Medical College of Wisconsin
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Contributions of thrombin targets to tissue factor-dependent metastasis in hyperthrombotic mice. J Thromb Haemost 2014 Jan;12(1):71-81

Date

11/02/2013

Pubmed ID

24175924

Pubmed Central ID

PMC3947224

DOI

10.1111/jth.12442

Scopus ID

2-s2.0-84891898669 (requires institutional sign-in at Scopus site)   30 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 (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 IbĪ± 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.

Author List

Yokota N, Zarpellon A, Chakrabarty S, Bogdanov VY, Gruber A, Castellino FJ, Mackman N, Ellies LG, Weiler H, Ruggeri ZM, Ruf W



MESH terms used to index this publication - Major topics in bold

Animals
Base Sequence
Cell Line, Tumor
DNA Primers
Mice
Mice, Inbred C57BL
Neoplasm Metastasis
Platelet Activation
Polymerase Chain Reaction
Thrombin
Thromboplastin
Thrombosis