Role of platelets in the control of EMT and invasion of CTCs. CTC-mediated platelet activation depends on platelet/tumor cell interaction involving the nonrestricted list of platelet adhesive molecule P-selectin, GPIIb-IIIa (α_IIbβ₃ integrin),⁴¹  and interaction of C-type lectin-like receptor (CLEC)-2 with tumor-derived podoplanin.⁴⁵  Tumor cells secrete ADP that interacts with P2Y12, high-mobility group box1 protein 1 (HMGB1) that interacts with TLR-4 and express the tissue factor that activates the coagulation factors (VIIa/Xa) leading to thrombin production. All these factors mediate platelet activation and secretion of TGF-b.^30,32,49  Then, TGF-β activates the TGF-β–RI/II–Smad signaling pathway that combines with an unidentified platelet adhesion-dependent mechanism leading to NF-κB activation, which induces EMT on CTCs.²⁴  Released PDGF can activate Notch1 and STAT1 signaling pathways, inducing and/or maintaining EMT on CTCs.^25,26  Direct interaction of platelet membranes exposes active P-selectin and GPIIb-IIIa,⁴¹  and the secretion of LPA by activated platelets supports CTC invasion^39,40  and ATP promotes transendothelial cell migration.³⁷  Figure was generated using the database of images from Servier Medical Art from Servier (http://creativecommons.org/licenses/by/3.0/fr/).