Targeting neutrophil extracellular traps with thrombomodulin prevents pancreatic cancer metastasis
Targeting neutrophil extracellular traps with thrombomodulin prevents pancreatic cancer metastasis
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DOI：
10.1016/j.canlet.2020.10.015
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发表时间：
2021-01-28
期刊：
影响因子：
9.7
通讯作者：
Fujiwara, Toshiyoshi
中科院分区：
文献类型：
--
作者：
Kajioka, Hiroki;Kagawa, Shunsuke;Fujiwara, Toshiyoshi
手术是胰腺癌的唯一根治性治疗选择，但患者往往会出现术后复发。手术的侵袭性可能与复发有关。研究了手术引起的炎症、中性粒细胞和癌症转移之间的关系。首先，在临床标本中检查中性粒细胞胞外陷阱（NETs），并在转移性肿瘤周围观察到NETs。为了探索NETs是如何被诱导的，中性粒细胞与胰腺癌或在癌症条件培养基中培养。当中性粒细胞与胰腺癌或甚至其条件培养基一起培养时，它们形成NET。在体外和体内进一步研究了NET对癌细胞的作用。NET诱导癌细胞的上皮向间质转化，从而促进其迁移和侵袭。来源于NETs的HMGB1似乎增强了癌细胞的恶性度。在伴有炎症的肝转移小鼠模型中，NET通过增强外渗参与转移过程。有趣的是，血栓调节蛋白降解HMGB1，从而抑制NET的诱导，从而防止胰腺癌转移到肝脏。总之，NETs与胰腺癌细胞相互作用，在炎症相关转移中发挥关键作用。用血栓调节蛋白靶向NET可以成为改善胰腺癌患者手术结果的新策略。
Surgery is the only curative treatment option for pancreatic cancer, but patients often develop postoperative recurrence. Surgical invasiveness might be involved in the mechanism of recurrence. The associations among inflammation caused by surgery, neutrophils, and cancer metastasis were investigated. At first, neutrophil extracellular traps (NETs) were examined in clinical specimens, and NETs were observed around metastatic tumors. To explore how NETs were induced, neutrophils were cultured with pancreatic cancer or in cancerconditioned medium. Neutrophils formed NETs when they were cultured with pancreatic cancer or even its conditioned medium. The effects of NETs on cancer cells were further investigated in vitro and in vivo. NETs induced the epithelial to mesenchymal transition in cancer cells and thereby promoted their migration and invasion. HMGB1 derived from NETs appeared to potentiate the malignancy of cancer cells. In a mouse model of liver metastasis with inflammation, NETs participated in the metastatic process by enhancing extravasation. Interestingly, thrombomodulin degraded HMGB1 and consequently inhibited the induction of NETs, thereby preventing pancreatic cancer metastasis to the liver. In conclusion, NETs interact reciprocally with pancreatic cancer cells, which play a pivotal role in inflammation-associated metastasis. Targeting NETs with thrombomodulin can be a novel strategy to improve the surgical outcome of pancreatic cancer patients.