Cancer Research Program and the LD MacLean Surgical Research Laboratories, Department of Surgery, McGill University Health Center (MUHC), Montreal, Québec, Canada.
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
JCI Insight. 2019 Jul 25;5(16):128008. doi: 10.1172/jci.insight.128008.
Targeting the dynamic tumor immune microenvironment (TIME) can provide effective therapeutic strategies for cancer. Neutrophils are the predominant leukocyte population in mice and humans, and mounting evidence implicates these cells during tumor growth and metastasis. Neutrophil extracellular traps (NETs) are networks of extracellular neutrophil DNA fibers that are capable of binding tumor cells to support metastatic progression. Here we demonstrate for the first time that circulating NET levels are elevated in advanced esophageal, gastric and lung cancer patients compared to healthy controls. Using pre-clinical murine models of lung and colon cancer in combination with intravital video microscopy, we show that NETs functionally regulate disease progression and that blocking NETosis through multiple strategies significantly inhibits spontaneous metastasis to the lung and liver. Further, we visualize how inhibiting tumor-induced NETs decreases cancer cell adhesion to liver sinusoids following intrasplenic injection - a mechanism previously thought to be driven primarily by exogenous stimuli. Thus, in addition to neutrophil abundance, the functional contribution of NETosis within the TIME has critical translational relevance and represents a promising target to impede metastatic dissemination.
靶向肿瘤免疫微环境（TIME）可以为癌症提供有效的治疗策略。中性粒细胞是小鼠和人类中主要的白细胞群体，越来越多的证据表明这些细胞在肿瘤生长和转移过程中发挥作用。中性粒细胞胞外诱捕网（NETs）是由细胞外中性粒细胞 DNA 纤维组成的网络，能够结合肿瘤细胞以支持转移进展。在这里，我们首次证明，与健康对照组相比，晚期食管癌、胃癌和肺癌患者的循环 NET 水平升高。我们使用肺和结肠癌的临床前小鼠模型，并结合活体视频显微镜，表明 NETs 在功能上调节疾病进展，并且通过多种策略阻断 NETosis 可显著抑制自发性肺和肝转移。此外，我们观察到抑制肿瘤诱导的 NETs 如何减少脾脏内注射后癌细胞与肝窦的黏附——这一机制以前被认为主要是由外源性刺激驱动的。因此，除了中性粒细胞的丰度外，TIME 内 NETosis 的功能贡献具有重要的转化相关性，代表了一种有希望的抑制转移播散的靶点。
