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Cancer Gene Ther. 2015 Jun;22(6):326-34. doi: 10.1038/cgt.2015.21. Epub 2015 Apr 24.

The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer.

Author information

1
Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
2
1] Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA [2] Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA.
3
Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA.
4
Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.

Abstract

Neutrophil extracellular traps (NETs) are formed when neutrophils expel their DNA, histones and intracellular proteins into the extracellular space or circulation. NET formation is dependent on autophagy and is mediated by citrullination of histones to allow for the unwinding and subsequent expulsion of DNA. NETs have an important role in the pathogenesis of several sterile inflammatory diseases, including malignancy, therefore we investigated the role of NETs in the setting of pancreatic ductal adenocarcinoma (PDA). Neutrophils isolated from two distinct animal models of PDA had an increased propensity to form NETs following stimulation with platelet activating factor (PAF). Serum DNA, a marker of circulating NET formation, was elevated in tumor bearing animals as well as in patients with PDA. Citrullinated histone H3 expression, a marker of NET formation, was observed in pancreatic tumors obtained from murine models and patients with PDA. Inhibition of autophagy with chloroquine or genetic ablation of receptor for advanced glycation end products (RAGE) resulted in decreased propensity for NET formation, decreased serum DNA and decreased citrullinated histone H3 expression in the pancreatic tumor microenvironment. We conclude that NETs are upregulated in pancreatic cancer through RAGE-dependent/autophagy mediated pathways.

PMID:
25908451
PMCID:
PMC4470814
DOI:
10.1038/cgt.2015.21
[Indexed for MEDLINE]
Free PMC Article

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