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Platelets are highly reactive cellular effectors of hemostasis, immunity, and inflammation.1 The concept that platelets play key roles in cancer growth and metastasis is long-standing. In fact, the clinical observation that thrombocytosis (defined as a platelet count of >450,000 per cubic millimeter) occurs in patients with solid tumors was made more than 100 years ago.2,3
Given the short life span of a circulating platelet, approximately 1011 platelets must be produced daily to maintain a normal platelet count in adults.6,7 This high baseline level of production has the potential to markedly increase in the context of cancer. The mechanisms underlying this surge in platelets as well as its biologic significance are not well understood and are the focus of the current study. We investigated the potential clinical and biologic implications of a paracrine circuit that promotes megakaryopoiesis and thrombocytosis in the context of ovarian cancer.
Methods
Clinical Data
After approval by the local institutional review boards, clinical data, including history of coexisting inflammatory conditions, were collected on 619 consecutive patients with primary epithelial ovarian cancer from four U.S. academic medical centers. The effect of treatment with an antihuman interleukin-6 antibody (siltuximab [CNTO 328], at a dose of 5.4 mg per kilogram of ideal body weight infused once every 2 weeks) on platelet counts in 18 patients with ovarian cancer was evaluated as part of a phase 1 and 2 study (EudraCT number, 2006-005704-13).8 Patients provided written informed consent for participation in this trial and for use of their banked specimens in the laboratory studies pertaining to this investigation.
Mouse Models
All in vivo experiments in animals were approved by the institutional animal care and use committee. The development and characterization of the orthotopic mouse models of epithelial ovarian cancer have been described...