Involvement of platelet-derived VWF in metastatic growth of melanoma in the brain

TY - JOUR

T1 - Involvement of platelet-derived VWF in metastatic growth of melanoma in the brain

AU - Robador, Jose R

AU - Feinauer, Manuel J

AU - Schneider, Stefan W

AU - Mayer, Frank T

AU - Gorzelanny, Christian

AU - Sacharow, Artur

AU - Liu, Xiaobo

AU - Berghoff, Anna

AU - Brehm, Maria A

AU - Hirsch, Daniela

AU - Stadler, Julia

AU - Vidal-Y-Si, Sabine

AU - Wladykowski, Ewa

AU - Asong, Marisse

AU - Nowak, Kai

AU - Seiz-Rosenhagen, Marcel

AU - Umansky, Viktor

AU - Mess, Christian

AU - Pantel, Klaus

AU - Winkler, Frank

AU - Bauer, Alexander T

N1 - © The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

PY - 2021

Y1 - 2021

N2 - Background: The prognosis of patients with brain metastases (BM) is poor despite advances in our understanding of the underlying pathophysiology. The high incidence of thrombotic complications defines tumor progression and the high mortality rate. We, therefore, postulated that von Willebrand factor (VWF) promotes BM via its ability to induce platelet aggregation and thrombosis.Methods: We measured the abundance of VWF in the blood and intravascular platelet aggregates of patients with BM, and determined the specific contribution of endothelial and platelet-derived VWF using in vitro models and microfluidics. The relevance for the brain metastatic cascade in vivo was demonstrated in ret transgenic mice, which spontaneously develop BM, and by the intracardiac injection of melanoma cells.Results: Higher levels of plasma VWF in patients with BM were associated with enhanced intraluminal VWF fiber formation and platelet aggregation in the metastatic tissue and peritumoral regions. Platelet activation triggered the formation of VWF multimers, promoting platelet aggregation and activation, in turn enhancing tumor invasiveness. The absence of VWF in platelets, or the blocking of platelet activation, abolished platelet aggregation, and reduced tumor cell transmigration. Anticoagulation and platelet inhibition consistently reduced the number of BM in preclinical animal models.Conclusions: Our data indicate that platelet-derived VWF is involved in cerebral clot formation and in metastatic growth of melanoma in the brain. Targeting platelet activation with low-molecular-weight heparins represents a promising therapeutic approach to prevent melanoma BM.

AB - Background: The prognosis of patients with brain metastases (BM) is poor despite advances in our understanding of the underlying pathophysiology. The high incidence of thrombotic complications defines tumor progression and the high mortality rate. We, therefore, postulated that von Willebrand factor (VWF) promotes BM via its ability to induce platelet aggregation and thrombosis.Methods: We measured the abundance of VWF in the blood and intravascular platelet aggregates of patients with BM, and determined the specific contribution of endothelial and platelet-derived VWF using in vitro models and microfluidics. The relevance for the brain metastatic cascade in vivo was demonstrated in ret transgenic mice, which spontaneously develop BM, and by the intracardiac injection of melanoma cells.Results: Higher levels of plasma VWF in patients with BM were associated with enhanced intraluminal VWF fiber formation and platelet aggregation in the metastatic tissue and peritumoral regions. Platelet activation triggered the formation of VWF multimers, promoting platelet aggregation and activation, in turn enhancing tumor invasiveness. The absence of VWF in platelets, or the blocking of platelet activation, abolished platelet aggregation, and reduced tumor cell transmigration. Anticoagulation and platelet inhibition consistently reduced the number of BM in preclinical animal models.Conclusions: Our data indicate that platelet-derived VWF is involved in cerebral clot formation and in metastatic growth of melanoma in the brain. Targeting platelet activation with low-molecular-weight heparins represents a promising therapeutic approach to prevent melanoma BM.

U2 - 10.1093/noajnl/vdab175

DO - 10.1093/noajnl/vdab175

M3 - SCORING: Journal article

C2 - 34993481

VL - 3

JO - NEURO-ONCOL ADV

JF - NEURO-ONCOL ADV

SN - 2632-2498

IS - 1

M1 - vdab175

ER -