Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer‑associated fibroblasts

Shin Takesue, Kenoki Ohuchida, Tomohiko Shinkawa, Yoshiki Otsubo, Sokichi Matsumoto, Akiko Sagara, Akiko Yonenaga, Yohei Ando, Shin Kibe, Hiromichi Nakayama, Chika Iwamoto, Koji Shindo, Taiki Moriyama, Kohei Nakata, Yoshihiro Miyasaka, Takao Ohtsuka, Hiroki Toma, Yohei Tominaga, Kazuhiro Mizumoto, Makoto HashizumeMasafumi Nakamura

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)596-605
Number of pages10
JournalInternational journal of oncology
Volume56
Issue number2
DOIs
Publication statusPublished - Jan 1 2020

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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