von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans

TY - JOUR

T1 - von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans

AU - Bauer, Alexander T

AU - Suckau, Jan

AU - Frank, Kathrin

AU - Desch, Anna

AU - Goertz, Lukas

AU - Wagner, Andreas H

AU - Hecker, Markus

AU - Goerge, Tobias

AU - Umansky, Ludmila

AU - Beckhove, Philipp

AU - Utikal, Jochen

AU - Gorzelanny, Christian

AU - Diaz-Valdes, Nancy

AU - Umansky, Viktor

AU - Schneider, Stefan W

N1 - © 2015 by The American Society of Hematology.

PY - 2015/5/14

Y1 - 2015/5/14

N2 - Tumor-mediated procoagulatory activity leads to venous thromboembolism and supports metastasis in cancer patients. A prerequisite for metastasis formation is the interaction of cancer cells with endothelial cells (ECs) followed by their extravasation. Although it is known that activation of ECs and the release of the procoagulatory protein von Willebrand factor (VWF) is essential for malignancy, the underlying mechanisms remain poorly understood. We hypothesized that VWF fibers in tumor vessels promote tumor-associated thromboembolism and metastasis. Using in vitro settings, mouse models, and human tumor samples, we showed that melanoma cells activate ECs followed by the luminal release of VWF fibers and platelet aggregation in tumor microvessels. Analysis of human blood samples and tumor tissue revealed that a promoted VWF release combined with a local inhibition of proteolytic activity and protein expression of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type I repeats 13) accounts for this procoagulatory milieu. Blocking endothelial cell activation by the low-molecular-weight heparin tinzaparin was accompanied by a lack of VWF networks and inhibited tumor progression in a transgenic mouse model. Our findings implicate a mechanism wherein tumor-derived vascular endothelial growth factor-A (VEGF-A) promotes tumor progression and angiogenesis. Thus, targeting EC activation envisions new therapeutic strategies attenuating tumor-related angiogenesis and coagulation.

AB - Tumor-mediated procoagulatory activity leads to venous thromboembolism and supports metastasis in cancer patients. A prerequisite for metastasis formation is the interaction of cancer cells with endothelial cells (ECs) followed by their extravasation. Although it is known that activation of ECs and the release of the procoagulatory protein von Willebrand factor (VWF) is essential for malignancy, the underlying mechanisms remain poorly understood. We hypothesized that VWF fibers in tumor vessels promote tumor-associated thromboembolism and metastasis. Using in vitro settings, mouse models, and human tumor samples, we showed that melanoma cells activate ECs followed by the luminal release of VWF fibers and platelet aggregation in tumor microvessels. Analysis of human blood samples and tumor tissue revealed that a promoted VWF release combined with a local inhibition of proteolytic activity and protein expression of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type I repeats 13) accounts for this procoagulatory milieu. Blocking endothelial cell activation by the low-molecular-weight heparin tinzaparin was accompanied by a lack of VWF networks and inhibited tumor progression in a transgenic mouse model. Our findings implicate a mechanism wherein tumor-derived vascular endothelial growth factor-A (VEGF-A) promotes tumor progression and angiogenesis. Thus, targeting EC activation envisions new therapeutic strategies attenuating tumor-related angiogenesis and coagulation.

KW - ADAM Proteins

KW - ADAMTS13 Protein

KW - Animals

KW - Blood Coagulation

KW - Blood Platelets

KW - Disease Models, Animal

KW - Disease Progression

KW - Endothelial Cells

KW - Enzyme Activation

KW - Fibrinolytic Agents

KW - Heparin, Low-Molecular-Weight

KW - Humans

KW - Melanoma

KW - Mice

KW - Mice, Transgenic

KW - Microvessels

KW - Neovascularization, Pathologic

KW - Platelet Aggregation

KW - Protein Binding

KW - Proto-Oncogene Proteins c-ret

KW - Vascular Endothelial Growth Factor A

KW - von Willebrand Factor

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1182/blood-2014-08-595686

DO - 10.1182/blood-2014-08-595686

M3 - SCORING: Journal article

C2 - 25977583

VL - 125

SP - 3153

EP - 3163

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 20

ER -