Contributions of thrombin targets to tissue factor-dependent metastasis in hyperthrombotic mice

N. Yokota, A. Zarpellon, S. Chakrabarty, V. Y. Bogdanov, A. Gruber, F. J. Castellino, N. Mackman, L. G. Ellies, H. Weiler, Z. M. Ruggeri, W. Ruf

Research output: Contribution to journalArticle

21 Scopus citations

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 (TMPro 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 TMPro 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 TMPro mice. Genetic deletion of the thrombin receptor PAR1 or endothelial thrombin signaling targets alone did not diminish enhanced metastasis in TMPro mice. Combined deficiency of PAR1 on tumor cells and the host reduced metastasis in TMPro mice. Conclusions: Metastasis in the hyperthrombotic TMPro mouse model is mediated by platelet hyperreactivity and contributions of PAR1 signaling on tumor and host cells.

Original languageEnglish (US)
Pages (from-to)71-81
Number of pages11
JournalJournal of Thrombosis and Haemostasis
Volume12
Issue number1
DOIs
StatePublished - Jan 2014

Keywords

  • Hypercoagulability
  • Metastasis
  • Platelets
  • Thrombin
  • Tissue factor

ASJC Scopus subject areas

  • Hematology

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    Yokota, N., Zarpellon, A., Chakrabarty, S., Bogdanov, V. Y., Gruber, A., Castellino, F. J., Mackman, N., Ellies, L. G., Weiler, H., Ruggeri, Z. M., & Ruf, W. (2014). Contributions of thrombin targets to tissue factor-dependent metastasis in hyperthrombotic mice. Journal of Thrombosis and Haemostasis, 12(1), 71-81. https://doi.org/10.1111/jth.12442