Paraneoplastic thrombocytosis in ovarian cancer.

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. 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. 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.).

DOI: 10.1056/NEJMoa1110352

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@article{Stone2012ParaneoplasticTI, title={Paraneoplastic thrombocytosis in ovarian cancer.}, author={Rebecca L. Stone and Alpa M. Nick and I McNeish and Frances R. Balkwill and Hee Dong Han and Justin N. Bottsford-Miller and Rajesha Rupairmoole and Guillermo N. Armaiz-Pena and Chad Victor Pecot and Jermaine I G Coward and Michael T. Deavers and Hernan G. Vasquez and Diana L. Urbauer and Charles N. Landen and Wei Hu and Hannah Gershenson and Koji Matsuo and Mian M. K. Shahzad and Erin R. King and Ibrahim Tekedereli and Bulent Ozpolat and Edward Ahn and Virginia K Bond and Rui Wang and Angela F. Drew and Francisca Cecilia Gushiken and Donald M. Lamkin and Katherine Collins and Koen Degeest and Susan K. Lutgendorf and Wah Chiu and Gabriel L{\'o}pez-Berestein and Vahid Afshar-Kharghan and Anil K . Sood}, journal={The New England journal of medicine}, year={2012}, volume={366 7}, pages={610-8} }