Thromb Haemost 2002; 87(03): 394-401
DOI: 10.1055/s-0037-1613016
Review Article
Schattauer GmbH

The Mechanism of Action of Angiostatin: Can You Teach an Old Dog New Tricks?

Tammy L. Moser
1   Department of Pathology, Duke University Medical Center, Durham, NC
,
M. Sharon Stack
2   Department of Cell and Molecular Biology, North western University Medical School, Chicago, IL
,
Miriam L. Wahl
3   Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, PA, USA
,
Salvatore V. Pizzo
1   Department of Pathology, Duke University Medical Center, Durham, NC
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 06. November 2001

Accepted 05. Dezember 2001

Publikationsdatum:
14. Dezember 2017 (online)

Summary

What is angiostatin? In 1994, Folkman and colleagues published a landmark paper describing anti-tumor effects in mice with a purified fragment of plasminogen they named angiostatin (1). Although many papers have been published describing activities of cryptic polypeptides derived from plasminogen fragments, this was the first report which associated plasminogen kringles 1–4 as a suppressor of metastasis development. This review will describe what is known about the mechanism of action of angiostatin from the current literature.

 
  • References

  • 1 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.
  • 2 Sottrup-Jensen L, Claeys H, Zajdel M, Petersen TE, Magnusson S. Progress in Chemical Fibrinolysis and Thrombolysis. Vol. 3 Raven Press; New York: 1978
  • 3 Castellino FJ. Biochemistry of human plasminogen. Semin Thromb Hemost 1984; 10: 18-23.
  • 4 Hayes ML, Castellino JF. Carbohydrate of the human plasminogen variants. I. Carbohydrate composition, glycopeptide isolation, and characterization. J Biol Chem 1979; 254: 8768-71.
  • 5 Davidson DJ, Castellino FJ. Oligosaccharide structures present on asparagine-289 of recombinant human plasminogen expressed in a Chinese hamster ovary cell line. Biochemistry 1991; 30: 625-33.
  • 6 Pirie-Shepherd SR, Stevens RD, Andon NL, Enghild JJ, Pizzo SV. Evidence for a novel O-linked sialylated trisaccharide on Ser-248 of human plasminogen 2. J Biol Chem 1997; 272: 7408-11.
  • 7 Castellino F. Recent advances in the chemistry of the fibrinolytic system. Chem Rev 1981; 81: 431-6.
  • 8 Robbins KC, Summaria Hsieh B, Shah RJ. The peptide chains of human plasmin. Mechanism of activation of human plasminogen to plasmin. J Biol Chem 1967; 242: 2333-42.
  • 9 McMullen BA, Fujikawa K. Amino acid sequence of the heavy chain of human alpha-factor XIIa (activated Hageman factor). J Biol Chem 1985; 260: 5328-41.
  • 10 Magnusson S, Petersen TE, Sottrup-Jensen L, Claeys H. Complete primary structure of prothrombin: isolation and reactivity of ten carboxylated glutamic residues and regulation of prothrombin activation by thrombin. Cold Spring Harbor; New York: 1975
  • 11 O’Reilly MS, Pirie-Shepherd S, Lane WS, Folkman J. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin [see comments]. Science 1999; 285: 1926-8.
  • 12 Pennica D, Holmes WE, Kohr WJ, Harkins RN, Vehar GA, Ward CA, Bennett WF, Yelverton E, Seeburg PH, Heyneker HL, Goeddel DV, Collen D. Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature 1983; 301: 214-21.
  • 13 Steffens GJ, Gunzler WA, Otting F, Frankus E, Flohe L. The complete amino acid sequence of low molecular mass urokinase from human urine. Hoppe Seylers Z Physiol Chem 1982; 363: 1043-58.
  • 14 Gherardi E, Stoker M. Hepatocyte growth factor – scatter factor: mitogen, motogen, and met. Cancer Cells 1991; 03: 227-32.
  • 15 Bussolino F, Di Renzo MF, Ziche M, Bocchietto E, Olivero M, Naldini L, Gaudino G, Tamagnone L, Coffer A, Comoglio PM. Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 1992; 119: 629-41.
  • 16 McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 1987; 330: 132-7.
  • 17 Schwartz ML, Pizzo SV, Sullivan JB, Hill RL, McKee PA. A comparative study of crosslinked and noncrosslinked fibrin from the major classes of vertebrates. Thromb Diath Haemorrh 1973; 29: 313-38.
  • 18 Bachman F. The plasminogen-plasmin enzyme system. Vol. 3 JB Lippincott, Philadelphia; 1994
  • 19 Cao R, Wu HL, Veitonmaki N, Linden P, Farnebo J, Shi GY, Cao Y. Suppression of angiogenesis and tumor growth by the inhibitor K1-5 generated by plasmin-mediated proteolysis. Proc Natl Acad Sci USA 1999; 96: 5728-33.
  • 20 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.
  • 21 Moser TL, Stack MS, Asplin I, Enghild JJ, Hojrup P, Everitt L, Hubchak S, Schnaper HW, Pizzo SV. Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc Natl Acad Sci USA 1999; 96: 2811-6.
  • 22 Weidong-Richard JI, Castellino FJ, Chang Y, Deford ME, Gray H, Villarreal X, Kondri ME, Marti DN, Llinas M, Schaller J, Kramer RA, Trail PA. Characterization of kringle domains of angiostatin as antagonists of endothelial cell migration, an important process in angiogenesis. Faseb J 1998; 12: 1731-8.
  • 23 MacDonald NJ, Murad AC, Fogler WE, Lu Y, Sim BK. The tumorsuppressing activity of angiostatin protein resides within kringles 1 to 3. Biochem Biophys Res Commun 1999; 264: 469-77.
  • 24 Mulichak AM, Tulinsky A, Ravichandran KG. Crystal and molecular structure of human plasminogen kringle 4 refined at 1.9-A resolution. Biochemistry 1991; 30: 10576-88.
  • 25 Abad MC, Arni RK, Grella DK, Castellino FJ, Tulinsky A, Geiger JH. The x-ray crystallographic structure of the angiogenesis inhibitor angiostatin. Submitted to Journal of Molecular Biology. 2001
  • 26 Lucas R, Holmgren L, Garcia I, Jimenez B, Mandriota SJ, Borlat F, Sim BK, Wu Z, Grau GE, Shing Y, Soff GA, Bouck N, Pepper MS. Multiple forms of angiostatin induce apoptosis in endothelial cells. Blood 1998; 92: 4730-41.
  • 27 Siefring Jr GE, Castellino FJ. The role of sialic acid in the determination of distinct properties of the isozymes of rabbit plasminogen. J Biol Chem 1974; 249: 7742-6.
  • 28 Pirie-Shepherd SR, Serrano RL, Andon NL, Gonzalez-Gronow M, Pizzo SV. The role of carbohydrate in the activation of plasminogen 2 glycoforms by streptokinase. Fibrinolysis 1996; 10: 49-53.
  • 29 Pirie-Shepherd SR. Role of carbohydrate on angiostatin in the treatment of cancer. J Lab Clin Med 1999; 134: 553-60.
  • 30 Gonzalez-Gronow M, Pizzo SV. Angiostatin inhibits human prostate cell invasion by blocking plasminogen binding to the CD26 cellular receptor. Thromb Haemost. 2001 86. Abstract P2738.
  • 31 Soff GA. Angiostatin and angiostatin-related proteins. Cancer Metastasis Rev 2000; 19: 97-107.
  • 32 Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? G. H. A. Clowes memorial Award lecture. Cancer Res 1986; 46: 467-73.
  • 33 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.
  • 34 Good DJ, Polverini PJ, Rastinejad F, Le Beau MM, Lemons RS, Frazier WA, Bouck NP. A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci U S A 1990; 87: 6624-8.
  • 35 Rastinejad F, Polverini PJ, Bouck NP. Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene. Cell 1989; 56: 345-55.
  • 36 Ferrara N, Clapp C, Weiner R. The 16K fragment of prolactin specifically inhibits basal or fibroblast growth factor stimulated growth of capillary endothelial cells. Endocrinology 1991; 129: 896-900.
  • 37 Clapp C, Martial JA, Guzman RC, Rentier-Delure F, Weiner RI. The 16-kilodalton N-terminal fragment of human prolactin is a potent inhibitor of angiogenesis. Endocrinology 1993; 133: 1292-9.
  • 38 Brouty-Boye D, Zetter BR. Inhibition of cell motility by interferon. Science 1980; 208: 516-8.
  • 39 Sidky YA, Borden EC. Inhibition of angiogenesis by interferons: effects on tumor- and lymphocyte-induced vascular responses. Cancer Res 1987; 47: 5155-61.
  • 40 Kuebler JP, Oberley TD, Meisner LF, Sidky YA, Reznikoff CA, Borden EC, Cummings KB, Bryan GT. Effect of interferon alpha, interferon beta, and interferon gamma on the in vitro growth of human renal adenocarcinoma cells. Invest New Drugs 1987; 05: 21-9.
  • 41 Taylor S, Folkman J. Protamine is an inhibitor of angiogenesis. Nature 1982; 297: 307-12.
  • 42 Colorado PC, Torre A, Kamphaus G, Maeshima Y, Hopfer H, Takahashi K, Volk R, Zamborsky ED, Herman S, Sarkar PK, Ericksen MB, Dhanabal M, Simons M, Post M, Kufe DW, Weichselbaum RR, Sukhatme VP, Kalluri R. Anti-angiogenic cues from vascular basement membrane collagen. Cancer Res 2000; 60: 2520-6.
  • 43 Maeshima Y, Colorado PC, Kalluri R. Two RGD-independent alpha v beta 3 integrin binding sites on tumstatin regulate distinct anti-tumor properties. J Biol Chem 2000; 275: 23745-50.
  • 44 Lee TH, Rhim T, Kim SS. Prothrombin kringle-2 domain has a growth inhibitory activity against basic fibroblast growth factor-stimulated capillary endothelial cells. J Biol Chem 1998; 273: 28805-12.
  • 45 O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88: 277-85.
  • 46 Cao Y. Endogenous angiogenesis inhibitors: angiostatin, endostatin, and other proteolytic fragments. Prog Mol Subcell Biol 1998; 20: 161-76.
  • 47 Cao Y. Endogenous angiogenesis inhibitors and their therapeutic implications. Int J Biochem Cell Biol 2001; 33: 357-69.
  • 48 O’Reilly MS, Holmgren L, Chen C, Folkman J. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 1996; 02: 689-92.
  • 49 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.
  • 50 Gately S, Twardowski P, Stack MS, Cundiff DL, Grella D, Castellino FJ, Enghild J, Kwaan HC, Lee F, Kramer RA, Volpert O, Bouck N, Soff GA. The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. Proc Natl Acad Sci U S A 1997; 94: 10868-72.
  • 51 O’Mahony CA, Seidel A, Albo D, Chang H, Tuszynski GP, Berger DH. Angiostatin generation by human pancreatic cancer. J Surg Res 1998; 77: 55-8.
  • 52 Falcone DJ, Khan KM, Layne T, Fernandes L. Macrophage formation of angiostatin during inflammation. A byproduct of the activation of plasminogen. J Biol Chem 1998; 273: 31480-5.
  • 53 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.
  • 54 Stathakis P, Lay AJ, Fitzgerald M, Schlieker C, Matthias LJ, Hogg PJ. Angiostatin formation involves disulfide bond reduction and proteolysis in kringle 5 of plasmin. J Biol Chem 1999; 274: 8910-6.
  • 55 Lay AJ, Jiang XM, Kisker O, Flynn E, Underwood A, Condron R, Hogg PJ. Phosphoglycerate kinase acts in tumour angiogenesis as a disulphide reductase. Nature 2000; 408: 869-73.
  • 56 Heidtmann HH, Nettelbeck DM, Mingels A, Jager R, Welker HG, Kontermann RE. Generation of angiostatin-like fragments from plasminogen by prostate-specific antigen. Br J Cancer 1999; 81: 1269-73.
  • 57 O’Reilly MS, Wiederschain D, Stetler-Stevenson WG, Folkman J, Moses MA. Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance. J Biol Chem 1999; 274: 29568-71.
  • 58 Lijnen HR, Ugwu F, Bini A, Collen D. Generation of an angiostatin-like fragment from plasminogen by stromelysin-1 (MMP-3). Biochemistry 1998; 37: 4699-702.
  • 59 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.
  • 60 Dong Z, Kuma R, Yang X, Fidler IJ. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 1997; 88: 801-10.
  • 61 Gonzalez-Gronow M, Grenett HE, Weber MR, Gawdi G, Pizzo SV. Interaction of plasminogen with dipeptidyl peptidase IV initiates a signal transduction mechanism which regulates expression of matrix metallo-proteinase-9 by prostate cancer cells. Biochem J 2001; 355: 397-407.
  • 62 Cornelius LA, Nehring LC, Harding E, Bolanowski M, Welgus HG, Kobayashi DK, Pierce RA, Shapiro SD. Matrix metalloproteinases generate angiostatin: effects on neovascularization. J Immunol 1998; 161: 6845-52.
  • 63 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.
  • 64 Walter JJ, Sane DC. Angiostatin binds to smooth muscle cells in the coronary artery and inhibits smooth muscle cell proliferation and migration in vitro. Arterioscler Thromb Vasc Biol 1999; 19: 2041-8.
  • 65 Claesson-Welsh L, Welsh M, Ito N, Anand-Apte B, 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.
  • 66 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.
  • 67 Mauceri HJ, Hanna NN, Beckett MA, Gorski DH, Staba MJ, Stellato KA, Bigelow K, Heimann R, Gately S, Dhanabal M, Soff GA, Sukhatme VP, Kufe DW, Weichselbaum RR. Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature 1998; 394: 287-91.
  • 68 Lannutti BJ, Gately ST, Quevedo ME, Soff GA, Paller AS. Human angiostatin inhibits murine hemangioendothelioma tumor growth in vivo. Cancer Res 1997; 57: 5277-80.
  • 69 Ji WR, Castellino FJ, Chang Y, Deford ME, Gray H, Villarreal X, Kondri ME, Marti DN, Llinas M, Schaller J, Kramer RA, Trail PA. Characterization of kringle domains of angiostatin as antagonists of endothelial cell migration, an important process in angiogenesis. Faseb J 1998; 12: 1731-8.
  • 70 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.
  • 71 Matsuda KM, Madoiwa S, Hasumi Y, Kanazawa T, Saga Y, Kume A, Mano H, Ozawa K, Matsuda M. A novel strategy for the tumor angiogenesis-targeted gene therapy: generation of angiostatin from endogenous plasminogen by protease gene transfer. Cancer Gene Ther 2000; 07: 589-96.
  • 72 Gorski DH, Mauceri HJ, Salloum RM, Gately S, Hellman S, Beckett MA, Sukhatme VP, Soff GA, Kufe DW, Weichselbaum RR. Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin. Cancer Res 1998; 58: 5686-9.
  • 73 Soff GA, Hong J, Fishman D, Schultz R, Cundiff DL, Park S, Enghild JJ, Stack MS, Gately S. Angiostatin 4.5: a naturally occurring human angiogenesis inhibitor. Proc Am Assoc Canc Res 1999; 40: 4088.
  • 74 Cao Y, Veitonmaki N, Keough K, Cheng H, Lee LS, Zurakowski D. Elevated levels of urine angiostatin and plasminogen/plasmin in cancer patients. Int J Mol Med 2000; 05: 547-51.
  • 75 Sack RA, Beaton AR, Sathe S. Diurnal variations in angiostatin in human tear fluid: a possible role in prevention of corneal neovascularization. Curr Eye Res 1999; 18: 186-93.
  • 76 Moser TL, Kenan DJ, Ashley TA, Roy JA, Goodman MD, Misra UK, Cheek DJ, Pizzo SV. Endothelial cell surface F1-FO ATP synthase is active in ATP synthesis and is inhibited by angiostatin. Proc Natl Acad Sci USA 2001; 98: 6656-61.
  • 77 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.
  • 78 Plopper GE, McNamee HP, Dike LE, Bojanowski K, Ingber DE. Convergence of integrin and growth factor receptor signaling pathways within the focal adhesion complex. Mol Biol Cell 1995; 06: 1349-65.
  • 79 Akasaka T, van Leeuwen RL, Yoshinaga IG, Mihm Jr MC, Byers HR. Focal adhesion kinase (p125FAK) expression correlates with motility of human melanoma cell lines. J Invest Dermatol 1995; 105: 104-8.
  • 80 Owen CS. Dependence of proton generation on aerobic or anaerobic metabolism and implications for tumour pH. Int J Hyperthermia 1996; 12: 495-9.
  • 81 Wike-Hooley JL, Van der Zee J, van Rhoon GC, Van den Berg AP, Reinhold HS. Human tumour pH changes following hyperthermia and radiation therapy. Eur J Cancer Clin Oncol 1984; 20: 619-23.
  • 82 Yamagata M, Tannock IF. The chronic administration of drugs that inhibit the regulation of intracellular pH: in vitro and anti-tumour effects. Br J Cancer 1996; 73: 1328-34.
  • 83 Wahl ML, Grant DS. Effects of microenvironmental extracellular pH and extracellular matrix proteins on angiostatin’s activity and on intracellular pH. J Gen Pharm (Vascular). in press 2001
  • 84 Wahl ML, Owen CS, Grant DS. Angiostatin induces intracellular acidosis and anoikis in endothelial cells at a tumor-like low pH. Submitted to Endothelium. 2001
  • 85 Baumgartner HR, Muggli R, Tschopp TB. Interaction of Platelets with subendothelium in flowing blood. John Wiley & Sons; Rehovot, Israel: 1980
  • 86 Hellem AJ. The adhesiveness of human blood platelets in vitro. Scandinavian Journal of Clinical and Laboratory Investigation 1960; 12.
  • 87 Ralevic V, Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev 1998; 50: 413-92.
  • 88 Dubyak GR, el-Moatassim C. Signal transduction via P2-purinergic receptors for extracellular ATP and other nucleotides. Am J Physiol 1993; 265: C577-606.
  • 89 Gonzalez-Gronow M, Gawdi G, Pizzo SV. Characterization of the plasminogen receptors of normal and rheumatoid arthritis human synovial fibroblasts. J Biol Chem 1994; 269: 4360-6.
  • 90 Jiang L, Jha V, Dhanabal M, Sukhatme VP, Alper SL. Intracellular Ca(2+) signaling in endothelial cells by the angiogenesis inhibitors endostatin and angiostatin. Am J Physiol Cell Physiol 2001; 280: C1140-50.
  • 91 Wahl ML, Page AR, Tootell M, Zahaczewsky M, Owen CS, Grant DS. Low extracellular pH promotes the anti-angiogenic response of endothelial cells to rh-angiostatin. Proc Am Assoc Canc 2001; 59.