title: Contributions of thrombin targets to tissue factor-dependent metastasis in hyperthrombotic mice.
abstract: BACKGROUND
  Tumor cell tissue factor (TF)-initiated coagulation supports hematogenous metastasis by fibrin formation, platelet activation and monocyte/macrophage recruitment. Recent studies identified host anticoagulant mechanisms as a major impediment to successful hematogenous tumor cell metastasis.
  
  
  OBJECTIVE
  Here we address mechanisms that contribute to enhanced metastasis in hyperthrombotic mice with functional thrombomodulin deficiency (TM(Pro) mice).
  
  
  METHODS
  Pharmacological and genetic approaches were combined to characterize relevant thrombin targets in a mouse model of experimental hematogenous metastasis.
  
  
  RESULTS
  TF-dependent, but contact pathway-independent, syngeneic breast cancer metastasis was associated with marked platelet hyperreactivity and formation of leukocyte-platelet aggregates in immune-competent TM(Pro) mice. Blockade of CD11b or genetic deletion of platelet glycoprotein Ibα excluded contributions of these receptors to enhanced platelet-dependent metastasis in hyperthrombotic mice. Mice with very low levels of the endothelial protein C receptor (EPCR) did not phenocopy the enhanced metastasis seen in TM(Pro) mice. Genetic deletion of the thrombin receptor PAR1 or endothelial thrombin signaling targets alone did not diminish enhanced metastasis in TM(Pro) mice. Combined deficiency of PAR1 on tumor cells and the host reduced metastasis in TM(Pro) mice.
  
  
  CONCLUSIONS
  Metastasis in the hyperthrombotic TM(Pro) mouse model is mediated by platelet hyperreactivity and contributions of PAR1 signaling on tumor and host cells.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Yokota
authors.forename: A
authors.initials: A
authors.lastname: Zarpellon
authors.forename: S
authors.initials: S
authors.lastname: Chakrabarty
authors.forename: V Y
authors.initials: VY
authors.lastname: Bogdanov
authors.forename: A
authors.initials: A
authors.lastname: Gruber
authors.forename: F J
authors.initials: FJ
authors.lastname: Castellino
authors.forename: N
authors.initials: N
authors.lastname: Mackman
authors.forename: L G
authors.initials: LG
authors.lastname: Ellies
authors.forename: H
authors.initials: H
authors.lastname: Weiler
authors.forename: Z M
authors.initials: ZM
authors.lastname: Ruggeri
authors.forename: W
authors.initials: W
authors.lastname: Ruf
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D015539:Platelet Activation; D016133:Polymerase Chain Reaction; D013917:Thrombin / Q000378:metabolism*; D013925:Thromboplastin / Q000378:metabolism*; D013927:Thrombosis / Q000378:metabolism / Q000473:pathology*
chemical_list: D017931:DNA Primers; D013925:Thromboplastin; D013917:Thrombin
keywords: hypercoagulability; metastasis; platelets; thrombin; tissue factor