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Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties

Glioblastoma is characterized by extensive necrotic areas with surrounding hypoxia. The cancer cell response to hypoxia in these areas is well-described; it involves a metabolic shift and an increase in stem cell-like characteristics. Less is known about the hypoxic response of tumor-associated astr...

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Autores principales: Pantazopoulou, Vasiliki, Jeannot, Pauline, Rosberg, Rebecca, Berg, Tracy J., Pietras, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999295/
https://www.ncbi.nlm.nih.gov/pubmed/33802060
http://dx.doi.org/10.3390/cells10030613
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author Pantazopoulou, Vasiliki
Jeannot, Pauline
Rosberg, Rebecca
Berg, Tracy J.
Pietras, Alexander
author_facet Pantazopoulou, Vasiliki
Jeannot, Pauline
Rosberg, Rebecca
Berg, Tracy J.
Pietras, Alexander
author_sort Pantazopoulou, Vasiliki
collection PubMed
description Glioblastoma is characterized by extensive necrotic areas with surrounding hypoxia. The cancer cell response to hypoxia in these areas is well-described; it involves a metabolic shift and an increase in stem cell-like characteristics. Less is known about the hypoxic response of tumor-associated astrocytes, a major component of the glioma tumor microenvironment. Here, we used primary human astrocytes and a genetically engineered glioma mouse model to investigate the response of this stromal cell type to hypoxia. We found that astrocytes became reactive in response to intermediate and severe hypoxia, similarly to irradiated and temozolomide-treated astrocytes. Hypoxic astrocytes displayed a potent hypoxia response that appeared to be driven primarily by hypoxia-inducible factor 2-alpha (HIF-2α). This response involved the activation of classical HIF target genes and the increased production of hypoxia-associated cytokines such as TGF-β1, IL-3, angiogenin, VEGF-A, and IL-1 alpha. In vivo, astrocytes were present in proximity to perinecrotic areas surrounding HIF-2α expressing cells, suggesting that hypoxic astrocytes contribute to the glioma microenvironment. Extracellular matrix derived from hypoxic astrocytes increased the proliferation and drug efflux capability of glioma cells. Together, our findings suggest that hypoxic astrocytes are implicated in tumor growth and potentially stemness maintenance by remodeling the tumor microenvironment.
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spelling pubmed-79992952021-03-28 Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties Pantazopoulou, Vasiliki Jeannot, Pauline Rosberg, Rebecca Berg, Tracy J. Pietras, Alexander Cells Article Glioblastoma is characterized by extensive necrotic areas with surrounding hypoxia. The cancer cell response to hypoxia in these areas is well-described; it involves a metabolic shift and an increase in stem cell-like characteristics. Less is known about the hypoxic response of tumor-associated astrocytes, a major component of the glioma tumor microenvironment. Here, we used primary human astrocytes and a genetically engineered glioma mouse model to investigate the response of this stromal cell type to hypoxia. We found that astrocytes became reactive in response to intermediate and severe hypoxia, similarly to irradiated and temozolomide-treated astrocytes. Hypoxic astrocytes displayed a potent hypoxia response that appeared to be driven primarily by hypoxia-inducible factor 2-alpha (HIF-2α). This response involved the activation of classical HIF target genes and the increased production of hypoxia-associated cytokines such as TGF-β1, IL-3, angiogenin, VEGF-A, and IL-1 alpha. In vivo, astrocytes were present in proximity to perinecrotic areas surrounding HIF-2α expressing cells, suggesting that hypoxic astrocytes contribute to the glioma microenvironment. Extracellular matrix derived from hypoxic astrocytes increased the proliferation and drug efflux capability of glioma cells. Together, our findings suggest that hypoxic astrocytes are implicated in tumor growth and potentially stemness maintenance by remodeling the tumor microenvironment. MDPI 2021-03-10 /pmc/articles/PMC7999295/ /pubmed/33802060 http://dx.doi.org/10.3390/cells10030613 Text en © 2021 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 (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Pantazopoulou, Vasiliki
Jeannot, Pauline
Rosberg, Rebecca
Berg, Tracy J.
Pietras, Alexander
Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties
title Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties
title_full Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties
title_fullStr Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties
title_full_unstemmed Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties
title_short Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties
title_sort hypoxia-induced reactivity of tumor-associated astrocytes affects glioma cell properties
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999295/
https://www.ncbi.nlm.nih.gov/pubmed/33802060
http://dx.doi.org/10.3390/cells10030613
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