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Semin Thromb Hemost 2004; 30(1): 95-108
DOI: 10.1055/s-2004-822974
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Platelets and Angiogenesis in Malignancy

Ewa Sierko1 , 2 , Marek Z. Wojtukiewicz2
  • 1Staff Physician
  • 2Department of Oncology, Medical University, Bialystok, Poland
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Publikationsverlauf

Publikationsdatum:
22. März 2004 (online)

    Lizenzen und Reprints

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.

KEYWORDS

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
    PubMedGoogle Scholar
  • 2 de Gaetano G. Historical overview of the role of platelets in hemostasis and thrombosis.  Haematologica. 2001;  86 349-356
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 4 MacKay W. The blood platelet: its clinical significance.  Q J Med. 1930;  24 285-293
    PubMedGoogle Scholar
  • 5 Billroth T. Lectures on Surgical Pathology and Therapeutics: A New Handbook for Students and Practitioners. London; The New Syndenham Society 1878: 355
    Google Scholar
  • 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
    PubMedGoogle Scholar
  • 7 Rickles F R, Levine M, Edwards R L. Hemostatic alterations in cancer patients.  Cancer Metastasis Rev. 1992;  11 237-248
    CrossrefPubMedGoogle Scholar
  • 8 Francis J L, Biggerstaff J, Amirkhosravi A. Hemostasis and malignancy.  Semin Thromb Hemost. 1998;  24 93-109
    PubMedGoogle Scholar
  • 9 Kies M S, Posch J J, Giolama J P, Rubin R N. Hemostatic function in cancer patients.  Cancer. 1980;  46 831-837
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 13 Moller-Pedresen L, Milman N. Prognostic significance of thrombocytosis in patients with primary lung cancer.  Eur Respir J. 1996;  9 1826-1830
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 18 Gücer F, Moser F, Tamussino K et al.. Thrombocytosis as a prognostic factor in endometrial carcinoma.  Gynecol Oncol. 1998;  70 210-214
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 20 Nakano T, Fujii J, Tamura S, Hada T, Higashino K. Thrombocytosis in patients with malignant mesothelioma.  Cancer. 1986;  58 1699-1701
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 23 Schwartz R E. Platelet counts and prognosis of pancreatic cancer.  Lancet. 1999;  353 2158-2159
    PubMedGoogle Scholar
  • 24 Slichter S J, Harker L A. Hemostasis in malignancy.  Ann N Y Acad Sci. 1974;  230 252-262
    PubMedGoogle Scholar
  • 25 Tang D G, Honn K V. Adhesion molecules and tumor metastasis: an update.  Invasion Metastasis. 1994-95;  14 109-122
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 27 Folkman J. Tumor angiogenesis: therapeutic implications.  N Engl J Med. 1971;  285 1182-1186
    CrossrefPubMedGoogle Scholar
  • 28 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other diseases.  Nat Med. 1995;  1 27-31
    CrossrefPubMedGoogle Scholar
  • 29 Wojtukiewicz M Z, Sierko E, Klement P, Rak J. The hemostatic system and angiogenesis in malignancy.  Neoplasia. 2001;  3 371-384
    Google Scholar
  • 30 Heemskerk J WM, Bevers E M, Lindhout T. Platelet activation and blood coagulation.  Thromb Haemost. 2002;  88 186-193
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 33 Kamata T, Takada Y. Platelet integrin alphaIIbbeta3-ligand interactions: what can we learn from the structure?.  Int J Hematol. 2001;  74 382-389
    PubMedGoogle Scholar
  • 34 Coughlin S R. Protease-activated receptors and platelet function.  Thromb Haemost. 1999;  82 353-356
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 37 Serrano K, Devine D V. Intracellular factor XIII crosslinks platelet cytoskeletal elements upon platelet activation.  Thromb Haemost. 2002;  88 315-320
    PubMedGoogle Scholar
  • 38 Rendu F, Brohard-Bohn B. The platelet release reaction: granules' constituents, secretion and functions.  Platelets. 2001;  12 261-273
    CrossrefPubMedGoogle Scholar
  • 39 Nieswandt B, Watson S P. Platelet collagen interaction: is GPVI the central receptor?.  Blood. 2003;  102 449-461
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 42 Corbett G, Perry D J. Significance of thrombocytosis.  Lancet. 1983;  1 77-79
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 48 Suzuki A, Takahashi T, Nakamura K et al.. Thrombocytosis in patients with tumors producing colony-stimulating factor.  Blood. 1992;  80 2052-2059
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 59 Clauss M. Molecular biology of the VEGF and the VEGF receptor family.  Semin Thromb Hemost. 2000;  26 561-569
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 60 Ferrara N. Vascular endothelial growth factor: molecular and biological aspects.  Curr Top Microbiol Immunol. 1999;  237 1-30
    PubMedGoogle Scholar
  • 61 Tavassoli M, Aoki M. Localization of megakaryocytes in the bone marrow.  Blood Cells. 1989;  15 3-14
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 63 Ferriere J P, Bernard D, Legros M et al.. β-thromboglobulin in patients with breast cancer.  Am J Hematol. 1985;  19 47-53
    PubMedGoogle Scholar
  • 64 Milroy R, Douglas J T, Campbell J et al.. Abnormal haemostasis in small cell lung cancer.  Thorax. 1988;  43 978-981
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 67 Abbasciano V, Bianchi M P, Trevisani L et al.. Platelet activation and fibrinolysis in large bowel cancer.  Oncology. 1995;  52 381-384
    PubMedGoogle Scholar
  • 68 Wehmeier A, Tschope D, Esser J et al.. Circulating activated platelets in myeloproliferative disorders.  Thromb Res. 1991;  61 271-278
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 71 Olas B, Mielicki W P, Wachowicz B et al.. Cancer procoagulant stimulates platelet adhesion.  Thromb Res. 1999;  94 199-203
    CrossrefPubMedGoogle Scholar
  • 72 Falanga A, Rickles F R. Pathophysiology of the thrombophilic state in the cancer patient.  Semin Thromb Hemost. 1999;  25 173-182
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 74 Karpatkin S, Nierodzik M L, Klepfish A. Role of platelets, thrombin in cancer.  Vessels. 1996;  2 17-23
    PubMedGoogle Scholar
  • 75 Pinedo H M, Verheul H MW, D'Amato R J, Folkman J. Involvement of platelets in tumor angiogenesis?.  Lancet. 1998;  352 1775-1777
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 86 Jelkman W. Pitfalls in the measurement of circulating vascular endothelial growth factor.  Clin Chem. 2001;  47 617-623
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 90 McEver R P. Adhesive interactions of leukocytes, platelets, and the vessel wall during hemostasis and inflammation.  Thromb Haemost. 2001;  86 746-756
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 93 Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow?.  Lancet. 2001;  357 539-545
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 103 Schultz G S, Grant M B. Neovascular growth factors.  Eye. 1991;  5 170-180
    PubMedGoogle Scholar
  • 104 Betsholtz C, Karlson L, Lindahl P. Developmental roles of platelet-derived growth factors.  Bioessays. 2001;  23 494-507
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 109 Taylor S, Folkman J. Protamine is an inhibitor of angiogenesis.  Nature. 1982;  297 307-312
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 115 Friesel R E, Maciag T. Fibroblast growth factor prototype release and fibroblast growth factor receptor signaling.  Thromb Haemost. 1999;  82 748-754
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 132 Huang X, Lee C. From TGF-beta to cancer therapy.  Curr Drug Targets. 2003;  4 243-250
    CrossrefPubMedGoogle Scholar
  • 133 Rich J N. The role of transforming growth factor-beta in primary brain tumors.  Front Biosci. 2003;  8 e245-260
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 140 Davis S, Yancopoulos G D. Yin and yang in angiogenesis.  Curr Top Microbiol Immunol. 1999;  237 173-185
    PubMedGoogle Scholar
  • 141 Thurston G, Rudge J S, Ioffe E et al.. Angiopoietin-1 protects the adult vasculature against leakage.  Nat Med. 2000;  6 460-463
    CrossrefPubMedGoogle Scholar
  • 142 Suri C, McClain J, Thurston G et al.. Increased vascularisation in mice overexpressing angiopoietin-1.  Science. 1998;  282 468-471
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 145 Teuscher E, Weidlich V. Adenosine nucleotides, adenosine and adenine as angiogenesis factors.  Biomed Biochim Acta. 1985;  44 493-495
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 150 Browder T, Folkman J, Pirie-Shepherd S. The hemostatic system as a regulator of angiogenesis.  J Biol Chem. 2000;  275 1521-1524
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 153 Selheim F, Holmsen H, Vassbotn F S. Identification of functional VEGF receptors on human platelets.  FEBS Lett. 2002;  512 107-110
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 159 Sawicki G, Salas E, Murat J et al.. Release of gelatinase A during platelet activation mediates aggregation.  Nature. 1997;  386 616-619
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 166 Wick W, Platten M, Weller M. Glioma cell invasion: regulation of metalloproteinase activity by TGF-beta.  J Neurooncol. 2001;  53 177-185
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 170 Coller B S. Anti-GpIIb/IIIa drugs: current strategies and future directions.  Thromb Haemost. 2001;  86 427-443
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 173 Engelberg H. Actions of heparins that may affect the malignant process.  Cancer. 1999;  85 257-272
    CrossrefPubMedGoogle Scholar
  • 174 Butenas S, Cawthern K, Veer C et al.. Antiplatelet agents in tissue factor-induced blood coagulation.  Blood. 2001;  97 2314-2322
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar

Ewa SierkoM.D. 

Department of Oncology, Medical University

12 Ogrodowa St., 15-027 Bialystok, Poland

eMail: ewa.sierko@iq.pl