Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Surgery, West Virginia University, Morgantown, WV, USA.
Oncoimmunology. 2019 Jun 11;8(9):e1605822. doi: 10.1080/2162402X.2019.1605822. eCollection 2019.
Neutrophil extracellular trap (NET) formation results in the expulsion of granulocyte proteins and DNA into the extracellular space. This process is mediated by the enzyme peptidyl arginine deiminase 4 (PADI4) and translocation of elastase to the nucleus. NET formation, marked by increased levels of extracellular DNA, promotes pancreatic cancer proliferation and metastasis. Mice deficient in Padi4 demonstrate decreased pancreatic tumor growth, associated with a reduction in circulating extracellular DNA levels, diminished pancreatic stromal activation and improved survival in murine orthotopic pancreatic adenocarcinoma. Transplantation of Padi4 bone marrow into genetically engineered mice with Kras driven pancreatic adenocarcinoma (Pdx1-Cre:Kras, KC mice) limits the frequency of invasive cancers when compared with syngeneic controls. DNA from neutrophils activates pancreatic stellate cells that form dense, fibrous stroma which can promote and enable tumor proliferation. DNase treatment diminishes murine tumor growth and stromal activation to reverse the effect of NETs within the tumor microenvironment. Furthermore, deletion of the receptor for advanced glycation end products (RAGE) in pancreatic stellate cells abrogates the effects of DNA in promoting stellate cell proliferation and decreases tumor growth. Circulating neutrophil-derived DNA correlates with the stage in patients with pancreatic ductal adenocarcinoma, confirming the role of NETs in human pancreatic cancer. These findings support further investigation into targeting of NETs, PADI4 and extracellular DNA as a potential treatment strategy in patients with pancreatic cancer. : This study reports correlative data from a clinical trial registered with clinicaltrials.gov, NCT01978184 (November 7, 2013).
中性粒细胞胞外诱捕网（NET）的形成导致颗粒蛋白和 DNA 被排出到细胞外空间。这一过程由酶肽基精氨酸脱亚氨酶 4（PADI4）和弹性蛋白酶向核内易位介导。NET 形成，以细胞外 DNA 水平的增加为标志，促进胰腺癌的增殖和转移。缺乏 Padi4 的小鼠表现出胰腺肿瘤生长减少，与循环细胞外 DNA 水平降低、胰腺基质激活减少以及在鼠原位胰腺腺癌中的存活率提高相关。将 Padi4 骨髓移植到具有 Kras 驱动的胰腺腺癌的基因工程小鼠（Pdx1-Cre:Kras，KC 小鼠）中，与同基因对照相比，限制了侵袭性癌症的频率。中性粒细胞的 DNA 激活了形成致密纤维基质的胰腺星状细胞，从而可以促进和支持肿瘤增殖。DNase 处理可减少鼠肿瘤生长和基质激活，以逆转肿瘤微环境中 NET 的作用。此外，在胰腺星状细胞中删除晚期糖基化终产物受体（RAGE）可消除 DNA 促进星状细胞增殖的作用并降低肿瘤生长。循环中性粒细胞衍生的 DNA 与胰腺导管腺癌患者的分期相关，证实了 NET 在人类胰腺癌中的作用。这些发现支持进一步研究 NET、PADI4 和细胞外 DNA 作为胰腺癌患者潜在治疗策略的靶向作用。：本研究报告了在临床研究注册中心（clinicaltrials.gov，NCT01978184）注册的临床试验的相关数据（2013 年 11 月 7 日）。
