Figure 6.

Crosstalk between the coagulation cascade and autophagy on tumor-associated endothelial cells. Thrombin-induced endothelial hyperpermeability and endothelial secretion of thrombosis-promoting factors are dependent on autophagy. Activation of the coagulation cascade and PAR1 induces an increase in intracellular Ca⁺², which allows activation of AMPK by CaMKKB. Thus, the activation of AMPK induced by PARs could induce autophagy. Disassembly and degradation of VE-cadherin and the formation of actin stress fibers promoted by thrombin through autophagy could allow endothelial hyperpermeability. The secretion of vWF and P-selectin is mediated by the secretory pathway autophagy. Autophagosomes contain vWF and allow its release from endothelial cells. The secretion of vWF and P-selectin stimulated by ox-LDL is mediated by the inhibition of Sirt1/FoxO1 signaling by preventing fusion of autophagosome with lysosome. These factors allow adhesion of cancer cells and platelets to the endothelium, thus promoting cancer-related thrombosis and metastasis. FVII, factor VII; FX, factor X; FXa, factor X activated; TF, tissue factor; PAR1, protease-activated receptor 1; TRPC, transient receptor potential canonical; PLC, phospholipase C; PKC, protein kinase C; CaMKKB, calcium/calmodulin-dependent protein kinase kinase B; AMPK, AMP-activated protein kinase; mTORC1, mammalian target of rapamycin complex 1; VE-cadherin, vascular endothelial cadherin; vWF, von Willebrand factor; WBP, Weibel-Palade bodies; Sirt1, sirtuin 1; FoxO1, forkhead box protein O1; ox-LDL, oxidized low-density lipoprotein.