Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer-associated fibroblasts
Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer-associated fibroblasts
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DOI：
10.3892/ijo.2019.4951
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发表时间：
2020-02-01
影响因子：
5.2
通讯作者：
Nakamura, Masafumi
中科院分区：
文献类型：
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作者：
Takesue, Shin;Ohuchida, Kenoki;Nakamura, Masafumi
癌症相关成纤维细胞（CAF）通过肿瘤-基质相互作用促进胰腺导管腺癌（PDAC）的进展。中性粒细胞胞外陷阱（NETs）是由中性粒细胞释放的胞外DNA网络，与蛋白水解酶一起对抗外来病原体。新兴的研究表明它们对几种类型癌症的肝转移有贡献。在此，为了研究NET在PDAC肝转移中的作用，评价NET抑制剂对自发PDAC小鼠模型的作用。结果表明，DNase I，NET抑制剂，抑制肝转移。为了进一步研究，进一步关注肝微转移，并使用通过脾内肿瘤注射产生的实验性肝转移小鼠模型。此外，DNase I还抑制肝微转移，并且显著地，转移灶中积聚的CAF的数量显著减少。体外实验显示胰腺癌细胞诱导NET形成，因此NET增强肝星状细胞的迁移，这可能是肝转移中CAFs的来源。总之，这些结果表明NETs通过激活CAFs促进PDAC的肝微转移。
Cancer-associated fibroblasts (CAFs) promote the progression of pancreatic ductal adenocarcinoma (PDAC) via tumor-stromal interactions. Neutrophil extracellular traps (NETs) are extracellular DNA meshworks released from neutrophils together with proteolytic enzymes against foreign pathogens. Emerging studies suggest their contribution to liver metastasis in several types of cancer. Herein, in order to investigate the role of NETs in liver metastasis in PDAC, the effects of NET inhibitors on spontaneous PDAC mouse models were evaluated. It was demonstrated that DNase I, a NET inhibitor, suppressed liver metastasis. For further investigation, further attention was paid to liver micrometastasis and an experimental liver metastasis mouse model was used that was generated by intrasplenic tumor injection. Furthermore, DNase I also suppressed liver micrometastasis and notably, CAFs accumulated in metastatic foci were significantly decreased in number. In vitro experiments revealed that pancreatic cancer cells induced NET formation and consequently NETs enhanced the migration of hepatic stellate cells, which was the possible origin of CAFs in liver metastasis. On the whole, these results suggest that NETs promote liver micrometastasis in PDAC via the activation of CAFs.