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

Boone, Brian A.; Orlichenko, Lidiya; Schapiro, Nicole E.; Loughran, Patricia; Gianfrate, Gianmarino C.; Ellis, Jarrod T.; Singhi, Aatur D.; Kang, Rui; Tang, Daolin; Lotze, Michael T.; Zeh, Herbert J.

doi:10.1038/cgt.2015.21

Cited by 144 publications

(156 citation statements)

References 63 publications

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“…Interestingly, in addition to its role in the internalization of NETs, RAGE activation is also a trigger for NETosis. 46 In addition to its role in the induction of EndMT, the degradation of VE-cadherin by NET-associated elastase also caused a rapid phase of increased vascular permeability, as demonstrated by transendothelial albumin passage assays. Because the integrity of intercellular junctions, mediated particularly through VE-cadherin, is a prerequisite for maintaining a restrictive endothelial barrier, 47,48 NETs may thus play a role in the development of edema and proteinuria by increasing .…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Pieterse

Rother

Garsen

et al. 2017

ATVB

192

150

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Objective— An excessive release and impaired degradation of neutrophil extracellular traps (NETs) leads to the continuous exposure of NETs to the endothelium in a variety of hematologic and autoimmune disorders, including lupus nephritis. This study aims to unravel the mechanisms through which NETs jeopardize vascular integrity. Approach and Results— Microvascular and macrovascular endothelial cells were exposed to NETs, and subsequent effects on endothelial integrity and function were determined in vitro and in vivo. We found that endothelial cells have a limited capacity to internalize NETs via the receptor for advanced glycation endproducts. An overflow of the phagocytic capacity of endothelial cells for NETs resulted in the persistent extracellular presence of NETs, which rapidly altered endothelial cell–cell contacts and induced vascular leakage and transendothelial albumin passage through elastase-mediated proteolysis of the intercellular junction protein VE-cadherin. Furthermore, NET-associated elastase promoted the nuclear translocation of junctional β-catenin and induced endothelial-to-mesenchymal transition in cultured endothelial cells. In vivo, NETs could be identified in kidney samples of diseased MRL/lpr mice and patients with lupus nephritis, in whom the glomerular presence of NETs correlated with the severity of proteinuria and with glomerular endothelial-to-mesenchymal transition. Conclusions— These results indicate that an excess of NETs exceeds the phagocytic capacity of endothelial cells for NETs and promotes vascular leakage and endothelial-to-mesenchymal transition through the degradation of VE-cadherin and the subsequent activation of β-catenin signaling. Our data designate NET-associated elastase as a potential therapeutic target in the prevention of endothelial alterations in diseases characterized by aberrant NET release.

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Section: Discussionmentioning

confidence: 99%

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Pieterse

Rother

Garsen

et al. 2017

ATVB

192

150

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“…To date, one other study has described a NET mechanism that exhibited both rapid and ROS-independent mechanism of NET release, which was induced by the Gram-positive bacteria Staphylococcus aureus [37]. Furthermore, Boone, et al [40] have recently studied NETs in PaCa in vivo, and reported that NETs released in PaCa are mediated through autophagy pathways. Specifically, the receptor for advanced glycation end products (RAGE) which mediates autophagy in PaCa was found to be necessary for NET release, as neutrophils from RAGE knockout mice were less prone to release NETs.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic Cancer-Induced Neutrophil Extracellular Traps: A Potential Contributor to Cancer-Associated Thrombosis

Razak

Elaskalani

Metharom

2017

IJMS

117

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Pancreatic cancer (PaCa) is a highly metastatic cancer, and patients are at high risk of developing venous thromboembolism (VTE). Neutrophil extracellular traps (NETs) have been associated with cancer metastasis and cancer-associated thrombosis, but the ability of cancer to stimulate NET release is not known. The release of NETs has been shown to be a slow process and requires reactive oxygen species (ROS) production. Studies suggest that activated platelets are important mediators in the release. Here, we show that PaCa cells can stimulate the rapid release of NETs, independently of ROS production. We further assessed the role of platelets in PaCa-induced NETs and observed a trend of increased the NET release by PaCa-primed platelets. Additionally, NETs promoted thrombus formation under venous shear stress ex vivo. Taken together, our results suggest that PaCa-induced NETs can contribute to the high risk of venous thromboembolism development in PaCa patients, and reveal NETs as a potential therapeutic target.

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“…NETs have been observed in both murine and human tumors: sarcomas, pancreatic adenocarcinoma and LLC lung carcinomas [11][12][13][14] and have been shown to promote metastasis following septicemia in mice. 15 To evaluate if the presence of PAD4/ NETs in the host affects primary tumor growth, we compared tumor progression in WT mice to PAD4-deficient mice whose neutrophils are defective in NET formation.…”

Section: Presence Of Nets Increases Lewis Lung Carcinoma (Llc) Tumor mentioning

confidence: 99%

Priming of neutrophils toward NETosis promotes tumor growth

et al. 2016

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Neutrophils play a major role in cancer biology and both pro-and antitumoral functions of tumorinfiltrating neutrophils have been described. We have shown that tumors, by releasing G-CSF into the bloodstream, prime circulating neutrophils to form neutrophil extracellular traps (NETs) and we have detected the presence of NETs within the tumor microenvironment. Here, we report, using PAD4-deficient mice with a defect in neutrophil chromatin decondensation and NET formation, that the priming of neutrophils toward NETosis favors tumor growth. Interestingly, in a tumor model that does not release G-CSF and in which neutrophils are not primed for NETosis, PAD4-deficiency did not reduce tumor growth. However, supplying exogenous G-CSF to the wild-type (WT) host promoted intratumoral NETosis and tumor growth. Taken together, our results suggest that the priming of neutrophils for NETosis by the tumor or its environment leads to the accumulation of intratumoral NETs and a growth advantage to the tumor. Our work unveiled a pro-tumoral role for NETs which strengthens their potential as a new target in the fight against cancer.

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

Cited by 144 publications

References 63 publications

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Pancreatic Cancer-Induced Neutrophil Extracellular Traps: A Potential Contributor to Cancer-Associated Thrombosis

Priming of neutrophils toward NETosis promotes tumor growth

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