guest editorial: platelets and cancer
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Guest Editorial: Platelets and Cancer
Brian I. Carr MD, FRCP, PhD.
PII: S0093-7754(14)00116-XDOI: http://dx.doi.org/10.1053/j.seminoncol.2014.04.011Reference: YSONC51709
To appear in: Semin Oncol
Cite this article as: Brian I. Carr MD, FRCP, PhD., Guest Editorial: Platelets andCancer, Semin Oncol, http://dx.doi.org/10.1053/j.seminoncol.2014.04.011
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Guest Editorial: Platelets and Cancer
Platelets have a well-studied role in coagulation and in thromboembolism. The latter was recognized to
be a feature of occult cancer over 100 years ago. It has been increasingly appreciated, that as a
component of the tumor microenvironment, platelets also have important functions in the mechanisms
involved in carcinogenesis, tumor growth, tumor angiogenesis, tumor-related host organ inflammation
and immune responses, tumor metastasis and in the modulation of tumor therapy. Therapeutic
alteration of platelet numbers and function has increasingly gained attention for cancer prevention,
survival prolongation and possibly for therapy. The idea that systemic response to the presence of
cancer, including the platelet lymphocyte ratio (PLR) is an independent prognostic factor in many
tumor types, has recently gained support. Platelets are thus seen as predictors of cancer prognosis,
mediators of cancer biology and the subject of therapeutic intervention.
Venous thromboembolism was first noted to be associated with cancer by Trousseau (1). It tends to be
recurrent, migratory, involves multiple body sites and can be resistant to anticoagulation (2, 3). This
cancer-associated thromboembolism was also found to be associated with thrombocytosis (4, 5).
Platelets have come to be viewed, both as a systemic reaction to the presence of cancer (6-9) as well
integral mediators of cancer biology (10-13). The actions of platelets on tumors may be direct (14, 15)
or as part of the tumor microenvironment (16, 17), although these are not mutually exclusive.
Thrombocytosis can occur in association with many cancers, including those of ovary (18), GI tract
(19) and liver (20, 21). Platelets typically derive from pro-platelet protrusions of megakaryocyte
cytoplasm, by processes that depend on cell-cell interactions in the bone marrow microenvironment
(22), as well as cytokines such as thrombopoietin, which is produced in the liver and by many tumors.
Recent clinical evidence points to a feed-back loop involving interleukin-6, thrombopoietin and
thrombocytosis, as described for ovarian cancer patients (18).
Several mechanisms have been suggested for the involvement of platelets in cancer development,
including their actions as a shield on tumor cells from immune attack, their role in tumor
vasculogenesis/vascularity, and their contribution to tumor growth via direct interactions and through
secreted inflammatory cytokines (23) and multiple tumor growth factors (24) carried in their granules
or in growth factor-rich platelet microvesicles that are shed from the surfaces of activated platelets.
These factors include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF),
serotonin, platelet-derived growth factors (PDGF), insulin-like growth factor-1 (IGF-1), epidermal
growth factor (EGF), transforming growth factor beta (TGF) and interleukins.
Many studies have addressed the involvement of platelets in tumor cell tethering, spreading, migration
and invasion (25-29), processes that are associated with metastasis, and platelet depletion has been
shown to diminish metastasis, apparently without altering the growth of the primary tumor (30).
Furthermore, platelets have also been shown to modify the response of tumors to cancer chemotherapy
Furthermore, epidemiologic studies on the use of anti-platelet agents such as aspirin, have provided
recent evidence for an effect both in cancer prevention, as well as in improvement in survival of
patients with a diagnosis of cancer (33,34). The first four articles in this special Platelets and Cancer
issue, deal with the effects of cancer on platelets and the treatments for cancer-associated
thromboembolism. The subsequent ten articles, conversely, deal with the effects of platelets in
modulating cancer biology and possible therapeutic interventions to alter these effects.
1. Trousseau A. Phlegmasia alba dolens. Clinic Medicale de l'Hotel-Dieu de Paris. 1865; 3:654-
2. Edwards EA. Migrating thrombophlebitis associated with carcinoma. New Engl J Med 1949;
3. Srensen HT, Mellemkjaer L, Steffensen FH, Olsen JH, Nielsen GL. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J
4. Riess I. Zur pathologischen anatomie des blutes. Arch Anat Physiol Wissensch Med 1872, 39:
5. Levin J, Conley CL. Thrombocytosis associated with malignant disease. Arch Intern
6. Proctor MJ, Morrison DS, Talwar D et al. A comparison of inflammation-based prognostic
scores in patients with cancer. A Glasgow Inflammation Outcome Study. Eur. J. Cancer 2011;
7. Krenn-Pilko, S, Langsenlehner U, Thurner E-M et al. The elevated pre-operative platelet-to-
lymphocyte ratio predicts poor prognosis in breast cancer patients. Brit. J. Cancer 2014; March
8. Kwon HC, Kim SH, Oh SY et al. Clinical significance of preoperative neutrophil-lymphocyte
versus platelet-lymphocyte ratio in patients with operable colorectal cancer. Biomarkers 2012;
9. Lai Q, Castro Santa E, Rico Juri JM et al. Neutrophil and platelet-to-lymphocyte ratio as new
predictors of dropout and recurrence after liver transplantation for hepatocellular carcinoma.
Tranpl Int 2014; 27: 32-41
10. Leslie M. Cell biology: beyond clotting: the powers of platelets. Science.2010; 328:5624.
11. Buergy D, Wenz F, Groden C, Brockmann MA. Tumor-platelet interaction in solid tumors. Int.
J. Cancer 2012; 130: 2747-2760.
12. Goubran HA, Burnouf T, Radosevic M, El-Ekiaby M. The platelet-cancer loop. Eur. J.Intern.
Med 2013; 24: 393-400.
13. Bambace NM, Holmes CE. The platelet contribution to cancer progression. J. Thromb.
Hemostat. 2011; 9: 237-49.
14. 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: 576-90.
15. Sharma D, Brummel-Ziedins KE, Bouchard BA, Holme CE Platelets in Tumor Progression: A
Host Factor that Offers Multiple Potential Targets in the Treatment of Cancer. J Cell
Physiol. 2013 Dec 20 Epub
16. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008; 454:
17. Ju Dong Yang, Ikuo Nakamura, and Lewis R Roberts. The Tumor Microenvironment in
Hepatocellular Carcinoma: Current Status and Therapeutic Targets. Seminars in Cancer
Biology 2011; 21: 35-43
18. Stone RL, Nick AM, McNeish IA et al. Paraneoplastic thrombocytosis in ovarian cancer. N.
Engl J Med 2012; 366: 610-18
19. Voutsadakis IA. Thrombocytosis as a prognostic marker in gastrointestinal cancers. World J.
Gastrointest. Oncol. 2014; 6: 36-40
20. Hwang SJ, Luo JC, Li CP et al. Thrombocytosis: a paraneoplastic syndrome in patients with
hepatocellular carcinoma. World J Gastroenterol. 2004;10:2472-7.
21. Carr BI, Guerra V. Thrombocytosis and hepatocellular carcinoma. Dig. Dis. Sci. 2013; 58:
22. Psaila B, Lyden D, Roberts I. Megakaryocytes, malignancy and bone marrow vascular niches.
J. Thromb Haemost 2012;10: 177-178
23. 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 U S
24. Carr BI, Cavallini A, D'Alessandro R et al. Platelet extracts induce growth, migration and
invasion in human hepatocellular carcinoma in vitro. BMC Cancer. 2014; 14: 43 Epub
25. Borsig L. The role of platelet activation in tumor metastasis. Expert Rev Anticancer
Ther. 2008; 8:124755.
26. Dashevsky O, Varon D, Brill A. Platelet-derived microparticles promote invasiveness of
prostate cancer cells via upregulation of MMP-2 production. Int. J. Cancer 2009; 124:1173-7
27. Li R, Ren M, Chen N et al. Presence of intratumoral platelets is associated with tumor vessel
structure and metastasis. BMC Cancer 2014; 14: 167
28. 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
29. Gasic GJ, Gasic TB, Stewart CC. Antimetastatic effects associated with platelet reduction. Proc Natl