Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis
Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis
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DOI：
10.1073/pnas.1200419109
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发表时间：
2012-08-07
影响因子：
11.1
通讯作者：
Wagner, Denisa D.
中科院分区：
文献类型：
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作者：
Demers, Melanie;Krause, Daniela S.;Wagner, Denisa D.
癌症相关血栓形成往往缺乏明确的病因。然而，它与预后不良有关，是癌症患者死亡的第二大原因。最近的研究表明，染色质通过产生中性粒细胞外陷阱(Net)而释放到血液中，是促凝和促血栓形成的。利用慢性粒细胞白血病的小鼠模型，我们发现恶性和非恶性中性粒细胞更容易形成网状结构。在乳腺癌和肺癌模型中也观察到了对Net生成的这种增加的敏感性，这表明癌症通过对宿主的全身作用，可以诱导外周血中性粒细胞的增加，而后者容易形成Net。此外，在乳腺癌模型的晚期，伴随着肺内静脉血栓的出现而发生网织红细胞增多症。此外，在荷瘤小鼠中模拟轻微的全身感染，但不是对照，会导致大量染色质的释放和血栓前状态。中性粒细胞数量的增加和它们的启动是由粒细胞集落刺激因子(G-CSF)介导的，G-CSF积聚在荷瘤小鼠的血液中。G-CSF联合小剂量脂多糖治疗小鼠可复制肿瘤血栓前状态，并导致血小板减少和微血栓形成。综上所述，我们的结果确定了通过净形成释放的细胞外染色质是癌症相关血栓形成的原因，并揭示了降低癌症患者血栓发生率的目标。
Cancer-associated thrombosis often lacks a clear etiology. However, it is linked to a poor prognosis and represents the second-leading cause of death in cancer patients. Recent studies have shown that chromatin released into blood, through the generation of neutrophil extracellular traps (NETs), is procoagulant and prothrombotic. Using a murine model of chronic myelogenous leukemia, we show that malignant and nonmalignant neutrophils are more prone to NET formation. This increased sensitivity toward NET generation is also observed in mammary and lung carcinoma models, suggesting that cancers, through a systemic effect on the host, can induce an increase in peripheral blood neutrophils, which are predisposed to NET formation. In addition, in the late stages of the breast carcinoma model, NETosis occurs concomitant with the appearance of venous thrombi in the lung. Moreover, simulation of a minor systemic infection in tumor-bearing, but not control, mice results in the release of large quantities of chromatin and a prothrombotic state. The increase in neutrophil count and their priming is mediated by granulocyte colony-stimulating factor (G-CSF), which accumulates in the blood of tumor-bearing mice. The prothrombotic state in cancer can be reproduced by treating mice with G-CSF combined with low-dose LPS and leads to thrombocytopenia and microthrombosis. Taken together, our results identify extracellular chromatin released through NET formation as a cause for cancer-associated thrombosis and unveil a target in the effort to decrease the incidence of thrombosis in cancer patients.