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Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma
Large numbers of neutrophils infiltrate tumors and comprise a notable component of the inflammatory tumor microenvironment. While it is established that tumor cells exhibit the Warburg effect for energy production, the contribution of the neutrophil metabolic state to tumorigenesis is unknown. Here,...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9821271/ https://www.ncbi.nlm.nih.gov/pubmed/36614196 http://dx.doi.org/10.3390/ijms24010753 |
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author | Sieow, Je Lin Penny, Hweixian Leong Gun, Sin Yee Tan, Ling Qiao Duan, Kaibo Yeong, Joe Poh Sheng Pang, Angela Lim, Diana Toh, Han Chong Lim, Tony Kiat Hon Engleman, Edgar Rotzschke, Olaf Ng, Lai Guan Chen, Jinmiao Tan, Suet Mien Wong, Siew Cheng |
author_facet | Sieow, Je Lin Penny, Hweixian Leong Gun, Sin Yee Tan, Ling Qiao Duan, Kaibo Yeong, Joe Poh Sheng Pang, Angela Lim, Diana Toh, Han Chong Lim, Tony Kiat Hon Engleman, Edgar Rotzschke, Olaf Ng, Lai Guan Chen, Jinmiao Tan, Suet Mien Wong, Siew Cheng |
author_sort | Sieow, Je Lin |
collection | PubMed |
description | Large numbers of neutrophils infiltrate tumors and comprise a notable component of the inflammatory tumor microenvironment. While it is established that tumor cells exhibit the Warburg effect for energy production, the contribution of the neutrophil metabolic state to tumorigenesis is unknown. Here, we investigated whether neutrophil infiltration and metabolic status promotes tumor progression in an orthotopic mouse model of pancreatic ductal adenocarcinoma (PDAC). We observed a large increase in the proportion of neutrophils in the blood and tumor upon orthotopic transplantation. Intriguingly, these tumor-infiltrating neutrophils up-regulated glycolytic factors and hypoxia-inducible factor 1-alpha (HIF-1α) expression compared to neutrophils from the bone marrow and blood of the same mouse. This enhanced glycolytic signature was also observed in human PDAC tissue samples. Strikingly, neutrophil-specific deletion of HIF-1α (HIF-1αΔNφ) significantly reduced tumor burden and improved overall survival in orthotopic transplanted mice, by converting the pro-tumorigenic neutrophil phenotype to an anti-tumorigenic phenotype. This outcome was associated with elevated reactive oxygen species production and activated natural killer cells and CD8+ cytotoxic T cells compared to littermate control mice. These data suggest a role for HIF-1α in neutrophil metabolism, which could be exploited as a target for metabolic modulation in cancer. |
format | Online Article Text |
id | pubmed-9821271 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-98212712023-01-07 Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma Sieow, Je Lin Penny, Hweixian Leong Gun, Sin Yee Tan, Ling Qiao Duan, Kaibo Yeong, Joe Poh Sheng Pang, Angela Lim, Diana Toh, Han Chong Lim, Tony Kiat Hon Engleman, Edgar Rotzschke, Olaf Ng, Lai Guan Chen, Jinmiao Tan, Suet Mien Wong, Siew Cheng Int J Mol Sci Article Large numbers of neutrophils infiltrate tumors and comprise a notable component of the inflammatory tumor microenvironment. While it is established that tumor cells exhibit the Warburg effect for energy production, the contribution of the neutrophil metabolic state to tumorigenesis is unknown. Here, we investigated whether neutrophil infiltration and metabolic status promotes tumor progression in an orthotopic mouse model of pancreatic ductal adenocarcinoma (PDAC). We observed a large increase in the proportion of neutrophils in the blood and tumor upon orthotopic transplantation. Intriguingly, these tumor-infiltrating neutrophils up-regulated glycolytic factors and hypoxia-inducible factor 1-alpha (HIF-1α) expression compared to neutrophils from the bone marrow and blood of the same mouse. This enhanced glycolytic signature was also observed in human PDAC tissue samples. Strikingly, neutrophil-specific deletion of HIF-1α (HIF-1αΔNφ) significantly reduced tumor burden and improved overall survival in orthotopic transplanted mice, by converting the pro-tumorigenic neutrophil phenotype to an anti-tumorigenic phenotype. This outcome was associated with elevated reactive oxygen species production and activated natural killer cells and CD8+ cytotoxic T cells compared to littermate control mice. These data suggest a role for HIF-1α in neutrophil metabolism, which could be exploited as a target for metabolic modulation in cancer. MDPI 2023-01-01 /pmc/articles/PMC9821271/ /pubmed/36614196 http://dx.doi.org/10.3390/ijms24010753 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Sieow, Je Lin Penny, Hweixian Leong Gun, Sin Yee Tan, Ling Qiao Duan, Kaibo Yeong, Joe Poh Sheng Pang, Angela Lim, Diana Toh, Han Chong Lim, Tony Kiat Hon Engleman, Edgar Rotzschke, Olaf Ng, Lai Guan Chen, Jinmiao Tan, Suet Mien Wong, Siew Cheng Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma |
title | Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma |
title_full | Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma |
title_fullStr | Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma |
title_full_unstemmed | Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma |
title_short | Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma |
title_sort | conditional knockout of hypoxia-inducible factor 1-alpha in tumor-infiltrating neutrophils protects against pancreatic ductal adenocarcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9821271/ https://www.ncbi.nlm.nih.gov/pubmed/36614196 http://dx.doi.org/10.3390/ijms24010753 |
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