Paraneoplastic thrombocytosis in ovarian cancer

Stone, R.L. et al. (2012) Paraneoplastic thrombocytosis in ovarian cancer. New England Journal of Medicine, 366(7), pp. 610-618. (doi: 10.1056/NEJMoa1110352)

Abstract

<p>Background: The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear.</p> <p>Methods: We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained.</p> <p>Results: Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumorderived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti–interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis.</p> <p>Conclusions: These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. We speculate that countering paraneoplastic thrombocytosis either directly or indirectly by targeting these cytokines may have therapeutic potential. </p>

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Mcneish, Professor Iain
• Authors: Stone, R.L., Nick, A.M., Mcneish, I.A., Balkwill, F., Han, H.D., Bottsford-Miller, J., Rupairmoole, R., Armaiz-Pena, G.N., Pecot, C.V., Coward, J., Deavers, M.T., Vasquez, H.G., Urbauer, D., Landen, C.N., Hu, W., Gershenson, H., Matsuo, K., Shahzad, M.M.K., King, E.R., Tekedereli, I., Ozpolat, B., Ahn, E.H., Bond, V.K., Wang, R., Drew, A.F., Gushiken, F., Lamkin, D., Collins, K., DeGeest, K., Lutgendorf, S.K., Chiu, W., Lopez-Berestein, G., Afshar-Kharghan, V., and Sood, A.K.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: New England Journal of Medicine
• Publisher: Massachusetts Medical Society
• ISSN: 0028-4793
• ISSN (Online): 1533-4406
• Published Online: 16 February 2012
• Copyright Holders: Copyright © 2012 Massachusetts Medical Society
• First Published: First published in New England Journal of Medicine 366(7):610-618
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher