Contributions of thrombin targets to tissue factor‐dependent metastasis in hyperthrombotic mice. (January 2014)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 12:Number 1(2014:Jan.)
• Page Start: 71
• Page End: 81
• Publication Date: 2014-01
• Subjects: Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.12442
• Languages: English
• ISSNs: 1538-7933

Abstract

<abstract abstract-type="main" id="jth12442-abs-0001"> <title>Summary</title> <sec id="jth12442-sec-0001" sec-type="section"> <title>Background</title> <p>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.</p> </sec> <sec id="jth12442-sec-0002" sec-type="section"> <title>Objective</title> <p>Here we address mechanisms that contribute to enhanced metastasis in hyperthrombotic mice with functional thrombomodulin deficiency (TM<sup>Pro</sup> mice).</p> </sec> <sec id="jth12442-sec-0003" sec-type="section"> <title>Methods</title> <p>Pharmacological and genetic approaches were combined to characterize relevant thrombin targets in a mouse model of experimental hematogenous metastasis.</p> </sec> <sec id="jth12442-sec-0004" sec-type="section"> <title>Results</title> <p>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<sup>Pro</sup> 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<sup>Pro</sup> mice. Genetic deletion of the thrombin receptor PAR1 or endothelial thrombin signaling targets alone did not diminish enhanced metastasis in TM<sup>Pro</sup> mice. Combined deficiency of PAR1 on tumor cells and the host reduced metastasis in TM<sup>Pro</sup> mice.</p> </sec> <sec id="jth12442-sec-0005" sec-type="section"> <title>Conclusions</title> <p>Metastasis in the hyperthrombotic TM<sup>Pro</sup> mouse model is mediated by platelet hyperreactivity and contributions of PAR1 signaling on tumor and host cells.</p> </sec> </abstract>