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Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line and patient-derived primary cancer cells by ult...

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Autores principales: Zhao, Jiangang, Schlößer, Hans A., Wang, Zhefang, Qin, Jie, Li, Jiahui, Popp, Felix, Popp, Marie Christine, Alakus, Hakan, Chon, Seung-Hun, Hansen, Hinrich P., Neiss, Wolfram F., Jauch, Karl-Walter, Bruns, Christiane J., Zhao, Yue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628179/
https://www.ncbi.nlm.nih.gov/pubmed/31234517
http://dx.doi.org/10.3390/cancers11060874
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author Zhao, Jiangang
Schlößer, Hans A.
Wang, Zhefang
Qin, Jie
Li, Jiahui
Popp, Felix
Popp, Marie Christine
Alakus, Hakan
Chon, Seung-Hun
Hansen, Hinrich P.
Neiss, Wolfram F.
Jauch, Karl-Walter
Bruns, Christiane J.
Zhao, Yue
author_facet Zhao, Jiangang
Schlößer, Hans A.
Wang, Zhefang
Qin, Jie
Li, Jiahui
Popp, Felix
Popp, Marie Christine
Alakus, Hakan
Chon, Seung-Hun
Hansen, Hinrich P.
Neiss, Wolfram F.
Jauch, Karl-Walter
Bruns, Christiane J.
Zhao, Yue
author_sort Zhao, Jiangang
collection PubMed
description Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line and patient-derived primary cancer cells by ultracentrifugation. The protein content of EVs was analyzed by mass spectrometry. The effects of PDAC-derived EVs on natural kill (NK) cells were investigated by flow cytometry. The serum EVs’ TGF-β1 levels were quantified by ELISA. We found that integrins were enriched in PDAC-derived EVs. The expression of NKG2D, CD107a, TNF-α, and INF-γ in NK cells was significantly downregulated after co-culture with EVs. NK cells also exhibited decreased levels of CD71 and CD98, as well as impaired glucose uptake ability. In addition, NK cell cytotoxicity against pancreatic cancer stem cells was attenuated. Moreover, PDAC-derived EVs induced the phosphorylation of Smad2/3 in NK cells. Serum EVs’ TGF-β1 was significantly increased in PDAC patients. Our findings emphasize the immunosuppressive role of PDAC-derived EVs and provide new insights into our understanding of NK cell dysfunction regarding pre-metastatic niche formation in PDAC.
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spelling pubmed-66281792019-07-23 Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer Zhao, Jiangang Schlößer, Hans A. Wang, Zhefang Qin, Jie Li, Jiahui Popp, Felix Popp, Marie Christine Alakus, Hakan Chon, Seung-Hun Hansen, Hinrich P. Neiss, Wolfram F. Jauch, Karl-Walter Bruns, Christiane J. Zhao, Yue Cancers (Basel) Article Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line and patient-derived primary cancer cells by ultracentrifugation. The protein content of EVs was analyzed by mass spectrometry. The effects of PDAC-derived EVs on natural kill (NK) cells were investigated by flow cytometry. The serum EVs’ TGF-β1 levels were quantified by ELISA. We found that integrins were enriched in PDAC-derived EVs. The expression of NKG2D, CD107a, TNF-α, and INF-γ in NK cells was significantly downregulated after co-culture with EVs. NK cells also exhibited decreased levels of CD71 and CD98, as well as impaired glucose uptake ability. In addition, NK cell cytotoxicity against pancreatic cancer stem cells was attenuated. Moreover, PDAC-derived EVs induced the phosphorylation of Smad2/3 in NK cells. Serum EVs’ TGF-β1 was significantly increased in PDAC patients. Our findings emphasize the immunosuppressive role of PDAC-derived EVs and provide new insights into our understanding of NK cell dysfunction regarding pre-metastatic niche formation in PDAC. MDPI 2019-06-22 /pmc/articles/PMC6628179/ /pubmed/31234517 http://dx.doi.org/10.3390/cancers11060874 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhao, Jiangang
Schlößer, Hans A.
Wang, Zhefang
Qin, Jie
Li, Jiahui
Popp, Felix
Popp, Marie Christine
Alakus, Hakan
Chon, Seung-Hun
Hansen, Hinrich P.
Neiss, Wolfram F.
Jauch, Karl-Walter
Bruns, Christiane J.
Zhao, Yue
Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer
title Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer
title_full Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer
title_fullStr Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer
title_full_unstemmed Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer
title_short Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer
title_sort tumor-derived extracellular vesicles inhibit natural killer cell function in pancreatic cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628179/
https://www.ncbi.nlm.nih.gov/pubmed/31234517
http://dx.doi.org/10.3390/cancers11060874
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