Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals
Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals
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DOI：
10.1158/0008-5472.can-14-3299
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发表时间：
2015-07-01
期刊：
影响因子：
11.2
通讯作者：
Olsson, Anna-Karin
中科院分区：
文献类型：
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作者：
Cedervall, Jessica;Zhang, Yanyu;Olsson, Anna-Karin
除了恶性肿瘤本身，癌症还会对患者产生各种副作用，包括对远端器官功能的威胁。然而，这种效应的基础，无论是与原发肿瘤或转移肿瘤相关，通常都知之甚少。在这项研究中，我们展示了在两种不同的转基因小鼠癌症模型(胰岛素瘤RIP1-Tag2模型和乳腺癌MMTV-PyMT模型)中，由于肿瘤形成而在这些组织中积累的中性粒细胞如何损害心脏和肾脏的血管功能。全身注射抗Gr1抗体可以减少中性粒细胞，改善血管灌注量，防止肾血管渗漏。我们还观察到了血小板-中性粒细胞复合体的积累，这是中性粒细胞细胞外陷阱(NET)的特征，在健康的非荷瘤小鼠的肾脏中完全缺失。血管系统中的净积聚与促炎黏附分子ICAM-1、VCAM-1和E-选择素以及促炎细胞因子IL1β、IL6和趋化因子CXCL1上调有关。注射DNase I来溶解DNA含量很高的Net，可以将肾脏和心脏的血流恢复到非荷瘤小鼠的水平，还可以防止这些器官血管系统的血管渗漏。综上所述，我们的研究结果强烈表明，Net介导了肿瘤对远端器官的负面附带影响，损害了血管功能，并加剧了这些部位的炎症。(C)2015年AACR。
Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1 beta, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites. (C)2015 AACR.