Tumor-Derived Exosomes Induce the Formation of Neutrophil Extracellular Traps: Implications For The Establishment of Cancer-Associated Thrombosis.
Tumor-Derived Exosomes Induce the Formation of Neutrophil Extracellular Traps: Implications For The Establishment of Cancer-Associated Thrombosis.
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DOI：
10.1038/s41598-017-06893-7
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发表时间：
2017-07-25
影响因子：
4.6
通讯作者：
Monteiro RQ
中科院分区：
文献类型：
--
作者：
Leal AC;Mizurini DM;Gomes T;Rochael NC;Saraiva EM;Dias MS;Werneck CC;Sielski MS;Vicente CP;Monteiro RQ
癌症患者发生血栓栓塞并发症的风险增加。已经提出了几种机制来解释癌症相关的血栓形成，包括肿瘤源性细胞外囊泡的释放和宿主血管细胞的激活。有人提出，中性粒细胞胞外陷阱（NET）有助于在癌症中的血栓形成表型。在这项研究中，我们评估了肿瘤来源的外泌体和NET在癌症相关血栓形成中的可能合作。雌性BALB/c小鼠原位注射4 T1乳腺癌细胞。除了循环中性粒细胞数量显著增加外，荷瘤动物还表现出血浆DNA和髓过氧化物酶水平升高。对小鼠进行虎红/激光诱导的静脉血栓形成或氯化铁诱导的动脉血栓形成模型。与无肿瘤动物相比，荷瘤小鼠在两种模型中均表现出加速的血栓形成。在两种模型中，用重组人DNA酶1治疗逆转了荷瘤小鼠的血栓形成前表型。值得注意的是，4 T1衍生的外泌体诱导来自用粒细胞集落刺激因子（G-CSF）处理的小鼠的中性粒细胞中的NET形成。此外，肿瘤来源的外泌体在静态条件下与NET相互作用。因此，将4 T1衍生的外来体静脉内施用到G-CSF处理的小鼠中显著加速了体内静脉血栓形成。综上所述，我们的观察结果表明，肿瘤源性外泌体和中性粒细胞可能在建立癌症相关血栓形成中起协同作用。
Cancer patients are at an increased risk of developing thromboembolic complications. Several mechanisms have been proposed to explain cancer-associated thrombosis including the release of tumor-derived extracellular vesicles and the activation of host vascular cells. It was proposed that neutrophil extracellular traps (NETs) contribute to the prothrombotic phenotype in cancer. In this study, we evaluated the possible cooperation between tumor-derived exosomes and NETs in cancer-associated thrombosis. Female BALB/c mice were orthotopically injected with 4T1 breast cancer cells. The tumor-bearing animals exhibited increased levels of plasma DNA and myeloperoxidase in addition to significantly increased numbers of circulating neutrophils. Mice were subjected to either Rose Bengal/laser-induced venous thrombosis or ferric chloride-induced arterial thrombosis models. The tumor-bearing mice exhibited accelerated thrombus formation in both models compared to tumor-free animals. Treatment with recombinant human DNase 1 reversed the prothrombotic phenotype of tumor-bearing mice in both models. Remarkably, 4T1-derived exosomes induced NET formation in neutrophils from mice treated with granulocyte colony-stimulating factor (G-CSF). In addition, tumor-derived exosomes interacted with NETs under static conditions. Accordingly, the intravenous administration of 4T1-derived exosomes into G-CSF-treated mice significantly accelerated venous thrombosis in vivo. Taken together, our observations suggest that tumor-derived exosomes and neutrophils may act cooperatively in the establishment of cancer-associated thrombosis.
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影响因子：
11.2
作者：
Bobrie, Angelique;Krumeich, Sophie;Thery, Clotilde
通讯作者：
Thery, Clotilde
影响因子：
11.2
作者：
Cedervall, Jessica;Zhang, Yanyu;Olsson, Anna-Karin
通讯作者：
Olsson, Anna-Karin
影响因子：
3.3
作者：
Amer, Magid H
通讯作者：
Amer, Magid H
影响因子：
5.7
作者：
Demers M;Wagner DD
通讯作者：
Wagner DD
DOI：
10.1111/j.1538-7836.2011.04544.x
发表时间：
2012-01
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Brill A;Fuchs TA;Savchenko AS;Thomas GM;Martinod K;De Meyer SF;Bhandari AA;Wagner DD
通讯作者：
Wagner DD