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

Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, 223 63 Lund, Sweden
Author to whom correspondence should be addressed.
Academic Editor: Adrian Harris
Cells 2021, 10(3), 613;
Received: 19 February 2021 / Revised: 4 March 2021 / Accepted: 8 March 2021 / Published: 10 March 2021
(This article belongs to the Special Issue Hypoxia and Cancer: New Aspects)
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. View Full-Text
Keywords: astrocytes; glioma microenvironment; tumor hypoxia astrocytes; glioma microenvironment; tumor hypoxia
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MDPI and ACS Style

Pantazopoulou, V.; Jeannot, P.; Rosberg, R.; Berg, T.J.; Pietras, A. Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties. Cells 2021, 10, 613.

AMA Style

Pantazopoulou V, Jeannot P, Rosberg R, Berg TJ, Pietras A. Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties. Cells. 2021; 10(3):613.

Chicago/Turabian Style

Pantazopoulou, Vasiliki, Pauline Jeannot, Rebecca Rosberg, Tracy J. Berg, and Alexander Pietras. 2021. "Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties" Cells 10, no. 3: 613.

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