• Rebecca L Stone, Alpa M Nick, Iain A McNeish, Frances Balkwill, Hee Dong Han, Justin Bottsford-Miller, Rajesha Rupairmoole, Guillermo N Armaiz-Pena, Chad V Pecot, Jermaine Coward, Michael T Deavers, Hernan G Vasquez, Diana Urbauer, Charles N Landen, Wei Hu, Hannah Gershenson, Koji Matsuo, Mian M K Shahzad, Erin R King, Ibrahim Tekedereli, Bulent Ozpolat, Edward H Ahn, Virginia K Bond, Rui Wang, Angela F Drew, Francisca Gushiken, Donald Lamkin, Katherine Collins, Koen DeGeest, Susan K Lutgendorf, Wah Chiu, Gabriel Lopez-Berestein, Vahid Afshar-Kharghan, and Anil K Sood.
• Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX 77230-1439, USA.
• N. Engl. J. Med. 2012 Feb 16; 366 (7): 610-8.

BackgroundThe mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear.MethodsWe 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.ResultsThrombocytosis 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. Tumor-derived 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.ConclusionsThese 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. (Funded by the National Cancer Institute and others.).

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