High prevalence and risk factors of thromboembolism in stage IV melanoma

Sparsa, A.; Durox, H.; Doffoël-Hantz, V.; Munyangango, E.M.; Bédane, Christophe; Cendras, J; Gantois, Clément; Boulinguez, S.; Bonnetblanc, J.‐M.

doi:10.1111/j.1468-3083.2010.03795.x

Cited by 27 publications

(28 citation statements)

References 30 publications

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“…In addition, a promising in vitro data for the PAR-1 antagonist, SCH79797, has been recently reported (34). Furthermore, a correlation between thrombosis and cancer patients has been reported in several cancers including melanoma, and it was demonstrated that anti-coagulant therapy prolonged the survival term in cancer patients (7, 35). Nevertheless, platelet activation can be induced by another PAR, at high thrombin concentrations (5).…”

Section: Par-1 As a Therapeutic Target In Melanoma Patientsmentioning

confidence: 95%

PAR-1 and Thrombin: The Ties That Bind the Microenvironment to Melanoma Metastasis

et al. 2011

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Progression of melanoma is dependent on cross-talk between tumor cells and the adjacent microenvironment. The thrombin receptor, Protease Activated Receptor-1 (PAR-1) plays a key role in exerting this function during melanoma progression. PAR-1 and its activating factors, which are expressed on tumor cells and the surrounding stroma, induce not only coagulation, but also cell signaling which promotes the metastatic phenotype. Several adhesion molecules, cytokines, growth factors and proteases have recently been identified as downstream targets of PAR-1 and have been shown to modulate interactions between tumor cells and the microenvironment in the process of melanoma growth and metastasis. Inhibition of these interactions by targeting PAR-1 could be utilized as a potential therapeutic modality for melanoma patients.

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Section: Par-1 As a Therapeutic Target In Melanoma Patientsmentioning

confidence: 95%

PAR-1 and Thrombin: The Ties That Bind the Microenvironment to Melanoma Metastasis

et al. 2011

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“…Among the different cancer types, the VTE incidence is especially high in malignant melanoma, occurring in approximately 25% of melanoma patients [3]. An association between an enhanced risk of thrombotic complications and an increase of von Willebrand factor (VWF) levels in plasma and tumor tissue of patients with distinct malignancies has been described by multiple clinical studies for specific malignancies [4–7].…”

Section: Introductionmentioning

confidence: 99%

Heparins that block VEGF-A-mediated von Willebrand factor fiber generation are potent inhibitors of hematogenous but not lymphatic metastasis

et al. 2016

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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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“…[15][16][17] Especially in malignant melanoma patients, the incidence of venous thromboembolism (VTE) is ;25%. 18 Moreover, clinical studies demonstrate that treatment with anticoagulant low-molecular-weight heparins (LMWHs) improves the outcome of distinct cancer patients. 19 Based on these observations, we postulate that EC activation, followed by the generation of VWF fibers in tumor vasculature, promotes cancer-associated hypercoagulopathy and facilitates metastasis.…”

mentioning

confidence: 99%

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

Bauer

Suckau

Frank

et al. 2015

Blood

117

128

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Key Points• Tumor-derived VEGF-A mediates endothelial cell activation, VWF release, and platelet aggregation provoking coagulation in tumor patients.• Local ADAMTS13 inhibition promotes VWF fiber formation in tumor microvessels.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 disintegrinlike 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. (Blood. 2015;125(20):3153-3163) IntroductionTo form new metastatic lesions, circulating melanoma cells have to interact with endothelial cells (ECs) and migrate through the vessel wall.1,2 In this context, our own in vitro studies show that melanoma cells activate ECs by an indirect, tissue factor (TF)-mediated thrombin generation.3 Next to this indirect melanoma-induced EC activation, recent findings identified melanoma-derived vascular endothelial growth factor-A (VEGF-A) as main mediator of direct EC activation. 4,5 Both the thrombin-and the VEGF-A-dependent pathways induce EC activation followed by Weibel-Palade body (WPB) exocytosis and the release of inflammatory cytokines and the highly procoagulatory glycoprotein von Willebrand factor (VWF), linking inflammation and coagulation. 6 On the one hand, luminally released VWF fibers are involved in hemostasis and vessel repair as mediators of platelet adhesion to the endothelium. 7,8 On the other hand, we showed that tumor cell-induced ultra-large VWF (ULVWF) fibers have the highest potential for platelet binding and aggregation.9,10 This effect may contribute not only to pathophysiologic vessel occlusion, 11 but also to the establishment of metastasis as platelets facilitate tumor cell extravasation. 12-14Indeed, it is well-known that cancer pati...

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High prevalence and risk factors of thromboembolism in stage IV melanoma

Cited by 27 publications

References 30 publications

PAR-1 and Thrombin: The Ties That Bind the Microenvironment to Melanoma Metastasis

PAR-1 and Thrombin: The Ties That Bind the Microenvironment to Melanoma Metastasis

Heparins that block VEGF-A-mediated von Willebrand factor fiber generation are potent inhibitors of hematogenous but not lymphatic metastasis

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

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