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Review
. 2020 Apr 15;12(4):979.
doi: 10.3390/cancers12040979.

Hypoxia Inducible Factors' Signaling in Pediatric High-Grade Gliomas: Role, Modelization and Innovative Targeted Approaches

Quentin Fuchs  1 , Marina Pierrevelcin  1 , Melissa Messe  1 , Benoit Lhermitte  1   2 , Anne-Florence Blandin  3 , Christophe Papin  4 , Andres Coca  5 , Monique Dontenwill  1 , Natacha Entz-Werlé  1   6
Affiliations
Review

Hypoxia Inducible Factors' Signaling in Pediatric High-Grade Gliomas: Role, Modelization and Innovative Targeted Approaches

Quentin Fuchs et al. Cancers (Basel). .

Abstract

The brain tumor microenvironment has recently become a major challenge in all pediatric cancers, but especially in brain tumors like high-grade gliomas. Hypoxia is one of the extrinsic tumor features that interacts with tumor cells, but also with the blood-brain barrier and all normal brain cells. It is the result of a dramatic proliferation and expansion of tumor cells that deprive the tissues of oxygen inflow. However, cancer cells, especially tumor stem cells, can endure extreme hypoxic conditions by rescheduling various genes' expression involved in cell proliferation, metabolism and angiogenesis and thus, promote tumor expansion, therapeutic resistance and metabolic adaptation. This cellular adaptation implies Hypoxia-Inducible Factors (HIF), namely HIF-1α and HIF-2α. In pediatric high-grade gliomas (pHGGs), several questions remained open on hypoxia-specific role in normal brain during gliomagenesis and pHGG progression, as well how to model it in preclinical studies and how it might be counteracted with targeted therapies. Therefore, this review aims to gather various data about this key extrinsic tumor factor in pHGGs.

Keywords: HIFs; high-grade gliomas; hypoxia; pediatric.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Specific questions on pediatric high-grade gliomas (pHGGs): hypoxia links with locations (orange), cell properties (grey), propensity to migrate especially from and in a subventricular zone (SVZ) (yellow) and the neuronal/blood–brain barrier environment (blue).
Figure 2
Figure 2
Organization of hypoxic regions across tumors. The pediatric high-grade gliomas are composed by necrotic regions surrounded by pseudopalissade structures and associated with stem cell niches. Neovascularization is starting from the periphery of the tumor and is decreasing in the center. Three hypoxic profiles are, then, described within pHGG tumors: acute, cyclic and/or chronic oxygen tensions.
Figure 3
Figure 3
Effects of Hypoxia-Inducible Factors’ (HIF-1α and HIF-2α) hyperexpressions in pediatric high-grade gliomas. HIFs have a specific role in metabolism, radioresistance, cell survival and stemness maintenance, but also in vascularization, neuronal activity and pHGG cell migration. (OxPHOS = mitochondrial oxidative phosphorylation system, ROS = Reactive Oxygen Species).
See this image and copyright information in PMC

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