title: The tick-derived inhibitor Ixolaris prevents tissue factor signaling on tumor cells.
abstract: BACKGROUND
  Tissue factor (TF) is frequently overexpressed in cancer cells and correlated with more aggressive tumor phenotypes and poor prognosis. In addition to promoting coagulation-dependent metastasis and cancer-associated thrombosis, tumor cell-expressed TF mediates direct cell signaling involving the protease-activated receptor (PAR) 2. Ixolaris is a tick-derived inhibitor of the TF-factor (F)VIIa-Xa coagulation initiation complex which blocks primary tumor growth and angiogenesis in glioblastoma and melanoma models.
  
  
  METHODS
  In this study we address the anti-tumor effects of Ixolaris in TF-VIIa-PAR2 signaling-dependent breast cancer models, a xenograft model of highly aggressive human MDA-MB-231 mfp cells and a syngeneic model of PAR2-deficient and replete PyMT mouse mammary carcinoma cells.
  
  
  RESULTS
  Ixolaris potently inhibited the procoagulant activity of human MDA-MB-231mfp or murine PyMT breast cancer cells. Ixolaris blocked signaling by the ternary TF-FVIIa-FXa complex, and, surprisingly, at higher concentrations also the binary TF-FVIIa complex on MDA-MB-231 cells. We show that Ixolaris interacts with certain residues in the human VIIa protease domain that are involved in PAR2 cleavage. In contrast to human VIIa, Ixolaris was a poor inhibitor of murine TF-FVIIa signaling and did not attenuate PAR2-dependent tumor growth in a syngeneic mouse model of breast cancer progression.
  
  
  CONCLUSIONS
  These data show that Ixolaris inhibits PAR2 cleavage specifically by human TF signaling complexes and suggest that Ixolaris may block tumor growth of human cell models with ectopic FVIIa expression through inhibition of direct TF-FVIIa-PAR2 signaling as well as its anticoagulant activity.
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA, USA.
authors: T C
authors: TC
authors: Carneiro-Lobo
authors: F
authors: F
authors: Schaffner
authors: J
authors: J
authors: Disse
authors: H
authors: H
authors: Ostergaard
authors: I M B
authors: IM
authors: Francischetti
authors: R Q
authors: RQ
authors: Monteiro
authors: W
authors: W
authors: Ruf
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015942:Factor VIIa / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D012471:Salivary Proteins and Peptides / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013925:Thromboplastin / Q000378:metabolism*
chemical_list: C455900:Ixolaris protein, Ixodes scapularis; D012471:Salivary Proteins and Peptides; D013925:Thromboplastin; D015942:Factor VIIa