Platelets and Angiogenesis in Malignancy

There is increasing evidence that platelets play an important role in the process of tumor angiogenesis. Thrombocytosis is a frequent finding in cancer patients (10-57%). Although the mechanisms underlying thrombocytosis are not yet fully elucidated, tumor-derived factors with thrombopoietin-like activity and growth factors, platelet-derived microparticles, and factors secreted from bone marrow endothelial cells, as well as growth factors released by megakaryocytes (acting via an autocrine loop), are postulated to influence this process.

The progression of cancer is associated with hypercoagulability, which results from direct influences of tumor cells and diverse indirect mechanisms. Activated platelets serve as procoagulant surfaces amplifying the coagulation reactions. It is well known that hemostatic proteins are involved in different steps of the angiogenic process. Furthermore, platelets adhering to endothelium facilitate adhesion of mononuclear cells (which exert various proangiogenic activities) to endothelial cells and their transmigration to the extravascular space. It was also documented that platelets induce angiogenesis in vivo. Platelets are a rich source of proangiogenic factors. They also store and release angiogenesis inhibitors. In addition, platelets express surface growth factor receptors, which may regulate the process of angiogenesis. Platelets also contribute directly to the process of basement membrane and extracellular matrix proteolysis by releasing proteinases, or indirectly via inducing endothelial cells and tumor cells to release proteolytic enzymes, as well as through the proteolytic activities of platelet-derived growth factors.

The multidirectional activities of platelets in the process of new blood vessel formation during tumor development and metastasis formation may create the possibility of introducing antiplatelet agents for antiangiogenic therapy in cancer patients. Thus far experimental studies employing inhibitors of glycoprotein IIb-IIIa have yielded promising results.

Platelets - angiogenesis - cancer

REFERENCES

• 1 Bizzozero J. Über einen neuen Formbestandteil des Blutes und dessen Rolle bei der Thrombose und Blutgerinnung.  Virchow's Arch Path Anat Physiol. 1882;  90 262-332
• 2 de Gaetano G. Historical overview of the role of platelets in hemostasis and thrombosis.  Haematologica. 2001;  86 349-356
• 3 Roscamp J. Contribution à l'étude de la physiologie normale et pathologique du globulin (plaquettes de Bizzozero).  Arch Int Physiol. 1923;  20 240-249
• 4 MacKay W. The blood platelet: its clinical significance.  Q J Med. 1930;  24 285-293
• 5 Billroth T. Lectures on Surgical Pathology and Therapeutics: A New Handbook for Students and Practitioners. London; The New Syndenham Society 1878: 355
• 6 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
• 7 Rickles F R, Levine M, Edwards R L. Hemostatic alterations in cancer patients.  Cancer Metastasis Rev. 1992;  11 237-248
• 8 Francis J L, Biggerstaff J, Amirkhosravi A. Hemostasis and malignancy.  Semin Thromb Hemost. 1998;  24 93-109
• 9 Kies M S, Posch J J, Giolama J P, Rubin R N. Hemostatic function in cancer patients.  Cancer. 1980;  46 831-837
• 10 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
• 11 Miller S P, Sanchez-Avalos J, Stefanski T, Zuckerman L. Coagulation disorders in cancer. I. Clinical and laboratory studies.  Cancer. 1967;  20 1452-1465
• 12 Costantini V, Zacharski L R, Moritz T E, Edwards R L. The platelet count in carcinoma of the lung and colon.  Thromb Haemost. 1990;  64 501-505
• 13 Moller-Pedresen L, Milman N. Prognostic significance of thrombocytosis in patients with primary lung cancer.  Eur Respir J. 1996;  9 1826-1830
• 14 Ikeda M, Furukawa H, Imamura H et al.. Poor prognosis associated with thrombocytosis in patients with gastric cancer.  Ann Surg Oncol. 2002;  9 287-291
• 15 Symbas N P, Townsend M F, El Galley R, Keane T W, Graham S D, Petros J A. Poor prognosis associated with thrombocytosis in patients with renal cell carcinoma.  BJU Int. 2000;  86 203-207
• 16 Ribeiro M, Ruff P, Falkson G. Low serum testosterone and a younger age predict for a poor outcome in metastatic prostate cancer.  Am J Clin Oncol. 1997;  20 605-608
• 17 Lopez A, Daras V, Cross P A et al.. Thrombocytosis as a prognostic factor in women with cervical cancer.  Cancer. 1994;  74 90-92
• 18 Gücer F, Moser F, Tamussino K et al.. Thrombocytosis as a prognostic factor in endometrial carcinoma.  Gynecol Oncol. 1998;  70 210-214
• 19 Zeimet A G, Marth C, Muller Holzner E, Daxenbichler G, Dapunt O. Significance of thrombocytosis in patients with epithelial ovarian cancer.  Am J Obstet Gynecol. 1994;  170 549-554
• 20 Nakano T, Fujii J, Tamura S, Hada T, Higashino K. Thrombocytosis in patients with malignant mesothelioma.  Cancer. 1986;  58 1699-1701
• 21 Gasic G J, Gasic T B, Steward C C. Antimetastatic effects associated with platelet reduction.  Proc Natl Acad Sci USA. 1968;  61 46-52
• 22 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
• 23 Schwartz R E. Platelet counts and prognosis of pancreatic cancer.  Lancet. 1999;  353 2158-2159
• 24 Slichter S J, Harker L A. Hemostasis in malignancy.  Ann N Y Acad Sci. 1974;  230 252-262
• 25 Tang D G, Honn K V. Adhesion molecules and tumor metastasis: an update.  Invasion Metastasis. 1994-95;  14 109-122
• 26 Honn K V, Tang G T, Chen Y Q. Platelets and cancer metastasis: more than an epiphenomenon [review].  Semin Thromb Hemost. 1992;  18 392-415
• 27 Folkman J. Tumor angiogenesis: therapeutic implications.  N Engl J Med. 1971;  285 1182-1186
• 28 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other diseases.  Nat Med. 1995;  1 27-31
• 29 Wojtukiewicz M Z, Sierko E, Klement P, Rak J. The hemostatic system and angiogenesis in malignancy.  Neoplasia. 2001;  3 371-384
• 30 Heemskerk J WM, Bevers E M, Lindhout T. Platelet activation and blood coagulation.  Thromb Haemost. 2002;  88 186-193
• 31 Andrews R K, Shen Y, Gardiner E E, Berndt M C. Platelet adhesion receptors and (patho)physiological thrombus formation.  Histol Histopathol. 2001;  16 969-980
• 32 Chen H, Locke D, Liu Y, Kahn M L. The platelet receptor GPVI mediates both adhesion and signaling responses to collagen in a receptor density-dependent fashion.  J Biol Chem. 2002;  277 3011-3019
• 33 Kamata T, Takada Y. Platelet integrin alphaIIbbeta3-ligand interactions: what can we learn from the structure?.  Int J Hematol. 2001;  74 382-389
• 34 Coughlin S R. Protease-activated receptors and platelet function.  Thromb Haemost. 1999;  82 353-356
• 35 Di Virgilio F, Chiozzi P, Ferrari D et al.. Nucleotide receptors: an emerging family of regulatory molecules in blood cells.  Blood. 2001;  97 587-600
• 36 Hartwig J M, DeSisto M. The cytoskeleton of the resting human blood platelets: structure of the membrane skeleton and its attachment to actin filaments.  J Cell Biol. 1991;  112 407-425
• 37 Serrano K, Devine D V. Intracellular factor XIII crosslinks platelet cytoskeletal elements upon platelet activation.  Thromb Haemost. 2002;  88 315-320
• 38 Rendu F, Brohard-Bohn B. The platelet release reaction: granules' constituents, secretion and functions.  Platelets. 2001;  12 261-273
• 39 Nieswandt B, Watson S P. Platelet collagen interaction: is GPVI the central receptor?.  Blood. 2003;  102 449-461
• 40 Dormann D, Clemetson K J, Kehrel B E. The GPIb thrombin-binding site is essential for thrombin-induced platelet procoagulant activity.  Blood. 2000;  96 2469-2478
• 41 De Candia E, Hall S W, Rutella S, Landolfi R, Andrews R K, De Cristofaro R. Binding of thrombin to glycoprotein Ib accelerates the hydrolysis of PAR-1 on intact platelets.  J Biol Chem. 2001;  276 4692-4698
• 42 Corbett G, Perry D J. Significance of thrombocytosis.  Lancet. 1983;  1 77-79
• 43 Gastl G, Plante M, Finstad C L et al.. High IL-6 levels in ascitic fluid correlate with reactive thrombocytosis in patients with epithelial ovarian cancer.  Br J Haematol. 1993;  83 433-441
• 44 Estrov A, Talpaz M, Mavlight G et al.. Elevated plasma thrombopoietic activity in patients with metastatic cancer-related thrombocytosis.  Am J Med. 1995;  98 551-558
• 45 Salgado R, Vermeulen P B, Benoy I et al.. Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels of advanced cancer patients.  Br J Cancer. 1999;  80 892-897
• 46 Kato N, Yasukawa K, Onozuka T, Kimura K. Paraneoplastic syndromes of leukocytosis, thrombocytosis, and hypercalcemia associated with squamous cell carcinoma.  J Dermatol. 1999;  26 352-358
• 47 Higashihara M, Sunaga S, Tange T, Oohashi H, Kurokawa K. Increased secretion of interleukin-6 in malignant mesothelioma cells from a patient with marked thrombosis.  Cancer. 1992;  70 2105-2108
• 48 Suzuki A, Takahashi T, Nakamura K et al.. Thrombocytosis in patients with tumors producing colony-stimulating factor.  Blood. 1992;  80 2052-2059
• 49 Uppenkamp M, Makarove E, Petrasch S, Brittinger G. Thrombopoietin serum concentration in patients with reactive and myeloproliferative thrombocytosis.  Ann Hematol. 1998;  77 217-223
• 50 Baj-Krzyworzecka M, Majka M, Pratico D et al.. Platelet-derived microparticles stimulate proliferation, survival, adhesion, and chemotaxis of hematopoietic cells.  Exp Hematol. 2002;  30 450-459
• 51 Rafi S, Shapiro F, Pettengeli R et al.. Human bone marrow microvascular endothelial cells support long-term proliferation and differentiation of myeloid and megakaryocytic progenitors.  Blood. 1995;  86 3353-3363
• 52 Rafi S, Mohle R, Shapiro F, Frey B M, Moore M A. Regulation of hematopoesis by microvascular endothelium.  Leuk Lymphoma. 1997;  27 375-386
• 53 Wickenhauser C, Lorenzen J, Thiele J et al.. Secretion of cytokines (interleukins-1 alpha, -3, and granulocyte-macrophage colony-stimulating factor) by normal human bone marrow megakaryocytes.  Blood. 1995;  85 685-691
• 54 Jones C L, Witte D P, Feller M J, Fugman D A, Dorn G W, Liebermann M A. Response of human megakaryocytic cell line to thrombin: increase in intracellular free calcium and mitogen release.  Biochim Biophys Acta. 1992;  1136 272-282
• 55 Möhle 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
• 56 Avraham H, Banu N, Scadden D T, Abraham J, Groopman J E. Modulation of megakaryocytopoiesis by human basic fibroblast growth factor.  Blood. 1994;  83 2126-2132
• 57 Broxmeyer H E, Cooper S, Li Z H et al.. Myeloid progenitor cell regulatory effects of vascular endothelial cell growth factor.  Int J Hematol. 1995;  62 203-215
• 58 Casella I, Feccia T, Chelucci C et al.. Autocrine-paracrine VEFG loops potentiate the maturation of megakaryocytic precursors through Flt-1 receptor.  Blood. 2003;  101 1316-1323
• 59 Clauss M. Molecular biology of the VEGF and the VEGF receptor family.  Semin Thromb Hemost. 2000;  26 561-569
• 60 Ferrara N. Vascular endothelial growth factor: molecular and biological aspects.  Curr Top Microbiol Immunol. 1999;  237 1-30
• 61 Tavassoli M, Aoki M. Localization of megakaryocytes in the bone marrow.  Blood Cells. 1989;  15 3-14
• 62 Yazaki T, Inage H, Iizumi T et al.. Studies on platelet function in patients with prostatic cancer. Preliminary report.  Urology. 1987;  30 60-63
• 63 Ferriere J P, Bernard D, Legros M et al.. β-thromboglobulin in patients with breast cancer.  Am J Hematol. 1985;  19 47-53
• 64 Milroy R, Douglas J T, Campbell J et al.. Abnormal haemostasis in small cell lung cancer.  Thorax. 1988;  43 978-981
• 65 Prisco D, Paniccia R, Coppo M et al.. Platelet activation and lipid composition in pulmonary cancer.  Prostaglandins Leukot Essent Fatty Acids. 1995;  53 65-68
• 66 Abbasciano V, Tassinari D, Sartori S et al.. Usefulness of coagulation markers in staging of gastric cancer.  Cancer Detect Prev. 1995;  19 331-336
• 67 Abbasciano V, Bianchi M P, Trevisani L et al.. Platelet activation and fibrinolysis in large bowel cancer.  Oncology. 1995;  52 381-384
• 68 Wehmeier A, Tschope D, Esser J et al.. Circulating activated platelets in myeloproliferative disorders.  Thromb Res. 1991;  61 271-278
• 69 Blann A D, Gurney M, Wadley D, Bareford D, Stonelake P, Lip G Y. Increased soluble P-selectin in patients with haematological and breast cancer: a comparison with fibrinogen, plasminogen activator inhibitor and von Willebrand factor.  Blood Coagul Fibrinolysis. 2001;  12 43-50
• 70 Bastida E, Ordinas A, Giardina S et al.. Differentiation of platelet aggregating effects of human tumor cell lines based on inhibition studies with apyase, hirudin, and phospholipase.  Cancer Res. 1982;  42 4348-4352
• 71 Olas B, Mielicki W P, Wachowicz B et al.. Cancer procoagulant stimulates platelet adhesion.  Thromb Res. 1999;  94 199-203
• 72 Falanga A, Rickles F R. Pathophysiology of the thrombophilic state in the cancer patient.  Semin Thromb Hemost. 1999;  25 173-182
• 73 Kitagawa H, Yamamoto N, Yamamoto K et al.. Involvement of platelet membrane glycoprotein Ib and glycoprotein IIb/IIIa complex in thrombin-dependent and -independent platelet aggregations induced by tumor cells.  Cancer Res. 1989;  49 537-541
• 74 Karpatkin S, Nierodzik M L, Klepfish A. Role of platelets, thrombin in cancer.  Vessels. 1996;  2 17-23
• 75 Pinedo H M, Verheul H MW, D'Amato R J, Folkman J. Involvement of platelets in tumor angiogenesis?.  Lancet. 1998;  352 1775-1777
• 76 Verheul H M, Jorna A S, Hoekman K et al.. Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets.  Blood. 2000;  96 4216-4221
• 77 Pipili-Synestos E, Papadimitriou E, Maragoudakis M E. Evidence that platelets promote tube formation by endothelial cells on matrigel.  Br J Pharmacol. 1998;  125 1252-1257
• 78 Slupsky J R, Kalbas M, Willuwelt A. Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40.  Thromb Haemost. 1998;  80 1008-1014
• 79 Karmann K, Min W, Fanslow W C, Pober J S. Activation and homologus desensitization of human endothelial cells by CD40 ligand, tumor necrosis factor and interleukin 1.  J Exp Med. 1996;  184 173-182
• 80 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
• 81 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
• 82 Wartiovaara U, Salven P, Mikkola Heta I. Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation.  Thromb Haemost. 1998;  80 171-175
• 83 Banks R E, Forbes M A, Kinsey S E et al.. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology.  Br J Cancer. 1998;  77 956-964
• 84 Benoy I, Salgado R, Copaert C et al.. Serum interleukin 6, plasma VEGF, serum VEGF, and VEGF platelet load in breast cancer patients.  Clin Breast Cancer. 2002;  2 311-315
• 85 Werther K, Christensen I J, Nielsen H J. Determination of vascular endothelial growth factor (VEGF) in circulating blood: significance of VEGF in various leucocytes and platelets.  Scand J Clin Lab Invest. 2002;  62 343-350
• 86 Jelkman W. Pitfalls in the measurement of circulating vascular endothelial growth factor.  Clin Chem. 2001;  47 617-623
• 87 Brekken R A, Huang X, King S W et al.. Vascular endothelial growth factor as a marker of tumor endothelium.  Cancer Res. 1998;  58 1952-1959
• 88 Chen F H, Crist S A, Zhang G J, Iwamoto Y, See W A. Interleukin-6 production by human bladder tumor cell lines is up-regulated by bacillus Calmette-Guerin through nuclear factor-kappaB and Ap-1 via an immediate early pathway.  J Urol. 2002;  168 786-797
• 89 Brock T A, Dvorak H F, Senger D R. Tumour secreted vascular permeability factor increases cytosolic Ca²⁺ and von Willebrand factor release in human cells.  Am J Pathol. 1991;  138 213-221
• 90 McEver R P. Adhesive interactions of leukocytes, platelets, and the vessel wall during hemostasis and inflammation.  Thromb Haemost. 2001;  86 746-756
• 91 Clauss M, Gerlach M, Gerlach H et al.. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration.  J Exp Med. 1990;  172 1535-1545
• 92 Ohta M, Kitadai Y, Tanaka S et al.. Monocyte chemoatractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human gastric carcinomas.  Int J Oncol. 2003;  22 773-778
• 93 Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow?.  Lancet. 2001;  357 539-545
• 94 Coussens L M, Wilfred W R, Berges G et al.. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis.  Genes Dev. 1999;  13 1382-1397
• 95 Feoktistov I, Ryzhov S, Goldstein A E, Biaggioni I. Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors.  Circ Res. 2003;  92 485-492
• 96 Wijelath E S, Murray J, Rahman S et al.. Novel vascular endothelial growth factor binding domains of fibronectin enhance vascular endothelial growth factor biological activity.  Circ Res. 2002;  91 25-31
• 97 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
• 98 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
• 99 Karey K P, Marquardt H, Sirbasku D A. Human platelets-derived mitogens. I. Identification of insulin-like growth factors I and II by purification and N-terminal amino acid sequence analysis.  Blood. 1989;  74 1084-1092
• 100 Karey K P, Sirbasku D A. Human platelets-derived mitogens.II. Subcellular localization of insulin-like growth factor I to the alpha granule and release in response to thrombin.  Blood. 1989;  74 1093-1100
• 101 Ben-Ezra J, Sheibani K, Hwang D L, Lev-Ran A. Megakaryocyte synthesis is the source of epidermal growth factor in human platelets.  Am J Pathol. 1990;  137 755-759
• 102 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
• 103 Schultz G S, Grant M B. Neovascular growth factors.  Eye. 1991;  5 170-180
• 104 Betsholtz C, Karlson L, Lindahl P. Developmental roles of platelet-derived growth factors.  Bioessays. 2001;  23 494-507
• 105 Ceni E, Granchi D, Vancini M, Pizzoferrato A. Platelet release of transforming growth factor-beta and beta-thromboglobulin after in vitro contact with acrylic bone cements.  Biomaterials. 2002;  23 1479-1484
• 106 Li J J, Huang Y Q, Basch R, Karpatkin S. Thrombin induces the release of angiopoietin-1 from platelets.  Thromb Haemost. 2001;  85 204-206
• 107 McMahon G A, Petitclerc E, Stefansson S et al.. Plasminogen activator inhibitor-1 regulates tumor growth and angiogenesis.  J Biol Chem. 2001;  276 33964-33968
• 108 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
• 109 Taylor S, Folkman J. Protamine is an inhibitor of angiogenesis.  Nature. 1982;  297 307-312
• 110 Ma L, Hollenberg M D, Wallace J L. Thrombin-induced platelet endostatin release is blocked by a protamine activated receptor-4 (PAR-4) antagonist.  Br J Pharmacol. 2001;  134 701-704
• 111 Nakabayashi M, Morishita R, Nakagami H et al.. HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model.  Diabetologia. 2003;  46 115-123
• 112 Pizurki L, Zhou Z, Glynos K, Roussos C, Papapetropoulos A. Angiopoietin-1 inhibits endothelial permeability, neutrophil adherence and IL-8 production.  Br J Pharmacol. 2003;  139 329-336
• 113 Stoeltzing O, Ahmad S A, Liu W et al.. Angiopoietin-1 inhibits tumor growth and ascites formation in a murine model of peritoneal carcinomatosis.  Br J Cancer. 2002;  87 1182-1187
• 114 Yokoyama Y, Charnock-Jones D S, Licence D et al.. Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 3, as a prognostic factor in endometrial carcinoma.  Clin Cancer Res. 2003;  9 1361-1369
• 115 Friesel R E, Maciag T. Fibroblast growth factor prototype release and fibroblast growth factor receptor signaling.  Thromb Haemost. 1999;  82 748-754
• 116 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
• 117 Okusa Y, Ichikura T, Mochizuki H. Prognostic impact of stromal cell-derived urokinase-type plasminogen activator in gastric carcinoma.  Cancer. 1999;  85 1033-1038
• 118 Tomita N, Morishita R, Taniyama Y et al.. Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis ets-1.  Circulation. 2003;  107 1411-1417
• 119 Camussi G, Montrucchio G, Lupia E et al.. Angiogenesis induced in vivo by hepatocyte growth factor is mediated by platelet-activating factor synthesis from macrophages.  J Immunol. 1997;  158 1302-1309
• 120 Camussi G, Montrucchio G, Lupia E et al.. Platelet-activating factor directly stimulates in vitro migration of endothelial cells and in vivo angiogenesis by heparin-dependent mechanism.  J Immunol. 1995;  154 6492-6501
• 121 Montrucchio G, Lupia E, Battaglia E et al.. Platelet-activating factor enhances endothelial growth factor-induced endothelial cell motility and neoangiogenesis in a murine matrigel model.  Arterioscler Thromb Vasc Biol. 2000;  20 80-88
• 122 Bustin S A, Dorudi S, Phillips S M et al.. Local expression of insulin-like growth factor-1 affects angiogenesis in colorectal cancer.  Tumour Biol. 2002;  23 130-138
• 123 Bermont L, Lamielle F, Fauconnet S et al.. Regulation of vascular endothelial growth factor expression by insulin-like growth factor-1 in endometrial adenocarcinoma cells.  Int J Cancer. 2000;  85 117-123
• 124 Lee O H, Bae S K, Bae M H et al.. Identification of angiogenic properties of insulin-like growth factor II in in vitro angiogenesis models.  Br J Cancer. 2000;  82 385-391
• 125 Ritter M R, Dorrell M I, Edmonds J et al.. Insulin-like growth factor 2 and potential regulators of hemangioma involution identified by large-scale expression analysis.  Proc Natl Acad Sci USA. 2002;  99 7455-7460
• 126 Dunn S E, Torres J V, Nihei N, Barrett J C. The insulin growth factor-1 elevates urokinase-type plasminogen activator-1 in human breast cancer cells: a new avenue for breast cancer therapy.  Mol Carcinog. 2000;  27 10-17
• 127 Valter M M, Wietler O D, Pietsche T, Pietsch T. Differential control of VEGF synthesis and secretion in human glioma cells by IL-1 and EGF.  Int J Dev Neurosci. 1999;  17 565-577
• 128 Ravindranath N, Wion D, Brachet P, Djakiew D. Epidermal growth factor modulates the expression of vascular endothelial growth factor in the human prostate.  J Androl. 2001;  22 432-443
• 129 Harris V K, Coticchia C M, Kagan B L et al.. Induction of the angiogenic modulator fibroblast growth factor-binding protein by epidermal growth factor is mediated through both MEK/ERK and p53 signal transduction pathways.  J Biol Chem. 2000;  275 10802-10811
• 130 Brown N S, Jones A, Fujiyama C et al.. Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors.  Cancer Res. 2000;  60 6298-6302
• 131 Guo P, Gu W, Xu L et al.. Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment.  Am J Pathol. 2003;  162 1083-1093
• 132 Huang X, Lee C. From TGF-beta to cancer therapy.  Curr Drug Targets. 2003;  4 243-250
• 133 Rich J N. The role of transforming growth factor-beta in primary brain tumors.  Front Biosci. 2003;  8 e245-260
• 134 Teraoka H, Sawada T, Nishihara T et al.. Enhanced VEGF production and decreased immunogenicity induced by TGF-beta 1 promote liver metastasis of pancreatic cancer.  Br J Cancer. 2001;  85 612-617
• 135 Breier G, Blum S, Peli J et al.. Transforming growth factor-beta and Ras regulate the VEGF/VEGF-receptor system during tumor angiogenesis.  Int J Cancer. 2002;  97 142-148
• 136 Renner U, Lohrer P, Schaaf L et al.. Transforming growth factor-beta stimulates vascular endothelial growth factor production by folliculostellate pituitary cells.  Endocrinology. 2002;  143 3759-3765
• 137 Vinals F, Pouyssegur J. Transforming growth factor beta 1 (TGF-beta1) promotes endothelial cell survival during in vitro angiogenesis via an autocrine mechanism implicating TGF-alpha signaling.  Mol Cell Biol. 2001;  21 7218-7230
• 138 Darland D C, D'Amore P A. TGF beta is required for the formation of capillary-like structures in three-dimensional cocultures of 10T1/2 and endothelial cells.  Angiogenesis. 2001;  4 11-20
• 139 Hoying J B, Yin M, Diebold R, Ormsby I, Becker A, Doetschman T. Transforming growth factor beta 1 enhances platelet aggregation through a nontranscriptional effect on the fibrinogen receptor.  J Biol Chem. 1999;  274 31008-31013
• 140 Davis S, Yancopoulos G D. Yin and yang in angiogenesis.  Curr Top Microbiol Immunol. 1999;  237 173-185
• 141 Thurston G, Rudge J S, Ioffe E et al.. Angiopoietin-1 protects the adult vasculature against leakage.  Nat Med. 2000;  6 460-463
• 142 Suri C, McClain J, Thurston G et al.. Increased vascularisation in mice overexpressing angiopoietin-1.  Science. 1998;  282 468-471
• 143 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
• 144 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
• 145 Teuscher E, Weidlich V. Adenosine nucleotides, adenosine and adenine as angiogenesis factors.  Biomed Biochim Acta. 1985;  44 493-495
• 146 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
• 147 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
• 148 Gengrinovitch S, Greenberg S M, Cohen T. Platelet factor-4 inhibits the mitogenic activity of VEGF-121 and VEGF-165 using several concurrent mechanisms.  J Biol Chem. 1995;  270 15059-15065
• 149 Maione T E, Gray G S, Hunt A J, Sharpe R J. Inhibition of tumor growth in mice by an analogue of platelet factor 4 that lacks affinity for heparin and retains potent angiostatic activity.  Cancer Res. 1991;  51 2077-2083
• 150 Browder T, Folkman J, Pirie-Shepherd S. The hemostatic system as a regulator of angiogenesis.  J Biol Chem. 2000;  275 1521-1524
• 151 Mast A E, Stadanlick J E, Lockett M et al.. Tissue factor pathway inhibitor binds to platelet thrombospondin-1.  J Biol Chem. 2000;  275 31715-31721
• 152 Selheim F, Fukami M H, Holmsen H, Vassbotn F S. Platelet-derived-growth-factor-induced signalling in human platelets: phosphoinositide-3-kinase-dependent inhibition of platelet activation.  Biochem J. 2000;  350(pt 2) 469-475
• 153 Selheim F, Holmsen H, Vassbotn F S. Identification of functional VEGF receptors on human platelets.  FEBS Lett. 2002;  512 107-110
• 154 Chui C M, Li K, Yang M et al.. Platelet-derived growth factor up-regulates the expression of transcriptional factors NF-E2, GATA-1, and c-fos in megakaryocytic cell lines.  Cytokine. 2003;  21 51-64
• 155 Tsiamis A C, Hayes P, Box H et al.. Characterization and regulation of the receptor tyrosine kinase Tie-1 in platelets.  J Vasc Res. 2000;  37 437-442
• 156 Sato T N, Tozawa Y, Deutsch U et al.. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation.  Nature. 1995;  376 70-74
• 157 Tseng L M, Hsu C Y, Wang H C et al.. Tie-1 tyrosine kinase is an independent prognostic indicator for invasive breast cancer.  Anticancer Res. 2001;  21 2163-2170
• 158 Lin W C, Li A F, Chi C W et al.. Tie-1 protein tyrosine kinase: a novel independent prognostic marker for gastric cancer.  Clin Cancer Res. 1999;  5 1745-1751
• 159 Sawicki G, Salas E, Murat J et al.. Release of gelatinase A during platelet activation mediates aggregation.  Nature. 1997;  386 616-619
• 160 Menashi S, He L, Soria C, Soria J, Thomaidis A, Legrand Y. Modulation of endothelial cells fibrinolytic activity by platelets.  Thromb Haemost. 1991;  165 77-81
• 161 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
• 162 Huang S, Van Arsdall M, Tedjarati S et al.. Contribution of stromal metalloproteinase 9 to angiogenesis and growth of human ovarian carcinoma in mice.  J Natl Cancer Inst. 2002;  94 1134-1142
• 163 Kazes I, Elalamy I, Sraer J D et al.. Platelet release of trimolecular complex components MT1-TIMP2-MMP2: involvement in MMP2 activation and platelet aggregation.  Blood. 2000;  96 3064-3069
• 164 Pepper M S, Ferrara N, Orci L, Monteasano R. Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells.  Biochem Biophys Res Commun. 1991;  181 902-906
• 165 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
• 166 Wick W, Platten M, Weller M. Glioma cell invasion: regulation of metalloproteinase activity by TGF-beta.  J Neurooncol. 2001;  53 177-185
• 167 Vlodavsky I, Eldor A, Haimovitz-Friedman A et al.. Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation.  Invasion Metastasis. 1992;  12 112-127
• 168 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
• 169 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 thrombastenic-like state in normal platelets and binds to glycoproteins IIb and/or IIIa.  J Clin Invest. 1983;  72 325-328
• 170 Coller B S. Anti-GpIIb/IIIa drugs: current strategies and future directions.  Thromb Haemost. 2001;  86 427-443
• 171 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
• 172 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
• 173 Engelberg H. Actions of heparins that may affect the malignant process.  Cancer. 1999;  85 257-272
• 174 Butenas S, Cawthern K, Veer C et al.. Antiplatelet agents in tissue factor-induced blood coagulation.  Blood. 2001;  97 2314-2322
• 175 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
• 176 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
• 177 Mehta P, Lawson D, Ward M B et al.. Effect of thromboxane A2 inhibition on osteogenic sarcoma cell-induced platelet aggregation.  Cancer Res. 1986;  46 5061-5063
• 178 Karpatkin S, Ambrogio C, Pearlstein E. Lack of effect on in vivo prostacyclin on the development of pulmonary metastases in mice following intravenous injection of CT26 colon carcinoma, Lewis lung carcinoma or B16 amelanotic melanoma cells.  Cancer Res. 1984;  44 3880-3883
• 179 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