Prostaglandin E synthase is upregulated by Gas6 during cancer-induced venous thrombosis.

Venous thromboembolism (VTE) is a common complication of cancer. Based on recent evidence that (i) Gas6 regulates the expression of tissue factor during venous thrombosis and (ii) cancer promotes a pro-coagulant milieu, we hypothesize that Gas6 may be involved in cancer-induced coagulopathy. Venous thrombi were induced in both wild type (WT) and Gas6 deficient (-/-) mice with cancer. WT mice with cancer developed larger thrombi than their healthy counterparts; these larger thrombi induced by cancer were not seen in Gas6(-/-) mice. Whole genome microarray analysis of differential gene expression in WT and Gas6(-/-) endothelial cells exposed to M27 murine lung carcinoma cells reveal that Gas6 increases prostaglandin E synthase (Ptges) expression in endothelial cells. This was confirmed using real-time PCR and immunofluorescence staining. Culture of WT endothelial cells with M27 increases the secretion of PGE2, the enzymatic product of Ptges, in WT but not in Gas6(-/-) endothelial cells. In WT endothelial cells, Ptges expression was regulated through ERK1/2 phosphorylation. In vitro, PGE2 activates platelets after binding to its receptor, EP3. In vivo, EP3 receptor antagonism reversed the effect of cancer-induced thrombosis in WT mice. These results show that Gas6, through upregulation of PGE2, contributes to cancer-induced venous thrombosis.