Onkologische Welt 2016; 07(03): 123-132
DOI: 10.1055/s-0038-1625016
Review supportive care
Schattauer GmbH

Platelets in cancer

From basic research to therapeutic implicationsBlutplättchen und KrebsVon der Grundlagenforschung zur therapeutischen Relevanz
E. Mammadova-Bach
1   UMR_S949, Inserm, Strasbourg, France; Etablissement Français du Sang-Alsace, Strasbourg, France; Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, France
,
P. Mangin
1   UMR_S949, Inserm, Strasbourg, France; Etablissement Français du Sang-Alsace, Strasbourg, France; Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, France
,
F. Lanza
1   UMR_S949, Inserm, Strasbourg, France; Etablissement Français du Sang-Alsace, Strasbourg, France; Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, France
,
C. Gachet
1   UMR_S949, Inserm, Strasbourg, France; Etablissement Français du Sang-Alsace, Strasbourg, France; Université de Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, France
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
10. Januar 2018 (online)

Summary

Platelets are well-known for their major role in primary hemostasis and thrombosis. Cancer patients frequently manifest thrombotic events and present abnormalities in blood coagulation which appear to be linked to altered platelet function and turnover. Moreover, numerous studies indicate an intimate cross-talk between platelets and tumor growth, angiogenesis and metastatic dissemination. Finally, several experimental data and clinical trials suggest possible benefits of anti-platelet drugs on some cancers. Here, we will review the current state of basic biological research regarding the role of platelets in cancer progression. We also critically review the possible clinical applicability of some anti-platelet therapies to limit tumor growth and prevent metastatic dissemination.

Zusammenfassung

Die wichtige Rolle der Plättchen in der primären Hämostase und Thrombose ist gut bekannt. Krebspatienten weisen häufig thrombotische Ereignisse und Unregelmäßigkeiten der Blutgerinnung auf, die mit Veränderungen der Plättchenfunktion und des Thrombozyten-Turnover verbunden zu sein scheinen. Außerdem wiesen zahlreiche Studien auf eine enge Wechselwirkungen zwischen Plättchen,Tumorwachstum, Angiogenese und Metastasierung hin. Schließlich lassen experimentelle Daten und klinische Studien einen möglichen Nutzen von Thrombozytenaggregationshemmern bei einigen Krebsarten vermuten.

Wir geben einen Überblick zum aktuellen Stand der biologischen Grundlagenforschung bzgl. der Rolle der Plättchen bei der Krebsprogression. Auch die Eignung einiger Thrombozytenaggregationshemmer zur Eindämmung des Tumorwachstums und zur Prophylaxe der metastatischen Tumorausbreitung haben wir kritisch geprüft.

 
  • References

  • 1 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-674.
  • 2 Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012; 21: 309-322.
  • 3 Olson OC, Joyce JA. Microenvironment-mediated resistance to anticancer therapies. Cell Res 2013; 23: 179-181.
  • 4 Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood 2007; 110: 1723-1729.
  • 5 Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol 2005; 06: 401-410.
  • 6 Tranum BL, Haut A. Thrombocytosis: platelet kinetics in neoplasia. J Lab Clin Med 1974; 84: 615-619.
  • 7 Khorana AA. Cancer and coagulation. Am J Hematol 2012; 87 (Suppl. 01) S82-S87.
  • 8 Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New fundamentals in hemostasis. Physiol Rev 2013; 93: 327-358.
  • 9 Nurden AT. Platelets, inflammation and tissue regeneration. Thromb Haemost 2011; 105 (Suppl. 01) S13-S33.
  • 10 Bertozzi CC, Hess PR, Kahn ML. Platelets: covert regulators of lymphatic development. Arterioscler Thromb Vasc Biol 2010; 30: 2368-2371.
  • 11 Semple JW, Italiano Jr JE, Freedman J. Platelets and the immune continuum. Nature reviews. Immunology 2011; 11: 264-274.
  • 12 Stegner D, Dutting S, Nieswandt B. Mechanistic explanation for platelet contribution to cancer metastasis. Thromb Res 2014; 133 (Suppl. 02) S149-S157.
  • 13 Riedl J, Pabinger I, Ay C. Platelets in cancer and thrombosis. Hämostaseologie 2014; 34: 54-62.
  • 14 Goubran HA, Stakiw J, Radosevic M, Burnouf T. Platelet-cancer interactions. Semin Thromb Hemost 2014; 40: 296-305.
  • 15 Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nature reviews. Cancer 2011; 11: 123-134.
  • 16 Di Nisio M, Porreca E, Otten HM, Rutjes AW. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. The Cochrane database of systematic reviews 2014; 08: CD008500.
  • 17 Stone RL. et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med 2013; 366: 610-618.
  • 18 Sasaki Y. et al. Production of thrombopoietin by human carcinomas and its novel isoforms. Blood 1999; 94: 1952-1960.
  • 19 Rank A. et al. Circulating microparticles in patients with benign and malignant ovarian tumors. Anticancer Res 2012; 32: 2009-2014.
  • 20 Jurasz P, Alonso-Escolano D, Radomski MW. Platelet--cancer interactions: mechanisms and pharmacology of tumour cell-induced platelet aggregation. Br J Pharmacol 2004; 143: 819-826.
  • 21 Raica M, Cimpean AM, Ribatti D. The role of podoplanin in tumor progression and metastasis. Anticancer Res 2008; 28 5B 2997-3006.
  • 22 Dang Q, Liu J, Li J, Sun Y. Podoplanin: a novel regulator of tumor invasion and metastasis. Med Oncol 2014; 31: 24.
  • 23 Lowe KL, Navarro-Nunez L, Watson SP. Platelet CLEC-2 and podoplanin in cancer metastasis. Thromb Res 2012; 129 (Suppl. 01) S30-S37.
  • 24 Takagi S. et al. Platelets promote tumor growth and metastasis via direct interaction between Aggrus/ podoplanin and CLEC-2. PloS one 2013; 08: e73609.
  • 25 Han X, Guo B, Li Y, Zhu B. Tissue factor in tumor microenvironment: a systematic review. J Hematol Oncol 2014; 07: 54.
  • 26 Demers M. et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci USA 2012; 109: 13076-13081.
  • 27 Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 2011; 473: 298-307.
  • 28 Italiano Jr JE. et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 2008; 111: 1227-1233.
  • 29 Battinelli EM, Markens BA, Italiano Jr JE. Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis. Blood 2011; 118: 1359-1369.
  • 30 Bambace NM, Levis JE, Holmes CE. The effect of P2Y-mediated platelet activation on the release of VEGF and endostatin from platelets. Platelets 2010; 21: 85-93.
  • 31 Kamykowski J, Carlton P, Sehgal S, Storrie B. Quantitative immunofluorescence mapping reveals little functional coclustering of proteins within platelet alpha-granules. Blood 2011; 118: 1370-1373.
  • 32 Jonnalagadda D, Izu LT, Whiteheart SW. Platelet secretion is kinetically heterogeneous in an agonist-responsive manner. Blood 2012; 120: 5209-5216.
  • 33 Klement GL. et al. Platelets actively sequester angiogenesis regulators. Blood 2009; 113: 2835-2842.
  • 34 Feng W. et al. A novel role for platelet secretion in angiogenesis: mediating bone marrow-derived cell mobilization and homing. Blood 2011; 117: 3893-3902.
  • 35 Kuznetsov HS. et al. Identification of luminal breast cancers that establish a tumor-supportive macroenvironment defined by proangiogenic platelets and bone marrow-derived cells. Cancer discovery 2012; 02: 1150-1165.
  • 36 Pipili-Synetos E, Papadimitriou E, Maragoudakis ME. Evidence that platelets promote tube formation by endothelial cells on matrigel. Br J Pharmacol 1998; 125: 1252-1257.
  • 37 Qi J, Goralnick S, Kreutzer DL. Fibrin regulation of interleukin-8 gene expression in human vascular endothelial cells. Blood 1997; 90: 3595-3602.
  • 38 Kim HK, Song KS, Chung JH, Lee KR, Lee SN. Platelet microparticles induce angiogenesis in vitro. Br J Haematol 2004; 124: 376-384.
  • 39 Janowska-Wieczorek A. et al. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. International journal of cancer. J Int Cancer 2005; 113: 752-760.
  • 40 Brill A, Dashevsky O, Rivo J. et al. Platelet-derived microparticles induce angiogenesis and stimulate post-ischemic revascularization. Cardiovasc Res 2005; 67: 30-38.
  • 41 Helley D. et al. Platelet microparticles: a potential predictive factor of survival in hormone-refractory prostate cancer patients treated with docetaxelbased chemotherapy. Eur Urol 2009; 56: 479-484.
  • 42 Kim HK. et al. Elevated levels of circulating platelet microparticles, VEGF, IL-6 and RANTES in patients with gastric cancer: possible role of a metastasis predictor. Eur J Cancer 2003; 39: 184-191.
  • 43 Twombly R. Avastin’s uncertain future in breast cancer treatment. J Natl Cancer Inst 2011; 103: 458-460.
  • 44 Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nature reviews. Cancer 2003; 03: 453-458.
  • 45 Gasic GJ, Gasic TB, Stewart CC. Antimetastatic effects associated with platelet reduction. Proc Natl Acad Sci USA 1968; 61: 46-52.
  • 46 Karpatkin S, Pearlstein E, Ambrogio C, Coller BS. Role of adhesive proteins in platelet tumor interaction in vitro and metastasis formation in vivo. J Clin Invest 1988; 81: 1012-1019.
  • 47 Camerer E. et al. Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Blood 2004; 104: 397-401.
  • 48 Labelle M, Hynes RO. The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination. Cancer Discovery 2012; 02: 1091-1099.
  • 49 Nieswandt B, Hafner M, Echtenacher B, Mannel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 1999; 59: 1295-1300.
  • 50 Placke T. et al. Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Res 2012; 72: 440-448.
  • 51 Palumbo JS. et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 2005; 105: 178-185.
  • 52 Skov PMadsen, Hokland P, Hokland M. Secretory products from thrombin-stimulated human platelets exert an inhibitory effect on NK-cytotoxic activity. Acta pathologica, microbiologica, et immunologica Scandinavica. Section C, Immunology 1986; 94: 193-200.
  • 53 Kopp HG, Placke T, Salih HR. Platelet-derived transforming growth factor-beta down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Cancer Res 2009; 69: 7775-7783.
  • 54 Lee JC, Lee KM, Kim DW, Heo DS. Elevated TGFbeta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol 2004; 172: 7335-7340.
  • 55 Coupland LA, Chong BH, Parish CR. Platelets and P-selectin control tumor cell metastasis in an organ-specific manner and independently of NK cells. Cancer Res 2012; 72: 4662-4671.
  • 56 Steinestel K, Eder S, Schrader AJ, Steinestel J. Clinical significance of epithelial-mesenchymal transition. Clin Transl Med 2014; 03: 17.
  • 57 Dovizio M. et al. Pharmacological inhibition of platelet-tumor cell cross-talk prevents platelet-induced overexpression of cyclooxygenase-2 in HT29 human colon carcinoma cells. Mol Pharmacol 2013; 84: 25-40.
  • 58 Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer cell 2011; 20: 576-590.
  • 59 Alves CS, Burdick MM, Thomas SN. et al. The dual role of CD44 as a functional P-selectin ligand and fibrin receptor in colon carcinoma cell adhesion. Am J Physiol Cell Physiol 2008; 294: C907-916.
  • 60 Qi CL. et al. P-selectin-mediated platelet adhesion promotes the metastasis of murine melanoma cells. PLoS One 2014; 09: e91320.
  • 61 Coupland LA, Parish CR. Platelets, selectins, and the control of tumor metastasis. Semin Oncol 2014; 41: 422-434.
  • 62 McCarty OJ, Mousa SA, Bray PF, Konstantopoulos K. Immobilized platelets support human colon carcinoma cell tethering, rolling, and firm adhesion under dynamic flow conditions. Blood 2000; 96: 1789-1797.
  • 63 Zhang C. et al. Modified heparins inhibit integrin alpha(IIb)beta(3) mediated adhesion of melanoma cells to platelets in vitro and in vivo. International journal of cancer. J Int Cancer 2009; 125: 2058-2065.
  • 64 Bakewell SJ. et al. Platelet and osteoclast beta3 integrins are critical for bone metastasis. Proc Natl Acad Sci USA 2003; 100: 14205-14210.
  • 65 Boucharaba A. et al. Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J Clin Invest 2004; 114: 1714-1725.
  • 66 Pilch J, Habermann R, Felding-Habermann B. Unique ability of integrin alpha(v)beta 3 to support tumor cell arrest under dynamic flow conditions. J Biol Chem 2002; 277: 21930-21938.
  • 67 Morimoto K. et al. Interaction of cancer cells with platelets mediated by Necl-5/poliovirus receptor enhances cancer cell metastasis to the lungs. Oncogene 2008; 27: 264-273.
  • 68 Leblanc R. et al. Interaction of platelet-derived autotaxin with tumor integrin alphaVbeta3 controls metastasis of breast cancer cells to bone. Blood 2014; 124: 3141-3150.
  • 69 Jain S. et al. Platelet glycoprotein Ib alpha supports experimental lung metastasis. Proc Natl Acad Sci USA 2007; 104: 9024-9028.
  • 70 Erpenbeck L, Nieswandt B, Schon M. et al. Inhibition of platelet GPIb alpha and promotion of melanoma metastasis. J Invest Dermatol 2010; 130: 576-586.
  • 71 Schumacher D, Strilic B, Sivaraj KK. et al. Plateletderived nucleotides promote tumor-cell transendothelial migration and metastasis via P2Y2 receptor. Cancer Cell 2013; 24: 130-137.
  • 72 Guerrero JA. et al. Gray platelet syndrome: Pro-inflammatory megakaryocytes and alpha-granule loss cause myelofibrosis and confer resistance to cancer metastasis in mice. Blood 2014; 124: 3624-3635.
  • 73 Jain S, Russell S, Ware J. Platelet glycoprotein VI facilitates experimental lung metastasis in syngenic mouse models. J Thromb Haemost 2009; 07: 1713-1717.
  • 74 Zahid M. et al. The future of glycoprotein VI as an antithrombotic target. J Thromb Haemost 2012; 10: 2418-2427.
  • 75 Schaphorst KL. et al. Role of sphingosine-1 phosphate in the enhancement of endothelial barrier integrity by platelet-released products. Am J Physiol 2003; 285: L258-L267.
  • 76 Yin F, Watsky MA. LPA and S1P increase corneal epithelial and endothelial cell transcellular resistance. Invest Ophthalmol Vis Sci 2005; 46: 1927-1933.
  • 77 Cote F, Fligny C, Fromes Y. et al. Recent advances in understanding serotonin regulation of cardiovascular function. Trends Mol Med 2004; 10: 232-238.
  • 78 Skolnik G, Bagge U, Blomqvist G. et al. The role of calcium channels and serotonin (5-HT2) receptors for tumour cell lodgement in the liver. Clin Exp Metastasis 1989; 07: 169-174.
  • 79 Kuna P. et al. RANTES, a monocyte and T lymphocyte chemotactic cytokine releases histamine from human basophils. J Immunol 1992; 149: 636-642.
  • 80 Medina VA, Rivera ES. Histamine receptors and cancer pharmacology. Br J Pharmacol 2010; 161: 755-767.
  • 81 Cools-Lartigue J. et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Invest 2013; 123: 3446-3458.
  • 82 Yu LX. et al. Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein. Nature Commun 2014; 05: 5256.
  • 83 Labelle M, Begum S, Hynes RO. Platelets guide the formation of early metastatic niches. Proc Natl Acad Sci USA 2014; 111: E3053-E3061.
  • 84 Oskarsson T. et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nature Med 2011; 17: 867-874.
  • 85 O’Connell JT. et al. VEGF-A and Tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization. Proc Natl Acad Sci USA 2011; 108: 16002-16007.
  • 86 Schaff M. et al. Novel function of tenascin-C, a matrix protein relevant to atherosclerosis, in platelet recruitment and activation under flow. Arterioscler Thromb Vasc Biol 2011; 31: 117-124.
  • 87 Brellier F. et al. Tenascin-C triggers fibrin accumulation by downregulation of tissue plasminogen activator. FEBS letters 2011; 585: 913-920.
  • 88 Patrono C, Baigent C, Hirsh J. et al. Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2008; 133 (Suppl. 06) 199S-233S.
  • 89 Gasic GJ, Gasic TB, Galanti N. et al. Platelettumor-cell interactions in mice. The role of platelets in the spread of malignant disease. Int J Cancer 1973; 11: 704-718.
  • 90 Alfonso L, Ai G, Spitale RC, Bhat GJ. Molecular targets of aspirin and cancer prevention. Br J Cancer 2014; 111: 61-67.
  • 91 Chulada PC. et al. Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res 2000; 60: 4705-4708.
  • 92 Sciulli MG. et al. Platelet activation in patients with colorectal cancer. Prostaglandins Leukot Essent Fatty Acids 2005; 72: 79-83.
  • 93 Flossmann E, Rothwell PM. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 2007; 369: 1603-1613.
  • 94 Rothwell PM. et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012; 379: 1591-1601.
  • 95 Reimers MS. et al. Aspirin use after diagnosis improves survival in older adults with colon cancer: a retrospective cohort study. J Am Geriatr Soc 2012; 60: 2232-2236.
  • 96 Zhang S. et al. Cyclooxygenase inhibitors use is associated with reduced risk of esophageal adenocarcinoma in patients with Barrett’s esophagus: a meta-analysis. Br J Cancer 2014; 110: 2378-2388.
  • 97 Cuzick J. et al. Preventive therapy for breast cancer: a consensus statement. Lancet Oncol 2011; 12: 496-503.
  • 98 Stark LA. et al. Aspirin activates the NF-kappaB signalling pathway and induces apoptosis in intestinal neoplasia in two in vivo models of human colorectal cancer. Carcinogenesis 2007; 28: 968-976.
  • 99 Bos CL. et al. Effect of aspirin on the Wnt/betacatenin pathway is mediated via protein phosphatase 2A. Oncogene 2006; 25: 6447-6456.
  • 100 Din FV. et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 2012; 142: 1504-1515.
  • 101 Neugut AI. Aspirin as adjuvant therapy for stage III colon cancer: standard of care?. JAMA Int Med 2014; 174: 739-741.
  • 102 Seshasai SR. et al. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Int Med 2013; 172: 209-216.
  • 103 Sostres C, Lanas A. Gastrointestinal effects of aspirin. Nature reviews. Gastroenterol Hepatol 2011; 08: 385-394.
  • 104 McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med 2006; 119: 624-638.
  • 105 Gachet C. Regulation of platelet functions by P2 receptors. Annu Rev Pharmacol Toxicol 2006; 46: 277-300.
  • 106 Gachet C. P2 receptors, platelet function and pharmacological implications. Thromb Haemost 2008; 99: 466-472.
  • 107 Cattaneo M. New P2Y(12) inhibitors. Circulation 2010; 121: 171-179.
  • 108 Berger JS. et al. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation 2009; 120: 2337-2344.
  • 109 Bastida E, Escolar G, Almirall L, Ordinas A. Platelet activation induced by a human neuroblastoma tumor cell line is reduced by prior administration of ticlopidine. Thromb Haemost 1986; 55: 333-337.
  • 110 Mezouar S, Darbousset R, Dignat-George F. et al. Inhibition of platelet activation prevents the P-selectin and integrin-dependent accumulation of cancer cell microparticles and reduces tumor growth and metastasis in vivo. Int J Cancer 2015; 136: 462-475.
  • 111 Gebremeskel S, LeVatte T, Liwski RS. et al. The reversible P2Y12 inhibitor ticagrelor inhibits metastasis and improves survival in mouse models of cancer. Int J Cancer 2015; 136: 234-240.
  • 112 Wang Y. et al. Platelet P2Y12 is involved in murine pulmonary metastasis. PloS One 2013; 08: e80780.
  • 113 Rohr S. et al. Quantitative image analysis of angiogenesis in rats implanted with a fibrin gel chamber. Nouvelle Revue Francaise d’Hematologie 1992; 34: 287-294.
  • 114 Klein-Soyer C. et al. Angiogenesis inhibitor SR 25989 upregulates thrombospondin-1 expression in human vascular endothelial cells and foreskin fibroblasts. Biol Cell 1997; 89: 295-307.
  • 115 Mah-Becherel MC. et al. Anti-angiogenic effects of the thienopyridine SR 25989 in vitro and in vivo in a murine pulmonary metastasis model. Br J Cancer 2002; 86: 803-810.
  • 116 Gachet C. P2Y(12) receptors in platelets and other hematopoietic and non-hematopoietic cells. Purinergic Signal 2012; 08: 609-619.
  • 117 Su X. et al. The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling. J Clin Invest 2012; 122: 3579-3592.
  • 118 Nanau RM, Delzor F, Neuman MG. Efficacy and safety of prasugrel in acute coronary syndrome patients. Clin Biochem 2014; 47: 516-528.
  • 119 Buckley LA. et al. Nonclinical assessment of carcinogenic risk and tumor growth enhancement potential of prasugrel, a platelet-inhibiting therapeutic agent. Int J Toxicol 2012; 31: 317-325.
  • 120 Bledzka K, Smyth SS, Plow EF. Integrin alphaIIbbeta3: from discovery to efficacious therapeutic target. Circ Res 2013; 112: 1189-1200.
  • 121 Timar J. et al. Platelet-mimicry of cancer cells: epiphenomenon with clinical significance. Oncology 2005; 69: 185-201.
  • 122 Zhang W. et al. A humanized single-chain antibody against beta 3 integrin inhibits pulmonary metastasis by preferentially fragmenting activated platelets in the tumor microenvironment. Blood 2013; 120: 2889-2898.
  • 123 Stoll P. et al. Targeting ligand-induced binding sites on GPIIb/IIIa via single-chain antibody allows effective anticoagulation without bleeding time prolongation. Arterioscler Thromb Vasc Biol 2007; 27: 1206-1212.
  • 124 Sarkar S, Alam MA, Shaw J, Dasgupta AK. Drug delivery using platelet cancer cell interaction. Pharm Res 2013; 30: 2785-2794.
  • 125 Tanaka K. et al. In vivo optical imaging of cancer metastasis using multiphoton microscopy: a short review. Am J Transl Res 2014; 06: 179-187.