Boone B A, Orlichenko L, Schapiro N E, Loughran P, Gianfrate G C, Ellis J T, Singhi A D, Kang R, Tang D, Lotze M T, Zeh H J
Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
1] Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA [2] Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA.
Cancer Gene Ther. 2015 Jun;22(6):326-34. doi: 10.1038/cgt.2015.21. Epub 2015 Apr 24.
Neutrophil extracellular traps (NETs) are formed when neutrophils expel their DNA, histones and intracellular proteins into the extracellular space or circulation. NET formation is dependent on autophagy and is mediated by citrullination of histones to allow for the unwinding and subsequent expulsion of DNA. NETs have an important role in the pathogenesis of several sterile inflammatory diseases, including malignancy, therefore we investigated the role of NETs in the setting of pancreatic ductal adenocarcinoma (PDA). Neutrophils isolated from two distinct animal models of PDA had an increased propensity to form NETs following stimulation with platelet activating factor (PAF). Serum DNA, a marker of circulating NET formation, was elevated in tumor bearing animals as well as in patients with PDA. Citrullinated histone H3 expression, a marker of NET formation, was observed in pancreatic tumors obtained from murine models and patients with PDA. Inhibition of autophagy with chloroquine or genetic ablation of receptor for advanced glycation end products (RAGE) resulted in decreased propensity for NET formation, decreased serum DNA and decreased citrullinated histone H3 expression in the pancreatic tumor microenvironment. We conclude that NETs are upregulated in pancreatic cancer through RAGE-dependent/autophagy mediated pathways.
中性粒细胞胞外诱捕网（NETs）是当中性粒细胞将其DNA、组蛋白和细胞内蛋白质释放到细胞外空间或循环中时形成的。NET形成依赖于自噬，并由组蛋白瓜氨酸化介导，以使DNA解旋并随后排出。NETs在包括恶性肿瘤在内的几种无菌性炎症疾病的发病机制中起重要作用，因此我们研究了NETs在胰腺导管腺癌（PDA）中的作用。从两种不同的PDA动物模型中分离出的中性粒细胞在受到血小板活化因子（PAF）刺激后形成NETs的倾向增加。血清DNA是循环中NET形成的标志物，在荷瘤动物以及PDA患者中均升高。在从鼠模型和PDA患者获得的胰腺肿瘤中观察到瓜氨酸化组蛋白H3表达，这是NET形成的标志物。用氯喹抑制自噬或对晚期糖基化终产物受体（RAGE）进行基因敲除导致胰腺肿瘤微环境中NET形成倾向降低、血清DNA降低以及瓜氨酸化组蛋白H3表达降低。我们得出结论，NETs在胰腺癌中通过RAGE依赖性/自噬介导的途径上调。
