Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma.

Autor: Sieow JL; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore., Penny HL; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore., Gun SY; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore., Tan LQ; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore., Duan K; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore., Yeong JPS; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.; Department of Anatomical Pathology, Singapore General Hospital, Singapore 169856, Singapore., Pang A; Department of Haematology-Oncology, National University Cancer Institute, Singapore 119228, Singapore., Lim D; Department of Pathology, National University Health System, Singapore 119074, Singapore., Toh HC; Department of Oncology, National Cancer Centre, Singapore 169610, Singapore., Lim TKH; Department of Anatomical Pathology, Singapore General Hospital, Singapore 169856, Singapore., Engleman E; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA., Rotzschke O; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore., Ng LG; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore., Chen J; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore., Tan SM; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore., Wong SC; Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2023 Jan 01; Vol. 24 (1). Date of Electronic Publication: 2023 Jan 01.
DOI: 10.3390/ijms24010753
Abstrakt: 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.
Databáze: MEDLINE
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