Hyperpolarized 13C-glucose magnetic resonance highlights reduced aerobic glycolysis in vivo in infiltrative glioblastoma

Abstract

Glioblastoma (GBM) is the most aggressive brain tumor type in adults. GBM is heterogeneous, with a compact core lesion surrounded by an invasive tumor front. This front is highly relevant for tumor recurrence but is generally non-detectable using standard imaging techniques. Recent studies demonstrated distinct metabolic profiles of the invasive phenotype in GBM. Magnetic resonance (MR) of hyperpolarized 13C-labeled probes is a rapidly advancing field that provides real-time metabolic information. Here, we applied hyperpolarized 13C-glucose MR to mouse GBM models. Compared to controls, the amount of lactate produced from hyperpolarized glucose was higher in the compact GBM model, consistent with the accepted “Warburg effect”. However, the opposite response was observed in models reflecting the invasive zone, with less lactate produced than in controls, implying a reduction in aerobic glycolysis. These striking differences could be used to map the metabolic heterogeneity in GBM and to visualize the infiltrative front of GBM.

Simultaneous fMRI and metabolic MRS of hyperpolarized [1‐13C]pyruvate during nicotine stimulus in rat

“…26 Recent reports on mice suggest that hyperpolarized glucose might show greater response to alterations in cellular energy metabolism, due to it entering the cells via more effective glucose transporters and reporting on actual de novo synthesis of lactate. 45,46 However, experimental use of hyperpolarized glucose is complicated by short T 1 and has so far been successfully demonstrated only in mice.…”

Therapeutic Response Assessment of High-Grade Gliomas During Early-Phase Drug Development in the Era of Molecular and Immunotherapies

“…Several noninvasive imaging techniques are available for quantifying these downstream effects beyond those previously mentioned. For example, hyperpolarized 13 C-glucose or 13 C-pyruvate MRI/MRS can be used to examine metabolic characteristics including glucose uptake, metabolite generation, and lactate production 65–67 . Alternatively, investigators recently demonstrated that glucose enhanced MRI can be performed using chemical exchange saturation transfer (CEST) imaging of hydroxyl (-OH) groups on glucose after infusion (glucoCEST) 68–70 .…”

“…For example, hyperpolarized 13 C-glucose or 13 C-pyruvate MRI/MRS can be used to examine metabolic characteristics including glucose uptake, metabolite generation, and lactate production. [65][66][67] Alternatively, investigators recently demonstrated that glucose enhanced MRI can be performed using chemical exchange saturation transfer (CEST) imaging of hydroxyl (-OH) groups on glucose after infusion (glucoCEST). [68][69][70] Lactate production, a product of glycolysis, can also be quantified using either lactate MRS 71,72 or pHweighted amine CEST imaging.…”

Metabolic and transcriptomic profiles of glioblastoma invasion revealed by comparisons between patients and corresponding orthotopic xenografts in mice

“…The implanted cells give rise to tumors that recapitulate many relevant characteristics of the parental tumors, including diffuse infiltration [ 17 , 24 , 51 , 59 ]. Glioma cells are metabolically reprogrammed in order to support proliferation, migration and invasion, and to survive in a hostile environment lacking oxygen and nutrients [ 5 , 26 , 35 , 36 ]. In vivo detection of altered metabolic profiles in GBM, which can be achieved with ultra-high field 1 H MR spectroscopy ( 1 H MRS) yielding highly resolved spectra provides an opportunity to gain insights into the mechanisms of tumor progression [ 8 , 22 , 27 ].…”