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

Vasiliki Pantazopoulou,Alexander Pietras,Pauline Jeannot,Rebecca Rosberg,Tracy J Berg

doi:10.3390/cells10030613

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 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.

Highlights

Glioblastoma (GBM) is the most common high-grade glioma and represents one of the most aggressive tumor types, with a dismal five-year survival [1]
We found that astrocytes become reactive in response to intermediate and severe hypoxia, and that extracellular matrix produced by hypoxic astrocytes increased proliferation and drug efflux capabilities of glioma cells
Astrocytes treated with temozolomide, a chemotherapeutic agent frequently administered after or while patients undergo radiation treatment [1], showed an increase in features of reactive astrogliosis (Figure 1A), similar to that observed after irradiation

Summary

Introduction

Glioblastoma (GBM) is the most common high-grade glioma and represents one of the most aggressive tumor types, with a dismal five-year survival [1]. The ensuing tumor recurrence, has been associated with the presence of tumor cells with stem-like cell properties [3] that are located in different tumor areas such as the hypoxic niche [4]. The HIF factors are regulated in an oxygendependent manner by prolyl hydroxylases and an asparagine hydroxylase [8] or in an oxygen-independent manner by various growth factors or the hypoxia-associated factor, amongst other mechanisms [9]. Hypoxia has been associated with an increase in glioma stem-like cell properties [4,10,11], glioma growth [12], and treatment resistance [13,14], as well as changes in cancer cell metabolism and pH [15,16]. Hypoxic niches contain tumor cells, and other cell types in the tumor microenvironment [5,22] that are affected by low oxygen tension

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