Paraneoplastic thrombocytosis in ovarian cancer

Rebecca L. Stone, Alpa M. Nick, Iain A. McNeish, Frances Balkwill, Hee Dong Han, Justin Bottsford-Miller, Rajesha Rupaimoole, 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 TekedereliBulent Ozpolat, Edward H. Ahn, Virginia K. Bond, Rui Wang, Angela F. Drew, Francisca Gushiken, Katherine Collins, Koen DeGeest, Koenraad De Geest, Wah Chiu, Gabriel Lopez-Berestein, Vahid Afshar-Kharghan, Anil K. Sood

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Abstract

Background: The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear. 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. 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. 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. (Funded by the National Cancer Institute and others.)

Original languageEnglish (US)
Pages (from-to)610-618
Number of pages9
JournalNew England Journal of Medicine
Volume366
Issue number7
DOIs
Publication statusPublished - Feb 16 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

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Stone, R. L., Nick, A. M., McNeish, I. A., Balkwill, F., Han, H. D., Bottsford-Miller, J., ... Sood, A. K. (2012). Paraneoplastic thrombocytosis in ovarian cancer. New England Journal of Medicine, 366(7), 610-618. https://doi.org/10.1056/NEJMoa1110352