Interfering with Hemostatic System Components: Possible New Approaches to Antiangiogenic Therapy

Inhibition of angiogenesis has progressed from a theoretical and esoteric discipline scrutinized in but a few laboratories far removed from the clinic, to mainstream experimental clinical cancer therapeutics. Dramatic progress in this field represents a triumph of the concept of translational biomedical research. Growth of knowledge in this discipline has brought to light a bewildering yet tantalizing array of interacting enzymatic algorithms that participate in the highly orchestrated process of new blood vessel formation critical for tumor growth and dissemination. It is clear that pathways of blood coagulation (in broad context) and angiogenesis are inextricably linked. The facts that much is already known about many components of these pathways and that stalling of tumor growth has already been demonstrated for several interventions aimed at participants in these reactions send a clear signal that more effective and less toxic cancer therapy may be at hand in the near future. There is no lack of candidate targets for intervention brought to light by preclinical scientists. Numerous well-characterized investigational agents are on hand for testing. The challenge is clearly in the hands of the clinical investigators to proceed with human intervention studies while armed with knowledge of opportunities and pitfalls that should guide insightful clinical trial design. A particularly compelling feature of this treatment paradigm is that it is not aimed directly at distruction of tumor through inhibition of the DNA replication machinery of the cell. Rather it is aimed at restoring the normal state by modulating the dysregulated interaction of tumor cells with their environment that is characteristic of cancer.

KEYWORDS

Cancer - hemostasis - angiogenesis - cancer therapy - angiogenesis inhibitors

REFERENCES

• 1 Folkman J. Tumor angiogenesis: therapeutic implications.  N Engl J Med. 1971;  285 1182-1186
• 2 Folkman J, Browder T, Palmblad J. Angiogenesis research: guidelines for translation to the clinic.  Thromb Haemost. 2001;  86 23-33
• 3 Holash J, Maisonpierre P C, Compton D et al.. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF.  Science. 1999;  284 1994-1998
• 4 Dvorak H F. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy.  J Clin Oncol. 2002;  20 4368-4380
• 5 Lyden D, Hattori K, Dias S et al.. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth.  Nat Med. 2001;  7 1194-1201
• 6 Rak J W, St Croix B D, Kerbel R S. Consequences of angiogenesis for tumor progression, metastasis and cancer therapy.  Anticancer Drugs. 1995;  6 3-18
• 7 Wojtukiewicz M Z, Sierko E, Klement P, Rak J. The hemostatic system and angiogenesis in malignancy.  Neoplasia. 2001;  3 371-384
• 8 Holmgren L, O'Reilly M S, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression.  Nat Med. 1995;  1 149-153
• 9 O'Reilly M S, Boehm T, Shing Y et al.. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.  Cell. 1997;  88 277-285
• 10 Dameron K M, Volpert O V, Tainsky M A, Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1.  Science. 1994;  265 1582-1584
• 11 Kerbel R S. Inhibition of tumor angiogenesis as a strategy to circumvent resistance to anticancer therapeutic agents.  Bioessays. 1991;  13 31-36
• 12 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
• 13 Yang J C, Haworth L, Sherry R M et al.. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.  N Engl J Med. 2003;  349 427-434
• 14 Kuenen B C, Tabernero J, Baselga J et al.. Efficacy and toxicity of the angiogenesis inhibitor SU5416 as a single agent in patients with advanced renal cell carcinoma, melanoma, and soft tissue sarcoma.  Clin Cancer Res. 2003;  9 1648-1655
• 15 Albanell J, Codony J, Rovira A et al.. Mechanism of action of anti-HER2 monoclonal antibodies: scientific update on trastuzumab and 2C4.  Adv Exp Med Biol. 2003;  532 253-268
• 16 Hurwitz H, Fehrenbacher L, Cartwright T et al.. Bevacizumab (Avastin, a monoclonal antibody to vascular endothelial growth factor) prolongs survival in first-line colorectal cancer (CRC): results of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin) as first-line therapy in subjects with metastatic CRC. In: Program and abstracts of the 39th Annual Meeting of the American Society of Clinical Oncology; May 31-June 3, 2003; Chicago, IL;
• 17 Burstein H J, Parker L M, Savoie J et al.. Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer. In: Program and abstracts of the 25th Annual San Antonio Breast Cancer Symposium; December 11-14, 2002; San Antonio, TX;
• 18 Viloria-Petit A, Crombet T, Jothy S et al.. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis.  Cancer Res. 2001;  61 5090-5101
• 19 Relf M, LeJeune S, Scott P A et al.. Expression of the angiogenic factors vascular endothelial 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
• 20 Yu J L, Rak J W, Carmeliet P, Nagy A, Kerbel R S, Coomber B L. Heterogeneous vascular dependence of tumor cell populations.  Am J Pathol. 2001;  158 1325-1334
• 21 Kerbel R S, Yu J, Tran J et al.. Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches.  Cancer Metastasis Rev. 2001;  20 79-86
• 22 Kerbel R S, Viloria-Petit A, Klement G, Rak J. ‘Accidental’ anti-angiogenic drugs, anti-oncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples.  Eur J Cancer. 2000;  36 1248-1257
• 23 Hahnfeldt P, Folkman J, Hlatky L. Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis.  J Theor Biol. 2003;  220 545-554
• 24 Cao Y. Endogenous angiogenesis inhibitors: angiostatin, endostatin and other proteolytic fragments.  Prog Mol Subcell Biol. 1998;  20 161-176
• 25 O'Reilly M S, Holmgren L, Shing Y et al.. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by Lewis lung carcinoma.  Cell. 1994;  79 315-328
• 26 Jung S P, Siegrist B, Hornick C A et al.. Effect of human recombinant Endostatin protein on human angiogenesis.  Angiogenesis. 2002;  5 111-118
• 27 O'Reilly M S, Holmgreen L, Chen C, Folkman J. Angiostatin induces and sustains dormancy of human primary tumors in mice.  Nat Med. 1996;  2 689-692
• 28 Soff G A, Hong J, Fishman D et al.. Angiostatin 4.5′: a naturally occurring human angiogenesis inhibitor.  Blood. 1998;  92(suppl) 174a , (abst)
• 29 Cao R, Wu H L, Veitonmaki N et al.. Suppression of angiogenesis and tumor growth by the inhibitor K1-5 generated by plasmin-mediated proteolysis.  Proc Natl Acad Sci USA. 1999;  96 5728-5733
• 30 Cao Y. Therapeutic potentials of angiostatin in the treatment of cancer.  Haematologica. 1999;  84 643-650
• 31 Prox D, Becker C, Pirie-Shepard S R, Celik I, Folkman J, Kisker O. Treatment of human pancreatic cancer in mice with angiogenic inhibitors.  World J Surg. 2003;  27 405-411
• 32 Folkman J. Role of angiogenesis in tumor and metastasis.  Semin Oncol. 2002;  29 15-18
• 33 Galaup A, Opolon P, Bouquet C et al.. Combined effects of docetaxel and angiostatin gene therapy in prostate tumor model.  Mol Ther. 2003;  7 731-740
• 34 Mauceri H J, Seetharam S, Beckett M A et al.. Angiostatin potentiates cyclophosphamide treatment of metastatic disease.  Cancer Chemother Pharmacol. 2002;  50 412-418
• 35 Camhausen K, Moses M A, Beecken W D, Khan M K, Folkman J, O'Reilly M S. Radiation therapy to a primary tumor accelerates metastatic growth in mice.  Cancer Res. 2001;  61 2207-2211
• 36 Mauceri H J, Hanna N N, Beckett M A et al.. Combined effects of angiostatin and ionizing radiation in antitumor therapy.  Nature. 1998;  394 287-291
• 37 Gorski D H, Mauceri H J, Salloum R M et al.. Potentiation of the antitumor effect of ionizing radiation by brief concomitant exposures to angiostatin.  Cancer Res. 1998;  58 5686-5689
• 38 Sim B KL, MacDonald N J, Gubish E R. Angiostatin and endostatin: endogenous inhibitors of tumor growth.  Cancer Metastasis Rev. 2000;  19 181-190
• 39 Mundhenke C, Thomas J P, Wilding G et al.. Tissue examination to monitor antiangiogenic therapy: a phase I trial with endostatin.  Clin Cancer Res. 2001;  7 3366-3374
• 40 Eder Jr J P, Supko J G, Clark J W et al.. Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated daily.  J Clin Oncol. 2002;  20 3772-3784
• 41 Feldman A L, Libutti S K. Progress in antiangiogenic gene therapy of cancer.  Cancer. 2000;  89 1181-1194
• 42 Matsuda K M, Madoiwa S, Hasumi Y et al.. A novel strategy for the tumor angiogenesis-targeted gene therapy: generation of angiostatin from endogenous plasminogen by protease gene transfer.  Cancer Gene Ther. 2000;  7 589-596
• 43 Gorrin-Rivas M J, Arii S, Furutani M et al.. Mouse macrophage metalloelastase gene transfer into a murine melanoma suppresses primary tumor growth by halting angiogenesis.  Clin Cancer Res. 2000;  6 1647-1654
• 44 Browder T, Folkman J, Pirie-Shepherd S. The hemostatic system as regulator of angiogenesis.  J Biol Chem. 2000;  275 1521-1524
• 45 Lee T H, RhimTH, Kim S S. Prothrombin kringle-2 domain has a growth inhibitory activity against basic fibroblast growth factor-stimulated capillary endothelial cells.  J Biol Chem. 1998;  273 28805-28812
• 46 Rhim T H, Park C S, Kim E, Kim S S. Human prothrombin fragment 1 and 2 inhibit bFGF-induced BCE cell growth.  Biochem Biophys Res Commun. 1998;  252 513-516
• 47 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
• 48 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
• 49 Kisker O, Onizuka S, Banyard J et al.. Generation of multiple angiogenesis inhibitors by human pancreatic cancer.  Cancer Res. 2001;  61 7298-7304
• 50 Larsson H, Sjoblom T, Dixelius J et al.. Antiangiogenic effects of latent antithrombin through perturbated cell-matrix interactions and apoptosis of endothelial cells.  Cancer Res. 2000;  60 6723-6729
• 51 Larsson H, Akerud P, Nordling K, Rauh-Segall E, Claesson-Welsh L, Bjork I. A novel anti-angiogenic form of antithrombin with retained proteinase binding ability and heparin affinity.  J Biol Chem. 2001;  276 11996-12002
• 52 Pahl M V, Vaziri N D, Oveisi F, Wang J, Ding Y. Antithrombin III inhibits mesangial cell proliferation.  J Am Soc Nephrol. 1996;  7 2249-2253
• 53 Souter P J, Thomas S, Hubbard A R, Poole S, Römisch J, Gray E. Antithrombin inhibits lipopolysaccharide-induced tissue factor and interleukin-6 production by mononuclear cells, human umbilical vein endothelial cells, and whole blood.  Crit Care Med. 2001;  29 134-139
• 54 Bombeli T, Mueller M, Haeberii A. Anticoagulant properties of the vascular endothelium.  Thromb Haemost. 1997;  77 408-423
• 55 Sato Y, Shimada H, Takaki R. Autocrinological role of basic fibroblast growth factor on tube formation of vascular endothelial cells in vitro.  Biochem Biophys Res Commun. 1991;  180 1098-1102
• 56 Pluda J M, Parkinson D R. Clinical implications of tumor-associated neovascularisation and current antiangiogenic strategies for the treatment of malignancies of pancreas.  Cancer. 1996;  78(suppl) 680-687
• 57 Gengrinovitch S, Greenberg S M, Cohen T et al.. Platelet factor-4 inhibits the mitogenic activity of VEGF¹²¹ and VEGF¹⁶⁵ using several concurrent mechanisms.  J Biol Chem. 1995;  270 15059-15065
• 58 Perollet C, Han Z C, Savona C, Caen J P, Bikfalvi A. Platelet factor-4 modulates fibroblast growth factor 2 (FGF-2) activity and inhibits FGF-2 dimerization.  Blood. 1998;  91 3289-3299
• 59 Hampl M, Tanaka T, Albert P S, Lee J, Ferrari N, Fine H A. Therapeutic effects of viral vector-mediated antiangiogenic gene transfer in malignant ascites.  Hum Gene Ther. 2001;  12 1713-1729
• 60 Callendar N S, Varki N, Rao L V. Immunohistochemical identification of tissue factor in solid tumors.  Cancer. 1992;  70 1194-1201
• 61 Rao L VM. Tissue factor as a tumor procoagulant.  Cancer Metastasis Rev. 1992;  11 249-266
• 62 Zacharski L R, Wojtukiewicz M Z, Costantini V, Ornstein D L, Memoli V A. Pathways of coagulation/fibrinolysis activation in malignancy.  Semin Thromb Hemost. 1992;  18 104-116
• 63 Rottingen J A, Enden T, Camerer E, Iversen J G, Prydz H. Binding of human factor VIIa to tissue factor induces Ca²⁺ signals in J82 cells, transfected COS-1 cells, MDCK cells and in human endothelial cells induced to synthesize tissue factor.  J Biol Chem. 1995;  270 4650-4660
• 64 Camerer E, Rottingen J A, Iversen J G, Prydz H. Coagulation factors VII and X induce Ca²⁺ oscillations in Madin-Darby canine kidney cells only when proteolytically active.  J Biol Chem. 1996;  271 29034-29042
• 65 Prydz H, Camerer E, Rottingen J A, Wiiger M T, Gjernes E. Cellular consequences of the initiation of blood coagulation.  Thromb Haemost. 1999;  82 183-192
• 66 Sorensen B B, Freskgard P O, Nielsen L S, Rao L V, Ezban M, Peterson L C. Factor VIIa-induced p44/42 mitogen-activated protein activation requires the proteolytic activity of factor VIIa and is independent of the tissue factor cytoplasmic domain.  J Biol Chem. 1999;  274 21349-21354
• 67 Versteeg H H, Hoedemaeker I, Diks S H et al.. Factor VIIa/tissue factor-induced signaling via the activation of Src-like kinases, phosphatidylinositol 3-kinase, and Rac.  J Biol Chem. 2000;  275 28750-28756
• 68 Ollivier V, Bentolila S, Chabbat J, Hakim J, Prost D. Tissue factor-dependent vascular endothelial growth factor production by human fibroblasts in response to activated factor VII.  Blood. 1998;  91 2698-2703
• 69 Ollivier V, Chabbat J, Herbert J M, Hakim J, de Prost D. Vascular endothelial growth factor production by fibroblasts in response to factor VIIa binding to tissue factor involves thrombin and factor Xa.  Arterioscler Thromb Vasc Biol. 2000;  20 1374-1381
• 70 Abe K, Shoji M, Chen J et al.. Regulation of vascular endothelial growth production and angiogenesis by the cytoplasmic tail of tissue factor.  Proc Natl Acad Sci USA. 1999;  96 8663-8668
• 71 Zioncheck T F, Roy S, Vehar G A. The cytoplasmic domain of tissue factor is phosphorylated by a protein kinase C-dependent mechanism.  J Biol Chem. 1992;  267 3561-3564
• 72 Zhang Y, Deng Y, Luther T et al.. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice.  J Clin Invest. 1994;  94 1320-1327
• 73 Shoji M, Abe K, Nawroth P P, Rickles R. Molecular mechanisms linking thrombosis and angiogenesis in cancer.  Trends Cardiovasc Med. 1997;  7 52-59
• 74 Contrino J, Hair G, Kreutzer D L, Rickles F R. In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease.  Nat Med. 1996;  2 209-215
• 75 Takano S, Tsuboi K, Tomono Y, Mitsui Y, Nose T. Tissue factor, osteopontin, α_vβ₃ integrin expression in microvasculature of gliomas associated with vascular endothelial growth factor expression.  Br J Cancer. 2000;  82 1967-1973
• 76 Koomagi R, Volm M. Tissue-factor expression in human non-small-cell lung carcinoma measured by immunohistochemistry: correlation between tissue factor and angiogenesis.  Int J Cancer. 1998;  79 19-22
• 77 Ueno T, Toi M, Koike M, Nakamura S, Tominaga T. Tissue factor expression in breast cancer tissues: its correlation with prognosis and plasma concentration.  Br J Cancer. 2000;  83 164-170
• 78 Bajaj M S, Bajaj S P. Tissue factor pathway inhibitor: potential therapeutic applications.  Thromb Haemost. 1997;  78 471-477
• 79 Bromberg M E, Capello M. Cancer and blood coagulation: molecular aspects.  Cancer J. 1999;  5 132-138
• 80 Preissner K T. Hemostatic protease receptors and endothelial cell function: insights from gene targeting in mice.  Semin Thromb Hemost. 2000;  26 451-461
• 81 Fernandez Pujol B, Lucibello F C, Gehling U M. Endothelial-like cells derived from human CD14 positive monocytes.  Differentiation. 2000;  65 287-300
• 82 Gude R P, Binda M M, Boquete A L, Bonfil R D. Inhibition of endothelial cell proliferation and tumor-induced angiogenesis by pentoxifylline.  J Cancer Res Clin Oncol. 2001;  127 625-630
• 83 Amirkhosravi A, Meyer T, Warnes G et al.. Pentoxifylline inhibits hypoxia-induced upregulation of tumor cell tissue factor and vascular endothelial growth factor.  Thromb Haemost. 1998;  80 598-602
• 84 Vincent L, Chen W, Hong L et al.. Inhibition of endothelial cell migration by cerivastatin, an HMG-CoA reductase inhibitor: contribution to its anti-angiogenic effect.  FEBS Lett. 2001;  495 159-166
• 85 Kureishi Y, Luo Z, Shiojima I et al.. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals.  Nat Med. 2000;  6 1004-1010
• 86 Brouet A, Sonveaux P, Dessy C, Moniotte S, Balligand J L, Feron O. Hsp90 and caveolin are key targets for the proangiogenic nitric oxide-mediated effects of statins.  Circ Res. 2001;  89 866-873
• 87 Weis M, Heeschen C, Glassford A J, Cooke J P. Statins have biphasic effects on angiogenesis.  Circulation. 2002;  105 739-745
• 88 Fenton 2nd J W, Shen G X, Minnear F L et al.. Statins induce hypothrombotic states?.  Clin Appl Thromb Hemost. 2000;  6 18-21
• 89 Golino P, Ragini M, Cirillo P et al.. Antithrombotic effects of recombinant human active site-blocked factor VIIa in a rabbit model of recurrent arterial thrombosis.  Circ Res. 1998;  82 39-46
• 90 Clauss M. Molecular biology of the VEGF and the VEGF receptor family [review].  Semin Thromb Hemost. 2000;  26 561-569
• 91 Rosen L. Antiangiogenic strategies and agents in clinical trials [review].  Oncologist. 2000;  5(suppl 1) 20-27
• 92 Svidhar S S, Shepherd F A. Targeting angiogenesis: a review of angiogenesis inhibitors in the treatment of lung cancer.  Lung Cancer. 2003;  42(suppl 1) 581-591
• 93 Rapaport S I, Rao L VM. The tissue factor pathway: how it become a “Prima Ballerina”.  Thromb Haemost. 1995;  74 7-17
• 94 Mousa S A, Mohamed S. Anti-angiogenesis efficacy of the low molecular weight heparin (LMWH) tinzaparin and tissue factor pathway inhibitor (TFPI).  Blood. 1999;  94(suppl) , 22a, 82-I (Abst)
• 95 Amirkhosravi A, Francis J, Mousa S A. Anti-metastatic effect of the low molecular weight heparin (LMWH) tinzaparin and tissue factor pathway inhibitor (TFPI).  Thromb Haemost. 2001;  15 149,-A118 , (Abst)
• 96 Bajaj M S, Bajaj S P. Tissue factor pathway inhibitor: potential therapeutic applications.  Thromb Haemost. 1997;  78 471-477
• 97 Rao C N, Cook B, Liu Y et al.. HT-1080 fibrosarcoma cell matrix degradation and invasion are inhibited by the matrix-associated serine protease inhibitor TFPI-2/33 kDa MSPI.  Int J Cancer. 1998;  76 749-756
• 98 Rao C N, Mohanam S, Puppala A, Rao J S. Regulation of pro-MMP-1 and pro-MMP-3 activation by tissue factor pathway inhibitor-2/matrix associated serine protease inhibitor.  Biochem Biophys Res Commun. 1999;  255 94-98
• 99 Iino M, Foster D C, Kisiel W. Quantification and characterization of human endothelial cell-derived tissue factor pathway inhibitor-2.  Arterioscler Thromb Vasc Biol. 1998;  18 40-46
• 100 Wojtukiewicz M Z, Sierko E, Zimnoch L, Kozlowski L, Kisiel W. Immunohistochemical localization of tissue factor pathway inhibitor-2 in human tumor tissue.  Thromb Haemost. 2003;  90 140-146
• 101 Zacharski L R, Costantini V, Wojtukiewicz M Z, Memoli V A, Kudryk B J. Anticoagulants as cancer therapy.  Semin Oncol. 1990;  17 217-227
• 102 Tsopanoglou N E, Pipili-Synestos E, Maragoudakis M E. Thrombin promotes angiogenesis by a mechanism independent of fibrin formation.  Am J Physiol. 1993;  264 1302-1307
• 103 Möhle R, Green D, Moore M AS, 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
• 104 Wojtukiewicz M Z, Tang D G, Ben-Josef E, Renaud C, Walz D A, Honn K V. Solid tumor cells express functional “tethered-ligand” thrombin receptor.  Cancer Res. 1995;  55 698-704
• 105 Ukropec J A, Hollinger M K, Salva S M, Woolkalis M J. SHP2 association with VE-cadherin complexes in human endothelial cells is regulated by thrombin.  J Biol Chem. 2000;  275 5983-5986
• 106 Belloni P N, Carney D H, Nicolson G L. Organ-derived microvessel endothelial cells exhibit differential responsiveness to thrombin and other growth factors.  Microvasc Res. 1992;  43 20-45
• 107 Wojtukiewicz M Z, Tang D G, Nelson K K, Walz D A, Diglio C A, Honn K V. Thrombin enhances tumor cell adhesive and metastatic properties via increased αIIbβ3 expression on the cell surface.  Thromb Res. 1992;  68 233-245
• 108 BenEzra M, Vlodavsky I, Ishai-Michaeli R, Neufeld G, Bar-Shavit R. Thrombin-induced release of active basic fibroblast growth factor-heparan sulfate complexes from subendothelial extracellular matrix.  Blood. 1993;  81 3324-3331
• 109 Tsopanoglou N E, Maragoudakis M E. On the mechanism of thrombin-induced angiogenesis.  J Biol Chem. 1999;  274 23969-23976
• 110 Markwardt F. Development of direct thrombin inhibitors in comparison with glycosaminoglycans.  Semin Thromb Hemost. 2001;  27 523-530
• 111 Hassan A AK, Amenta S, Schmaier A H. Bradykinin and its metabolite, Arg-Pro-Pro-Gly-Phe, are selective inhibitors of α-thrombin-induced platelet activation.  Circulation. 1996;  94 517-528
• 112 Hassan A A, Warnock M, Srikanth S, Schmaier A H. Developing peptide inhibitors to thrombin activation of platelets from bradykinin analogs.  Thromb Res. 2001;  104 451-465
• 113 Bahou W F, Coller B S, Potter C L, Norton K J, Kutok J L, Goligorsky M S. The thrombin receptor extracellular domain contains sites crucial for peptide ligand-induced activation.  J Clin Invest. 1993;  91 1405-1413
• 114 Cook J J, Sitko G R, Bednar B et al.. An antibody against the exo-site of the cloned thrombin receptor inhibits experimental arterial thrombosis in the African green monkey.  Circulation. 1995;  91 2961-2971
• 115 Derian C K, Maryanoff B E, Zhang H-C, Andrade-Gordon P. Therapeutic potential of protease-activated receptor-1 antagonists.  Expert Opin Investig Drugs. 2003;  12 209-221
• 116 Engelberg H. Action of heparin that may affect the malignant process.  Cancer. 1999;  85 257-272
• 117 Hull R D, Raskob G E, Pineo G F et al.. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis.  N Engl J Med. 1992;  326 975-982
• 118 Prandoni P, Lensing A WA, Büller H R et al.. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis.  Lancet. 1992;  339 441-445
• 119 Hirsh J, Siragusa S, Cosmi B, Ginsberg J S. Low molecular weight heparins (LMWH) in the treatment of patients with acute venous thromboembolism.  Thromb Haemost. 1995;  74 360-363
• 120 Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg J S. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis.  Am J Med. 1996;  100 269-277
• 121 Norrby K. Heparin and angiogenesis: a low-molecular-weight-fraction inhibits and a high-molecular-weight fraction stimulates angiogenesis systemically.  Haemostasis. 1993;  23(suppl 1) 141-149
• 122 Norrby K, Østergaard P. A 5.0-kD heparin fraction systemically suppresses VEGF¹⁶⁵-mediated angiogenesis.  Int J Microcirc Clin Exp. 1997;  17 314-321
• 123 Norrby K, Østergaard P. Basic fibroblast growth factor-mediated de novo angiogenesis is more effectively suppressed by low-molecular-weight than by high-molecular-weight heparin.  Int J Microcirc Clin Exp. 1996;  16 8-15
• 124 Lepri A, Benelli U, Bernardini N et al.. Effect of low molecular weight heparan sulphate on angiogenesis in the rat cornea after chemical cauterization.  J Ocul Pharmacol. 1994;  10 273-280
• 125 Folkman J, Langer R, Linhardt R J, Haudenschild C, Taylor S. Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone.  Science. 1983;  221 719-725
• 126 Jacobson A M, Hahnenberger R. Antiangiogenic effect of heparin and other sulphated glycosaminoglycans in the chick chorioallantoic membrane.  Pharmacol Toxicol. 1991;  69 122-126
• 127 Norrby K. 2.5 kD and 5 kD heparin fragments specifically inhibit microvessel sprouting and network formation in VEGF¹⁶⁵-mediated mammalian angiogenesis.  Int J Exp Pathol. 2000;  81 191-198
• 128 Sasisekharan R, Ernst S, Venkataraman G. On the regulation of fibroblast growth factor activity by heparin-like glycosaminoglycans.  Angiogenesis. 1997;  1 45-54
• 129 Colin S, Jeanny J C, Mascarelli F et al.. In vivo involvement of heparan sulfate proteoglycan in the bioavailability, internalization, and catabolism of exogenous basic fibroblast growth factor.  Mol Pharmacol. 1999;  55 74-82
• 130 Saksela O, Moscatelli D, Sommer A, Rifkin D B. Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation.  J Cell Biol. 1988;  107 743-751
• 131 Rusnati M, Presta M. Interaction of angiogenic basic fibroblast growth factor with endothelial cell heparan sulfate proteoglycans. Biological implications in neovascularization.  Int J Clin Lab Res. 1996;  26 15-23
• 132 Presta M, Maier J A, Rusnati M, Ragnotti G. Basic fibroblast growth factor is released from endothelial extracellular matrix in a biologically active form.  J Cell Physiol. 1989;  140 68-74
• 133 Ishai-Michaeli R, Eldor A, Vlodavsky I. Heparanase activity expressed by platelets, neutrophils, and lymphoma cells releases active fibroblast growth factor from extracellular matrix.  Cell Regul. 1990;  1 833-842
• 134 Vlodavsky I, Ishai-Michaeli R, Mohsen M et al.. Modulation of neovascularization and metastasis by species of heparin.  Adv Exp Med Biol. 1992;  313 317-327
• 135 Folkman J, Klagsbrun M, Sasse J, Wadzinski M, Ingber D, Vlodavsky I. A heparin-binding angiogenic protein-basic fibroblast growth factor-is stored within basement membrane.  Am J Pathol. 1988;  130 393-400
• 136 D'Amore P A. Heparin-endothelial cell interactions.  Haemostasis. 1990;  20(suppl 1) 159-165
• 137 Taniguchi T, Toi M, Tominaga T. Rapid induction of hepatocyte growth factor by heparin.  Lancet. 1994;  344 470
• 138 Yamazaki H, Oi H, Matsushita M et al.. Heparin induces rapid and remarkable elevation of hepatocyte growth factor/scatter factor during trans arterial embolization of renal cell carcinoma.  Anticancer Res. 1997;  17 1435-1437
• 139 Mason I J. The ins and outs of fibroblast growth factors.  Cell. 1994;  78 547-552
• 140 Tessler S, Rockwell P, Hicklin D et al.. Heparin modulates the interaction of VEGF¹⁶⁵ with soluble and cell associated flk-1 receptors.  J Biol Chem. 1994;  269 12456-12461
• 141 Schlessinger J, Lax I, Lemmon M. Regulation of growth factor activation by proteoglycans: what is the role of the low affinity receptors?.  Cell. 1995;  83 357-360
• 142 Soker S, Goldstaub D, Svahn C M, Vlodavsky I, Levi B Z, Neufeld G. Variations in the size and sulfation of heparin modulate the effect of heparin on the binding of VEGF¹⁶⁵ to its receptors.  Biochem Biophys Res Commun. 1994;  203 1339-1347
• 143 Jayson G C, Gallagher J T. Heparin oligosaccharides: Inhibitors of the biological activity of bFGF on Caco-2 cells.  Br J Cancer. 1997;  75 9-16
• 144 Pinedo H M, Verheul H MW, D'Amato R J, Folkman J. Involvement of platelets in tumor angiogenesis?.  Lancet. 1998;  352 1775-1777
• 145 Verheul H MW, Hoekman K, Lupu F et al.. Platelet and coagulation activation with vascular endothelial growth factor generation in soft tissue sarcomas.  Clin Cancer Res. 2000;  6 166-171
• 146 Edwards R L, Rickles F R, Moritz T E et al.. Abnormalities of blood coagulation tests in patients with cancer.  Am J Clin Pathol. 1987;  88 596-602
• 147 Verheul H MW, Hoekman K, Luykx-de Bakker S et al.. Platelet transporter of vascular endothelial growth factor.  Clin Cancer Res. 1997;  3 2187-2190
• 148 Brunner G, Nguyen H, Gabrilove J et al.. Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells.  Blood. 1993;  81 631-638
• 149 Nakamura T, Teramoto H, Ichihara A. Purification and characterization of a growth factor from rat platelets for mature parenchymal hepatocytes in primary culture.  Proc Natl Acad Sci USA. 1986;  83 6489-6493
• 150 Griffiths L, Stratford I J. Platelet-derived endothelial cell growth factor thymidine phosphorylase in tumor growth and response to therapy.  Br J Cancer. 1997;  76 689-693
• 151 Good D J, Polverini P J, Rastinejad F et al.. A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistiguishable from a fragment of thrombospondin.  Proc Natl Acad Sci USA. 1990;  87 6624-6628
• 152 Taylor S, Folkman J. Protamine is an inhibitor of angiogenesis.  Nature. 1982;  297 307-312
• 153 Selheim F, Holmsen H, Vassbotn F S. Identification of functional VEGF receptors on human platelets.  FEBS Lett. 2002;  512 107-110
• 154 Sawicki G, Salas E, Murat J et al.. Release of gelatinase A during platelet activation mediates aggregation.  Nature. 1997;  386 616-619
• 155 Menashi S, He L, Soria C et al.. Modulation of endothelial cells fibrinolytic activity by platelets.  Thromb Haemost. 1991;  65 77-81
• 156 Belloc C, Lu H, Soria C et al.. The effect of platelets on invasiveness and protease production of human mammary tumor cells.  Int J Cancer. 1995;  60 413-417
• 157 Mandriota S J, Seghezzi G, Vassali J D et al.. Vascular endothelial growth factor increases urokinase receptor expression in vascular endothelial cells.  J Biol Chem. 1995;  270 9709-9716
• 158 Friesel R E, Maciag T. Fibroblast growth factor prototype release and fibroblast growth factor receptor signaling.  Thromb Haemost. 1999;  82 748-754
• 159 Honn K V, Tang G T, Chen Y Q. Platelets and cancer metastasis: more than an epiphenomenon.  Semin Thromb Hemost. 1992;  18 392-415
• 160 Felding-Habermann B, O'Toole T E, Smith J W et al.. Integrin activation controls metastasis in human breast cancer.  Proc Natl Acad Sci USA. 2001;  98 1853-1858
• 161 Coller B S, Peerschke E L, Scudder L E, Sullivan C A. A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins IIb and/or IIIa.  J Clin Invest. 1983;  72 325-328
• 162 Coller B S. Anti-GpIIb/IIIa drugs: current strategies and future directions.  Thromb Haemost. 2001;  86 427-443
• 163 Nierodzik M L, Klepfish A, Karpatkin S. Role of platelets, thrombin, integrin IIb-IIIa, fibronectin and von Willebrand factor on tumor adhesion in vitro and metastasis in vivo.  Thromb Haemost. 1995;  74 282-290
• 164 Amirkhosravi A, Amaya M, Siddiqui F et al.. Blockade of GpIIb/IIIa inhibits the release of vascular endothelial growth factor (VEGF) from tumor-cell-activated platelets and experimental metastasis.  Platelets. 1999;  10 285-292
• 165 Trikha M, Zhou Z, Jordan J, Nakada M T. ReoPro and m7E3 F(ab′)₂ inhibit β3 integrin mediated tumor growth and angiogenesis.  Proc Am Assoc Cancer Res. 2000;  42 824,-A3678
• 166 Butenas S, Cawthern K, Veer C et al.. Antiplatelet agents in tissue factor-induced blood coagulation.  Blood. 2001;  97 2314-2322
• 167 Waltermann A, Wolzt M, Petersmann K et al.. Large amounts of vascular endothelial growth factor at the site of hemostatic plug formation in vivo.  Arterioscler Thromb Vasc Biol. 1999;  19 1757-1760
• 168 Borsig L, Wong R, Feramisco J et al.. Heparin and cancer revised: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis.  Proc Natl Acad Sci USA. 2001;  98 3352-3357
• 169 Ma L, Elliott S N, Ciriano G et al.. Platelets modulate gastric ulcer healing: role of endostatin and vascular endothelial growth factor release.  Proc Natl Acad Sci USA. 2001;  98 6470-6475
• 170 Foekens J A, Peters H A, Look M P et al.. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients.  Cancer Res. 2000;  60 636-643
• 171 Kuhn W, Schmalfeld B, Reuning U et al.. Prognostic significance of urokinase (uPA) and its inhibitor PAI-1 for survival in advanced ovarian carcinoma stage FIGO IIIC.  Br J Cancer. 1999;  79 1746-1751
• 172 Witte J H, Sweep C GJ, Klijn J GM et al.. Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer.  Br J Cancer. 1999;  80 286-294
• 173 Schleef R R, Loskutoff D J. Fibrinolytic system of vascular endothelial cells. Role of plasminogen activator inhibitors.  Haemostasis. 1988;  18 328-341
• 174 Kroon M E, Koolwijk P, van Goor H et al.. Role and localization of urokinase receptor in the formation of new microvascular structures in fibrin matrices.  Am J Pathol. 1999;  154 1731-1742
• 175 Blasi F. Proteolysis, cell adhesion, chemotaxis, and invasiveness are regulated by the u-PA-u-PAR-PAI-1 system.  Thromb Haemost. 1999;  82 298-304
• 176 Bajou K, Noel A, Gerard R D et al.. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularisation.  Nat Med. 1998;  4 923-927
• 177 Carmeliet P, Moons L, Dewerchin A et al.. Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and plasminogen system.  Ann NY Acad Sci. 1997;  811 191-206
• 178 Heymans S, Luttun A, Nuyens D et al.. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure.  Nat Med. 1999;  5 1135-1142
• 179 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
• 180 Mandelli F, Diverio D, Avvisati G et al.. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malottie Ematologiche Maligna dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups.  Blood. 1997;  90 1014-1021
• 181 Horne III M K, Figg W D, Arlen P et al.. Increased frequency of venous thromboembolism with the combination of docetaxel and thalidomide in patients with metastatic androgen-independent prostate cancer.  Pharmacotherapy. 2003;  23 315-318
• 182 Desai A A, Vogelzang N J, Rini B I, Ansari R, Krauss S, Stadler W M. A high rate of venous thromboembolism in a multi-institutional phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil and daily thalidomide in patients with metastatic renal cell carcinoma.  Cancer. 2002;  95 1629-1636
• 183 Wun T, Law L, Harvey D, Sieracki B, Scudder S A, Ryu J K. Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin.  Cancer. 2003;  98 1514-1520
• 184 Verso M, Agnelli G. Venous thromboembolism associated with long-term use of central venous catheters in cancer patients.  J Clin Oncol. 2003;  21 3665-3675
• 185 Lee A Y, Levine M N. The thrombophilic state induced by therapeutic agents in the cancer patient.  Semin Thromb Hemost. 1999;  25 137-145
• 186 Khushal A, Quinlan D, Alikhan R, Gardner J, Bailey C, Cohen A. Thromboembolic disease in surgery for malignancy-rationale for prolonged thromboprophylaxis.  Semin Thromb Hemost. 2002;  28 569-576
• 187 Zacharski L R. Anticoagulants in cancer treatment: malignancy as a solid phase coagulopathy.  Cancer Lett. 2002;  186 1-9
• 188 Zacharski L R. Malignancy as a solid phase coagulopathy: implications for the etiology, pathogenesis, and treatment of cancer.  Semin Thromb Hemost. 2003;  29 239-246