title: von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans.
abstract: 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.
authors.affiliation: Experimental Dermatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany;
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Bauer
authors.affiliation: Experimental Dermatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany;
authors.forename: Jan
authors.initials: J
authors.lastname: Suckau
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany;
authors.forename: Kathrin
authors.initials: K
authors.lastname: Frank
authors.affiliation: Experimental Dermatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany;
authors.forename: Anna
authors.initials: A
authors.lastname: Desch
authors.affiliation: Experimental Dermatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany;
authors.forename: Lukas
authors.initials: L
authors.lastname: Goertz
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany;
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Wagner
authors.affiliation: Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
authors.affiliation: Department of Dermatology, University of Muenster, Muenster, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Goerge
authors.affiliation: Department of Translational Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; and.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Umansky
authors.affiliation: Department of Translational Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; and.
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany;
authors.forename: Jochen
authors.initials: J
authors.lastname: Utikal
authors.affiliation: Experimental Dermatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Gorzelanny
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany; Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Nancy
authors.initials: N
authors.lastname: Diaz-Valdes
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany;
authors.forename: Viktor
authors.initials: V
authors.lastname: Umansky
authors.affiliation: Experimental Dermatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany;
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Schneider
mesh_terms: D051722:ADAM Proteins / Q000097:blood / Q000378:metabolism; D000071120:ADAMTS13 Protein; D000818:Animals; D001777:Blood Coagulation; D001792:Blood Platelets; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D055806:Microvessels / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010974:Platelet Aggregation; D011485:Protein Binding; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D000078222:Tinzaparin; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D042461:Vascular Endothelial Growth Factor A; D014841:von Willebrand Factor; D000078222:Tinzaparin; D051096:Proto-Oncogene Proteins c-ret; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human