The tick-derived inhibitor Ixolaris prevents tissue factor signaling on tumor cells

Tatiana Lobo, F. Schaffner, J. Disse, H. Ostergaard, I. M B Francischetti, R. Q. Monteiro, W. Ruf

Research output: Contribution to journalArticle

26 Citations (Scopus)

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-231mfp 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)1849-1858
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume10
Issue number9
DOIs
Publication statusPublished - 1 Sep 2012
Externally publishedYes

Fingerprint

Thromboplastin
Ticks
Neoplasms
Breast Neoplasms
Factor VIIa
Growth
PAR-2 Receptor
Glioblastoma
Heterografts
Human Activities
Anticoagulants
Melanoma
Thrombosis
Peptide Hydrolases
Neoplasm Metastasis
Phenotype

Keywords

  • Angiogenesis
  • Breast cancer
  • Protease activated receptor

ASJC Scopus subject areas

  • Hematology

Cite this

Lobo, T., Schaffner, F., Disse, J., Ostergaard, H., Francischetti, I. M. B., Monteiro, R. Q., & Ruf, W. (2012). The tick-derived inhibitor Ixolaris prevents tissue factor signaling on tumor cells. Journal of Thrombosis and Haemostasis, 10(9), 1849-1858. https://doi.org/10.1111/j.1538-7836.2012.04864.x

The tick-derived inhibitor Ixolaris prevents tissue factor signaling on tumor cells. / Lobo, Tatiana; Schaffner, F.; Disse, J.; Ostergaard, H.; Francischetti, I. M B; Monteiro, R. Q.; Ruf, W.

In: Journal of Thrombosis and Haemostasis, Vol. 10, No. 9, 01.09.2012, p. 1849-1858.

Research output: Contribution to journalArticle

Lobo, T, Schaffner, F, Disse, J, Ostergaard, H, Francischetti, IMB, Monteiro, RQ & Ruf, W 2012, 'The tick-derived inhibitor Ixolaris prevents tissue factor signaling on tumor cells', Journal of Thrombosis and Haemostasis, vol. 10, no. 9, pp. 1849-1858. https://doi.org/10.1111/j.1538-7836.2012.04864.x
Lobo, Tatiana ; Schaffner, F. ; Disse, J. ; Ostergaard, H. ; Francischetti, I. M B ; Monteiro, R. Q. ; Ruf, W. / The tick-derived inhibitor Ixolaris prevents tissue factor signaling on tumor cells. In: Journal of Thrombosis and Haemostasis. 2012 ; Vol. 10, No. 9. pp. 1849-1858.
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AU - Monteiro, R. Q.

AU - Ruf, W.

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