(A) Biology of platelets and pharmacological inhibitors of platelet responses. (B) Proposed mechanism of COX-2 overexpression in tumour cells by the interaction with platelets. Unstimulated platelets interact rapidly with tumour cells through the binding of platelet collagen receptors (in particular, GPVI) and tumour components, such as galectin-3. This early event translates into platelet activation, as demonstrated by enhanced generation of TXA₂. Direct platelet-tumour cell interaction is associated with enhanced mRNA expression of COX-2 (but not COX-2 protein) and EMT-inducing transcription factors, such as zinc finger E-box binding homeobox 1 (ZEB1) and Twist1 and the mesenchymal marker vimentin. Later, platelet aggregates detach from tumour cells, possibly as a consequence of the shedding of platelet GPVI receptors and acquire the capacity to release their α-granule products, such as PDGF. The release of PDGF is associated with COX-2 mRNA stabilization via NHE–PI3K/PKCδ-dependent nucleo-cytoplasmic translocation of the mRNA-stabilizing protein HuR and COX-2 protein synthesis. In HT29 cells, overexpressed COX-2 and enhanced generation of PGE₂ emanate mitogenic and survival signalling pathways through the down-regulation of p21^WAF1/CIP1 and the up-regulation of cyclin B1 as well as of EMT-inducing transcription factors and mesenchymal markers, such as vimentin, in association with repression of epithelial markers, such as E-cadherin. Adapted from [18]: Dovizio, M., Maier, T.J., Alberti, S., Di Francesco, L., Marcantoni, E., Munch, G., John, C.M.,Suess, B., Sgambato, A., Steinhilber, D. and Patrignani, P.(2013) Pharmacological inhibition of platelet-tumour cell cross-talk prevents platelet-induced overexpression of cyclooxygenase-2 in HT29 human colon carcinoma cells. Mol. Pharmacol. 84, 25–40.