title: Cancer cells induced to express mesenchymal phenotype release exosome-like extracellular vesicles carrying tissue factor.
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.
authors.affiliation: Montreal Children's Hospital, RI MUHC, McGill University, Montreal, H3Z 2Z3 Quebec, Canada.
authors.forename: Delphine
authors.initials: D
authors.lastname: Garnier
authors.forename: Nathalie
authors.initials: N
authors.lastname: Magnus
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Lee
authors.forename: Victoria
authors.initials: V
authors.lastname: Bentley
authors.forename: Brian
authors.initials: B
authors.lastname: Meehan
authors.forename: Chloe
authors.initials: C
authors.lastname: Milsom
authors.forename: Laura
authors.initials: L
authors.lastname: Montermini
authors.forename: Thomas
authors.initials: T
authors.lastname: Kislinger
authors.forename: Janusz
authors.initials: J
authors.lastname: Rak
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002450:Cell Communication; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D055354:Exosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D013925:Thromboplastin; C512478:EGFR protein, human; D066246:ErbB Receptors