Targeting neutrophil extracellular traps with thrombomodulin prevents pancreatic cancer metastasis

Cancer Lett. 2021 Jan 28;497:1-13. doi: 10.1016/j.canlet.2020.10.015. Epub 2020 Oct 13.


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.

Keywords: Epithelial to mesenchymal transition; HMGB1; Ischemia-reperfusion model; Phorbol 12-myristate 13-acetate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Carcinogens / toxicity
  • Cell Proliferation
  • Disease Models, Animal*
  • Epithelial-Mesenchymal Transition
  • Extracellular Traps / metabolism*
  • Humans
  • Liver Neoplasms / etiology
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / prevention & control*
  • Liver Neoplasms / secondary
  • Mice
  • Neutrophils / metabolism*
  • Pancreatic Neoplasms / etiology
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / prevention & control*
  • Reperfusion Injury / etiology
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control*
  • Tetradecanoylphorbol Acetate / toxicity
  • Thrombomodulin / administration & dosage
  • Thrombomodulin / genetics
  • Thrombomodulin / metabolism*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Carcinogens
  • THBD protein, human
  • Thrombomodulin
  • Tetradecanoylphorbol Acetate