Coagulation factor Xa promotes melanoma metastasis through endothelial cell activation

Hypercoagulable state has been intimately linked to melanoma 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 experimental metastasis of the B16F10 mouse melanoma in a syngeneic model.

FXa administration increased lung, liver, kidney and lymph node metastasis of tail-vein injected B16F10 cells. Upon co-administration 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 acted upon endothelial cells to promote cytoskeleton contraction, disrupt membrane VE-Cadherin pattern, to heighten endothelial-hyperpermeability, to increase the inflammatory adhesion molecules ICAM-1 and VCAM-1 and enhance 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, which support the concept that the coagulation system is not merely a bystander in the process of cancer metastasis.

• Nombre: Maximiliano Arce Arata
• Laboratorio: Endocrinología y Reproducción
• Mención: Ciencias Fisiológicas
• Director Tesis: Gareth Owen