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

Pantazopoulou, Vasiliki LU orcid ; Jeannot, Pauline LU ; Rosberg, Rebecca LU orcid ; Berg, Tracy J. LU and Pietras, Alexander LU (2021) In Cells 10(3).
Abstract

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... (More)

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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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
astrocytes, glioma microenvironment, tumor hypoxia
in
Cells
volume
10
issue
3
publisher
MDPI AG
external identifiers
  • scopus:85103862657
  • pmid:33802060
ISSN
2073-4409
DOI
10.3390/cells10030613
language
English
LU publication?
yes
id
f41d81ff-a325-46ee-9236-cb37263af30f
date added to LUP
2021-04-19 09:44:57
date last changed
2024-04-06 02:25:12
@article{f41d81ff-a325-46ee-9236-cb37263af30f,
  abstract     = {{<p>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.</p>}},
  author       = {{Pantazopoulou, Vasiliki and Jeannot, Pauline and Rosberg, Rebecca and Berg, Tracy J. and Pietras, Alexander}},
  issn         = {{2073-4409}},
  keywords     = {{astrocytes; glioma microenvironment; tumor hypoxia}},
  language     = {{eng}},
  number       = {{3}},
  publisher    = {{MDPI AG}},
  series       = {{Cells}},
  title        = {{Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties}},
  url          = {{http://dx.doi.org/10.3390/cells10030613}},
  doi          = {{10.3390/cells10030613}},
  volume       = {{10}},
  year         = {{2021}},
}