Lower Lactate Levels and Lower Intracellular pH in Patients with IDH-Mutant versus Wild-Type Gliomas

Abstract

BACKGROUND AND PURPOSE: Preclinical evidence points toward a metabolic reprogramming in isocitrate dehydrogenase (IDH) mutated tumor cells with down-regulation of the expression of genes that encode for glycolytic metabolism. We noninvasively investigated lactate and Cr concentrations, as well as intracellular pH using 1 H/phosphorus 31 ( 31 P) MR spectroscopy in a cohort of patients with gliomas.MATERIALS AND METHODS: Thirty prospectively enrolled, mostly untreated patients with gliomas met the spectral quality criteria (World Health Organization IIMR imaging protocol included 3D 31 P chemical shift imaging and 1 H single-voxel spectroscopy (point-resolved spectroscopy sequence at TE ¼ 30 ms and TE ¼ 97 ms with optimized echo spacing for detection of 2-hydroxyglutarate) from the tumor area. Values for absolute metabolite concentrations were calculated (phantom replacement method). Intracellular pH was determined from 31 P chemical shift imaging.RESULTS: At TE ¼ 97 ms, lactate peaks can be fitted with little impact of lipid/macromolecule contamination. We found a significant difference in lactate concentrations, lactate/Cr ratios, and intracellular pH when comparing tumor voxels of patients with IDH-mutant with those of patients with IDH wild-type gliomas, with reduced lactate levels and near-normal intracellular pH in patients with IDH-mutant gliomas. We additionally found evidence for codependent effects of 1p/19q codeletion and IDH mutations with regard to lactate concentrations for World Health Organization tumor grades II and III, with lower lactate levels in patients exhibiting the codeletion. There was no statistical significance when comparing lactate concentrations between IDH-mutant World Health Organization II and III gliomas. CONCLUSIONS:We found indirect evidence for metabolic reprogramming in IDH-mutant tumors with significantly lower lactate concentrations compared with IDH wild-type tumors and a near-normal intracellular pH. ABBREVIATIONS: ATP ¼ adenosine triphosphate; CRLB ¼ Cramer-Rao Lower Bound; 2-HG ¼ 2-hydroxyglutarate; IDHmut ¼ isocitrate dehydrogenase mutant; IDHwt ¼ isocitrate dehydrogenase wild-type; MM ¼ macromolecules; NHE1 ¼ sodium-hydrogen antiporter 1; pH i ¼ intracellular pH; PRESS ¼ pointresolved spectroscopy sequence; SVS ¼ single-voxel spectroscopy; WHO ¼ World Health Organization

Prognostic value of lactate metabolism-related gene expression signature in adult primary gliomas and its impact on the tumor immune microenvironment

“…In this study, we discovered that the unsupervised clustering with LMG expression signature could stratify glioma samples into two consensus clusters, in which one was associated with IDH wildtype gliomas and was more likely to have a more sophisticated and immunosuppressive microenvironment. This result was consistent with the findings reported by Wenger et al that the higher level of glycolysis in the IDH wild type gliomas was associated with more lactate in TME, which could potentially disturb the distribution and functionality of immune cells (8).…”

“…Despite the massive research investment and clinical experiments reported worldwide, the treatment of glioma has not yet to be revolutionized and the prognosis of glioma patients is not ideal, causing loss of quality of life (QOL) and financial stress for patients and their family ( 38 , 39 ). Lactate is one of the components in the TME, whose concentration has been associated with the molecular features and prognosis of gliomas ( 8 ). Meanwhile, lactate metabolism has been considered to regulate tumor immunity through diverse mechanisms.…”

“…Clinical investigations have connected high level of lactate in the tumor microenvironment (TME) with poor prognosis in cervical cancer, breast cancer and head and neck squamous cell carcinomas (5)(6)(7). A magnetic resonance spectroscopy (MRS) study found that lactate concentration was significantly higher in isocitrate dehydrogenase (IDH) wild-type gliomas than the less aggressive IDH mutants (8).…”

The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma

“…Likewise, lactate levels are significantly increased in IDH wt gliomas. In contrast, IDH mutant cells exhibit reduced hyperpolarized lactate production along with decrease of LDH as well as MCT1 and MCT4 levels [ 120 , 121 , 122 , 123 ].…”

Magnetic Resonance Spectroscopy in Diagnosis and Follow-Up of Gliomas: State-of-the-Art

“…These results showed indications of faster cell reproduction in MGMT-methylated and EGFR-amplified tumors and higher apoptotic activity in EGFR-amplified tumors regardless of the MGMT-status [62]. Another study showed lower lactate levels and intracellular pH in IDH-mutant gliomas compared to IDH-wild type gliomas [63]. However, other 31P-MRS markers were not significantly altered and could not predict the IDH-mutation status [64].…”