title: Thrombin induces osteosarcoma growth, a function inhibited by low molecular weight heparin in vitro and in vivo: procoagulant nature of osteosarcoma.
abstract: BACKGROUND
  Procoagulant states, leading to activation of the coagulation protease thrombin, are common in cancer and portend a poor clinical outcome. Although procoagulant states in osteosarcoma patients have been described, studies exploring osteosarcoma cells' ability to directly contribute to procoagulant activity have not been reported. This study explores the hypothesis that osteosarcoma can regulate thrombin generation and proliferate in response to thrombin, and that attenuating thrombin generation with anticoagulants can slow tumor growth.
  
  
  METHODS
  Pathologic analysis of osteosarcoma with adjacent venous thrombus was performed. In vitro proliferation assays, cell-based coagulant activity assays, and quantification of coagulation cofactor expression were performed on human and murine osteosarcoma cell lines with varying aggressiveness. The efficacy of low molecular weight heparin (LMWH) attenuation of tumor-dependent thrombin generation and growth in vitro and in vivo was determined.
  
  
  RESULTS
  Venous thrombi adjacent to osteosarcoma were found to harbor tumor surrounded by fibrin expressing coagulation cofactors, a finding associated with poor clinical outcome. More aggressive osteosarcoma cell lines had greater surface expression of procoagulant factors and generated more thrombin than less aggressive cell lines and were found to proliferate in response to thrombin. Treatment with LMWH reduced in vitro osteosarcoma proliferation and procoagulant activity as well as tumor growth in vivo.
  
  
  CONCLUSIONS
  These findings suggest that elements of the coagulation cascade may play a role in and represent a pharmaceutical target to disrupt osteosarcoma growth. They also have broader implications, as they suggest that, to be effective, dosing of anticoagulants must take into account an individual tumor's capacity to generate thrombin.
authors.affiliation: Department of Orthopaedics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-9565, USA.
authors.forename: Jiro
authors.initials: J
authors.lastname: Ichikawa
authors.forename: Heather A
authors.initials: HA
authors.lastname: Cole
authors.forename: Robert A
authors.initials: RA
authors.lastname: Magnussen
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Mignemi
authors.forename: Matthew
authors.initials: M
authors.lastname: Butler
authors.forename: Ginger E
authors.initials: GE
authors.lastname: Holt
authors.forename: Lynda
authors.initials: L
authors.lastname: O'Rear
authors.forename: Masato
authors.initials: M
authors.lastname: Yuasa
authors.forename: Baldeep
authors.initials: B
authors.lastname: Pabla
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Haro
authors.forename: Justin M M
authors.initials: JM
authors.lastname: Cates
authors.forename: Heidi E
authors.initials: HE
authors.lastname: Hamm
authors.forename: Herbert S
authors.initials: HS
authors.lastname: Schwartz
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Schoenecker
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001859:Bone Neoplasms / Q000150:complications*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D012516:Osteosarcoma / Q000150:complications*; D013917:Thrombin / Q000096:biosynthesis* / Q000502:physiology; D020246:Venous Thrombosis / Q000150:complications*; D055815:Young Adult
chemical_list: D006493:Heparin; D013917:Thrombin