Radiation Induced Metabolic Alterations Associate with Tumor Aggressiveness and Poor Outcome in Glioblastoma

Abstract

<jats:title>Abstract</jats:title><jats:p>Glioblastoma (GBM) is uniformly fatal with a one year median survival rate, despite the best available treatment, including radiotherapy (RT). Impacts of prior RT on tumor recurrence are poorly understood but may increase tumor aggressiveness. Metabolic changes have been investigated in radiation-induced brain injury; however, the tumor-promoting effect following prior radiation is lacking. Since RT is vital to GBM management, we quantified the tumor-promoting effects of prior radiotherapy (RT) on patient-derived intracranial GBM xenografts and characterized the metabolic alterations associated with the protumorigenic microenvironment. Human xenografts (GBM143) were implanted into nude mice 24h following 20Gy cranial radiation vs. sham animals. Tumors in pre-radiated mice were more proliferative and more infiltrative, yielding faster mortality (p&lt;0.0001). Histologic evaluation of tumor associated macrophage/microglia (TAMs) revealed cells with a more fully activated ameboid morphology in pre-radiated animals. Microdialyzates from the radiated brain at the margin of tumor infiltration contralateral to the site of implantation were analyzed by unsupervised liquid chromatography-mass spectrometry (LC-MS). In pre-radiated animals, metabolites known to be associated with tumor progression (like, modified nucleotides and polyols) were identified. Whole-tissue metabolomic analysis of the pre-radiated brain microenvironment for metabolic alterations in a separate cohort of nude mice using <jats:sup>1</jats:sup>H-NMR revealed significant decrease in levels of antioxidants (glutathione (GSH) and ascorbate (ASC)), NAD+, TCA intermediates, and increased ATP and GTP. Glutathione and ASC showed highest VIPpred (1.65) in OPLS-DA analysis. Involvement of ASC catabolism was further confirmed by GC-MS. To assess longevity of radiation effects, we compared survival with implantation occuring 2 months vs. 24h following radiation, finding worse survival in animals implanted at 2 months. These radiation-induced alterations are consistent with a chronic disease-like microenvironment characterized by reduced levels of antioxidants and NAD+, as well as elevated extracellular ATP and GTP serving as chemoattractants, promoting cell motility and vesicular secretion with decreased levels of GSH and ASC exacerbating oxidative stress. Taken together, these data suggest that IR induces tumor-permissive changes in the microenvironment with metabolomic alterations that may facilitate tumor aggressiveness with important implications for recurrent glioblastoma. Harnessing these metabolomic insights may provide opportunities to attenuate RT-associated aggressiveness of recurrent GBM.</jats:p>

Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion

“…Such bioenergetic flexibility appears to fit well into the increased capacity of tumors for metastasis [20][21][22] , in which the fatty acid (FA) is an alternative critical energy resource to meet the high-fuel consumption in aggressively growing cancer cells [23][24][25] . FAO is shown to play a critical step for mitochondrial lipid digestion that enhances GBM metabolism 26,27 , and targeting purine metabolism or NADPH biosynthesis increases the efficacy of GBM control 28,29 . Recently, two groups further reveal that FA metabolism accelerates the incidence of breast cancer brain metastasis 30 and that glycolysis is a less-essential uptake for GBM metabolism 31 .…”

Metabolic biomarkers of radiotherapy response in plasma and tissue of an IDH1 mutant astrocytoma mouse model

“…Taking all these changes together, a dysregulated glutamine metabolism in tumor tissue is observed as a consequence of RT treatment. The increased levels of ATP and GTP in the radiation group can be attributed to an increased transference of energy carriers from the microenvironment in order to maintain the proliferation levels despite the deleterious effects of RT (43). However, we have also observed an increase in the total levels of oxoglutarate and a higher flux from [U-13 C]-glutamine to succinate which may indicate an upregulation of the succinyl CoA synthase which yields GTP; intriguingly, the following metabolites, such as fumarate and oxaloacetate, within the TCA cycle, display lower levels in the radiation group which may indicate downregulation of succinate dehydrogenase due to RT.…”

Astrocyte, Lipid Metabolism in Alzheimer’s Disease and Glioblastoma

“…Metabolic reprogramming has been recognized as a fundamental hallmark for carcinogenesis and progression of multiple tumors including GBM [322][323][324], through which tumor cells meet the high-energy demands of rapid proliferation [325]. Except for the representative metabolic feature named the Warburg effect, a phenomenon in which GBM cells rely on glycolysis for energy production under oxygen-sufficient and oxygen-insufficient conditions [323,[325][326][327], GBM cells can also be fueled by fatty acid oxidation (FAO) as an alternative crucial energy resource to meet high-energy consumption in GBM aggressiveness [328][329][330][331][332], of which inhibition negatively impacted GBM proliferation and progression [333]. Oxidation of fatty acids is achieved by two major pathways, namely enzymatic oxidation mediated by peroxidases (e.g cyclooxygenase (COX), cytochrome P450 (CYP450), lipoxygenase (LOX) and phospholipase A2 (PLA2)) [334] as well as nonenzymatic self-catalyzed peroxidation (Figure 2A) of which 4-hydroxynonenal (4HNE) is an end-product showing elevated expression proportional to the grade of brain tumor malignancy [335][336][337].…”