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.
Highlights
Pediatric high-grade gliomas are aggressive and incurable tumors of the central nervous system (CNS)
Thepediatric pediatric high-grade gliomas composed by necrotic regions surroundedby bypseudopalissade pseudopalissade structures and associated withwith stemstem composed by necrotic regions surrounded structures and associated cell niches
Several mechanisms and targets can stop αα activity when inhibited: mRNA or protein Hypoxia-Inducible Factors (HIF) expression, HIF-α/HIF-β dimerization, DNA binding at HRE, transcriptional activity or increase of proteasomal degradation [71]
Summary
Pediatric high-grade gliomas (pHGG) are aggressive and incurable tumors of the central nervous system (CNS). One key of the brain microenvironment in pHGGs seems to be hypoxia, as a result of the dramatic proliferation and expansion of tumor cells that deprive the tissues of oxygen inflow [18,20,21,22,23,24,25]. Cancer cells, especially tumor stem cells, can endure extreme hypoxic conditions by rescheduling various genes’ expression involved in cell proliferation, metabolism and angiogenesis and promote tumor expansion, resistance, and metabolic adaptation This cellular adaptation implies HIFs (Hypoxia-Inducible Factors), namely HIF-1α, HIF-2α and HIF-3α [27,28,29]. Role of Brain Physiological Hypoxia Location or Brain Physioxia and the Sub-Ventricular Zone in pHGGs. Hypoxia is a general concept referring to decreased oxygen (O2 ) amounts reaching a tissue.
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