 1996;  379 88-91
  • 35 Semenza G. Signal transduction to hypoxia-inducible factor 1.  Biochem Pharmacol. 2002;  64 993-998
  • 36 Chandel N S, McClintock D S, Feliciano C E et al.. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1-alpha during hypoxia: a mechanism of O2 sensing.  J Biol Chem. 2000;  275 25130-25138
  • 37 Haddad J J, Olver R E, Land S C. Antioxidant/pro-oxidant equilibrium regulates HIF-1-alpha and NF-kappa B redox sensitivity. Evidence for inhibition by glutathione oxidation in alveolar epithelial cells.  J Biol Chem. 2000;  275 21130-21139
  • 38 Salceda S, Caro J. Hypoxia-inducible factor 1-alpha (HIF-1-alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes.  J Biol Chem. 1997;  272 22642-22647
  • 39 Huang L E, Gu J, Schau M, Bunn H F. Regulation of hypoxia-inducible factor 1-alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway.  Proc Natl Acad Sci USA. 1998;  95 7987-7892
  • 40 Kallio P J, Wilson W J, O'Brien S, Makino Y, Poellinger L. Regulation of the hypoxia-inducible transcription factor 1-alpha by the ubiquitin-proteasome pathway.  J Biol Chem. 1999;  274 6519-6525
  • 41 Hon W C, Wilson M I, Harlos K et al.. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL.  Nature. 2002;  417 975-978
  • 42 Wang G L, Jiang B H, Rue E A, Semenza G L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.  Proc Natl Acad Sci USA. 1995;  92 5510-5514
  • 43 Kallio P J, Okamoto K, O'Brien S et al.. Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1-alpha.  EMBO J. 1998;  17 6573-6586
  • 44 Semenza G L. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression.  Crit Rev Biochem Mol Biol. 2000;  35 71-103
  • 45 Zagzag D, Zhong H, Scalzitti J M, Laughner E, Simons J W, Semenza G L. Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression.  Cancer. 2000;  88 2606-2618
  • 46 Maxwell P H, Dachs G U, Gleadle J M. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth.  Proc Natl Acad Sci USA. 1997;  94 8104-8109
  • 47 Forsythe J A, Jiang B H, Iyer N V et al.. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.  Mol Cell Biol. 1996;  16 4604-4613
  • 48 Maxwell P H, Wiesener M S, Chang G W et al.. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.  Nature. 1999;  399 271-275
  • 49 Ravi R, Mookerjee B, Bhujwalla Z M et al.. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha.  Genes Dev. 2000;  14 34-44
  • 50 Sutter C H, Laughner E, Semenza G L. Hypoxia-inducible factor 1alpha protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations.  Proc Natl Acad Sci USA. 2000;  97 4748-4753
  • 51 Montesano R. 1992;  Mack Forster Award Lecture. Review. Regulation of angiogenesis in vitro.  Eur J Clin Invest. 1992;  22 504-515
  • 52 Ausprunk D H, Folkman J. Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis.  Microvasc Res. 1977;  14 53-65
  • 53 Benjamin L E. The controls of microvascular survival.  Cancer Metastasis Rev. 2000;  19 75-81
  • 54 Doherty M J, Canfield A E. Gene expression during vascular pericyte differentiation.  Crit Rev Eukaryot Gene Expr. 1999;  9 1-17
  • 55 Pepper M S. Extracellular proteolysis and angiogenesis.  Thromb Haemost. 2001;  86 346-355
  • 56 Chang C, Werb Z. The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis.  Trends Cell Biol. 2001;  11 S37-S43
  • 57 Mayer M. Biochemical and biological aspects of the plasminogen activation system.  Clin Biochem. 1990;  23 197-211
  • 58 Bell W R. The fibrinolytic system in neoplasia.  Semin Thromb Hemost. 1996;  22 459-478
  • 59 Pepper M S, Montesano R, Mandriota S J, Orci L, Vassalli J D. Angiogenesis: a paradigm for balanced extracellular proteolysis during cell migration and morphogenesis.  Enzyme Protein. 1996;  49 138-162
  • 60 Estreicher A, Muhlhauser J, Carpentier J L, Orci L, Vassalli J D. The receptor for urokinase-type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes.  J Cell Biol. 1990;  111 783-792
  • 61 Pepper M S, Sappino A P, Stocklin R, Montesano R, Orci L, Vassalli J D. Upregulation of urokinase receptor expression on migrating endothelial cells.  J Cell Biol. 1993;  122 673-684
  • 62 Chapman H A, Wei Y. Protease crosstalk with integrins: the urokinase receptor paradigm.  Thromb Haemost. 2001;  86 124-129
  • 63 Collen D, Lijnen H R. The fibrinolytic system in man.  Crit Rev Oncol Hematol. 1986;  4 249-301
  • 64 Lijnen H R. Elements of the fibrinolytic system.  Ann N Y Acad Sci. 2001;  936 226-236
  • 65 van Hinsbergh V W, Collen A, Koolwijk P. Angiogenesis and anti-angiogenesis: perspectives for the treatment of solid tumors.  Ann Oncol. 1999;  10(suppl 4) 60-63
  • 66 Bajou K, Noel A, Gerard R D et al.. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization.  Nat Med. 1998;  4 923-928
  • 67 Bajou K, Masson V, Gerard R D et al.. The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies.  J Cell Biol. 2001;  152 777-784
  • 68 Gutierrez L S, Schulman A, Brito-Robinson T et al.. Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1.  Cancer Res. 2000;  60 5839-5847
  • 69 Loskutoff D J, Curriden S A, Hu G, Deng G. Regulation of cell adhesion by PAI-1.  APMIS. 1999;  107 54-61
  • 70 Wojta J, Jones R L, Binder B R, Hoover R L. Reduction in pO2 decreases the fibrinolytic potential of cultured bovine endothelial cells derived from pulmonary arteries and lung microvasculature.  Blood. 1988;  71 1703-1706
  • 71 Kroon M E, Koolwijk P, van der Vecht B, van Hinsbergh V W. Urokinase receptor expression on human microvascular endothelial cells is increased by hypoxia: implications for capillary-like tube formation in a fibrin matrix.  Blood. 2000;  96 2775-2783
  • 72 Yee J A, Yan L, Dominguez J C, Allan E H, Martin T J. Plasminogen-dependent activation of latent transforming growth factor beta (TGF beta) by growing cultures of osteoblast-like cells.  J Cell Physiol. 1993;  157 528-534
  • 73 Mundy G R. Mechanisms of bone metastasis.  Cancer. 1997;  80 1546-1556
  • 74 Massague J, Blain S W, Lo R S. TGF-beta signaling in growth control, cancer, and heritable disorders.  Cell. 2000;  103 295-309
  • 75 Ribatti D, Leali D, Vacca A et al.. In vivo angiogenic activity of urokinase: role of endogenous fibroblast growth factor-2.  J Cell Sci. 1999;  112 4213-4221
  • 76 Murphy G, Docherty A J. The matrix metalloproteinases and their inhibitors.  Am J Respir Cell Mol Biol. 1992;  7 120-125
  • 77 Woessner J F. The metalloproteinase family. In: Parks WC, Mecham RP Matrix Metalloproteinases. San Diego, CA; Academic Press 1998: 1-14
  • 78 Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis.  Genes Dev. 2000;  14 163-176
  • 79 Woesner J F, Nagase H. Matrix Metalloproteinases and TIMPs (Protein Profile). Oxford, UK; Oxford University Press 2000
  • 80 Montesano R, Orci L. Tumor-promoting phorbol esters induce angiogenesis in vitro.  Cell. 1985;  42 469-477
  • 81 Ravanti L, Kahari V M. Matrix metalloproteinases in wound repair.  Int J Mol Med. 2000;  6 391-407
  • 82 Brew K, Dinakarpandian D, Nagase H. Tissue inhibitors of metalloproteinases: evolution, structure and function.  Biochim Biophys Acta. 2000;  1477 267-283
  • 83 Johansson N, Ahonen M, Kahari V M. Matrix metalloproteinases in tumor invasion.  Cell Mol Life Sci. 2000;  57 5-15
  • 84 Seiki M. Membrane-type matrix metalloproteinases.  APMIS. 1999;  107 137-143
  • 85 Murphy G, Stanton H, Cowell S et al.. Mechanisms for pro matrix metalloproteinase activation.  APMIS. 1999;  107 38-44
  • 86 Hiraoka N, Allen E, Apel I J, Gyetko M R, Weiss S J. Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins.  Cell. 1998;  95 365-377
  • 87 Bode W, Fernandez-Catalan C, Grams F et al.. Insights into MMP-TIMP interactions.  Ann N Y Acad Sci. 1999;  878 73-91
  • 88 Nagase H. Cell surface activation of progelatinase A (proMMP-2) and cell migration.  Cell Res. 1998;  8 179-186
  • 89 Brooks P C, Stromblad S, Sanders L C 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
  • 90 Lafleur M A, Handsley M M, Knauper V, Murphy G, Edwards D R. Endothelial tubulogenesis within fibrin gels specifically requires the activity of membrane-type-matrix metalloproteinases (MT-MMPs).  J Cell Sci. 2002;  115 3427-3438
  • 91 Collen A, Hanemaaijer R, Lupu F et al.. Membrane-type matrix metalloproteinase mediated angiogenesis in a fibrin-collagen matrix.  Blood. 2002;  101 1810-1817
  • 92 Hotary K B, Yana I, Sabeh F et al.. Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and -independent processes.  J Exp Med. 2002;  195 295-308
  • 93 Anand-Apte B, Pepper M S, Voest E et al.. Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3.  Invest Ophthalmol Vis Sci. 1997;  38 817-823
  • 94 Lafleur M A, Forsyth P A, Atkinson S J, Murphy G, Edwards D R. Perivascular cells regulate endothelial membrane type-1 matrix metalloproteinase activity.  Biochem Biophys Res Commun. 2001;  282 463-473
  • 95 Koolwijk P, Sidenius N, Peters E et al.. Proteolysis of the urokinase-type plasminogen activator receptor by metalloproteinase-12: implication for angiogenesis in fibrin matrices.  Blood. 2001;  97 3123-3131
  • 96 Andolfo A, English W R, Resnati M, Murphy G, Blasi F, Sidenius N. Metalloproteases cleave the urokinase-type plasminogen activator receptor in the D1-D2 linker region and expose epitopes not present in the intact soluble receptor.  Thromb Haemost. 2002;  88 298-306
  • 97 Festuccia C, Dolo V, Guerra F et al.. Plasminogen activator system modulates invasive capacity and proliferation in prostatic tumor cells.  Clin Exp Metastasis. 1998;  16 513-528
  • 98 Huet E, Brassart B, Cauchard J H et al.. Cumulative influence of elastin peptides and plasminogen on matrix metalloproteinase activation and type I collagen invasion by HT-1080 fibrosarcoma cells.  Clin Exp Metastasis. 2002;  19 107-117
  • 99 Lijnen H R. Plasmin and matrix metalloproteinases in vascular remodeling.  Thromb Haemost. 2001;  86 324-333
  • 100 Davis G E, Pintar Allen K A, Salazar R, Maxwell S A. Matrix metalloproteinase-1 and -9 activation by plasmin regulates a novel endothelial cell-mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices.  J Cell Sci. 2001;  114 917-930
  • 101 Raza S L, Nehring L C, Shapiro S D, Cornelius L A. Proteinase-activated receptor-1 regulation of macrophage elastase (MMP-12) secretion by serine proteinases.  J Biol Chem. 2000;  275 41243-41250
  • 102 Lijnen H R, Arza B, Van Hoef B, Collen D, Declerck P J. Inactivation of plasminogen activator inhibitor-1 by specific proteolysis with stromelysin-1 (MMP-3).  J Biol Chem. 2000;  275 37645-37650
  • 103 Lijnen H R, Van Hoef B, Collen D. Inactivation of the serpin alpha(2)-antiplasmin by stromelysin-1.  Biochim Biophys Acta. 2001;  1547 206-213
  • 104 Parks W C, Shapiro S D. Matrix metalloproteinases in lung biology.  Respir Res. 2001;  2 10-19
  • 105 McQuibban G A, Gong J H, Wong J P et al.. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo.  Blood. 2002;  100 1160-1167
  • 106 Mohan R, Chintala S K, Jung J C et al.. Matrix metalloproteinase gelatinase B (MMP-9) coordinates and effects epithelial regeneration.  J Biol Chem. 2002;  277 2065-2072
  • 107 Liu Z, Zhou X, Shapiro S D et al.. The serpin alpha1-proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo.  Cell. 2000;  102 647-655
  • 108 Noe V, Fingleton B, Jacobs K et al.. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1.  J Cell Sci. 2001;  114 111-118
  • 109 Wilson C L, Ouellette A J, Satchell D P et al.. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense.  Science. 1999;  286 113-117
  • 110 Coussens L M, Fingleton B, Matrisian L M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations.  Science. 2002;  295 2387-2392
  • 111 Overall C M, Lopez-Otin C. Strategies for MMP inhibition in cancer: innovations for the post-trial era.  Nat Rev Cancer. 2002;  2 657-672
  • 112 Goldberg G I, Frisch S M, He C, Wilhelm S M, Reich R, Collier I E. Secreted proteases. Regulation of their activity and their possible role in metastasis.  Ann N Y Acad Sci. 1990;  580 375-384
  • 113 Quax P H, van Muijen G N, Weening-Verhoeff E J et al.. Metastatic behavior of human melanoma cell lines in nude mice correlates with urokinase-type plasminogen activator, its type-1 inhibitor, and urokinase-mediated matrix degradation.  J Cell Biol. 1991;  115 191-199
  • 114 Duffy M J. Proteases as prognostic markers in cancer.  Clin Cancer Res. 1996;  2 613-618
  • 115 Ossowski L, Reich E. Antibodies to plasminogen activator inhibit human tumor metastasis.  Cell. 1983;  35 611-619
  • 116 Ossowski L. Plasminogen activator-dependent pathways in the dissemination of human tumor cells in the chick embryo.  Cell. 1988;  52 321-328
  • 117 Ossowski L, Russo-Payne H, Wilson E L. Inhibition of urokinase-type plasminogen activator by antibodies: the effect on dissemination of a human tumor in the nude mouse.  Cancer Res. 1991;  51 274-281
  • 118 Wilhelm O, Schmitt M, Hohl S, Senekowitsch R, Graeff H. Antisense inhibition of urokinase reduces spread of human ovarian cancer in mice.  Clin Exp Metastasis. 1995;  13 296-302
  • 119 Shapiro R L, Duquette J G, Roses D F et al.. Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (u-PA)-deficient and wild-type mice: cellular blue nevi invade but do not progress to malignant melanoma in u-PA-deficient animals.  Cancer Res. 1996;  56 3597-3604
  • 120 Bugge T H, Kombrinck K W, Xiao Q et al.. Growth and dissemination of Lewis lung carcinoma in plasminogen-deficient mice.  Blood. 1997;  90 4522-4531
  • 121 Palumbo J S, Kombrinck K W, Drew A F et al.. Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells.  Blood. 2000;  96 3302-3309
  • 122 Duffy M J, O'Grady P, Devaney D, O'Siorain L, Fennelly J J, Lijnen H J. Urokinase-plasminogen activator, a marker for aggressive breast carcinomas.  Cancer. 1988;  62 531-533
  • 123 Foekens J A, Schmitt M, van Putten W L et al.. Prognostic value of urokinase-type plasminogen activator in 671 primary breast cancer patients.  Cancer Res. 1992;  52 6101-6105
  • 124 Duffy M J. Urokinase plasminogen activator and its inhibitor, PAI-1, as prognostic markers in breast cancer: from pilot to level 1 evidence studies.  Clin Chem. 2002;  48 1194-1197
  • 125 Duffy M J, Maguire T M, McDermott E W, O'Higgins N. Urokinase plasminogen activator: a prognostic marker in multiple types of cancer.  J Surg Oncol. 1999;  71 130-135
  • 126 Curran S, Murray G I. Matrix metalloproteinases: molecular aspects of their roles in tumour invasion and metastasis.  Eur J Cancer. 2000;  36 1621-1630
  • 127 McCawley L J, Matrisian L M. Matrix metalloproteinases: multifunctional contributors to tumor progression.  Mol Med Today. 2000;  6 149-156
  • 128 Stetler-Stevenson W G. The role of matrix metalloproteinases in tumor invasion, metastasis, and angiogenesis.  Surg Oncol Clin N Am. 2001;  10 383-392
  • 129 Jiang Y, Goldberg I D, Shi Y E. Complex roles of tissue inhibitors of metalloproteinases in cancer.  Oncogene. 2002;  21 2245-2252
  • 130 Yana I, Seiki M. MT-MMPs play pivotal roles in cancer dissemination.  Clin Exp Metastasis. 2002;  19 209-215
  • 131 Nelson A R, Fingleton B, Rothenberg M L, Matrisian L M. Matrix metalloproteinases: biologic activity and clinical implications.  J Clin Oncol. 2000;  18 1135-1149
  • 132 Zucker S, Cao J, Chen W T. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment.  Oncogene. 2000;  19 6642-6650
  • 133 Hidalgo M, Eckhardt S G. Development of matrix metalloproteinase inhibitors in cancer therapy.  J Natl Cancer Inst. 2001;  93 178-193
  • 134 Murray G I, Duncan M E, O'Neil P, McKay J A, Melvin W T, Fothergill J E. Matrix metalloproteinase-1 is associated with poor prognosis in oesophageal cancer.  J Pathol. 1998;  185 256-261
  • 135 Sier C F, Kubben F J, Ganesh S et al.. Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma.  Br J Cancer. 1996;  74 413-417
  • 136 Ahmad A, Hanby A, Dublin E et al.. Stromelysin 3: an independent prognostic factor for relapse-free survival in node-positive breast cancer and demonstration of novel breast carcinoma cell expression.  Am J Pathol. 1998;  152 721-728
  • 137 Vihinen P, Kahari V M. Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets.  Int J Cancer. 2002;  99 157-166
  • 138 O'Reilly M S, Holmgren L, Shing Y et al.. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma.  Cell. 1994;  79 315-328
  • 139 O'Reilly M S, Boehm T, Shing Y et al.. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.  Cell. 1997;  88 277-285
  • 140 Boehm T, Folkman J, Browder T, O'Reilly M S. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance.  Nature. 1997;  390 404-407
  • 141 Dong Z, Kumar R, Yang X, Fidler I J. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma.  Cell. 1997;  88 801-810
  • 142 Lijnen H R, Ugwu F, Bini A, Collen D. Generation of an angiostatin-like fragment from plasminogen by stromelysin-1 (MMP-3).  Biochemistry. 1998;  37 4699-4702
  • 143 Gately S, Twardowski P, Stack M S et al.. Human prostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis inhibitor, angiostatin.  Cancer Res. 1996;  56 4887-4890
  • 144 Gately S, Twardowski P, Stack M S et al.. The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin.  Proc Natl Acad Sci USA. 1997;  94 10868-10872
  • 145 Chavakis E, Dimmeler S. Regulation of endothelial cell survival and apoptosis during angiogenesis.  Arterioscler Thromb Vasc Biol. 2002;  22 887-893
  • 146 Felbor U, Dreier L, Bryant R A, Ploegh H L, Olsen B R, Mothes W. Secreted cathepsin L generates endostatin from collagen XVIII.  EMBO J. 2000;  19 1187-1194
  • 147 Wen W, Moses M A, Wiederschain D, Arbiser J L, Folkman J. The generation of endostatin is mediated by elastase.  Cancer Res. 1999;  59 6052-6056
  • 148 Shichiri M, Hirata Y. Antiangiogenesis signals by endostatin.  FASEB J. 2001;  15 1044-1053
  • 149 Dhanabal M, Ramchandran R, Waterman M J et al.. Endostatin induces endothelial cell apoptosis.  J Biol Chem. 1999;  274 11721-11726
  • 150 Dixelius J, Larsson H, Sasaki T et al.. Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis.  Blood. 2000;  95 3403-3411
  • 151 Rehn M, Veikkola T, Kukk-Valdre E et al.. Interaction of endostatin with integrins implicated in angiogenesis.  Proc Natl Acad Sci USA. 2001;  98 1024-1029
  • 152 Maeshima Y, Sudhakar A, Lively J C et al.. Tumstatin, an endothelial cell-specific inhibitor of protein synthesis.  Science. 2002;  295 140-143
  • 153 Colman R W. Role of the light chain of high molecular weight kininogen in adhesion, cell-associated proteolysis and angiogenesis.  J Biol Chem. 2001;  382 65-70
  • 154 Taraboletti G, Morbidelli L, Donnini S et al.. The heparin binding 25 kDa fragment of thrombospondin-1 promotes angiogenesis and modulates gelatinase and TIMP-2 production in endothelial cells.  FASEB J. 2000;  14 1674-1676
  • 155 Tennant T R, Rinker-Schaeffer C W, Stadler W M. Angiogenesis inhibitors.  Curr Oncol Rep. 2000;  2 11-16
  • 156 Hanemaaijer R, van Lent N, Sorsa T, Salo T, Konttinen Y T, Lindeman J. Inhibition of matrixmetallorpoteinases (MMPs) by tetracyclins. In: Nelson M, Hillen W, Greenwald RA Tetracyclins in Biology, Chemistry and Medicine. Basel, Switzerland; Birkhäuser Verlag; 2001: 267-281
  • 157 Goldman C K, Kendall R L, Cabrera G et al.. Paracrine expression of a native soluble vascular endothelial growth factor receptor inhibits tumor growth, metastasis, and mortality rate.  Proc Natl Acad Sci USA. 1998;  95 8795-8800
  • 158 Zhai Y, Ni J, Jiang G W et al.. VEGI, a novel cytokine of the tumor necrosis factor family, is an angiogenesis inhibitor that suppresses the growth of colon carcinomas in vivo.  FASEB J. 1999;  13 181-189
  • 159 Maione T E, Gray G S, Petro J et al.. Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides.  Science. 1990;  247 77-79
  • 160 Fotsis T, Zhang Y, Pepper M S et al.. The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth.  Nature. 1994;  368 237-239
  • 161 Fidler I J. Angiogenesis and cancer metastasis.  Cancer J. 2000;  6 S134-S141
  • 162 Cervenak L, Morbidelli L, Donati D et al.. Abolished angiogenicity and tumorigenicity of Burkitt lymphoma by interleukin-10.  Blood. 2000;  96 2568-2573
  • 163 Halin C, Rondini S, Nilsson F et al.. Enhancement of the antitumor activity of interleukin-12 by targeted delivery to neovasculature.  Nat Biotechnol. 2002;  20 264-269
  • 164 Colorado P C, Torre A, Kamphaus G et al.. Anti-angiogenic cues from vascular basement membrane collagen.  Cancer Res. 2000;  60 2520-2526
  • 165 Kamphaus G D, Colorado P C, Panka D J et al.. Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth.  J Biol Chem. 2000;  275 1209-1215
  • 166 Liu N, Lapcevich R K, Underhill C B et al.. Metastatin: a hyaluronan-binding complex from cartilage that inhibits tumor growth.  Cancer Res. 2001;  61 1022-1028
  • 167 Cao Y, Chen A, An S S, Ji R W, Davidson D, Llinas M. Kringle 5 of plasminogen is a novel inhibitor of endothelial cell growth.  J Biol Chem. 1997;  272 22924-22928

 Prof.
Victor W M van Hinsbergh

Laboratory for Physiology

VU University Medical Center, van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands

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