Tissue Factor Induced by Epithelial-Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells.

Abstract

Epithelial-mesenchymal transition (EMT) is prominent in circulating tumor cells (CTC), but how it influences metastatic spread in this setting is obscure. Insofar as blood provides a specific microenvironment for tumor cells, we explored a potential link between EMT and coagulation that may provide EMT-positive CTCs with enhanced colonizing properties. Here we report that EMT induces tissue factor (TF), a major cell-associated initiator of coagulation and related procoagulant properties in the blood. TF blockade by antibody or shRNA diminished the procoagulant activity of EMT-positive cells, confirming a functional role for TF in these processes. Silencing the EMT transcription factor ZEB1 inhibited both EMT-associated TF expression and coagulant activity, further strengthening the link between EMT and coagulation. Accordingly, EMT-positive cells exhibited a higher persistance/survival in the lungs of mice colonized after intravenous injection, a feature diminished by TF or ZEB1 silencing. In tumor cells with limited metastatic capability, enforcing expression of the EMT transcription factor Snail increased TF, coagulant properties, and early metastasis. Clinically, we identified a subpopulation of CTC expressing vimentin and TF in the blood of metastatic breast cancer patients consistent with our observations. Overall, our findings define a novel EMT-TF regulatory axis that triggers local activation of coagulation pathways to support metastatic colonization of EMT-positive CTCs. Cancer Res; 76(14); 4270-82. ©2016 AACR.

• Authors: Morgane Bourcy, Meggy Suarez-Carmona, Justine Lambert, Marie-Emilie Francart, Hélène Schroeder, Céline Delierneux, Nicolas Skrypek, Erik W Thompson, Guy Jérusalem, Geert Berx, Marc Thiry, Silvia Blacher, Brett G Hollier, Agnès Noël, Cécile Oury, Myriam Polette, Christine Gilles
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 14 Pg. 4270-82 (07 15 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 27221703 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• ZEB1 protein, human
• Zinc Finger E-box-Binding Homeobox 1
• Thromboplastin

Topics

• Animals
• Blood Coagulation
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition
• Female
• Humans
• Lung Neoplasms (secondary)
• Mice
• Mice, Inbred BALB C
• Neoplastic Cells, Circulating (pathology)
• Thromboplastin (biosynthesis)
• Zinc Finger E-box-Binding Homeobox 1 (physiology)