Pediatric high grade glioma (pHGGs), including sus-tentorial and diffuse intrinsic pontine gliomas, are known to have a very dismal prognosis. For instance, even an increased knowledge on molecular biology driving this brain tumor entity, there is no treatment able to cure those patients. Therefore, we were focusing on a translational pathway able to increase the cell resistance to treatment and to reprogram metabolically tumor cells, which are, then, adapting easily to a hypoxic microenvironment. To establish, the crucial role of the hypoxic pathways in pHGGs, we, first, assessed their protein and transcriptomic deregulations in a pediatric cohort of pHGGs and in pHGG's cell lines, cultured in both normoxic and hypoxic conditions. Secondly, based on the concept of a bi-therapy targeting in pHGGs mTORC1 (rapamycin) and HIF-1α (irinotecan), we hypothesized that the balanced expressions between RAS/ERK, PI3K/AKT and HIF-1α/HIF-2α/MYC proteins or genes may provide a modulation of the cell response to this double targeting. Finally, we could evidence three protein, genomic and metabolomic profiles of response to rapamycin combined with irinotecan. The pattern of highly sensitive cells to mTOR/HIF-1α targeting was linked to a MYC/ERK/HIF-1α over-expression and the cell resistance to a major hyper-expression of HIF-2α.
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.
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