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TNF is a key cytokine mediating neutrophil cytotoxic activity in breast cancer patients

We have previously shown a novel antimetastatic role for neutrophils in the premetastatic lung of mice in models of breast cancer. Here we expand on those findings in the context of human breast cancer. We assessed the cytotoxicity of neutrophils from 90 newly diagnosed breast cancer patients, 24 du...

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Autores principales: Comen, Elizabeth, Wojnarowicz, Paulina, Seshan, Venkatraman E, Shah, Riddhi, Coker, Courtney, Norton, Larry, Benezra, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515342/
https://www.ncbi.nlm.nih.gov/pubmed/28721376
http://dx.doi.org/10.1038/npjbcancer.2016.9
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author Comen, Elizabeth
Wojnarowicz, Paulina
Seshan, Venkatraman E
Shah, Riddhi
Coker, Courtney
Norton, Larry
Benezra, Robert
author_facet Comen, Elizabeth
Wojnarowicz, Paulina
Seshan, Venkatraman E
Shah, Riddhi
Coker, Courtney
Norton, Larry
Benezra, Robert
author_sort Comen, Elizabeth
collection PubMed
description We have previously shown a novel antimetastatic role for neutrophils in the premetastatic lung of mice in models of breast cancer. Here we expand on those findings in the context of human breast cancer. We assessed the cytotoxicity of neutrophils from 90 newly diagnosed breast cancer patients, 24 ductal carcinoma in situ patients, 56 metastatic breast cancer patients, and 64 women with no history of cancer. We report that neutrophils from metastatic and newly diagnosed breast cancer patients are significantly more cytotoxic than neutrophils from cancer-free individuals. We hypothesized that tumor-secreted factors ‘prime’ neutrophils to become cytotoxic. To identify these factors we assayed for cytokines in serum from 54 breast cancer patients and 35 cancer-free controls. Tumor necrosis factor (TNFα), MCP-1 (CCL2), and IL1RA significantly correlated with cytotoxicity and directly stimulated neutrophil cytotoxicity ex vivo. RNA-seq analyses found protein kinase C iota (PRKCI) to be over expressed in patient neutrophils relative to neutrophils from cancer-free individuals. PRKCI has been implicated in NADPH oxidase assembly, required for neutrophil-mediated cell cytotoxicity. Treatment of human neutrophils with TNF-induced PRKCI expression and cytotoxicity in samples that had low basal levels of PRKCI expression. To date, this work is the first to demonstrate the cytotoxic role of neutrophils in the peripheral blood of a large cohort of breast cancer patients, and that select cytokines appear to mediate the stimulation of neutrophil cytotoxicity. Further functional studies are necessary to identify clinically relevant means of stimulating neutrophil cytotoxicity as an effective barrier against disease progression and metastasis.
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spelling pubmed-55153422017-07-18 TNF is a key cytokine mediating neutrophil cytotoxic activity in breast cancer patients Comen, Elizabeth Wojnarowicz, Paulina Seshan, Venkatraman E Shah, Riddhi Coker, Courtney Norton, Larry Benezra, Robert NPJ Breast Cancer Article We have previously shown a novel antimetastatic role for neutrophils in the premetastatic lung of mice in models of breast cancer. Here we expand on those findings in the context of human breast cancer. We assessed the cytotoxicity of neutrophils from 90 newly diagnosed breast cancer patients, 24 ductal carcinoma in situ patients, 56 metastatic breast cancer patients, and 64 women with no history of cancer. We report that neutrophils from metastatic and newly diagnosed breast cancer patients are significantly more cytotoxic than neutrophils from cancer-free individuals. We hypothesized that tumor-secreted factors ‘prime’ neutrophils to become cytotoxic. To identify these factors we assayed for cytokines in serum from 54 breast cancer patients and 35 cancer-free controls. Tumor necrosis factor (TNFα), MCP-1 (CCL2), and IL1RA significantly correlated with cytotoxicity and directly stimulated neutrophil cytotoxicity ex vivo. RNA-seq analyses found protein kinase C iota (PRKCI) to be over expressed in patient neutrophils relative to neutrophils from cancer-free individuals. PRKCI has been implicated in NADPH oxidase assembly, required for neutrophil-mediated cell cytotoxicity. Treatment of human neutrophils with TNF-induced PRKCI expression and cytotoxicity in samples that had low basal levels of PRKCI expression. To date, this work is the first to demonstrate the cytotoxic role of neutrophils in the peripheral blood of a large cohort of breast cancer patients, and that select cytokines appear to mediate the stimulation of neutrophil cytotoxicity. Further functional studies are necessary to identify clinically relevant means of stimulating neutrophil cytotoxicity as an effective barrier against disease progression and metastasis. Nature Publishing Group 2016-04-20 /pmc/articles/PMC5515342/ /pubmed/28721376 http://dx.doi.org/10.1038/npjbcancer.2016.9 Text en Copyright © 2016 Breast Cancer Research Foundation/Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Comen, Elizabeth
Wojnarowicz, Paulina
Seshan, Venkatraman E
Shah, Riddhi
Coker, Courtney
Norton, Larry
Benezra, Robert
TNF is a key cytokine mediating neutrophil cytotoxic activity in breast cancer patients
title TNF is a key cytokine mediating neutrophil cytotoxic activity in breast cancer patients
title_full TNF is a key cytokine mediating neutrophil cytotoxic activity in breast cancer patients
title_fullStr TNF is a key cytokine mediating neutrophil cytotoxic activity in breast cancer patients
title_full_unstemmed TNF is a key cytokine mediating neutrophil cytotoxic activity in breast cancer patients
title_short TNF is a key cytokine mediating neutrophil cytotoxic activity in breast cancer patients
title_sort tnf is a key cytokine mediating neutrophil cytotoxic activity in breast cancer patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515342/
https://www.ncbi.nlm.nih.gov/pubmed/28721376
http://dx.doi.org/10.1038/npjbcancer.2016.9
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