Major finding: A paracrine cytokine loop causes neoplastic thrombocytosis.
Mechanism: Tumor-derived IL-6 increases hepatic thrombopoietin production.
Impact: Inhibition of thrombopoietic cytokines may represent a therapeutic strategy for ovarian cancer.
It has long been observed that patients with solid tumors often have thrombocytosis, or a platelet count of greater than 450,000 per cubic millimeter. Although recent studies have shown that platelets play an active role in tumorigenesis, the mechanisms that underlie increased platelet production remain unclear. In a recent article, Stone and colleagues identified a paracrine circuit involving thrombopoietic cytokines that drives paraneoplastic thrombocytosis and tumor growth in ovarian cancer. The authors first established a clinical association between thrombocytosis and outcome in 619 patients with epithelial ovarian cancer. Thirty-one percent of patients had thrombocytosis at time of diagnosis, which was significantly associated with advanced disease and decreased survival. Elevated platelet counts also correlated with plasma levels of interleukin (IL)-6 and thrombopoietin, 2 critical thrombopoietic cytokines. The authors then investigated the mechanistic relationship between tumor growth and thrombocytosis in orthotopic mouse models of epithelial ovarian cancer. Tumor-bearing mice showed increases in both circulating platelets and expression of thrombopoietin in the liver that were abrogated in mice lacking functional hepatic IL-6 receptors, suggesting a critical role for IL-6 in hepatic thrombopoietin production. Indeed, antibody targeting of IL-6 reduced platelet number in both tumor-bearing mice and ovarian cancer patients. A direct reduction in platelet number in mice, achieved with the use of an antiplatelet antibody, resulted in a significant decrease in tumor growth and angiogenesis. Together, these findings elucidate a potentially targetable paracrine loop, in which tumor-derived IL-6 and hepatic thrombopoietin drive neoplastic thrombocytosis and tumor growth.
Stone RL, Nick AM, McNeish IA, Balkwill F, Dong Han H, Bottsford-Miller J, et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med 2012;366:610–8.
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