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Review
. 2020 Dec;77(24):5101-5119.
doi: 10.1007/s00018-020-03569-w. Epub 2020 Jun 6.

Metabolic heterogeneity and adaptability in brain tumors

Christian E Badr  1   2 , Daniel J Silver  3   4 , Florian A Siebzehnrubl  5 , Loic P Deleyrolle  6
Affiliations
Review

Metabolic heterogeneity and adaptability in brain tumors

Christian E Badr et al. Cell Mol Life Sci. 2020 Dec.

Abstract

The metabolic complexity and flexibility commonly observed in brain tumors, especially glioblastoma, is fundamental for their development and progression. The ability of tumor cells to modify their genetic landscape and adapt metabolically, subverts therapeutic efficacy, and inevitably instigates therapeutic resistance. To overcome these challenges and develop effective therapeutic strategies targeting essential metabolic processes, it is necessary to identify the mechanisms underlying heterogeneity and define metabolic preferences and liabilities of malignant cells. In this review, we will discuss metabolic diversity in brain cancer and highlight the role of cancer stem cells in regulating metabolic heterogeneity. We will also highlight potential therapeutic modalities targeting metabolic vulnerabilities and examine how intercellular metabolic signaling can shape the tumor microenvironment.

Keywords: Cell communication; Glioma; Immune cells; Metabolism; Slow-cycling cells; Tumor initiating cells; Tumor microenvironment (TME).

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Figures

Fig. 1
Fig. 1
Metabolic differences between cancer stem cells and non-stem cancer cells. Increased mitochondrial activity in GBM CSCs results in increased oxidative phosphorylation, leading to elevated oxidative stress from reactive oxygen species that promote genomic alterations and instability that ultimately lead to clonal heterogeneity. Increased fatty acid oxidation is linked to the relative proliferative quiescence of GBM CSCs. Other metabolites, such as the levels of α-ketoglutarate and 2-hydroxyglutarate, promote epigenetic alterations that contribute to stem cell maintenance. By contrast, non-stem cancer cells primarily depend on aerobic glycolysis that results in the Warburg effect and drives increased proliferation in these cells
Fig. 2
Fig. 2
Therapeutic strategies to target brain tumors’ metabolism. Metabolic targeting in brain tumors can be divided into four major strategies: depletion of extrinsic nutrients from the tumor milieu, blocking the uptake of extrinsic nutrients by tumor cells, inhibiting the biosynthesis of essential endogenous metabolites, or promoting the toxic accumulation of intermediary metabolites
Fig. 3
Fig. 3
Features of the tumor microenvironment in glioblastoma contributing to tumor initiation, progression, and recurrence. The composition and regulation of the tumor microenvironment is dependent on multiple interconnected factors including in a non-hierarchical order metabolism, therapies, niches, cell types, (epi)genetic alterations, and additional extrinsic effectors such as nutrients, oxygen (O2), pH, and apoptosis
See this image and copyright information in PMC

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