Antiangiogenic Antithrombin

 

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ABSTRACT

Angiogenesis is critical for several physiologic and pathophysiologic processes, and several angiogenesis inhibitors are now in clinical trials for the treatment of cancer. Antithrombin is a member of the serpin family of proteins and functions as an inhibitor of thrombin and other enzymes involved in the clotting cascade. While studying the inhibition of tumor growth by tumor mass in a human small cell lung cancer model, we discovered that the cleaved conformation of antithrombin has potent antiangiogenic and antitumor activity. The stable locked and latent forms of intact antithrombin, which are substantially similar in conformation to the cleaved form of the molecule, also inhibit angiogenesis and tumor growth in vivo and act selectively upon endothelial cells and the tumor vasculature. The intact native molecule does not have this effect. The discovery of antiangiogenic antithrombin provides further evidence that the clotting and fibrinolytic pathways are directly related to the regulation of angiogenesis. As for other endogenous angiogenesis inhibitors, the precise mechanism of action for antiangiogenic antithrombin has not been defined, but several studies now suggest that it may target the endothelial cell at multiple levels resulting in a profound blockade of the angiogenic cascade. In this paper, an overview of the angiogenesis inhibitor antiangiogenic antithrombin and a summary of the pertinent literature are provided.

REFERENCES

• 1 Folkman J. Tumor angiogenesis: therapeutic implications.  N Engl J Med. 1971;  285 1182-1186
  CrossrefPubMedGoogle Scholar
• 2 Fidler I J, Kerbel R S, Ellis L M. Biology of cancer: angiogenesis. In: DeVita VT, Hellman S, Rosenberg SA Cancer Principles and Practice of Oncology. 6th ed. Philadelphia, PA; Lippincott Williams & Wilkins 2001: 137-147
  Google Scholar
• 3 Dvorak H F. Tumors: wounds that do not heal.  N Engl J Med. 1986;  315 1650-1659
  CrossrefPubMedGoogle Scholar
• 4 Jain R K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.  Science. 2005;  307 58-62
  CrossrefPubMedGoogle Scholar
• 5 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease.  Nat Med. 1995;  1 27-31
  CrossrefPubMedGoogle Scholar
• 6 Good D J, Polverini P J, Rastinejad F et al.. A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin.  Proc Natl Acad Sci USA. 1990;  87 6624-6628
  PubMedGoogle Scholar
• 7 Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.  Cell. 1996;  86 353-364
  CrossrefPubMedGoogle Scholar
• 8 Sund M, Hamano Y, Sugimoto H et al.. Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors.  Proc Natl Acad Sci USA. 2005;  102 2934-2939
  CrossrefPubMedGoogle Scholar
• 9 Hurwitz H, Fehrenbacher L, Novotny W et al.. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.  N Engl J Med. 2004;  350 2335-2342
  CrossrefPubMedGoogle Scholar
• 10 Miller K D, Sledge Jr G W, Burstein H J. Angiogenesis inhibition in the treatment of breast cancer: a review of studies presented at the 2006 San Antonio breast cancer symposium.  Clin Adv Hematol Oncol. 2007;  5 1-12
  PubMedGoogle Scholar
• 11 Sandler A, Gray R, Perry M C et al.. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.  N Engl J Med. 2006;  355 2542-2550
  CrossrefPubMedGoogle Scholar
• 12 Beerepoot L V, Witteveen E O, Groenewegen G et al.. Recombinant human angiostatin by twice-daily subcutaneous injection in advanced cancer: a pharmacokinetic and long-term safety study.  Clin Cancer Res. 2003;  9 4025-4033
  PubMedGoogle Scholar
• 13 Herbst R S, Hess K R, Tran H T et al.. Phase I study of recombinant human endostatin in patients with advanced solid tumors.  J Clin Oncol. 2002;  20 3792-3803
  CrossrefPubMedGoogle Scholar
• 14 Kulke M H, Bergsland E K, Ryan D P et al.. Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors.  J Clin Oncol. 2006;  24 3555-3561
  CrossrefPubMedGoogle Scholar
• 15 Kurup A, Lin C W, Murry D J et al.. Recombinant human angiostatin (rhAngiostatin) in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer: a phase II study from Indiana University.  Ann Oncol. 2006;  17 97-103
  CrossrefPubMedGoogle Scholar
• 16 O'Reilly M S, Fidler I J. The development of antiangiogenic agents for the clinic. In: DeVita VT, Hellman S, Rosenberg SA Progress in Oncology 2002. Sudbury, MA; Jones and Bartlett 2002: 129-157
  Google Scholar
• 17 Camphausen K, Moses M A, Beecken W D et al.. Radiation therapy to a primary tumor accelerates metastatic growth in mice.  Cancer Res. 2001;  61 2207-2211
  PubMedGoogle Scholar
• 18 Gorelik E. Concomitant tumor immunity and the resistance to a second tumor challenge.  Adv Cancer Res. 1983;  39 71-120
  PubMedGoogle Scholar
• 19 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
  CrossrefPubMedGoogle Scholar
• 20 Prehn R T. The inhibition of tumor growth by tumor mass.  Cancer Res. 1991;  51 2-4
  PubMedGoogle Scholar
• 21 O'Reilly M S, Boehm T, Shing Y et al.. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.  Cell. 1997;  88 277-285
  CrossrefPubMedGoogle Scholar
• 22 O'Reilly M S, Pirie-Shepherd S, Lane W S, Folkman J. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin.  Science. 1999;  285 1926-1928
  CrossrefPubMedGoogle Scholar
• 23 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
  CrossrefPubMedGoogle Scholar
• 24 O'Reilly M S, Wiederschain D, Stetler-Stevenson W G, Folkman J, Moses M A. Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance.  J Biol Chem. 1999;  274 29568-29571
  CrossrefPubMedGoogle Scholar
• 25 Evans D L, Marshall C J, Christey P B, Carrell R W. Heparin binding site, conformational change, and activation of antithrombin.  Biochemistry. 1992;  31 12629-12642
  CrossrefPubMedGoogle Scholar
• 26 Mourey L, Samama J, Delarue M et al.. Crystal structure of cleaved bovine antithrombin III at 3.2 angstrom resolution.  J Mol Biol. 1993;  232 223-241
  CrossrefPubMedGoogle Scholar
• 27 Sasaki T, Larsson H, Tisi D et al.. Endostatins derived from collagens XV and XVIII differ in structural and binding properties, tissue distribution and anti-angiogenic activity.  J Mol Biol. 2000;  301 1179-1190
  CrossrefPubMedGoogle Scholar
• 28 Pike S E, Yao L, Jones K D et al.. Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth.  J Exp Med. 1998;  188 2349-2356
  CrossrefPubMedGoogle Scholar
• 29 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
  CrossrefPubMedGoogle Scholar
• 30 Maeshima Y, Colorado P C, Torre A et al.. Distinct antitumor properties of a type IV collagen domain derived from basement membrane.  J Biol Chem. 2000;  275 21340-21348
  CrossrefPubMedGoogle Scholar
• 31 Colorado P C, Torre A, Kamphaus G et al.. Anti-angiogenic cues from vascular basement membrane collagen.  Cancer Res. 2000;  60 2520-2526
  PubMedGoogle Scholar
• 32 Yi M, Ruoslahti E. A fibronectin fragment inhibits tumor growth, angiogenesis, and metastasis.  Proc Natl Acad Sci USA. 2001;  98 620-624
  CrossrefPubMedGoogle Scholar
• 33 Clapp C, Martial J A, Guzman R C, Rentier-Delure F, Weiner R I. The 16-kilodalton N-terminal fragment of human prolactin is a potent inhibitor of angiogenesis.  Endocrinology. 1993;  133 1292-1299
  CrossrefPubMedGoogle Scholar
• 34 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
  PubMedGoogle Scholar
• 35 Ge G, Fernandez C A, Moses M A, Greenspan D S. Bone morphogenetic protein 1 processes prolactin to a 17-kDa antiangiogenic factor.  Proc Natl Acad Sci USA. 2007;  104 10010-10015
  CrossrefPubMedGoogle Scholar
• 36 Jiang W G, Hiscox S E, Parr C et al.. Antagonistic effect of NK4, a novel hepatocyte growth factor variant, on in vitro angiogenesis of human vascular endothelial cells.  Clin Cancer Res. 1999;  5 3695-3703
  PubMedGoogle Scholar
• 37 Colman R W, Jameson B A, Lin Y, Johnson D, Mousa S A. Domain 5 of high molecular weight kininogen (kininostatin) down-regulates endothelial cell proliferation and migration and inhibits angiogenesis.  Blood. 2000;  95 543-550
  PubMedGoogle Scholar
• 38 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
  CrossrefPubMedGoogle Scholar
• 39 Tolsma S S, Volpert O V, Good D J et al.. Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity.  J Cell Biol. 1993;  122 497-511
  CrossrefPubMedGoogle Scholar
• 40 Rusk A, McKeegan E, Haviv F et al.. Preclinical evaluation of antiangiogenic thrombospondin-1 peptide mimetics, ABT-526 and ABT-510, in companion dogs with naturally occurring cancers.  Clin Cancer Res. 2006;  12 7444-7455
  CrossrefPubMedGoogle Scholar
• 41 Gupta S K, Hassel T, Singh J P. A potent inhibitor of endothelial cell proliferation is generated by proteolytic cleavage of the chemokine platelet factor 4.  Proc Natl Acad Sci USA. 1995;  92 7799-7803
  PubMedGoogle Scholar
• 42 Liotta L A, Stetler-Stevenson W G, Steeg P S. Cancer invasion and metastasis: positive and negative regulatory elements.  Cancer Invest. 1991;  9 543-551
  PubMedGoogle Scholar
• 43 Stetler-Stevenson W G. Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention.  J Clin Invest. 1999;  103 1237-1241
  PubMedGoogle Scholar
• 44 Mourey L, Samama J P, Delarue M et al.. Antithrombin III: structural and functional aspects.  Biochimie. 1990;  72 599-608
  CrossrefPubMedGoogle Scholar
• 45 Pratt C W, Church F C. Antithrombin: structure and function.  Semin Hematol. 1991;  28 3-9
  PubMedGoogle Scholar
• 46 Carrell R W, Evans D L, Stein P E. Mobile reactive centre of serpins and the control of thrombosis.  Nature. 1991;  353 576-578
  CrossrefPubMedGoogle Scholar
• 47 Huntington J A, Gettins P GW. Conformational conversion of antithrombin to a fully activated substrate of factor Xa without need for heparin.  Biochemistry. 1998;  37 3272-3277
  CrossrefPubMedGoogle Scholar
• 48 Schreuder H A, de Boer B, Dijkema R et al.. The intact and cleaved human antithrombin III complex as a model for serpin-proteinase interactions.  Nat Struct Biol. 1994;  1 48-54
  CrossrefPubMedGoogle Scholar
• 49 Wardell M R, Chang W W, Bruce D et al.. Preparative induction and characterization of L-antithrombin: a structural homologue of latent plasminogen activator inhibitor-1.  Biochemistry. 1997;  36 13133-13142
  CrossrefPubMedGoogle Scholar
• 50 Kisker O, Onizuka S, Banyard J et al.. Generation of multiple angiogenesis inhibitors by human pancreatic cancer.  Cancer Res. 2001;  61 7298-7304
  PubMedGoogle Scholar
• 51 Prox D, Becker C, Pirie-Shepherd S R et al.. Treatment of human pancreatic cancer in mice with angiogenic inhibitors.  World J Surg. 2003;  27 405-411
  CrossrefPubMedGoogle Scholar
• 52 Larsson H, Sjoblom T, Dixelius J et al.. Antiangiogenic effects of latent antithrombin through perturbed cell-matrix interactions and apoptosis of endothelial cells.  Cancer Res. 2000;  60 6723-6729
  PubMedGoogle Scholar
• 53 Larsson H, Akerud P, Nordling K et al.. A novel anti-angiogenic form of antithrombin with retained proteinase binding ability and heparin affinity.  J Biol Chem. 2001;  276 11996-12002
  CrossrefPubMedGoogle Scholar
• 54 Caunt M, Hu L, Tang T et al.. Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis.  Cancer Res. 2006;  66 4125-4132
  CrossrefPubMedGoogle Scholar
• 55 Mohle R, Green D, Moore M A, Nachman R L, Rafii S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets.  Proc Natl Acad Sci USA. 1997;  94 663-668
  CrossrefPubMedGoogle Scholar
• 56 Huang Y Q, Li J J, Hu L, Lee M, Karpatkin S. Thrombin induces increased expression and secretion of VEGF from human FS4 fibroblasts, DU145 prostate cells and CHRF megakaryocytes.  Thromb Haemost. 2001;  86 1094-1098
  PubMedGoogle Scholar
• 57 Tsopanoglou N E, Maragoudakis M E. On the mechanism of thrombin-induced angiogenesis. Potentiation of vascular endothelial growth factor activity on endothelial cells by up-regulation of its receptors.  J Biol Chem. 1999;  274 23969-23976
  CrossrefPubMedGoogle Scholar
• 58 Lockwood C J, Toti P, Arcuri F et al.. Thrombin regulates soluble fms-like tyrosine kinase-1 (sFlt-1) expression in first trimester decidua: implications for preeclampsia.  Am J Pathol. 2007;  170 1398-1405
  CrossrefPubMedGoogle Scholar
• 59 Zhang W, Chuang Y J, Jin T et al.. Antiangiogenic antithrombin induces global changes in the gene expression profile of endothelial cells.  Cancer Res. 2006;  66 5047-5055
  CrossrefPubMedGoogle Scholar
• 60 Crum R, Szabo S, Folkman J. A new class of steroids inhibits angiogenesis in the presence of heparin or a heparin fragment.  Science. 1985;  230 1375-1378
  PubMedGoogle Scholar
• 61 Folkman J, Weisz P B, Joullie M M, Li W W, Ewing W R. Control of angiogenesis with synthetic heparin substitutes.  Science. 1989;  243 1490-1493
  PubMedGoogle Scholar
• 62 Zhang W, Chuang Y J, Swanson R et al.. Antiangiogenic antithrombin down-regulates the expression of the proangiogenic heparan sulfate proteoglycan, perlecan, in endothelial cells.  Blood. 2004;  103 1185-1191
  PubMedGoogle Scholar
• 63 Zhang W, Swanson R, Xiong Y, Richard B, Olson S T. Antiangiogenic antithrombin blocks the heparan sulfate-dependent binding of proangiogenic growth factors to their endothelial cell receptors: evidence for differential binding of antiangiogenic and anticoagulant forms of antithrombin to proangiogenic heparan sulfate domains.  J Biol Chem. 2006;  281 37302-37310
  CrossrefPubMedGoogle Scholar
• 64 Yi M, Sakai T, Fassler R, Ruoslahti E. Antiangiogenic proteins require plasma fibronectin or vitronectin for in vivo activity.  Proc Natl Acad Sci USA. 2003;  100 11435-11438
  CrossrefPubMedGoogle Scholar
• 65 Zacharski L R. Small cell carcinoma of the lung: interaction with the blood coagulation mechanism and treatment with anticoagulants.  Onkologie. 1987;  10 264-270
  PubMedGoogle Scholar
• 66 Zacharski L R, Memoli V A, Rousseau S M, Kisiel W. Occurrence of blood coagulation factors in situ in small cell carcinoma of the lung.  Cancer. 1987;  60 2675-2681
  CrossrefPubMedGoogle Scholar
• 67 Akiyama K, Nakamura K, Makino I et al.. Antithrombin III producing hepatocellular carcinoma.  Thromb Res. 1993;  72 193-201
  CrossrefPubMedGoogle Scholar
• 68 Cao Y, Lundwall A, Gadaleanu V, Lilja H, Bjartell A. Anti-thrombin is expressed in the benign prostatic epithelium and in prostate cancer and is capable of forming complexes with prostate- specific antigen and human glandular kallikrein 2.  Am J Pathol. 2002;  161 2053-2063
  PubMedGoogle Scholar
• 69 Laschke M W, Cengiz Z, Hoffmann J N, Menger M D, Vollmar B. Latent antithrombin does not affect physiological angiogenesis: an in vivo study on vascularization of grafted ovarian follicles.  Life Sci. 2004;  75 203-213
  CrossrefPubMedGoogle Scholar
• 70 Browder T, Folkman J, Pirie-Shepherd S. The hemostatic system as a regulator of angiogenesis.  J Biol Chem. 2000;  275 1521-1524
  CrossrefPubMedGoogle Scholar
• 71 O'Reilly M S. Antiangiogenesis: basic principles. In: Rosenberg SA Principles and Practice of the Biologic Therapy of Cancer. 3rd ed. Philadelphia, PA; Lippincott Williams & Wilkins 2000: 827-843
  Google Scholar
• 72 Camphausen K, Purow B, Sproull M et al.. Influence of in vivo growth on human glioma cell line gene expression: convergent profiles under orthotopic conditions.  Proc Natl Acad Sci USA. 2005;  102 8287-8292
  CrossrefPubMedGoogle Scholar
• 73 Fidler I J, Kim S J, Langley R R. The role of the organ microenvironment in the biology and therapy of cancer metastasis.  J Cell Biochem. 2007;  101 927-936
  CrossrefPubMedGoogle Scholar
• 74 Nakamura T, Fidler I J, Coombes K R. Gene expression profile of metastatic human pancreatic cancer cells depends on the organ microenvironment.  Cancer Res. 2007;  67 139-148
  CrossrefPubMedGoogle Scholar

Michael S O'ReillyM.D. 

Department of Radiation Oncology, Unit 97, University of Texas M. D. Anderson Cancer Center

1515 Holcombe Boulevard, Houston, TX 77030

Email: moreilly@mdanderson.org