von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans
von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans
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DOI：
10.1182/blood-2014-08-595686
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发表时间：
2015-05-14
期刊：
影响因子：
20.3
通讯作者：
Schneider, Stefan W.
中科院分区：
文献类型：
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作者：
Bauer, Alexander T.;Suckau, Jan;Schneider, Stefan W.
肿瘤介导的促凝活性导致静脉血栓栓塞并支持癌症患者的转移。转移形成的先决条件是癌细胞与内皮细胞（EC）的相互作用，随后是它们的外渗。尽管已知内皮细胞的激活和促凝蛋白血管性血友病因子（VWF）的释放对恶性肿瘤是必不可少的，但其潜在机制仍知之甚少。我们假设肿瘤血管中的VWF纤维促进肿瘤相关血栓栓塞和转移。使用体外环境、小鼠模型和人类肿瘤样本，我们发现黑色素瘤细胞激活EC，随后在肿瘤微血管中释放VWF纤维和血小板聚集。对人类血液样本和肿瘤组织的分析表明，促进VWF释放加上对ADAMTS 13（一种具有血小板反应蛋白I型重复序列13的解整合素样金属蛋白酶）的蛋白水解活性和蛋白表达的局部抑制，导致了这种促凝环境。在转基因小鼠模型中，用低分子量肝素汀扎肝素阻断内皮细胞活化伴随着VWF网络的缺乏，并抑制了肿瘤的进展。我们的研究结果暗示了肿瘤源性血管内皮生长因子-A（VEGF-A）促进肿瘤进展和血管生成的机制。因此，靶向EC活化设想了减弱肿瘤相关的血管生成和凝血的新的治疗策略。
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.