Department of Laboratory Diagnosis, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
Cancer Biol Med. 2020 Feb 15;17(1):154-168. doi: 10.20892/j.issn.2095-3941.2019.0353.
Neutrophil extracellular traps (NETs) produced by tumor-infiltrating neutrophils (TINs) are associated with poor prognosis in patients with several types of cancer. However, the mechanisms underlying the involvement of NETs in glioma progression remain largely unknown. This study aimed to elucidate the roles of NETs in biological processes that drive the crosstalk between glioma progression and the tumor microenvironment. Neutrophil infiltration and NETs formation were investigated in glioma tissue through immunohistochemistry, and their relationships with clinicopathological features and outcomes were statistically evaluated. The effects of NETs on glioma cell progression were studied in a co-culture system. and experiments validated the reactive oxygen species activity and cytokine production of TINs, as well as the ERK signaling pathway activation and the metastasis of gliomas. Neutrophil infiltration and NETs formation were induced in high-grade glioma compared with low-grade glioma. NETs induced by TINs were determined to be an oncogenic marker of high-grade gliomas and to be involved in cell proliferation and invasion. NETs overproduction promoted glioma cell proliferation, migration, and invasion. Furthermore, HMGB1 was found to bind to RAGE and activate the NF-κB signaling pathway . In addition, NETs stimulated the NF-κB signaling pathway, thus promoting IL-8 secretion in glioblastoma. Subsequently, IL-8 recruited neutrophils which in turn mediated NETs formation the PI3K/AKT/ROS axis in TINs. Our results suggest that NETs produced by TINs mediate the crosstalk between glioma progression and the tumor microenvironment by regulating the HMGB1/RAGE/IL-8 axis. Targeting NETs formation or IL-8 secretion may be an effective approach to inhibit glioma progression.
肿瘤浸润中性粒细胞（TINs）产生的中性粒细胞胞外诱捕网（NETs）与多种癌症患者的预后不良相关。然而，NETs 参与胶质瘤进展的机制在很大程度上尚不清楚。本研究旨在阐明 NETs 在驱动胶质瘤进展与肿瘤微环境相互作用的生物学过程中的作用。通过免疫组织化学研究了胶质瘤组织中的中性粒细胞浸润和 NETs 形成，并对其与临床病理特征和结局的关系进行了统计学评估。在共培养系统中研究了 NETs 对胶质瘤细胞进展的影响。实验验证了 TINs 的活性氧物质和细胞因子产生、ERK 信号通路激活以及胶质瘤的转移。与低级别胶质瘤相比，高级别胶质瘤中诱导了中性粒细胞浸润和 NETs 形成。TINs 诱导的 NETs 被确定为高级别胶质瘤的致癌标志物，并且参与细胞增殖和侵袭。NETs 的过度产生促进了胶质瘤细胞的增殖、迁移和侵袭。此外，还发现 HMGB1 与 RAGE 结合并激活 NF-κB 信号通路。此外，NETs 刺激 NF-κB 信号通路，从而促进神经胶质瘤中 IL-8 的分泌。随后，IL-8 募集中性粒细胞，进而介导 NETs 的形成通过 TINs 中的 PI3K/AKT/ROS 轴。我们的结果表明，TINs 产生的 NETs 通过调节 HMGB1/RAGE/IL-8 轴介导胶质瘤进展与肿瘤微环境的相互作用。靶向 NETs 形成或 IL-8 分泌可能是抑制胶质瘤进展的有效方法。
