Abstract
Different functional states determine glioblastoma (GBM) heterogeneity. Brain cancer cells coexist with the glial cells in a functional syncytium based on a continuous metabolic rewiring. However, standard glioma therapies do not account for the effects of the glial cells within the tumor microenvironment. This may be a possible reason for the lack of improvements in patients with high-grade gliomas therapies. Cell metabolism and bioenergetic fitness depend on the availability of nutrients and interactions in the microenvironment. It is strictly related to the cell location in the tumor mass, proximity to blood vessels, biochemical gradients, and tumor evolution, underlying the influence of the context and the timeline in anti-tumor therapeutic approaches. Besides the cancer metabolic strategies, here we review the modifications found in the GBM-associated glia, focusing on morphological, molecular, and metabolic features. We propose to analyze the GBM metabolic rewiring processes from a systems biology perspective. We aim at defining the crosstalk between GBM and the glial cells as modules. The complex networking may be expressed by metabolic modules corresponding to the GBM growth and spreading phases. Variation in the oxidative phosphorylation (OXPHOS) rate and regulation appears to be the most important part of the metabolic and functional heterogeneity, correlating with glycolysis and response to hypoxia. Integrated metabolic modules along with molecular and morphological features could allow the identification of key factors for controlling the GBM-stroma metabolism in multi-targeted, time-dependent therapies.
Highlights
Licensee MDPI, Basel, Switzerland.Glioblastoma (GBM) classified as a grade IV astrocytoma is one of the most aggressive tumors to treat [1]
The use of new technologies like the single-cell RNA sequencing conjugated with fluorescence-activated cell sorting (FACS) screening allowed the definition of heterogeneous subpopulations of astrocytes from different brain regions, with unique gene signatures, distinct molecular and functional properties, corresponding to their analogs in malignant glioma defined by distinctive genomic alterations [133]
Conclusions nance, and standard glioma therapies do not account for the effects of the glial cells within
Summary
Amplified EGFR involves pathways to control glioma glycolysis and lipogenesis, while IDH mutations link the metabolism rewiring to epigenetic regulation (reviewed in [19] and further described ). Recent data on the CNS structure prompted the study of tumor metabolic rewiring as the expression of the networking modular activity of the different components, and of the cancer cells [18,25]. We will review here the metabolic strategies of cancer and the cellular alterations found in the glia associated with GBM, highlighting the morphological, molecular, and metabolic features. Morphological changes and the molecular expression profile can be associated with defined metabolic states, related to pathophysiological mechanisms that will offer new therapeutic strategies. Cancer Metabolic Strategies and the Role of the Microenvironment in Glioblastoma
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