Heparins that block VEGF-A-mediated von Willebrand factor fiber generation are potent inhibitors of hematogenous but not lymphatic metastasis
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Lukas Goertz1,*, Stefan Werner Schneider2,*, Anna Desch1, Frank Thomas Mayer1, Julian Koett1, Kai Nowak3, Ioannis Karampinis3, Michael K. Bohlmann4, Viktor Umansky5, Alexander Thomas Bauer1
1Experimental Dermatology, Department of Dermatology, Venereology, and Allergy, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
2Department of Dermatology and Venereology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
3Department of Surgery, Mannheim University Medical Center, Heidelberg University, Mannheim, Germany
4Department of Obstetrics and Gynaecology, Mannheim University Medical Center, Heidelberg University, Mannheim, Germany
5Skin Cancer Unit, German Cancer Research Center (DKFZ), Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
*These authors have contributed equally to this work
Alexander Thomas Bauer, email: [email protected]
Keywords: von Willebrand factor, metastasis, melanoma, angiogenesis, coagulation
Received: October 12, 2015 Accepted: August 21, 2016 Published: September 02, 2016
Von Willebrand factor (VWF) serves as a nidus for platelet aggregation and thrombosis. We hypothesize that VWF fibers contribute to the development of venous thromboembolism (VTE) and to metastasis formation. Here, we show that vascular and lymphatic endothelial cells (ECs) express VWF in vitro and release VWF fibers after activation by tumor cell supernatants. In contrast, an ex vivo analysis of primary mouse tumors revealed the presence of VWF fibers in the blood microvasculature but not in lymphatic vessels. Unlike the anticoagulant Fondaparinux, an inhibitor of thrombin generation, the low-molecular-weight heparin (LMWH) Tinzaparin inhibited VWF fiber formation and vessel occlusion in tumor vessels by blocking thrombin-induced EC activation and vascular endothelial growth factor-A (VEGF-A)-mediated VWF release. Intradermal tumor cell inoculation in VWF- and ADAMTS13-deficient mice did not alter lymph node metastases compared with wild type animals. Interestingly, multiple tumor-free distal organs exhibited hallmarks of malignancy-related VTE, including luminal VWF fibers, platelet-rich thrombi and vessel occlusions. Furthermore, ADAMTS13 deficiency, characterized by prolonged intraluminal VWF network lifetimes, resulted in a severely increased number of metastatic foci in an experimental model of hematogenous lung seeding. Treatment with Tinzaparin inhibited tumor-induced release of VWF multimers, impeded platelet aggregation and decreased lung metastasis. Thus, our data strongly suggest a critical role of luminal VWF fibers in determining the occurrence of thrombosis and cancer metastasis. Moreover, the findings highlight LMWHs as therapeutic strategy to treat thrombotic complications while executing anti-metastatic activities.
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