Coagulation Factor Xa Promotes Solid Tumor Growth, Experimental Metastasis and Endothelial Cell Activation

Abstract

Hypercoagulable state is linked to cancer progression; however, the precise role of the coagulation cascade is poorly described. Herein, we examined the contribution of a hypercoagulative state through the administration of intravenous Coagulation Factor Xa (FXa), on the growth of solid human tumors and the experimental metastasis of the B16F10 melanoma in mouse models. FXa increased solid tumor volume and lung, liver, kidney and lymph node metastasis of tail-vein injected B16F10 cells. Concentrating on the metastasis model, upon coadministration of the anticoagulant Dalteparin, lung metastasis was significantly reduced, and no metastasis was observed in other organs. FXa did not directly alter proliferation, migration or invasion of cancer cells in vitro. Alternatively, FXa upon endothelial cells promoted cytoskeleton contraction, disrupted membrane VE-Cadherin pattern, heightened endothelial-hyperpermeability, increased inflammatory adhesion molecules and enhanced B16F10 adhesion under flow conditions. Microarray analysis of endothelial cells treated with FXa demonstrated elevated expression of inflammatory transcripts. Accordingly, FXa treatment increased immune cell infiltration in mouse lungs, an effect reduced by dalteparin. Taken together, our results suggest that FXa increases B16F10 metastasis via endothelial cell activation and enhanced cancer cell-endothelium adhesion advocating that the coagulation system is not merely a bystander in the process of cancer metastasis.

Extracellular Vesicles (EVs) and Pancreatic Cancer: From the Role of EVs to the Interference with EV-Mediated Reciprocal Communication

“…In addition, restraining of its function retards cancer growth and metastasis [106]. Protease-activated receptors (PAR) and their downstream signaling factors, such as RhoA, are triggered by thrombin and FXa and responsible for the stimulation of endothelial hyperpermeability and metastasis [107,108]. The new findings suggested that TF in PCC-derived EVs activates ECs and converts them into inflammatory phenotypes via the FXa-PAR1 axis.…”

Deciphering the Role of the Coagulation Cascade and Autophagy in Cancer-Related Thrombosis and Metastasis

“…Subsequently, cancer cells migrate out of the bloodstream by the process of extravasation and establish metastatic foci at distant organs (223). Fundamental to both these processes is endothelial permeability, which is promoted by the coagulation factors thrombin and FXa (15,224). Interestingly, recent studies have shown that autophagy is involved in thrombin-induced endothelial dysfunction.…”

“…Interleukin-8 (IL-8) and IL-6 (14), allowing the PARs to mediate several processes in the coagulation-inflammation interplay, including those implicated in cancer progression (15,16). Thus, PARs regulate platelet activation, assist in maintaining vascular barrier function through adhesion molecules (17,18), and are associated with immune cell activation and migration (19)(20)(21).…”

“…However, the mechanisms remain elusive ( 13 ). The proteolytic cleavage of PARs activates numerous downstream signaling pathways, including intracellular Ca 2+ mobilization, ERK1/2, NFκB signaling pathways and the induction of cytokines such as Interleukin-8 (IL-8) and IL-6 ( 14 ), allowing the PARs to mediate several processes in the coagulation-inflammation interplay, including those implicated in cancer progression ( 15 , 16 ). Thus, PARs regulate platelet activation, assist in maintaining vascular barrier function through adhesion molecules ( 17 , 18 ), and are associated with immune cell activation and migration ( 19 – 21 ).…”

“…Mouse models of cancer have demonstrated that FXa can increase tumor growth ( 15 , 19 , 20 ). Moreover, FXa increased lung, lymph node, liver, kidney metastasis in a syngeneic melanoma model, while promoting vascular permeability and increased infiltration ( 15 ). How PAR activation impinges on the autophagic pathway and how this regulates both physiological and pathophysiological processes is still an area requiring further study.…”