title: 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.).
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX 77230-1439, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Stone
authors.forename: Alpa M
authors.initials: AM
authors.lastname: Nick
authors.forename: Iain A
authors.initials: IA
authors.lastname: McNeish
authors.forename: Frances
authors.initials: F
authors.lastname: Balkwill
authors.forename: Hee Dong
authors.initials: HD
authors.lastname: Han
authors.forename: Justin
authors.initials: J
authors.lastname: Bottsford-Miller
authors.forename: Rajesha
authors.initials: R
authors.lastname: Rupairmoole
authors.forename: Guillermo N
authors.initials: GN
authors.lastname: Armaiz-Pena
authors.forename: Chad V
authors.initials: CV
authors.lastname: Pecot
authors.forename: Jermaine
authors.initials: J
authors.lastname: Coward
authors.forename: Michael T
authors.initials: MT
authors.lastname: Deavers
authors.forename: Hernan G
authors.initials: HG
authors.lastname: Vasquez
authors.forename: Diana
authors.initials: D
authors.lastname: Urbauer
authors.forename: Charles N
authors.initials: CN
authors.lastname: Landen
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Hannah
authors.initials: H
authors.lastname: Gershenson
authors.forename: Koji
authors.initials: K
authors.lastname: Matsuo
authors.forename: Mian M K
authors.initials: MM
authors.lastname: Shahzad
authors.forename: Erin R
authors.initials: ER
authors.lastname: King
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Tekedereli
authors.forename: Bulent
authors.initials: B
authors.lastname: Ozpolat
authors.forename: Edward H
authors.initials: EH
authors.lastname: Ahn
authors.forename: Virginia K
authors.initials: VK
authors.lastname: Bond
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Angela F
authors.initials: AF
authors.lastname: Drew
authors.forename: Francisca
authors.initials: F
authors.lastname: Gushiken
authors.forename: Donald
authors.initials: D
authors.lastname: Lamkin
authors.forename: Katherine
authors.initials: K
authors.lastname: Collins
authors.forename: Koen
authors.initials: K
authors.lastname: DeGeest
authors.forename: Susan K
authors.initials: SK
authors.lastname: Lutgendorf
authors.forename: Wah
authors.initials: W
authors.lastname: Chiu
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Vahid
authors.initials: V
authors.lastname: Afshar-Kharghan
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001792:Blood Platelets / Q000276:immunology; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D053208:Kaplan-Meier Estimate; D051379:Mice; D018345:Mice, Knockout; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D010257:Paraneoplastic Syndromes; D010976:Platelet Count; D016016:Proportional Hazards Models; D019947:Receptors, Interleukin-6 / Q000172:deficiency; D015398:Signal Transduction; D013922:Thrombocytosis / Q000209:etiology*; D013926:Thrombopoietin / Q000037:antagonists & inhibitors / Q000097:blood; D000093242:Interleukin-6 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D013926:Thrombopoietin; D000093242:Interleukin-6 Inhibitors; C504234:siltuximab