angiostatins

Summary

Summary: Circulating 38-kDa proteins that are internal peptide fragments of PLASMINOGEN. The name derives from the fact that they are potent ANGIOGENESIS INHIBITORS. Angiostatins contain four KRINGLE DOMAINS which are associated with their potent angiostatic activity.

Top Publications

  1. Kang H, Bang W, Yu Y. Identification and characterization of a novel angiostatin-binding protein by the display cloning method. J Biochem Mol Biol. 2004;37:159-66 pubmed
    ..A Northern analysis indicated that the gene containing the angiostatin-binding sequence was expressed differentially in the developmental stages or cell types. ..
  2. te Velde E, Kusters B, Maass C, De Waal R, Borel Rinkes I. Histological analysis of defective colonic healing as a result of angiostatin treatment. Exp Mol Pathol. 2003;75:119-23 pubmed
  3. Peyruchaud O, Serre C, NicAmhlaoibh R, Fournier P, Clezardin P. Angiostatin inhibits bone metastasis formation in nude mice through a direct anti-osteoclastic activity. J Biol Chem. 2003;278:45826-32 pubmed
    ..Overall, these results indicate that, besides its well known anti-angiogenic activity, angiostatin must also be considered as a very effective inhibitor of bone resorption, broadening its potential clinical use in cancer therapy. ..
  4. Westphal J, Van t Hullenaar R, Peek R, Willems R, Crickard K, Crickard U, et al. Angiogenic balance in human melanoma: expression of VEGF, bFGF, IL-8, PDGF and angiostatin in relation to vascular density of xenografts in vivo. Int J Cancer. 2000;86:768-76 pubmed
    ..Inhibition of angiogenesis for therapeutic purposes, therefore, should preferably not concentrate on a single factor. ..
  5. Raikwar S, Temm C, Raikwar N, Kao C, Molitoris B, Gardner T. Adenoviral vectors expressing human endostatin-angiostatin and soluble Tie2: enhanced suppression of tumor growth and antiangiogenic effects in a prostate tumor model. Mol Ther. 2005;12:1091-100 pubmed
    ..These results suggest that a combinatorial antiangiogenic gene therapy approach involving Ad-hEndo-angio and Ad-sTie2 could become a novel form of treatment for localized human prostate cancer. ..
  6. Sharma M, Rothman V, Tuszynski G, Sharma M. Antibody-directed targeting of angiostatin's receptor annexin II inhibits Lewis Lung Carcinoma tumor growth via blocking of plasminogen activation: possible biochemical mechanism of angiostatin's action. Exp Mol Pathol. 2006;81:136-45 pubmed
    ..Plasmin is known to influence angiogenic, invasive and metastatic capability of tumors...
  7. Sharma M, Tuszynski G, Sharma M. Angiostatin-induced inhibition of endothelial cell proliferation/apoptosis is associated with the down-regulation of cell cycle regulatory protein cdk5. J Cell Biochem. 2004;91:398-409 pubmed
    ..These data suggest for the first time that neuron specific protein cdk5 may have significant role in the regulation of ECs proliferation, apoptosis, and angiogenesis and extends beyond its role in neurogenesis. ..
  8. Yang H, Xu Z, Iuvone P, Grossniklaus H. Angiostatin decreases cell migration and vascular endothelium growth factor (VEGF) to pigment epithelium derived factor (PEDF) RNA ratio in vitro and in a murine ocular melanoma model. Mol Vis. 2006;12:511-7 pubmed
    ..Angiostatin significantly decreases the ratio of VEGF/PEDF mRNA level in vitro and in hepatic micrometastatic melanoma cells. Angiostatin increases PEDF mRNA in melanoma metastases. ..
  9. Merchan J, Chan B, Kale S, Schnipper L, Sukhatme V. In vitro and in vivo induction of antiangiogenic activity by plasminogen activators and captopril. J Natl Cancer Inst. 2003;95:388-99 pubmed
    ..Treatment with rt-PA and captopril induced antiangiogenic activity in vitro and in vivo that appears to be independent of angiostatin. ..

More Information

Publications62

  1. Kim J, Ho S, Park E, Hahn W, Cho H, Jeong J, et al. Angiostatin gene transfer as an effective treatment strategy in murine collagen-induced arthritis. Arthritis Rheum. 2002;46:793-801 pubmed
    ..This suggests that transfer of the angiostatin gene, and potentially also its protein, may provide a new, effective approach to the treatment of rheumatoid arthritis. ..
  2. Claesson Welsh L, Welsh M, Ito N, Anand Apte B, Soker S, Zetter B, et al. Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD. Proc Natl Acad Sci U S A. 1998;95:5579-83 pubmed
  3. Wahl M, Moser T, Pizzo S. Angiostatin and anti-angiogenic therapy in human disease. Recent Prog Horm Res. 2004;59:73-104 pubmed
  4. Sima J, Zhang S, Shao C, Fant J, Ma J. The effect of angiostatin on vascular leakage and VEGF expression in rat retina. FEBS Lett. 2004;564:19-23 pubmed
    ..These results suggest that the effect of angiostatin on vascular leakage is mediated, at least in part, through blockade of VEGF overexpression. ..
  5. Hanford H, Wong C, Kassan H, Cundiff D, Chandel N, Underwood S, et al. Angiostatin(4.5)-mediated apoptosis of vascular endothelial cells. Cancer Res. 2003;63:4275-80 pubmed
    ..5) may function in vivo to block blood vessel formation by specifically inducing vascular endothelial cells to apoptose in a process likely involving both the intrinsic and extrinsic apoptosis pathways. ..
  6. Jurasz P, Santos Martinez M, Radomska A, Radomski M. Generation of platelet angiostatin mediated by urokinase plasminogen activator: effects on angiogenesis. J Thromb Haemost. 2006;4:1095-106 pubmed
    ..We conclude that; (i) platelets constitutively generate angiostatin on their membranes; (ii) this mechanism is dependent on uPA, but not, MMPs; and (iii) inhibition of platelet angiostatin generation can further promote angiogenesis. ..
  7. Gorski D, Mauceri H, Salloum R, Gately S, Hellman S, Beckett M, et al. Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin. Cancer Res. 1998;58:5686-9 pubmed
    ..001 compared with IR alone). These findings demonstrate that the efficacy of experimental radiation therapy is potentiated by brief concomitant exposure of the tumor vasculature to angiostatin. ..
  8. Prandini M, Desroches Castan A, Feraud O, Vittet D. No evidence for vasculogenesis regulation by angiostatin during mouse embryonic stem cell differentiation. J Cell Physiol. 2007;213:27-35 pubmed
    ..Taken together, these findings support a selective inhibitory effect on the sprouting angiogenesis response for angiostatin during embryonic vascular development. ..
  9. Nie S, Yuan S. Experimental study of gene therapy with angiostatin gene in pancreatic cancer. Hepatobiliary Pancreat Dis Int. 2002;1:452-7 pubmed
    ..This study demonstrated that the recombinant pRC/CMV-AS mediated by liposome may play a potential role in the treatment of pancreatic cancer in the future. ..
  10. de Groot Besseling R, Ruers T, van Kraats A, Poelen G, Ruiter D, de Waal R, et al. Anti-tumor activity of a combination of plasminogen activator and captopril in a human melanoma xenograft model. Int J Cancer. 2004;112:329-34 pubmed
    ..Administration of tPA alone had only a marginal effect on tumor growth. Captopril alone reduced tumor growth by about 60%, whereas treatment with both captopril and tPA resulted in 83% inhibition of tumor growth. ..
  11. Moser T, Stack M, Asplin I, Enghild J, Højrup P, Everitt L, et al. Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc Natl Acad Sci U S A. 1999;96:2811-6 pubmed
    ..Binding of angiostatin to the alpha/beta-subunits of ATP synthase on the cell surface may mediate its antiangiogenic effects and the down-regulation of endothelial cell proliferation and migration. ..
  12. Matsunaga T, Weihrauch D, Moniz M, Tessmer J, Warltier D, Chilian W. Angiostatin inhibits coronary angiogenesis during impaired production of nitric oxide. Circulation. 2002;105:2185-91 pubmed
    ..Our findings indicate that angiostatin inhibits coronary angiogenesis during compromised NO production and may underscore the impairment of coronary angiogenesis during endothelial dysfunction. ..
  13. Morikawa W, Yamamoto K, Ishikawa S, Takemoto S, Ono M, Fukushi J, et al. Angiostatin generation by cathepsin D secreted by human prostate carcinoma cells. J Biol Chem. 2000;275:38912-20 pubmed
  14. Ponnazhagan S, Mahendra G, Kumar S, Shaw D, Stockard C, Grizzle W, et al. Adeno-associated virus 2-mediated antiangiogenic cancer gene therapy: long-term efficacy of a vector encoding angiostatin and endostatin over vectors encoding a single factor. Cancer Res. 2004;64:1781-7 pubmed
  15. Jimenez B, Volpert O, Crawford S, Febbraio M, Silverstein R, Bouck N. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med. 2000;6:41-8 pubmed
    ..These results indicate that thrombospondin-1, and possibly other broad-spectrum natural inhibitors of angiogenesis, act in vivo by inducing receptor-mediated apoptosis in activated microvascular endothelial cells. ..
  16. Heidtmann H, Nettelbeck D, Mingels A, Jager R, Welker H, Kontermann R. Generation of angiostatin-like fragments from plasminogen by prostate-specific antigen. Br J Cancer. 1999;81:1269-73 pubmed
    ..This finding might help to understand growth characteristics of prostate cancer, which usually has low microvessel density and slow proliferation. ..
  17. Scapini P, Nesi L, Morini M, Tanghetti E, Belleri M, Noonan D, et al. Generation of biologically active angiostatin kringle 1-3 by activated human neutrophils. J Immunol. 2002;168:5798-804 pubmed
  18. Wajih N, Sane D. Angiostatin selectively inhibits signaling by hepatocyte growth factor in endothelial and smooth muscle cells. Blood. 2003;101:1857-63 pubmed
    ..Soluble c-met, produced by several tumor cell lines, could inhibit the antiangiogenic effect of angiostatin. The disruption of HGF/c-met signaling is a novel mechanism for the antiangiogenic effect of angiostatin. ..
  19. Galaup A, Opolon P, Bouquet C, Li H, Opolon D, Bissery M, et al. Combined effects of docetaxel and angiostatin gene therapy in prostate tumor model. Mol Ther. 2003;7:731-40 pubmed
    ..Our experimental data show that attacking both endothelial and tumoral compartments is an efficient and logical strategy, making this bitherapy approach clinically promising. ..
  20. Scappaticci F, Smith R, Pathak A, Schloss D, Lum B, Cao Y, et al. Combination angiostatin and endostatin gene transfer induces synergistic antiangiogenic activity in vitro and antitumor efficacy in leukemia and solid tumors in mice. Mol Ther. 2001;3:186-96 pubmed
    ..The data also suggest that novel combinations of antiangiogenic factors delivered into tumors require further investigation as therapeutic modalities. ..
  21. Matsunaga T, Chilian W, March K. Angiostatin is negatively associated with coronary collateral growth in patients with coronary artery disease. Am J Physiol Heart Circ Physiol. 2005;288:H2042-6 pubmed
    ..Perhaps therapies attempting to provoke coronary collateral growth should incorporate approaches to limit or neutralize the effects of growth inhibitors. ..
  22. Yamahara K, Min K, Tomoike H, Kangawa K, Kitamura S, Nagaya N. Pathological role of angiostatin in heart failure: an endogenous inhibitor of mesenchymal stem-cell activation. Heart. 2009;95:283-9 pubmed publisher
    ..The results suggest that angiostatin, which can attenuate the activity of MSC, might play a role in the progression of HF. ..
  23. Agarwal A, Munoz Najar U, Klueh U, Shih S, Claffey K. N-acetyl-cysteine promotes angiostatin production and vascular collapse in an orthotopic model of breast cancer. Am J Pathol. 2004;164:1683-96 pubmed
    ..These results suggest that systemic NAC therapy promotes anti-angiogenesis through angiostatin production, resulting in endothelial apoptosis and vascular collapse in the tumor. ..
  24. Benelli R, Morini M, Carrozzino F, Ferrari N, Minghelli S, Santi L, et al. Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation. FASEB J. 2002;16:267-9 pubmed
    ..These data show that angiostatin directly inhibits neutrophil migration and neutrophil-mediated angiogenesis and indicate that angiostatin might inhibit inflammation. ..
  25. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27-31 pubmed
    ..The extent to which the negative regulators are decreased during this switch may dictate whether a primary tumour grows rapidly or slowly and whether metastases grow at all. ..
  26. Goretzki L, Lombardo C, Stallcup W. Binding of the NG2 proteoglycan to kringle domains modulates the functional properties of angiostatin and plasmin(ogen). J Biol Chem. 2000;275:28625-33 pubmed
    ..Both of these effects of NG2 should make the proteoglycan a positive regulator of the cell migration and proliferation required for angiogenesis. ..
  27. Stack M, Gately S, Bafetti L, Enghild J, Soff G. Angiostatin inhibits endothelial and melanoma cellular invasion by blocking matrix-enhanced plasminogen activation. Biochem J. 1999;340 ( Pt 1):77-84 pubmed
  28. Uesato M, Gunji Y, Tomonaga T, Miyazaki S, Shiratori T, Matsubara H, et al. Synergistic antitumor effect of antiangiogenic factor genes on colon 26 produced by low-voltage electroporation. Cancer Gene Ther. 2004;11:625-32 pubmed
    ..These data suggest that in vivo delivery of antiangiogenic genes with low-voltage electroporation could be a possible therapeutic strategy for established solid tumors when both genes were applied in combination. ..
  29. Chavakis T, Athanasopoulos A, Rhee J, Orlova V, Schmidt Wöll T, Bierhaus A, et al. Angiostatin is a novel anti-inflammatory factor by inhibiting leukocyte recruitment. Blood. 2005;105:1036-43 pubmed
    ..These observations could provide the basis for new therapeutic applications of angiostatin to target chronic inflammatory processes in different pathologic situations. ..
  30. Igarashi T, Miyake K, Kato K, Watanabe A, Ishizaki M, Ohara K, et al. Lentivirus-mediated expression of angiostatin efficiently inhibits neovascularization in a murine proliferative retinopathy model. Gene Ther. 2003;10:219-26 pubmed
    ..These data suggest that the anti-angiogenic activity of angiostatin has therapeutic potential for the treatment of retinal neovascularization. ..
  31. Moulton K, Vakili K, Zurakowski D, Soliman M, Butterfield C, Sylvin E, et al. Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci U S A. 2003;100:4736-41 pubmed
    ..Inhibition of plaque angiogenesis and the secondary reduction of macrophages may have beneficial effects on plaque stability. ..
  32. O Reilly M, Holmgren L, Shing Y, Chen C, Rosenthal R, Moses M, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994;79:315-28 pubmed
    ..We here show that the inhibition of metastases by a primary mouse tumor is mediated, at least in part, by angiostatin. ..
  33. te Velde E, Vogten J, Gebbink M, van Gorp J, Voest E, Borel Rinkes I. Enhanced antitumour efficacy by combining conventional chemotherapy with angiostatin or endostatin in a liver metastasis model. Br J Surg. 2002;89:1302-9 pubmed
    ..5 per cent (P < 0.001). The addition of angiostatin or endostatin to conventional chemotherapy enhanced antitumoral efficacy in a murine model of early colorectal liver metastasis. ..
  34. Cao Y, Ji R, Davidson D, Schaller J, Marti D, Söhndel S, et al. Kringle domains of human angiostatin. Characterization of the anti-proliferative activity on endothelial cells. J Biol Chem. 1996;271:29461-7 pubmed
    ..However, as we also demonstrate, appropriate folding of kringle structures is essential for angiostatin to maintain its full anti-endothelial activity. ..
  35. Sima J, Ma J, Zhang S, Guo J. Study of the influence of angiostatin intravitreal injection on vascular leakage in retina and iris of the experimental diabetic rats. Yan Ke Xue Bao. 2006;22:252-8 pubmed
    ..Therefore, angiostatin may have a therapeutic potential in the treatment of diabetic macular edema, cystoid macular edema, uveitis and other diseases with vascular leakage. ..
  36. Moser T, Kenan D, Ashley T, Roy J, Goodman M, Misra U, et al. Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin. Proc Natl Acad Sci U S A. 2001;98:6656-61 pubmed
    ..We now have shown that antibodies directed against subunits of ATP synthase exhibit endothelial cell-inhibitory activities comparable to that of angiostatin, indicating that these antibodies function as angiostatin mimetics. ..
  37. Jurasz P, Ng D, Granton J, Courtman D, Stewart D. Elevated platelet angiostatin and circulating endothelial microfragments in idiopathic pulmonary arterial hypertension: a preliminary study. Thromb Res. 2010;125:53-60 pubmed publisher
    ..These results are consistent with an increase in EC dysfunction in patients with IPAH, possibly contributing to the progression of IPAH and its associated thrombosis. ..
  38. Jurasz P, Alonso D, Castro Blanco S, Murad F, Radomski M. Generation and role of angiostatin in human platelets. Blood. 2003;102:3217-23 pubmed
    ..We conclude that healthy human platelets contain angiostatin, which is released in active form during platelet aggregation, and platelet-derived angiostatin has the capacity to inhibit angiogenesis. ..
  39. Li X, Liu Y, Lee S, Gardner T, Jeng M, Kao C. Prostate-restricted replicative adenovirus expressing human endostatin-angiostatin fusion gene exhibiting dramatic antitumor efficacy. Clin Cancer Res. 2008;14:291-9 pubmed publisher
    ..This novel antiangiogenic PRRA represents a powerful agent feasible for future clinical trials for prostate cancer therapy. ..
  40. Bussolino F, Mantovani A, Persico G. Molecular mechanisms of blood vessel formation. Trends Biochem Sci. 1997;22:251-6 pubmed
    ..Changes in the relative balance of inducers and inhibitors activate the 'angiogenic switch', before stabilizer molecules activate the maturation of nascent blood vessels. ..
  41. Cao Y, O Reilly M, Marshall B, Flynn E, Ji R, Folkman J. Expression of angiostatin cDNA in a murine fibrosarcoma suppresses primary tumor growth and produces long-term dormancy of metastases. J Clin Invest. 1998;101:1055-63 pubmed
    ..Our data may also provide a novel approach for cancer therapy by antiangiogenic gene therapy with a specific angiogenesis inhibitor. ..
  42. Satchi Fainaro R, Mamluk R, Wang L, Short S, Nagy J, Feng D, et al. Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin. Cancer Cell. 2005;7:251-61 pubmed
    ..This activity likely contributes to TNP-470's antiangiogenic effect and suggests that caplostatin can be used in the treatment of cancer and inflammation. ..
  43. Weiss J, Shivakumar R, Feller S, Li L, Hanson A, Fogler W, et al. Rapid, in vivo, evaluation of antiangiogenic and antineoplastic gene products by nonviral transfection of tumor cells. Cancer Gene Ther. 2004;11:346-53 pubmed
    ..The consistency of our transfection results highlight the feasibility of directly electroporating tumor cells as a means to screen, identify, and validate in vivo potentially novel antiangiogenic and/or antineoplastic genes. ..
  44. Wahl M, Kenan D, Gonzalez Gronow M, Pizzo S. Angiostatin's molecular mechanism: aspects of specificity and regulation elucidated. J Cell Biochem. 2005;96:242-61 pubmed
  45. Cao Y, Chen A, An S, Ji R, Davidson D, Llinas M. Kringle 5 of plasminogen is a novel inhibitor of endothelial cell growth. J Biol Chem. 1997;272:22924-8 pubmed
    ..Thus, kringle 5 domain of human plasminogen is a novel endothelial inhibitor that is sufficiently potent to block the growth factor-stimulated endothelial cell growth. ..
  46. Abad M, Arni R, Grella D, Castellino F, Tulinsky A, Geiger J. The X-ray crystallographic structure of the angiogenesis inhibitor angiostatin. J Mol Biol. 2002;318:1009-17 pubmed
    ..Together the three kringles produce a central cavity suggestive of a unique domain where they may function in concert. ..
  47. Scappaticci F, Contreras A, Smith R, Bonhoure L, Lum B, Cao Y, et al. Statin-AE: a novel angiostatin-endostatin fusion protein with enhanced antiangiogenic and antitumor activity. Angiogenesis. 2001;4:263-8 pubmed
    ..The fusion gene demonstrates significantly greater inhibition of tumor growth compared with angiostatin, endostatin or the combination of genes. ..
  48. Mulligan Kehoe M, Wagner R, Wieland C, Powell R. A truncated plasminogen activator inhibitor-1 protein induces and inhibits angiostatin (kringles 1-3), a plasminogen cleavage product. J Biol Chem. 2001;276:8588-96 pubmed
    ..In a second mechanism, rPAI-1(23) can bind uPA and/or plasminogen to reduce the number of uPA and plasminogen interactions, hence reducing the amount of plasmin that is produced. ..
  49. Ji W, Castellino F, Chang Y, Deford M, Gray H, Villarreal X, et al. Characterization of kringle domains of angiostatin as antagonists of endothelial cell migration, an important process in angiogenesis. FASEB J. 1998;12:1731-8 pubmed
    ..Our data suggest that different kringle domains may contribute to the overall anti-angiogenic function of angiostatin by their distinct anti-migratory activities. ..
  50. Troyanovsky B, Levchenko T, Månsson 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 pubmed
    ..These findings indicate that angiostatin inhibits cell migration by interfering with angiomotin activity in endothelial cells. ..
  51. Patterson B, Sang Q. Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9). J Biol Chem. 1997;272:28823-5 pubmed
    ..These results indicate that MMP-7 and MMP-9 may regulate new blood vessel formation by cleaving plasminogen and generating angiostatin molecules. ..
  52. Gorrin Rivas M, Arii S, Mori A, Kaneda Y, Imamura M. Mouse macrophage metalloelastase gene delivery by HVJ-cationic liposomes in experimental antiangiogenic gene therapy for murine CT-26 colon cancer. Int J Cancer. 2001;93:731-5 pubmed
  53. Lai C, Wu W, Chen S, Xiao X, Tsai T, Huan S, et al. Suppression of choroidal neovascularization by adeno-associated virus vector expressing angiostatin. Invest Ophthalmol Vis Sci. 2001;42:2401-7 pubmed
    ..This and the absence of apoptosis and inflammation in chorioretinal tissue indicate the feasibility of a gene therapy approach for treatment of CNV disease. ..