von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans
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von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans. / Bauer, Alexander T; Suckau, Jan; Frank, Kathrin; Desch, Anna; Goertz, Lukas; Wagner, Andreas H; Hecker, Markus; Goerge, Tobias; Umansky, Ludmila; Beckhove, Philipp; Utikal, Jochen; Gorzelanny, Christian; Diaz-Valdes, Nancy; Umansky, Viktor; Schneider, Stefan W.
In: BLOOD, Vol. 125, No. 20, 14.05.2015, p. 3153-63.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -