Platelets in cancer and thrombosis

Summary

Platelets are the smallest circulating blood cells and their major function is the maintenance of haemostasis. They do not have a nucleus, but instead a multitude of granules that contain molecules important for several physiological processes. These granules can be released after platelet activation and thereby platelets take part in haemostasis, wound repair or immunological processes. Furthermore, platelets are also involved in the pathophysiology of several diseases, including cancer. Platelets can support various steps of cancer development and progression by promoting tumour growth, angiogenesis and metastasis. Moreover, platelets contribute to the hypercoagulable state frequently observed in cancer patients, leading to an increased risk of venous thromboembolism (VTE). In previous studies a high platelet count was repeatedly found to be associated with an elevated risk of VTE and a worse prognosis in patients with cancer.

The aim of this review is to give an overview of the most important alterations of platelet physiology in cancer patients and how these alterations may influence cancer disease and contribute to cancer-associated VTE.

Zusammenfassung

Thrombozyten sind die kleinsten zirkulierenden Blutzellen und stellen den zellulären Part des Blutgerinnungssystems dar. Sie enthalten keinen Zellkern, dafür jedoch eine Menge gerinnungsaktiver, angiogenetischer und immunwirksamer Substanzen, die sie bei Aktivierung ausschütten können. Dadurch sind sie neben der Blutgerinnung auch in verschiedenste andere physiologische Prozesse wie Wundheilung oder Immunabwehr eingebunden. Thrombozyten spielen jedoch auch in der Pathophysiologie von Krebserkrankungen eine Rolle. Sie können das Tumorwachstum, Gefäßneubildung und die Metastasierung fördern, zudem sind sie an der Entstehung eines prokoagulatorischen Zustandes beteiligt, der bei Krebspatienten oft beobachtet wird und zu einer erhöhten Thromboseneigung führt. In bisherigen Studien waren hohe Thrombozytenzahlen mit einer schlechten Prognose und einem erhöhten Risiko für venöse Thromboembolien (VTE) bei Krebspatienten assoziiert.

Dieses Review soll einen Überblick über die wichtigsten Veränderungen und Eigenschaften von Thrombozyten im Rahmen von Krebserkrankungen geben, sowie deren Einfluss auf die Entstehung einer krebs-assoziierten VTE beleuchten.

Keywords

Platelets - cancer - venous thromboembolism

Schlüsselwörter

Thrombozyten - Krebs - venöse - Thrombo- embolie

• References

• 1 Leslie M. Cell biology. Beyond clotting: the powers of platelets. Science 2010; 328: 562-564.
• 2 Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer 2005; 104: 2822-2829.
• 3 Simanek R, Vormittag R, Ay C. et al. High platelet count associated with venous thromboembolism in cancer patients. J Thromb Haemost 2010; 08: 114-120.
• 4 Buergy D, Wenz F, Groden C, Brockmann MA. Tumor-platelet interaction in solid tumors. Int J Cancer 2012; 130: 2747-2760.
• 5 Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer 2011; 11: 123-134.
• 6 Rothwell PM, Price JF, Fowkes FGR. et al. Shortterm effects of daily aspirin on cancer incidence, mortality, and non-vascular death. Lancet 2012; 379: 1602-1612.
• 7 Riess L. Zur pathologischen Anatomie des Blutes. Arch Anat Physiol Wissensch Med 1872; 39: 237-249.
• 8 Estrov Z, Talpaz M, Mavligit G. et al. Elevated plasma thrombopoietic activity in patients with metastatic cancer-related thrombocytosis. Am J Med 1995; 98: 551-558.
• 9 Sierko E, Wojtukiewicz MZ. Platelets and angiogenesis in malignancy. Semin Thromb Hemost 2004; 30: 95-108.
• 10 Stone RL, Nick AM, McNeish IA. et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med 2012; 366: 610-618.
• 11 Heinmöller E, Schropp T, Kisker O. et al. Tumor cell-induced platelet aggregation in vitro by human pancreatic cancer cell lines. Scand J Gastroenterol 1995; 30: 1008-1016.
• 12 Heinmöller E, Weinel RJ, Heidtmann HH. et al. Studies on tumor-cell-induced platelet aggregation in human lung cancer cell lines. J Cancer Res Clin Oncol 1996; 122: 735-744.
• 13 Radomski MW, Jenkins DC, Holmes L, Moncada S. Human colorectal adenocarcinoma cells: differential nitric oxide synthesis determines their ability to aggregate platelets. Cancer Res 1991; 51: 6073-6078.
• 14 Pearlstein E, Salk PL, Yogeeswaran G, Karpatkin S. Correlation between spontaneous metastatic potential, platelet-aggregating activity of cell surface extracts, and cell surface sialylation in 10 metastatic-variant derivatives of a rat renal sarcoma cell line. Proc Natl Acad Sci USA 1980; 77: 4336-4339.
• 15 Jurasz P, Alonso-Escolano D, Radomski MW. Platelet-cancer interactions. Br J Pharmacol 2004; 143: 819-826.
• 16 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.
• 17 Garcia J, Callewaert N, Borsig L. P-selectin mediates metastatic progression through binding to sulfatides on tumor cells. Glycobiology 2007; 17: 185-196.
• 18 Medina C, Jurasz P, Santos-Martinez MJ. et al. Platelet aggregation-induced by caco-2 cells. J Pharmacol Exp Ther 2006; 317: 739-745.
• 19 De Leval X, Benoit V, Delarge J. et al. Pharmacological evaluation of the novel thromboxane modulator BM-567 (II/II). Prostaglandins Leukot Essent Fatty Acids 2003; 68: 55-59.
• 20 Alonso-Escolano D, Strongin AY, Chung AW. et al. Membrane type-1 matrix metalloproteinase stimulates tumour cell-induced platelet aggregation. Br J Pharmacol 2004; 141: 241-252.
• 21 Kato Y, Fujita N, Kunita A. et al. Molecular identification of Aggrus/T1alpha as a platelet aggregation-inducing factor expressed in colorectal tumors. J Biol Chem 2003; 278: 51599-51605.
• 22 Suzuki-Inoue K, Fuller GLJ, García Á. et al. A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood 2006; 107: 542-549.
• 23 Medina C, Harmon S, Inkielewicz I. et al. Differential inhibition of tumour cell-induced platelet aggregation by the nicotinate aspirin prodrug (ST0702) and aspirin. Br J Pharmacol 2012; 166: 938-949.
• 24 Ferroni P, Riondino S, Vazzana N. et al. Biomarkers of platelet activation in acute coronary syndromes. Thromb Haemost 2012; 108: 1109-1123.
• 25 Leader A, Pereg D, Lishner M. Are platelet volume indices of clinical use?. Ann Med 2012; 44: 805-816.
• 26 Riedl J, Reitter E-M, Marosi C, Jaeger U, Schwarzinger I, Zielinski C. et al. Association of mean platelet volume with cancer-associated venous thromboembolism. Thromb Haemost. 2013 DOI: 10.1160/TH13–07–0603.
• 27 Thaler J, Ay C, Pabinger I. Clinical significance of circulating microparticles for venous thromboembolism in cancer patients. Hämostaseologie 2012; 32: 127-131.
• 28 Toth B, Liebhardt S, Steinig K. et al. Platelet-derived microparticles and coagulation activation in breast cancer patients. Thromb Haemost 2008; 100: 663-669.
• 29 Thaler J, Ay C, Weinstabl H. et al. Circulating procoagulant microparticles in cancer patients. Ann Hematol 2011; 90: 447-453.
• 30 Varon D, Hayon Y, Dashevsky O, Shai E. Involvement of platelet derived microparticles in tumor metastasis and tissue regeneration. Thromb Res 2012; 130 (Suppl. 01) S98-99.
• 31 Campello E, Spiezia L, Radu CM. et al. Endothelial, platelet, and tissue factor-bearing microparticles in cancer patients with and without venous thromboembolism. Thromb Res 2011; 127: 473-477.
• 32 Rothwell PM, Wilson M, Elwin C-E. et al. Longterm effect of aspirin on colorectal cancer incidence and mortality. Lancet 2010; 376: 1741-1750.
• 33 Bosetti C, Rosato V, Gallus S. et al. Aspirin and cancer risk. Ann Oncol 2012; 23: 1403-1415.
• 34 Kaiser J. Wondering How the Wonder Drug Works. Science 2012; 337: 1472-1472.
• 35 Dovizio M, Bruno A, Tacconelli S, Patrignani P. Mode of action of aspirin as a chemopreventive agent. Recent Results Cancer Res 2013; 191: 39-65.
• 36 Sitia G, Aiolfi R, Di Lucia P. et al. Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc Natl Acad Sci USA 2012; 109: E2165-2172.
• 37 Berger JS, Bhatt DL, Steinhubl SR. et al. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation 2009; 120: 2337-2344.
• 38 Ibele GM, Kay NE, Johnson GJ, Jacob HS. Human platelets exert cytotoxic effects on tumor cells. Blood 1985; 65: 1252-1255.
• 39 Sagawa T, Tominaga A, Kodama T, Okada M. Cytotoxicity of unstimulated and thrombin-activated platelets to human tumour cells. Immunology 1993; 78: 650-656.
• 40 Ahmad R, Menezes J, Knafo L, Ahmad A. Activated human platelets express Fas-L and induce apoptosis in Fas-positive tumor cells. J Leukoc Biol 2001; 69: 123-128.
• 41 Wang Y, Zhang H. Platelet-induced inhibition of tumor cell growth. Thromb Res 2008; 123: 324-330.
• 42 Cho MS, Bottsford-Miller J, Vasquez HG. et al. Platelets increase the proliferation of ovarian cancer cells. Blood 2012; 120: 4869-4872.
• 43 Radziwon-Balicka A, Medina C, O’Driscoll L. et al. Platelets increase survival of adenocarcinoma cells challenged with anticancer drugs. Br J Pharmacol 2012; 167: 787-804.
• 44 Folkman J. Tumor angiogenesis. N Engl J Med 1971; 285: 1182-1186.
• 45 Kisucka J, Butterfield CE, Duda DG. et al. Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage. Proc Natl Acad Sci USA 2006; 103: 855-860.
• 46 Italiano Jr JE, Richardson JL, Patel-Hett S. et al. Angiogenesis is regulated by a novel mechanism. Blood 2008; 111: 1227-1233.
• 47 Battinelli EM, Markens BA, Italiano Jr JE. Release of angiogenesis regulatory proteins from platelet alpha granules. Blood 2011; 118: 1359-1369.
• 48 Zaslavsky A, Baek K-H, Lynch RC. et al. Plateletderived thrombospondin-1 is a critical negative regulator and potential biomarker of angiogenesis. Blood 2010; 115: 4605-4613.
• 49 Klement GL, Yip T-T, Cassiola F. et al. Platelets actively sequester angiogenesis regulators. Blood 2009; 113: 2835-2842.
• 50 Cervi D, Yip T-T, Bhattacharya N. et al. Plateletassociated PF-4 as a biomarker of early tumor growth. Blood 2008; 111: 1201-1207.
• 51 Borsig L. The role of platelet activation in tumor metastasis. Expert Rev Anticancer Ther 2008; 08: 1247-1255.
• 52 Gasic GJ, Gasic TB, Stewart CC. Antimetastatic effects associated with platelet reduction. Proc Natl Acad Sci USA 1968; 61: 46-52.
• 53 Camerer E, Qazi AA, Duong DN. et al. Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Blood 2004; 104: 397-401.
• 54 Jain S, Zuka M, Liu J. et al. Platelet glycoprotein Ib alpha supports experimental lung metastasis. Proc Natl Acad Sci USA 2007; 104: 9024-9028.
• 55 Jain S, Russell S, Ware J. Platelet glycoprotein VI facilitates experimental lung metastasis in syngenic mouse models. J Thromb Haemost 2009; 07: 1713-1717.
• 56 Zhang W, Dang S, Hong T. et al. A humanized single-chain antibody against beta 3 integrin inhibits pulmonary metastasis by preferentially fragmenting activated platelets in the tumor microenvironment. Blood 2012; 120: 2889-2898.
• 57 Ware J. Fragmenting the platelet to reduce metastasis. Blood 2012; 120: 2779-2780.
• 58 Nieswandt B, Hafner M, Echtenacher B, Männel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 1999; 59: 1295-1300.
• 59 Schumacher D, Strilic B, Sivaraj KK. et al. Plateletderived nucleotides promote tumor-cell trans- endothelial migration and metastasis via P2Y2 receptor. Cancer Cell 2013; 24: 130-137.
• 60 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.
• 61 Rothwell PM, Wilson M, Price JF. 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.
• 62 Bambace NM, Holmes CE. The platelet contribution to cancer progression. J Thromb Haemost 2011; 09: 237-249.
• 63 Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in patients with cancer. PLoS Med 2012; 09: e1001275.
• 64 Ay C, Dunkler D, Marosi C. et al. Prediction of venous thromboembolism in cancer patients. Blood 2010; 116: 5377-5382.
• 65 Khorana AA, Kuderer NM, Culakova E. et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111: 4902-4907.
• 66 Ay C, Simanek R, Vormittag R. et al. High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients. Blood 2008; 112: 2703-2708.
• 67 Reitsma PH, Versteeg HH, Middeldorp S. Mechanistic view of risk factors for venous thromboembolism. Arterioscler Thromb Vasc Biol 2012; 32: 563-568.
• 68 Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008; 451: 914-918.
• 69 Sevitt S. Thrombosis and embolism after injury. J Clin Pathol Suppl 1970; 04: 86-101.
• 70 Vanschoonbeek K, Feijge MAH, Van Kampen RJW. et al. Initiating and potentiating role of platelets in tissue factor-induced thrombin generation in the presence of plasma. J Thromb Haemost 2004; 02: 476-484.
• 71 Joglekar MV, Ware J, Xu J. et al. Platelets, glycoprotein Ib-IX, and von Willebrand factor are required for FeCl3-induced occlusive thrombus formation in the inferior vena cava of mice. Platelets 2013; 24: 205-212.
• 72 Ay C, Jungbauer LV, Sailer T. et al. High concentrations of soluble P-selectin are associated with risk of venous thromboembolism and the P-selectin Thr715 variant. Clin Chem 2007; 53: 1235-1243.
• 73 Anderson DR, Dunbar MJ, Bohm ER. et al. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty. Ann Intern Med 2013; 158: 800-806.
• 74 Becattini C, Agnelli G, Schenone A. et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012; 366: 1959-1967.
• 75 Brighton TA, Eikelboom JW, Mann K. et al. Lowdose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012; 367: 1979-1987.
• 76 Larocca A, Cavallo F, Bringhen S. et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood 2012; 119: 933-939.
• 77 Poruk KE, Firpo MA, Huerter LM. et al. Serum platelet factor 4 is an independent predictor of survival and venous thromboembolism in patients with pancreatic adenocarcinoma. Cancer Epidemiol Biomark 2010; 19: 2605-2610.
• 78 Lyman GH, Khorana AA, Kuderer NM. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2013; 31: 2189-2204.
• 79 Caine GJ, Lip GYH, Stonelake PS. et al. Platelet activation, coagulation and angiogenesis in breast and prostate carcinoma. Thromb Haemost 2004; 92: 185-190.
• 80 Blann AD, Gurney D, Wadley M. et al. Increased soluble P-selectin in patients with haematological and breast cancer. Blood Coagul Fibrinolysis 2001; 12: 43-50.
• 81 Roselli M, Mineo TC, Martini F. et al. Soluble selectin levels in patients with lung cancer. Int J Biol Markers 2002; 17: 56-62.
• 82 Ferroni P, Roselli M, Martini F. et al. Prognostic value of soluble P-selectin levels in colorectal cancer. Int J Cancer 2004; 111: 404-408.
• 83 Dymicka-Piekarska V, Matowicka-Karna J, Osada J. et al. Changes in platelet CD 62P expression and soluble P-selectin concentration in surgically treated colorectal carcinoma. Adv Med Sci 2006; 51: 304-308.
• 84 Roselli M. Soluble CD40 ligand plasma levels in lung cancer. Clin Cancer Res 2004; 10: 610-614.
• 85 Caggiari L, Guidoboni M, Vaccher E. et al. High serum levels of soluble CD40-L in patients with undifferentiated nasopharyngeal carcinoma. Infect Agent Cancer 2007; 02: 5.
• 86 Huang J, Jochems C, Talaie T. et al. Elevated serum soluble CD40 ligand in cancer patients may play an immunosuppressive role. Blood 2012; 120: 3030-3038.
• 87 Starlinger P, Moll HP, Assinger A. et al. Thrombo- spondin-1: a unique marker to identify in vitro platelet activation when monitoring in vivo processes. J Thromb Haemost 2010; 08: 1809-1819.
• 88 Tuszynski GP, Smith M, Rothman VL. et al. Thrombospondin levels in patients with malignancy. Thromb Haemost 1992; 67: 607-611.
• 89 Dudek AZ, Mahaseth H. Circulating angiogenic cytokines in patients with advanced non-small cell lung cancer. Cancer Invest 2005; 23: 193-200.
• 90 Peterson JE, Zurakowski D, Italiano Jr JE. et al. VEGF, PF4 and PDGF are elevated in platelets of colorectal cancer patients. Angiogenesis 2012; 15: 265-273.
• 91 Tas F, Duranyildiz D, Soydinc HO. et al. Effect of maximum-tolerated doses and low-dose metronomic chemotherapy on serum vascular endothelial growth factor and thrombospondin-1 levels in patients with advanced nonsmall cell lung cancer. Cancer Chemother Pharmacol 2008; 61: 721-725.
• 92 Barthelemy-Brichant N, David JL, Bosquée L. et al. Increased TGFbeta1 plasma level in patients with lung cancer. Eur J Clin Invest 2002; 32: 193-198.
• 93 Ferriere JP, Bernard D, Legros M. et al. beta- Thromboglobulin in patients with breast cancer. Am J Hematol 1985; 19: 47-53.
• 94 Gong L, Cai Y, Zhou X, Yang H. Activated platelets interact with lung cancer cells through P-selectin glycoprotein ligand-1. Pathol Oncol Res POR 2012; 18: 989-996.
• 95 Mantur M, Kemona H, Kozlowski R, Kemona-Chetnik I. Effect of tumor stage and nephrectomy on CD62P expression and sP-selectin concentration in renal cancer. Neoplasma 2003; 50: 262-265.
• 96 Kedzierska M, Czernek U, Szydlowska-Pazera K. et al. The changes of blood platelet activation in breast cancer patients before surgery, after surgery, and in various phases of the chemotherapy. Platelets 2013; 24: 462-468.
• 97 Jurasz P, North S, Venner P, Radomski MW. Matrix metalloproteinase-2 contributes to increased platelet reactivity in patients with metastatic prostate cancer: a preliminary study. Thromb Res 2003; 112: 59-64.