title: The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer.
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.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Boone
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Orlichenko
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Schapiro
authors.affiliation: 1] Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA [2] Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Loughran
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: G C
authors.initials: GC
authors.lastname: Gianfrate
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Ellis
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Singhi
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Kang
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Tang
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Lotze
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Zeh
mesh_terms: D000818:Animals; D001343:Autophagy; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000503:physiopathology*; D065206:Extracellular Traps / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000503:physiopathology*; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000502:physiology*
chemical_list: D000067759:Receptor for Advanced Glycation End Products