Skip to main content
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;9(2):286–302. doi: 10.1111/j.1582-4934.2005.tb00356.x

Angiogenesis inhibitors found within the haemostasis pathway

Carolyn A Staton 1, Claire E Lewis 2,
PMCID: PMC6740137  PMID: 15963250

Abstract

Angiogenesis, the development of new blood vessels from the existing vasculature, and haemostasis, the coagulation cascade leading to formation of a clot, are among the most consistent host responses associated with cancer. Importantly, these two pathways interrelate, with blood coagulation and fibrinolysis influencing tumor angiogenesis directly, thereby contributing to tumor growth. Moreover, many endogenous inhibitors of angiogenesis are found within platelets or harboured as cryptic fragments of haemostatic proteins. In this review we outline ways in which angiogenesis is coordinated and regulated by haemostasis in human cancer. Then we detail the experimental and preclinical evidence for the ability of many of these endogenous proteins to inhibit tumor angiogenesis and thus their potential to be anti‐cancer agents, with particular reference to any clinical trials.

Keywords: angiogenesis, haemostasis, tumor, platelets, thrombospondin‐1, plasminogen, angiostatin, antithrombin, hepatocyte growth factor, Platelet Factor 4

References

  • 1. Sridhara S, Clarke BJ, Ofosu FA, High KA, Blajchman MA. The direct binding of human factor VII in plasma to recombinant human tissue factor. Thromb Res. 1993; 70: 307–16. [DOI] [PubMed] [Google Scholar]
  • 2. Elodi S, Elodi P, Surface‐governed molecular regulation of blood coagulation. Mol Aspects Med. 1983; 6: 291–353. [DOI] [PubMed] [Google Scholar]
  • 3. Kaplan AP, Silverberg M, Dunn JT, Miller G. Mechanisms for Hageman factor activation and role of HMW kininogen as a coagulation cofactor. Ann N Y Acad Sci. 1981; 370: 253–60. [DOI] [PubMed] [Google Scholar]
  • 4. Taran LD. Factor IX of the blood coagulation system: a review, Biochemistry (Mosc). 1997; 62: 685–93. [PubMed] [Google Scholar]
  • 5. Saenko EL, Shima M, Sarafanov AG. Role of activation of the coagulation factor VIII in interaction with vWf, phospholipid, and functioning within the factor Xase complex. Trends Cardiovasc Med. 1999; 9: 185–92. [DOI] [PubMed] [Google Scholar]
  • 6. Jirouskova M, Smyth SS, Kudryk B, Coller BS. A hamster antibody to the mouse fibrinogen gamma chain inhibits platelet‐fibrinogen interactions and FXIIIa‐mediated fibrin cross‐linking, and facilitates thrombolysis. Thromb Haemost. 2001; 86: 1047–56. [PubMed] [Google Scholar]
  • 7. Elssner A, Mazur G, Vogelmeier C. Inhibition of factor XIIIa‐mediated incorporation of fibronectin into fibrin by pulmonary surfactant. Am J Physiol. 1999; 276: L625–L30. [DOI] [PubMed] [Google Scholar]
  • 8. Heemskirk JW, Bevers EM, Lindhout T, Platelet activation and blood coagulation. Thromb Haemost. 2002; 88: 186–93. [PubMed] [Google Scholar]
  • 9. Ofosu FA, The blood platelet as a model for regulating blood coagulation on cell surfaces and its consequences, Biochemistry (Mosc). 2002; 67: 47–55. [DOI] [PubMed] [Google Scholar]
  • 10. Folkman J, Tumor angiogenesis: therapeutic implications, N. Engl. J. Med. 1971; 285: 1182–6. [DOI] [PubMed] [Google Scholar]
  • 11. Folkman J, Klagsbrun M, Angiogenic factors. Science. 1987; 235: 442–7. [DOI] [PubMed] [Google Scholar]
  • 12. Folkman J, What is the evidence that tumors are angiogenesis dependent. J Natl Cancer Inst. 1990; 82: 4–6. [DOI] [PubMed] [Google Scholar]
  • 13. Gasic GJ, Gasic TB, Stewart CC, Antimetastatic effects associated with platelet reduction. Proc Natl Acad Sci USA. 1968; 61: 46–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Roemisch J, Gray E, Hoffmann JN, Wiedermann CJ. Antithrombin: a new look at the actions of a serine protease inhibitor. Blood Coagul Fibrinolysis 2002; 13: 657–70. [DOI] [PubMed] [Google Scholar]
  • 15. Folkman J, Taylor S, Spillberg C, The role of heparin in angiogenesis. Ciba Found Symp. 1983; 100: 132–49. [DOI] [PubMed] [Google Scholar]
  • 16. Maione TE, Gray GS, Petro J, Hunt AJ, Donner AL, Bauer SI, Carson HF, Sharpe RJ. Inhibition of angiogenesis by recombinant human platelet factor‐4 and related peptides. Science. 1990; 247: 77–9. [DOI] [PubMed] [Google Scholar]
  • 17. Sharpe RJ, Byersm HR, Scott CF, Bauer SI, Maione TE. Growth inhibition of murine melanoma and human colon carcinoma by recombinant human platelet factor 4, J Natl Cancer Inst. 1990; 82: 848–53. [DOI] [PubMed] [Google Scholar]
  • 18. Perollet C, Han ZC, Savona C, Caen JP, Bikfalvi A. Platelet factor 4 modulates fibroblast growth factor 2 (FGF‐2) activity and inhibits FGF‐2 dimerization. Blood. 1998; 91: 3289–99. [PubMed] [Google Scholar]
  • 19. Hansell P, Maione TE, Borgstrom P. Selective binding of platelet factor 4 to regions to active angiogenesis in vivo. Am J Physiol. 1995; 269: H829–36. [DOI] [PubMed] [Google Scholar]
  • 20. Kolber DL, Knisely TL, Maione TE. Inhibition of development of murine melanoma lung metastases by systemic administration of recombinant platelet factor 4. J Natl Cancer Inst. 1995; 87: 304–9. [DOI] [PubMed] [Google Scholar]
  • 21. Hagedorn M, Zillerberg L, Lozano RM, Cuevas P, Canron X, Redondo R, Horcajo M, Gimenez‐Gallego G, Bikfalvi A. A short peptide domain of platelet factor 4 blocks angiogenic key events induced by FGF‐2. FASEB. 2001; 15: 550–2. [DOI] [PubMed] [Google Scholar]
  • 22. Hagedorn M, Zillerberg L, Wilting J, Canron X, Carrabba G, Giussani G, Pluderi M, Bello L, Bikfalvi A. Domain swapping in a COOH‐terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors. Cancer Res. 2002; 62: 6884–90. [PubMed] [Google Scholar]
  • 23. Gengrinovitch S, Greenberg SM, Cohen T, Gitay G, Rockwell P, Maione TE, Levi BZ, Neufeld G. Platelet factor‐4 inhibits the mitogenic activity of VEGF121 and VEGF165 using several concurrent mechanisms, J Biol Chem. 1995; 270: 15059–65. [DOI] [PubMed] [Google Scholar]
  • 24. Lasagni L, Francalanci M, Annunziato F, Lazzeri E, Gianni S, Cosmi S, Sagrinati C, Mazzinghi B, Orlando C, Maggi E, Marra F, Romagnani S, Serio M, Romagnani P. An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP‐10, Mig, and I‐TAC, and acts as functional receptor for platelet factor 4. J Exp Med. 2003; 197: 1537–49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Li Y, Jin Y, Chen H, Jie G, Tobelem G, Caen JP, Han ZC, Suppression of tumor growth by viral vectormediated gene transfer of N‐terminal truncated platelet factor 4. Cancer Biother Radiopharm. 2003; 18: 829–40. [DOI] [PubMed] [Google Scholar]
  • 26. Daly ME, Makris A, Reed M, Lewis CE. Haemostatic regulators of tumor angiogenesis: a source of antiangiogenic agents for cancer treatment. J Natl Cancer Inst. 2003; 95: 1660–73. [DOI] [PubMed] [Google Scholar]
  • 27. Lawler JW, Slayter HS, Coligan JE. Isolation and characterization of a high molecular weight glycoprotein from human blood platelets. J Biol Chem. 1978; 253: 8609–16. [PubMed] [Google Scholar]
  • 28. Jaffe EA, Leung LL, Nachman RL, Levin RI. Mosher DF. Thrombospondin is the endogenous lectin of human platelets. Nature. 1982; 295: 246–8. [DOI] [PubMed] [Google Scholar]
  • 29. DiPietro LA, Nissen NN, Gamelli RL, Koch AE, Pyle JM, Polverini PJ. Thrombospondin 1 synthesis and function in wound repair. Am J Pathol. 1996; 148: 1851–60. [PMC free article] [PubMed] [Google Scholar]
  • 30. DiPietro L. Polverini P.. Angiogenic macrophages produce the angiogenic inhibitor thrombospondin 1. Am J Pathol. 1993; 143: 678–84. [PMC free article] [PubMed] [Google Scholar]
  • 31. de Fraipont F, Nicholson AC, Feige JJ, Van M. Thrombospondins and tumor angiogenesis. Trends Mol Med. 2001; 7: 401–7. [DOI] [PubMed] [Google Scholar]
  • 32. Dameron KM, Volpert OV, Tainsky MA, Bouck N. The p53 tumor suppressor gene inhibits angiogenesis by stimulating the production of thrombospondin, Cold Spring Harb Symp Quant Biol. 1994; 59: 483–9. [DOI] [PubMed] [Google Scholar]
  • 33. Dawson DW, Pearce SF, Zhong R, Silverstein RL, Frazier WA, Bouck N. CD36 mediates the in vitro inhibitory effects of thrombospondin on endothelial cells. J Cell Biol. 1997; 138: 707–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Armstrong LC, Bornstein P. Thrombospondins 1 and 2 function as inhibitors of angiogenesis. Matrix Biol. 2003; 22: 63–71. [DOI] [PubMed] [Google Scholar]
  • 35. Tolsma SS, Stack MS, Bouck N. Lumen formation and other angiogenic activities of cultured capillary endothelial cells are inhibited by thrombospondin‐1. Microvasc Res. 1997; 54: 13–26. [DOI] [PubMed] [Google Scholar]
  • 36. Volpert OV. Modulation of endothelial cell survival by an inhibitor of angiogenesis thrombospondin‐1: a dynamic balance. Cancer Metastasis Rev. 2000; 19: 87–92. [DOI] [PubMed] [Google Scholar]
  • 37. Iruela‐Arispe ML, Luque A, Lee N. Thrombospondin modules and angiogenesis. Int J Biochem Cell Biol 1999; 36: 1070–8. [DOI] [PubMed] [Google Scholar]
  • 38. Rodriguez‐Manzaneque JC, Lane TF, Ortega MA, Hynes RO, Lawler J, Iruela‐Arispe ML. Thrombospondin‐1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase‐9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci. USA. 2001; 98: 12485–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. de Vos F, Hoekstra R, Gietema J. A phase 1 dose escalating study of the angiogenesis inhibitor thrombospondin mimetic (ABT‐510) in patients with advanced cancer [abstract], Proc Am Soc Clin Oncol. 2002; 21: 324a. [DOI] [PubMed] [Google Scholar]
  • 40. Gordon MS, Mendelson D, Guirguis M. ABT‐510, an antiangiogenic, thrombospondin‐1 mimetic peptide, exhibits favorable safety profile and early signs of activity in a randomized phase IB trial. Proc Am Soc Clin Oncol. 2003; 22: 780a. [Google Scholar]
  • 41. Rosen EM, Grant DS, Kleinman HK, Goldberg ID, Bhargava MM, Nickoloff BJ, Kinsella JL, Polverini P. Scatter factor (hepatocyte growth factor) is a potent angiogenesis factor in vivo , Symp Soc Exp Biol. 1993; 47: 227–34. [PubMed] [Google Scholar]
  • 42. Montesano R, Soriano JV, Malinda KM, Ponce ML, Bafico A, Kleinman HK, Bottaro DP, Aaronson SA. Differential effects of hepatocyte growth factor isoforms on epithelial and endothelial tubulogenesis. Cell Growth Differ. 1998; 9: 355–65. [PubMed] [Google Scholar]
  • 43. Rosen EM, Lamszus K, Laterra J, Polverini PJ, Rubin JS, Goldberg ID. HGF/SF in angiogenesis, Ciba Found Symp. 1997; 212: 215–26. [DOI] [PubMed] [Google Scholar]
  • 44. Kuba K, Matsumoto K, Ohnishi K, Shiratsuchi T, Tanaka M, Nakamura T. Kringle 1‐4 of hepatocyte growth factor inhibits proliferation and migration of human microvascular endothelial cells, Biochem. Biophys. Res. Commun. 2000; 279: 846–52. [DOI] [PubMed] [Google Scholar]
  • 45. Merkulova‐Rainon T, England P, Ding S, Demerens C, Tobelem G. The N‐terminal domain of hepatocyte growth factor inhibits the angiogenic behavior of endothelial cells independently from binding to the c‐met receptor. J. Biol. Chem. 2003; 278: 37400–8. [DOI] [PubMed] [Google Scholar]
  • 46. Tomioka D, Maehara N, Kuba K, Mizumoto K, Tanaka M, Matsumoto K, Nakamura T. Inhibition of growth, invasion and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model. Cancer Res. 2001; 61: 7518–24. [PubMed] [Google Scholar]
  • 47. Maemondo M, Narumi K, Saijo Y, Usui K, Tahara M, Tazawa R, Hagiwara K, Matsumoto K, Nakamura T, Nukiwa T. Targeting angiogenesis and HGF function using an adenoviral vector expressing the HGF antagonist NK4 for cancer therapy. Mol Ther. 2002; 5: 177–85. [DOI] [PubMed] [Google Scholar]
  • 48. Kubota T, Fujiwara H, Amaike H, Takashima K, Inada S, Atsuji K, Yoshimura M, Matsumoto K, Nakamura T, Yamagishi H. Growth suppression of subcutaneous tumor by CT26 expressing NK4 in syngeneic mice. Gan To Kagaku Ryoho. 2002; 29: 2258–60. [PubMed] [Google Scholar]
  • 49. Kushibiki T, Matsumoto K, Nakamura T, Tabata Y. Suppression of the progress of disseminated pancreatic cancer cells by NK4 plasmid DNA release from cationized gelatin microspheres. Pharm Res. 2004; 21: 1109–18. [DOI] [PubMed] [Google Scholar]
  • 50. Hill SA, Shaughnessy SG, Joshua P, Ribau J, Austin RC, Podor TJ. Differential mechanisms targeting type 1 plasminogen activator inhibitor and vitronectin into the storage granules of a human megakaryocytic cell line. Blood. 1996; 87: 5061–73. [PubMed] [Google Scholar]
  • 51. Soff GA, Sanderowitz J, Gately S, Verrusio E, Weiss I, Brem S, Kwaan HC. Expression of plasminogen activator inhibitor type 1 by human prostate carcinoma cells inhibits primary tumor growth, tumor‐associated angiogenesis, and metastasis to lung and liver in an athymic mouse model. J Clin Invest. 1995; 96: 2593–600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52. Stefansson S, Lawrence DA. The serpin PAI‐1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature. 1996; 383: 441–3. [DOI] [PubMed] [Google Scholar]
  • 53. Stefansson S, Petitclerc E, Wong MK, McMahon GA, Brooks PC, Lawrence DA. Inhibition of angiogenesis in vivo by plasminogen activator inhibitor‐1. J Biol Chem. 2001; 276: 8135–41. [DOI] [PubMed] [Google Scholar]
  • 54. Pepper MS, Lymphangiogenesis and tumor metastasis: myth or reality Clin Cancer Res. 2001; 7: 462–8. [PubMed] [Google Scholar]
  • 55. McMahon GA, Petitclerc E, Stefansson S, Smith E, Wong MK, Westrick RJ, Ginsburg D, Brooks PC, Lawrence DA. Plasminogen activator inhibitor‐1 regulates tumor growth and angiogenesis. J Biol Chem. 2001; 276: 33964–8. [DOI] [PubMed] [Google Scholar]
  • 56. Devy L, Blacher S, Grignet D, Bajou K, Masson V, Gerard RD, Gils A, Carmeliet G, Carmeliet P, Declerck PJ, Noel A, Foidart JM. The pro‐ or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J. 2002. 16: 147–54. [DOI] [PubMed] [Google Scholar]
  • 57. Cufer T, Borstnar S, Vrhovec I. Prognostic and predictive value of the urokinase‐type plasminogen activator (uPA) and its inhibitors PAI‐1 and PAI‐2 in operable breast cancer. Int J Biol Markers. 2003; 18: 106–15. [DOI] [PubMed] [Google Scholar]
  • 58. Sakakibara T, Hibi K, Kodera Y, Ito K, Akiyama S, Nakao A. Plasminogen activator inhibitor‐1 as a potential marker for the malignancy of esophageal squamous cell carcinoma. Clin Cancer Res. 2004; 10: 1375–8. [DOI] [PubMed] [Google Scholar]
  • 59. Bajou K, Noel A, Gerard RD, Masson V, Brunner N, Holst‐Hansen C, Skobe M, Fusenig NE, Carmeliet P, Collen D, Foidart JM. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization, Nat. Med. 1998; 4: 923–8. [DOI] [PubMed] [Google Scholar]
  • 60. Gutierrez LS, Schulman A, Brito‐Robinson T, Noria F, Ploplis VA, Castellino FJ. 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: 5839–47. [PubMed] [Google Scholar]
  • 61. Menashi S, Lu H, Soria C, Legrand Y. Endothelial cell proteases: physiological role and regulation. Baillieres Clin Haematol. 1993. 6: 559–76. [DOI] [PubMed] [Google Scholar]
  • 62. Nachman RL, Harpel PC. Platelet alpha2‐macroglobulin and alpha1‐antitrypsin. J Biol Chem. 1976; 251: 4512–21. [PubMed] [Google Scholar]
  • 63. LaMarre J, Wollenberg GK, Gonias SL, Hayes MA. Cytokine binding and clearance properties of proteinaseactivator alpha 2‐macroglobulins. Lab Invest. 1991; 65: 3–14. [PubMed] [Google Scholar]
  • 64. Soker S, Svahn CM, Neufeld G. Vascular endothelial growth factor is inactivated by binding to alpha 2‐macroglobulin and the binding is inhibited by heparin. J Biol Chem. 1993; 268: 7685–91. [PubMed] [Google Scholar]
  • 65. Fabrizi C, Businaro R, Lauro GM, Starace G, Fumagalli L. Activated alpha2macroglobulin increases beta‐amyloid (25‐35)‐induced toxicity in LAN5 human neuroblastoma cells. Exp Neurol. 1999; 155: 252–9. [DOI] [PubMed] [Google Scholar]
  • 66. Asplin IR, Wu SM, Mathew S, Bhattacharjee G, Pizzo SV. Differential regulation of the fibroblast growth factor (FGF) family by alpha(2)‐macroglobulin: evidence for selective modulation of FGF‐2‐induced angiogenesis. Blood 2001. 97: 3450–7. [DOI] [PubMed] [Google Scholar]
  • 67. Mathew S, Arandjelovic S, Beyer WF, Gonias SL, Pizzo SV. Characterization of the interaction between 2‐macroglobulin and fibroblast growth factor‐2: the role of hydrophobic interactions. Biochem J. 2003; 374: 123–29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. O'Reilly MS, Pirie S, Lane WS, Folkman J. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin. Science. 1999; 285: 1926–28. [DOI] [PubMed] [Google Scholar]
  • 69. Lijnen HR, Ugwu F, Bini A, Collen D. Generation of an angiostatin‐like fragment from plasminogen by stromelysin‐1 (MMP‐3). Biochemistry. 1998; 37: 4699–4702. [DOI] [PubMed] [Google Scholar]
  • 70. Patterson BC, Sang QA. Angiostatin‐converting enzyme activities of human matrilysin (MMP‐7) and gelatinase B/type IV collagenase (MMP‐9). J Biol Chem. 1997; 272: 28823–5. [DOI] [PubMed] [Google Scholar]
  • 71. Stathakis P, Fitzgerald M, Matthias LJ, Chesterman CN, Hogg PJ. Generation of angiostatin by reduction and proteolysis of plasmin. Catalysis by a plasmin reductase secreted by cultured cells. J Biol Chem. 1997; 272: 20641–5. [DOI] [PubMed] [Google Scholar]
  • 72. Dong Z, Kumar R, Yang X, Fidler IJ. Macrophagederived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell. 1997; 88: 801–10. [DOI] [PubMed] [Google Scholar]
  • 73. O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994; 79: 315–28. [DOI] [PubMed] [Google Scholar]
  • 74. Cao Y. Endogenous angiogenesis inhibitors and their therapeutic implications. Int J Biochem Cell Biol. 2004; 33: 357–69. [DOI] [PubMed] [Google Scholar]
  • 75. Gately S, Twardowski P, Stack MS, Patrick M, Boggio L, Cundiff DL, Schnaper HW, Madison L, Volpert O, Bouck N, Enghild J, Kwaan HC, Soff GA. Human prostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis inhibitor, angiostatin. Cancer Res. 1996; 56: 4887–90. [PubMed] [Google Scholar]
  • 76. Stack MS, Gately S, Bafetti LM, Enghild JJ, Soff GA. Angiostatin inhibits endothelial and melanoma cellular invasion by blocking matrix‐enhanced plasminogen activation. Biochem J. 1999; 340: 77–84. [PMC free article] [PubMed] [Google Scholar]
  • 77. Moser TL, Kenan DJ, Ashley TA, Goodman MD, Misra UK, Cheek DJ, Pizzo SV. Endothelial cell surface F1‐F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin. Proc Natl Acad Sci USA. 2001; 98: 6656–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78. Troyanovsky B, Levchenko T, Mansson G, Matvijenko O, Holmgren L. Angiomotin: an angiostatin binding protein that regulates endothelial cell migration and tube formation. J Cell Biol. 2001; 152: 1247–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79. Tarui T, Miles LA, Takada Y. Specific interaction of angiostatin with integrin alpha(v)beta(3) in endothelial cells. J Biol Chem. 2001; 276: 39562–8. [DOI] [PubMed] [Google Scholar]
  • 80. Claesson‐Welsh M, Ito N, Anand A, Soker S, Zetter B, O'Reilly M, Folkman J. Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin‐binding motif RGD. Proc Natl Acad Sci USA. 1998; 95: 5579–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81. Redlitz A, Daum G, Sage EH. Angiostatin diminishes activation of the mitogen‐activated protein kinases ERK‐1 and ERK‐2 in human dermal microvascular endothelial cells. J Vasc Res. 1999; 36: 28–34. [DOI] [PubMed] [Google Scholar]
  • 82. Cao Y, Ji RW, Davidson D, Schaller J, Marti D, Sohndel S, McCance SG, O'Reilly MS, Llinas M, Folkman J. Kringle domains of human angiostatin. Characterization of the anti‐proliferative activity on endothelial cells. J Biol Chem. 1996; 271: 29461–7. [DOI] [PubMed] [Google Scholar]
  • 83. O'Reilly MS, Holmgren L, Chen C, Folkman J. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med. 1996; 2: 689–92. [DOI] [PubMed] [Google Scholar]
  • 84. Beerepoot LV, Witteveen EO, Groenewegen G, Fogler WE, Sim BK, Sidor C, Zonnenberg BA, Schramel F, Gebbink MF, Voest EE. Recombinant human angiostatin by twice daily subcutaneous injection in advanced cancer: a pharmacokinetic and long‐term safety study. Clin Cancer Res. 2003; 9: 4025–2033. [PubMed] [Google Scholar]
  • 85. Voest EE, Beerepoot LV, Groenewegen G, Fogler WE, Sim KB, Sidor C. Phase I trial of recombinant human angiostatin by twice daily subcutaneous injection in patients with advanced cancer [abstract 322]. Proc ASCO. 2002; 21. [PubMed]
  • 86. Sun X, Krissansen GW, Fung PW, Xu S, Shi J, Man K, Fan ST, Xu R. Anti‐angiogenic therapy subsequent to adeno‐associated‐virus‐mediated immunotherapy eradicates lymphomas that disseminate to the liver. Int J Cancer. 2005; 113: 670–7. [DOI] [PubMed] [Google Scholar]
  • 87. Ma HI, Lin SZ, Chiang YH, Li J, Chen SL, Tsao YP, Xiao X. Intratumoral gene therapy of malignant brain tumor in a rat model with angiostatin delivered by adenoassociated viral (AAV) vector. Gene Ther. 2002; 9: 2–11. [DOI] [PubMed] [Google Scholar]
  • 88. Uesato M, Gunji Y, Tomonaga T, Miyazaki S, Shiratori T, Matsubara H, Kouzu T, Shimada H, Nomura F, Ochiai T. Synergistic antitumor effect of antiangiogenic factor genes on colon 26 produced by low‐voltage electroporation. Cancer Gene Ther. 2004; 11: 625–32. [DOI] [PubMed] [Google Scholar]
  • 89. Sacco MG, Caniatti M, Cato EM, Frattini A, Chiesa G, Ceruti R, Adorni F, Zecca L, Scanziani E, Vezzoni P. Liposome‐delivered angiostatin strongly inhibits tumor growth and metastatization in a transgenic model of spontaneous breast cancer. Cancer Res. 2000; 60: 2660–5. [PubMed] [Google Scholar]
  • 90. Dejana E, Languino LR, Polentarutti N, Balconi G, Ryckewaert JJ, Larrieu MJ, Donati MB, Mantovani A, Marguerie G. 1985. Interaction between fibrinogen and cultured endothelial cells. Induction of migration and specific binding. J Clin Invest. 1985; 75: 11–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91. Bootle‐Wilbraham CA, Tazzyman S, Marshall JM, Lewis CE. Fibrinogen E‐fragment inhibits the migration and tubule formation of human dermal microvascular endothelial cells in vitro . Cancer Res. 2000; 60: 4719–24. [PubMed] [Google Scholar]
  • 92. Staton CA, Brown NJ, Lewis CE. The role of fibrinogen and related fragments in tumor angiogenesis and metastasis. Expert Opin Biol Ther. 2003; 3: 1105–20. [DOI] [PubMed] [Google Scholar]
  • 93. Brown NJ, Staton CA, Rodgers GR, Corke KP, Underwood JC, Lewis CE. Fibrinogen E fragment selectively disrupts the vasculature and inhibits the growth of tumors in a syngeneic murine model. Br J Cancer. 2002; 86: 1813–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94. Staton CA, Brown NJ, Rodgers GR, Corke KP, Tazzyman S, Underwood JC, Lewis CE. Alphastatin, a 24‐amino acid fragment of human fibrinogen, is a potent new inhibitor of activated endothelial cells in vitro and in vivo . Blood. 2004; 103: 601–6. [DOI] [PubMed] [Google Scholar]
  • 95. Staton CA, Brown NJ, Rodgers G, Corke KP, Tazzyman S, Underwood JCE, Lewis CE. Alphastatin, a 24‐amino acid fragment of fibrinogen is a novel anti‐angiogenic and anti‐vascular agent. Microcirculation 2004; 11: 527–58 (OC9). [Google Scholar]
  • 96. Rhim TY, Park CS, Kim E, Kim SS. Human prothrombin fragment 1 and 2 inhibit bFGF‐induced BCE cell growth, Biochem Biophys Res Commun. 1998; 252: 513–6. [DOI] [PubMed] [Google Scholar]
  • 97. Kim BJ, Koo SY, Kim SS. A peptide derived from human prothrombin fragment 2 inhibits prothrombinase and angiogenesis. Thromb Res. 2002; 106: 81–7. [DOI] [PubMed] [Google Scholar]
  • 98. Kim TH, Kim E, Yoon D, Kim J, Rhim TY, Kim SS. Recombinant human prothrombin kringles have potent anti‐angiogenic activities and inhibit Lewis lung carcinoma tumor growth and metastases. Angiogenesis. 2002; 5: 191–201. [DOI] [PubMed] [Google Scholar]
  • 99. Larsson H, Akerud P, Nordling K, Raub S, Claesson‐Welsh M, Bjork I. A novel anti‐angiogenic form of antithrombin with retained proteinase binding ability and heparin affinity. J Biol Chem. 2001; 276: 11996–12002. [DOI] [PubMed] [Google Scholar]
  • 100. Larsson H, Sjoblom T, Dixelius J, Ostman A, Ylinenjarvi K, Bjork I, Claesson‐Welsh M. Antiangiogenic effects of latent antithrombin through perturbed cell‐matrix interactions and apoptosis of endothelial cells. Cancer Res. 2000; 60: 6723–9. [PubMed] [Google Scholar]
  • 101. Kisker O, Onizuka S, Banyard J, Komiyama T, Becker CM, Achilles EG, Barnes CM, O'Reilly MS, Folkman J, Pirie S. Generation of multiple angiogenesis inhibitors by human pancreatic cancer. Cancer Res. 2001; 61: 7298–7304. [PubMed] [Google Scholar]
  • 102. Zhang W, Chuang YJ, Swanson R, Li J, Seo K, Leung L, Lau LF, Olson ST. Antiangiogenic antithrombin down‐regulates the expression of the proangiogenic heparan sulfate proteoglycan, perlecan, in endothelial cells. Blood. 2004; 103: 1185–91. [DOI] [PubMed] [Google Scholar]
  • 103. Laschke MW, Cengiz Z, Hoffmann JN, Menger MD, Vollmar B. Latent anti‐thrombin does not affect physiological angiogenesis: An in vivo study on vascularization of grafted ovarian follicles. Life Sciences. 2004; 75: 203–13. [DOI] [PubMed] [Google Scholar]
  • 104. Weisel JW, Nagaswami C, Woodhead JL, DeLa C, Page JD, Colman RW. The shape of high molecular weight kininogen. Organization into structural domains, changes with activation, and interactions with prekallikrein, as determined by electron microscopy. J Biol Chem. 1994; 269: 10100–6. [PubMed] [Google Scholar]
  • 105. Colman RW, Jameson BA, Lin Y, Johnson D, Mousa SA. Domain 5 of high molecular weight kininogen (kininostatin) down‐regulates endothelial cell proliferation and migration and inhibits angiogenesis. Blood. 2000; 95: 543–50. [PubMed] [Google Scholar]
  • 106. Guo YL, Wang S, Colman RW. Kininostatin, an angiogenic inhibitor, inhibits proliferation and induces apoptosis of human endothelial cells. Arterioscler Thromb Vasc Biol. 2001; 21: 1427–33. [DOI] [PubMed] [Google Scholar]
  • 107. Guo YL, Wang S, Cao DJ, Colman RW. Apoptotic effect of cleaved high molecular weight kininogen is regulated by extracellular matrix proteins. J Cell Biochem. 2003; 89: 622–32. [DOI] [PubMed] [Google Scholar]
  • 108. Zhang JC, Claffey K, Sakthivel R, Darzynkiewicz Z, Shaw DE, Leal J, Wang YC, Lu FM, McCrae KR. Two‐chain high molecular weight kininogen induces endothelial cell apoptosis and inhibits angiogenesis: partial activity within domain 5. FASEB J. 2000; 14: 2589–600. [DOI] [PubMed] [Google Scholar]
  • 109. Guo YL, Wang S, Colman RW. Kininostatin as an antiangiogenic inhibitor: what we know and what we do not know. Int Immunopharmacol. 2002; 2: 1931–40. [DOI] [PubMed] [Google Scholar]
  • 110. Zhang JC, Donate F, Qi X, Ziats NP, Juarez JC, Mazar AP, Pang YP, McCrae KR. The antiangiogenic activity of cleaved high molecular weight kininogen is mediated through binding to endothelial cell tropomyosin. Proc Natl Acad Sci USA. 2002; 99: 12224–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111. Mauceri HJ, Seetharam S, Beckett MA, Schumm LP, Koons A, Gupta VK, Park JO, Manan A, Lee JY, Montag AG, Kufe DW, Weichselbaum RR. Angiostatin potentiates cyclophosphamide treatment of metastatic disease. Cancer Chemother Pharmacol. 2002; 50: 412–8. [DOI] [PubMed] [Google Scholar]
  • 112. Te Velde EA, Vogten JM, Gebbink MF, van Gorp JM, Voest EE, Borel R. Enhanced antitumor efficacy by combining conventional chemotherapy with angiostatin or endostatin in a liver metastasis model. Br J Surg. 2002; 89: 1302–9. [DOI] [PubMed] [Google Scholar]
  • 113. Galaup A, Opolon P, Bouquet C, Li H, Opolon D, Bissery MC, Tursz T, Perricaudet M, Griscelli F. Combined effects of docetaxel and angiostatin gene therapy in prostate tumor model. Mol Ther. 2003; 7: 731–40. [DOI] [PubMed] [Google Scholar]
  • 114. Devore R, Fehrenbacher L, Herbst R. A randomized Phase II trial comparing rhumab VEGF (recombinant humanized monoclonal antibody to vascular endothelial growth factor) plus carboplatin/paclitaxel (CP) to CP alone in patients with stage IIb/IV NSCLC.. Proc Am Soc Clin Oncol. 2000; 19:458a (Abstract 1896). [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES