Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress.
Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress.
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中性粒细胞胞外陷阱促进手术应激后肝转移的发生和进展。
DOI：
10.1158/0008-5472.can-15-1591
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发表时间：
2016-03-15
期刊：
影响因子：
11.2
通讯作者：
Tsung A
中科院分区：
文献类型：
--
作者：
Tohme S;Yazdani HO;Al-Khafaji AB;Chidi AP;Loughran P;Mowen K;Wang Y;Simmons RL;Huang H;Tsung A
手术切除后肿瘤复发的风险已经知道了几十年，但治疗失败的机制仍然知之甚少。中性粒细胞是手术应激后的一线反应者，可能在将炎症与癌症进展联系起来方面发挥重要作用。在应激反应中，中性粒细胞可以排出其蛋白质镶嵌的染色质，形成称为中性粒细胞胞外陷阱（NET）的局部陷阱。在这项研究中，我们询问是否由于其诱捕移动细胞的能力，NET形成可能促进手术应激后的转移。与这一假设相一致，在一组接受转移性结直肠癌根治性肝切除术的患者中，我们观察到术后NET形成增加与无病生存率降低>4倍相关。以类似的方式，在采用肝脏缺血-再灌注的手术应激的鼠模型中，我们观察到NET形成的增加与转移性疾病的加速发展和进展相关。通过用DNA酶局部处理或抑制对NET形成至关重要的肽基精氨酸脱氨酶来抑制小鼠中的NET形成，可以消除这些作用。在生长的转移性肿瘤中，我们发现肿瘤内缺氧加重NET的形成。体外机制研究表明，小鼠嗜中性粒细胞衍生的NET触发HMGB 1释放并激活癌细胞中的TLR 9依赖性通路，以促进其粘附、增殖、迁移和侵袭。综上所述，我们的研究结果暗示NET在手术应激后肝转移的发展中，表明它们的消除可能会降低肿瘤复发的风险。
Risks of tumor recurrence after surgical resection have been known for decades, but the mechanisms underlying treatment failures remain poorly understood. Neutrophils, first-line responders after surgical stress, may play an important role in linking inflammation to cancer progression. In response to stress, neutrophils can expel their protein-studded chromatin to form local snares known as neutrophil extracellular traps (NET). In this study, we asked whether, as a result of its ability to ensnare moving cells, NET formation might promote metastasis after surgical stress. Consistent with this hypothesis, in a cohort of patients undergoing attempted curative liver resection for metastatic colorectal cancer, we observed that increased postoperative NET formation was associated with a >4-fold reduction in disease-free survival. In like manner, in a murine model of surgical stress employing liver ischemia-reperfusion, we observed an increase in NET formation that correlated with an accelerated development and progression of metastatic disease. These effects were abrogated by inhibiting NET formation in mice through either local treatment with DNAse or inhibition of the enzyme peptidylarginine deaminase, which is essential for NET formation. In growing metastatic tumors, we found that intratumoral hypoxia accentuated NET formation. Mechanistic investigations in vitro indicated that mouse neutrophil-derived NET triggered HMGB1 release and activated TLR9-dependent pathways in cancer cells to promote their adhesion, proliferation, migration, and invasion. Taken together, our findings implicate NET in the development of liver metastases after surgical stress, suggesting that their elimination may reduce risks of tumor relapse.