TY - JOUR
T1 - Targeting neutrophil extracellular traps with thrombomodulin prevents pancreatic cancer metastasis
AU - Kajioka, Hiroki
AU - Kagawa, Shunsuke
AU - Ito, Atene
AU - Yoshimoto, Masashi
AU - Sakamoto, Shuichi
AU - Kikuchi, Satoru
AU - Kuroda, Shinji
AU - Yoshida, Ryuichi
AU - Umeda, Yuzo
AU - Noma, Kazuhiro
AU - Tazawa, Hiroshi
AU - Fujiwara, Toshiyoshi
N1 - Funding Information:
This work was supported by the Japan Society for the Promotion of Science [KAKENHI Grant Numbers JP15K15193 , JP16H05416 , JP18K08679 ] and grants from the Ministry of Health , Labour and Welfare, Japan [ 14525167 ].
PY - 2021/1/28
Y1 - 2021/1/28
N2 - 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 cancer-conditioned 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.
AB - 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 cancer-conditioned 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.
KW - Epithelial to mesenchymal transition
KW - HMGB1
KW - Ischemia-reperfusion model
KW - Phorbol 12-myristate 13-acetate
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U2 - 10.1016/j.canlet.2020.10.015
DO - 10.1016/j.canlet.2020.10.015
M3 - Article
AN - SCOPUS:85092637496
VL - 497
SP - 1
EP - 13
JO - Cancer Letters
JF - Cancer Letters
SN - 0304-3835
ER -