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Comment on Aghourian et al , page 769 Gas 6 fueling tumor-mediated thrombosis

VTE is a well-recognized complication of different malignancies and substantially contributes to cancer-associated mortality. Understanding how different tumorsmodulate hemostasis is of the utmost importance for the development of next generation anticancer therapeutics, as well as for modulating current treatment regimes (see later in text). The occurrence of cancer-associated VTE is explained partially by the ability of tumors themselves to promote a procoagulant milieu both locally and systemically. For example, tumors may express tissue factor (TF) themselves or secrete procoagulant tissue factor-bearing microvesicles and release proinflammatory cytokines and proteases, resulting in activation of the coagulation cascade and downregulation of anticoagulant pathways. Aghourian et al unravel a novel link between tumor-mediated thrombosis and Gas6, which may provide yet another explanation for the procoagulant phenotype of many tumors. Gas6 is a vitamin K-dependent ligand for the receptor tyrosine kinase family comprising Tyro3, Axl, and Mer (TAM). It has the ability to bind to negatively charged phospholipids, such as phosphatidylserine exposed on apoptotic cells, which allows Gas6 to bridge TAM-expressing phagocytes to apoptotic cells thus potentiating phagocytosis. The Gas6TAM system is a crucial anti-inflammatory signaling complex in immune cells, in addition to which it acts as a prosurvival factor, not only in tumors but also in the endothelium. Despite being homologous to the anticoagulant protein S, Gas6 has been shown to act mainly as a procoagulant factor. Gas6 mice are protected against lethal venous thrombosis, explained by a weakened platelet aggregation response and by decreased tissue factor expression in the endothelium. However, as the in vitro findings regarding platelet responses are of much milder character than what could be expected based on the striking phenotype ofGas6mice, it is likely that yet unknown functions of Gas6 in regulation of thrombosis will emerge. The work of Aghourian et al establishes a novel prothrombotic function of Gas6 independent of endothelial tissue factor regulation. In this study, the authors investigated changes in protein expression patterns on coculturing of endothelial cells from wild-type (WT) and Gas6 mice with M27 lung cell carcinoma. They identified the prostaglandin E synthase (Ptges) as a target protein upregulated in endothelium from WT mice but not in endothelium from Gas6 mice. Ptges is induced under proinflammatory stimuli, such as on exposure to cytokines, and the authors speculate that tumor-secreted cytokines or tumor-derived microvesicles might drive the increased endothelial Ptges. In a FeCl3-induced venous thrombosis model in either WT or Gas6 mice challenged with M27 cells or a B-cell lymphoma, the authors show that Gas6 deficiency protects the mice from a tumor-mediated increase in thrombus size. In Gas6-expressing endothelium, tumor cells were able to induce extracellular signalregulated kinase (Erk)1/2 activation, resulting in downstream upregulation of Ptges and subsequent production and release of PGE2. They further validate the biological significance of the increased PGE2 production by showing that PGE2 is able to activate In the presence of endothelium-derived Gas6, tumor cells induce phosphorylation of Erk1/2 in endothelial cells, leading to an upregulation of Ptges production. Ptges produces PGE2 from prostaglandin H2 (PGH2), which, on secretion, interacts with the EP3 receptor on platelets to trigger platelet activation and promote thrombosis. Whether the effects mediated by Gas6 are due to an interaction of Gas6 with the tumor cell or through an autocrine signaling in the endothelial cell is still unknown.