guest editorial: platelets and cancer

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  • Author's Accepted Manuscript

    Guest Editorial: Platelets and Cancer

    Brian I. Carr MD, FRCP, PhD.

    PII: S0093-7754(14)00116-XDOI: YSONC51709

    To appear in: Semin Oncol

    Cite this article as: Brian I. Carr MD, FRCP, PhD., Guest Editorial: Platelets andCancer, Semin Oncol,

    This is a PDF file of an unedited manuscript that has been accepted for publication. Asa service to our customers we are providing this early version of the manuscript. Themanuscript will undergo copyediting, typesetting, and review of the resulting galleyproof before it is published in its final citable form. Please note that during theproduction process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain.

  • 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

    (31, 32).

    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;

    240: 1031-1035

  • 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

    Med. 1998;338(17):11691173.

    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

    Med. 1964;114:497500.

    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;

    47: 2633-41

    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

    27. Epub

    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;

    17: 216-222

    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

    A. 2012;109(32):E2165-72.

    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