Targeting neutrophil extracellular traps with thrombomodulin prevents pancreatic cancer metastasis.
Animals
Apoptosis
Carcinogens
/ toxicity
Cell Proliferation
Disease Models, Animal
Epithelial-Mesenchymal Transition
Extracellular Traps
/ metabolism
Humans
Liver Neoplasms
/ etiology
Mice
Neutrophils
/ metabolism
Pancreatic Neoplasms
/ etiology
Reperfusion Injury
/ etiology
Tetradecanoylphorbol Acetate
/ toxicity
Thrombomodulin
/ administration & dosage
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Epithelial to mesenchymal transition
HMGB1
Ischemia-reperfusion model
Phorbol 12-myristate 13-acetate
Journal
Cancer letters
ISSN: 1872-7980
Titre abrégé: Cancer Lett
Pays: Ireland
ID NLM: 7600053
Informations de publication
Date de publication:
28 01 2021
28 01 2021
Historique:
received:
10
07
2020
revised:
02
10
2020
accepted:
09
10
2020
pubmed:
17
10
2020
medline:
6
5
2021
entrez:
16
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33065249
pii: S0304-3835(20)30543-7
doi: 10.1016/j.canlet.2020.10.015
pii:
doi:
Substances chimiques
Carcinogens
0
THBD protein, human
0
Thrombomodulin
0
Tetradecanoylphorbol Acetate
NI40JAQ945
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1-13Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.