Cancer Cells Induced to Express Mesenchymal Phenotype Release Exosome-like Extracellular Vesicles Carrying Tissue Factor |
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Authors: | Delphine Garnier Nathalie Magnus Tae Hoon Lee Victoria Bentley Brian Meehan Chloe Milsom Laura Montermini Thomas Kislinger Janusz Rak |
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Institution: | From the ‡Montreal Children''s Hospital, RI MUHC, McGill University, Montreal, H3Z 2Z3 Quebec, Canada.;the §Sunnybrook Research Institute, Toronto, M4N 3M5 Ontario, Canada, and ;the ¶Ontario Cancer Institute, Toronto, M5G 2M9 Ontario, Canada |
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Abstract: | Aggressive epithelial cancer cells frequently adopt mesenchymal characteristics and exhibit aberrant interactions with their surroundings, including the vasculature. Whether the release/uptake of extracellular vesicles (EVs) plays a role during these processes has not been studied. EVs are heterogeneous membrane structures that originate either at the surface (microparticles), or within (exosomes) activated or transformed cells, and are involved in intercellular trafficking of bioactive molecules. Here, we show that epithelial cancer cells (A431, DLD-1) adopt mesenchymal features (epithelial-to-mesenchymal transition-like state) upon activation of epidermal growth factor receptor (EGFR) coupled with blockade of E-cadherin. This treatment leads to a coordinated loss of EGFR and tissue factor (TF) from the plasma membrane and coincides with a surge in emission of small, exosome-like EVs containing both receptors. TF (but not EGFR) is selectively up-regulated in EVs produced by mesenchymal-like cancer cells and can be transferred to cultured endothelial cells rendering them highly procoagulant. We postulate that epithelial-to-mesenchymal transition-like changes may alter cancer cell interactions with the vascular systems through altered vesiculation and TF shedding. |
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Keywords: | Cancer Coagulation Factors E-cadherin EMT Endothelial Cell Epidermal Growth Factor Receptor (EGFR) Epithelial-to-mesenchymal Transition Exosomes Microparticles Tissue Factor |
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