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Schemes of metabolism involved in 2-HG biosynthesis (A), and of choline and ethanolamine phospholipid metabolism (B). Arrows, metabolic pathways. A, IDH1/2 catalyze oxidative decarboxylation of isocitrate to þ a -KG using NADP as a cofactor
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Many glioma patients harbor specific mutations in the isocitrate dehydrogenase gene IDH1, which associate with a relatively better prognosis. IDH1-mutated tumors produce the oncometabolite 2-hydroxyglutarate. Since IDH1 regulates several pathways leading to lipid synthesis, we hypothesized that IDH1 mutant tumors would display an altered phospholip...
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... in secondary GBMs, one of the genes for isocitrate dehydrogenase (IDH1 and IDH2) carry specific mutations, which are associated with prolonged overall survival (4-8). IDH1, the predominantly affected enzyme (>95%), catalyzes the conversion of isocitrate into a-ketoglutarate (a-KG) in the cytosol, using NADP as electron acceptor to generate NADPH (Fig. 1A). IDH1 can also catalyze the reductive carboxylation of a-KG to isocitrate that can be further processed to citrate and acetyl-and succinyl- CoA, important anabolic precursors for lipid synthesis (9). The mutation in IDH1, almost always affecting arginine R132, confers a neomorphic activity to the enzyme, which results in ...
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... of a-KG to isocitrate that can be further processed to citrate and acetyl-and succinyl- CoA, important anabolic precursors for lipid synthesis (9). The mutation in IDH1, almost always affecting arginine R132, confers a neomorphic activity to the enzyme, which results in NADPH-dependent conversion of a-KG to 2-hydroxygluta- rate (2-HG; Fig. 1A; ref. 10). The mutant enzyme lacks the capacity of reductive carboxylation (11). As 2-HG accumulates in mutated tumor cells and tissues (12)(13)(14), it has attracted attention as a potential biomarker in the diagnosis and prog- nosis of gliomas, in particular as the high levels of 2-HG can be detected noninvasively by 1 H MR ...
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... (MRS) in humans (8,(15)(16)(17)(18)(19). 1 H MRS has been explored extensively in the diagnosis and treatment evaluation of brain tumors in humans (20,21). MR spectra of the brain show a single spectral peak for the methyl protons of small choline compounds, which are involved in the Kennedy pathway of membrane lipid synthesis and breakdown (Fig. 1B). In brain tumors, choline metabolism is adapted to the needs of higher proliferation and to the physiologic microen- vironment (such as acidic extracellular pH; refs. 22,23), and the intensity of this peak (labeled as total choline or tCho) is often increased (24). Another prominent spectral change is a decrease of the peak for the ...
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... meaning of the change in phospholipid levels in IDH1-mutated glioma Many enzymes that are involved in lipid biosynthesis depend on appropriate levels of cytosolic NADPH and acetyl-CoA. The activity of IDH1 is an important source for cytosolic NADPH in the brain (ref. 51; see also Fig. 1A) and only for this reason, mutations in this enzyme are expected to affect lipid synthesis. This impact will be augmented by the fact that IDH1 is also involved in the reductive carboxylation of a-KG to isocitrate, especially under hypoxic conditions, isocitrate being the build- ing block for lipids via generation of acetyl-and ...
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... We attempted to determine nanomechanical profiles that are characteristic for the investigated cell phenotypes. The increased stiffness and Young's modulus of the IDH1 R132H mutant cells turned out to be highly indicative, which is probably mediated by both altered cytoskeleton and lipogenesis in mutant cells [24,46,61]. In this work, we first used the early-passage glioma cell cultures to compare hardness of IDH1 R132H mutant and IDH1 wild-type cells. ...
Atomic force microscopy (AFM) recently burst into biomedicine, providing morphological and functional characteristics of cancer cells and their microenvironment responsible for tumor invasion and progression, although the novelty of this assay needs to coordinate the malignant profiles of patients’ specimens to diagnostically valuable criteria. Applying high-resolution semi-contact AFM mapping on an extended number of cells, we analyzed the nanomechanical properties of glioma early-passage cell cultures with a different IDH1 R132H mutation status. Each cell culture was additionally clustered on CD44+/− cells to find possible nanomechanical signatures that differentiate cell phenotypes varying in proliferative activity and the characteristic surface marker. IDH1 R132H mutant cells compared to IDH1 wild-type ones (IDH1wt) characterized by two-fold increased stiffness and 1.5-fold elasticity modulus. CD44+/IDH1wt cells were two-fold more rigid and much stiffer than CD44-/IDH1wt ones. In contrast to IDH1 wild-type cells, CD44+/IDH1 R132H and CD44-/IDH1 R132H did not exhibit nanomechanical signatures providing statistically valuable differentiation of these subpopulations. The median stiffness depends on glioma cell types and decreases according to the following manner: IDH1 R132H mt (4.7 mN/m), CD44+/IDH1wt (3.7 mN/m), CD44-/IDH1wt (2.5 mN/m). This indicates that the quantitative nanomechanical mapping would be a promising assay for the quick cell population analysis suitable for detailed diagnostics and personalized treatment of glioma forms.
... These glycerophospholipid changes have been associated with pro-and anti-inflammatory activity via plasmalogen hydrolysis, cell membrane property changes, and inflammatory cascade triggering 56 . A switch from choline to ethanolamine metabolism has been previously shown as part of rapid cell growth and repair in environments such as tumour 57,58 . Moreover, a recent study by Fuchs et al. 38 showed a similar build-up of O-phosphoethanolamine in M1 macrophages, resulting in reduced mitochondrial respiration and a reduced inflammatory response 38 . ...
T-cell-driven immune responses are responsible for several autoimmune disorders, such as psoriasis vulgaris and rheumatoid arthritis. Identification of metabolic signatures in inflamed tissues is needed to facilitate novel and individualised therapeutic developments. Here we show the temporal metabolic dynamics of T-cell-driven inflammation characterised by nuclear magnetic resonance spectroscopy-based metabolomics, histopathology and immunohistochemistry in acute and chronic cutaneous delayed-type hypersensitivity reaction (DTHR). During acute DTHR, an increase in glutathione and glutathione disulfide is consistent with the ear swelling response and degree of neutrophilic infiltration, while taurine and ascorbate dominate the chronic phase, suggesting a switch in redox metabolism. Lowered amino acids, an increase in cell membrane repair-related metabolites and infiltration of T cells and macrophages further characterise chronic DTHR. Acute and chronic cutaneous DTHR can be distinguished by characteristic metabolic patterns associated with individual inflammatory pathways providing knowledge that will aid target discovery of specialised therapeutics. Nuclear magnetic resonance spectroscopy-based tissue metabolomics is used to define detailed temporal signatures of acute and chronic inflammation in cutaneous delayed-type hypersensitivity reaction.
... CHK1-Checkpoint kinase 1, AMPK-AMP-activated protein kinase, MAPK-Mitogen-activated protein kinase, RAF-rapidly accelerated fibrosarcoma, FAK-Focal adhesion kinase, STAT3-Signal Transducer And Activator Of Transcription 3, PDK1-3-Phosphoinositide-dependent kinase 1, NF-κB-Nuclear factor-kappa B, NO -Nitrogen oxide, TNF-α-Tumor necrosis factor-alpha, IL-6-interleukin-6, DPPH-2,2-diphenyl-1-picrylhydrazyl, ROS-Reactive oxygen species, Bax -BCL2-Associated X Protein, Bcl-2 -B-cell lymphoma 2, PI3k-phosphoinositide 3-kinase, mTOR-mammalian target of rapamycin, CRT -catenin response transcription, GADD -Growth Arrest and DNA Damage, PPARγ-Peroxisome proliferator-activated receptor gamma, mRNA-messenger ribonucleic acid, DR5 -Death receptor 5, BAD -BCL2 associated agonist of cell death, PARP -poly-ADP ribose polymerase, AR -Androgen receptor, ACC -Acetyl-CoA Carboxylase, FAS -fatty acid synthase. (Choi et al., 2021), and modified phospholipid profile of tumor cells (Esmaeili et al., 2014;Reitman et al., 2011;Zhou et al., 2019). Ubiquitination results in cancer initiation by influencing differentiation, inflammation, translation, and signal transduction (Deng et al., 2000;Huen et al., 2007;Mukhopadhyay and Riezman, 2007;Pickart, 2000;Spence et al., 2000). ...
Cancer is characterized by alterations that cause the over-proliferation of cells and hyperactivation of signaling pathways. Alterations of signaling molecules dysregulate physiological functions like cell growth, proliferation, metastasis, and cell death. Hence, the potential anticancer compounds primarily target signaling networks for therapeutic interventions in cancer. In the past few years, cancer therapy directed its focus on bioactive compounds that originated from marine sources considering their diverse and untapped nature. These Marine Bioactive Compounds (MBCs) are broadly classified into distinct categories such as alkaloids, carbohydrates, fatty acids, peptides, phenols, quinones, terpenes, and saponins. Bioactive compounds from each class initiate cell death via different signaling pathways. The primary objective of this review is to provide comprehensive information about the pathways that are predominantly followed by every class of MBCs by integrating data from several marine anticancer research. Here, we studied the signaling networks followed by each class of MBCs to inhibit various cancer types. As a result, we concluded that PI3K/AKT, ROS, and p53 are the three major signaling pathways targeted by the MBCs to induce apoptosis in cancer cells and these pathways are predominantly observed in classes like carbohydrates, peptides, and terpenes. Hence it is concluded that future anticancer research can be primarily focused on the MBCs derived from the scrutinized classes that adhere to pathways like PI3K/AKT, ROS, and p53 to achieve par excellence results.
... Therefore, we analyzed the lipidome composition in tumors with and without this mutation, with findings revealing a distinctive set of tentative lipids in the studied model ( Figure 5, Tables S4 and S6). This result may indicate that IDH 1/2 mutation not only leads to changes in the tricarboxylic acid cycle (TCA) pathway and oncometabolite accumulation, but that it may also initiate molecular alterations in the lipid profile [13,24,42,51,52] (Table S6). Similar to higher-grade gliomas, our findings showed that patients with worse outcomes (IDHw) had significantly upregulated LPCs, which can be related to alterations in the Lands cycle [44]. ...
The development of a fast and accurate intraoperative method that enables the differentiation and stratification of cancerous lesions is still a challenging problem in laboratory medicine. Therefore, it is important to find and optimize a simple and effective analytical method of enabling the selection of distinctive metabolites. This study aims to assess the usefulness of solid-phase microextraction (SPME) probes as a sampling method for the lipidomic analysis of brain tumors. To this end, SPME was applied to sample brain tumors immediately after excision, followed by lipidomic analysis via liquid chromatography-high resolution mass spectrometry (LC-HRMS). The results showed that long fibers were a good option for extracting analytes from an entire lesion to obtain an average lipidomic profile. Moreover, significant differences between tumors of different histological origin were observed. In-depth investigation of the glioma samples revealed that malignancy grade and isocitrate dehydrogenase (IDH) mutation status impact the lipidomic composition of the tumor, whereas 1p/19q co-deletion did not appear to alter the lipid profile. This first on-site lipidomic analysis of intact tumors proved that chemical biopsy with SPME is a promising tool for the simple and fast extraction of lipid markers in neurooncology.
... The following 2HG-mediated inhibition of aKG-dependent deoxygenases, such as TET2 and JMJD2A/C, promotes global gene expression changes, which along with the redox stress arising from the declined NADPH levels, reflect the tumorigenic impact of these mutations [124][125][126][127]. Likewise, even though the decreased levels of two lipogenesis components, NADPH and aKG [128] would be expected to abrogate lipid synthesis, certain lipid precursors, such as glycerol-phosphates and glycerophosphocholine, are present in elevated quantities; on the other hand, other lipid precursors, as for example myo-inositol phosphate, are present in reduced levels, compared to unaffected tumors, suggesting that cancer cells harboring IDH1 variants, alter their phospholipid expression profile, probably in a tumor-assisting manner [129][130][131]. ...
Cancer is the second leading cause of death globally. One of the main hallmarks in cancer is the functional deregulation of crucial molecular pathways via driver genetic events that lead to abnormal gene expression, giving cells a selective growth advantage. Driver events are defined as mutations, fusions and copy number alterations that are causally implicated in oncogenesis. Molecular analysis on tissues that have originated from a wide range of anatomical areas has shown that mutations in different members of several pathways are implicated in different cancer types. In recent decades, significant efforts have been made to incorporate this knowledge into daily medical practice, providing substantial insight towards clinical diagnosis and personalized therapies. However, since there is still a strong need for more effective drug development, a deep understanding of the involved signaling mechanisms and the interconnections between these pathways is highly anticipated. Here, we perform a systemic analysis on cancer patients included in the Pan-Cancer Atlas project, with the aim to select the ten most highly mutated signaling pathways (p53, RTK-RAS, lipids metabolism, PI-3-Kinase/Akt, ubiquitination, b-catenin/Wnt, Notch, cell cycle, homology directed repair (HDR) and splicing) and to provide a detailed description of each pathway, along with the corresponding therapeutic applications currently being developed or applied. The ultimate scope is to review the current knowledge on highly mutated pathways and to address the attractive perspectives arising from ongoing experimental studies for the clinical implementation of personalized medicine.
... As such, 31 P MRS(I) has been applied to patients with glioma for some time in several studies at clinical field strengths B 0 ≤ 3 T and has recently been shown to potentially predict therapy response via phospholipid metabolites (5) and the site of tumor progression via intracellular pH (6). Another recent study suggests that 31 P MRSI could in principle also detect the mutation status of the isocitrate dehydrogenase (IDH) via phospholipid metabolites (7), further highlighting the potential of applying 31 P MRSI in patients with glioma. However, the limited sensitivity of in vivo 31 P MRSI still hampers its broader application in clinical studies, particularly in the human brain where concentrations of 31 P metabolites are relatively low. ...
... For convenience, it was assumed that DPG intensities are distributed equally across PMEs. Additionally, maps of the eP i -to-P i ratio were generated for the interpretation of presented tP i intensities, as well as ratio maps for PMEs [(t)PC, (t)PE] and phosphodiesters (PDE; GPC, GPE), i.e., PC-to-PE, GPC-to-GPE, and GPC-to-PE, suggesting to discriminate the IDH mutation status according to the findings of Esmaeli et al. (7). Finally, to compensate for the intensity scaling induced via the coil sensitivity profile, and to improve the comparability of metabolite intensities between subjects, ratio maps of the individual metabolite intensities relative to the local α-ATP intensity were calculated (except for α-ATP itself, which is given subject to the coil sensitivity profile throughout this study). ...
Phosphorus magnetic resonance spectroscopic imaging (31P MRSI) is of particular interest for investigations of patients with brain tumors as it enables to non-invasively assess altered energy and phospholipid metabolism in vivo. However, the limited sensitivity of 31P MRSI hampers its broader application at clinical field strengths. This study aimed to identify the additional value of 31P MRSI in patients with glioma at ultra-high B0 = 7T, where the increase in signal-to-noise ratio may foster its applicability for clinical research. High-quality, 3D 31P MRSI datasets with an effective voxel size of 5.7 ml were acquired from the brains of seven patients with newly diagnosed glioma. An optimized quantification model was implemented to reliably extract an extended metabolic profile, including low-concentrated metabolites such as extracellular inorganic phosphate, nicotinamide adenine dinucleotide [NAD(H)], and uridine diphosphoglucose (UDPG), which may act as novel tumor markers; a background signal was extracted as well, which affected measures of phosphomonoesters beneficially. Application of this model to the MRSI datasets yielded high-resolution maps of 12 different 31P metabolites, showing clear metabolic differences between white matter (WM) and gray matter, and between healthy and tumor tissues. Moreover, differences between tumor compartments in patients with high-grade glioma (HGG), i.e., gadolinium contrast-enhancing/necrotic regions (C+N) and peritumoral edema, could also be suggested from these maps. In the group of patients with HGG, the most significant changes in metabolite intensities were observed in C+N compared to WM, i.e., for phosphocholine +340%, UDPG +54%, glycerophosphoethanolamine −45%, and adenosine-5′-triphosphate −29%. Furthermore, a prominent signal from mobile phospholipids appeared in C+N. In the group of patients with low-grade glioma, only the NAD(H) intensity changed significantly by −28% in the tumor compared to WM. Besides the potential of 31P MRSI at 7T to provide novel insights into the biochemistry of gliomas in vivo, the attainable spatial resolutions improve the interpretability of 31P metabolite intensities obtained from malignant tissues, particularly when only subtle differences compared to healthy tissues are expected. In conclusion, this pilot study demonstrates that 31P MRSI at 7T has potential value for the clinical research of glioma.
... In mutIDH1 glioma, alterations in phospholipid profiles have been observed in cultured cell models and tumors, as shown by LC-MS, MSI, in vitro and ex vivo 1 H and 31 P NMR, and in vivo MRS, 98,99,102,103 as summarized in part in Table 7. Independent studies using MRS/NMR show that phosphocholine (PCho) and glycerophosphocholine (GPCho) are increased in cultured glioma cells expressing mutIDH1 R132H , xenograft models, and PTBs compared with equivalent WT IDH1 glioma samples. 98,103 However, a study measuring PCho with LC-MS in cultured HOG cells expressing mutIDH1 R132H or mutIDH2 R172K found that PCho was significantly lower compared with HOG WT IDH cells 107 and reported GPCho to be increased. ...
... In mutIDH1 glioma, alterations in phospholipid profiles have been observed in cultured cell models and tumors, as shown by LC-MS, MSI, in vitro and ex vivo 1 H and 31 P NMR, and in vivo MRS, 98,99,102,103 as summarized in part in Table 7. Independent studies using MRS/NMR show that phosphocholine (PCho) and glycerophosphocholine (GPCho) are increased in cultured glioma cells expressing mutIDH1 R132H , xenograft models, and PTBs compared with equivalent WT IDH1 glioma samples. 98,103 However, a study measuring PCho with LC-MS in cultured HOG cells expressing mutIDH1 R132H or mutIDH2 R172K found that PCho was significantly lower compared with HOG WT IDH cells 107 and reported GPCho to be increased. In addition to PCho and GPCho, phosphoethanolamine (PE) was significantly lower in mutIDH1 R132H gliomas across all the sample types analyzed. ...
... In addition to PCho and GPCho, phosphoethanolamine (PE) was significantly lower in mutIDH1 R132H gliomas across all the sample types analyzed. 98 In an MSI study, four putatively identified PE lipids have been reported to be substantially increased in mu-tIDH1 R132H glioma mouse PDXs. 99 However, the NMR methods employed were insufficiently sensitive to differentiate between the different PEs. ...
The most frequently mutated metabolic genes in human cancer are those encoding the enzymes isocitrate dehydrogenase 1 (IDH1) and IDH2; these mutations have so far been identified in more than 20 tumor types. Since IDH mutations were first reported in glioma over a decade ago, extensive research has revealed their association with altered cellular processes. Mutations in IDH lead to a change in enzyme function, enabling efficient conversion of 2-oxoglutarate to R-2-hydroxyglutarate (R-2-HG). It is proposed that elevated cellular R-2-HG inhibits enzymes that regulate transcription and metabolism, subsequently affecting nuclear, cytoplasmic, and mitochondrial biochemistry. The significance of these biochemical changes for tumorigenesis and potential for therapeutic exploitation remains unclear. Here we comprehensively review reported direct and indirect metabolic changes linked to IDH mutations and discuss their clinical significance. We also review the metabolic effects of first-generation mutant IDH inhibitors and highlight the potential for combination treatment strategies and new metabolic targets.
... Increased steady state levels of choline compounds in tumors can be mapped by 1 H MR spectroscopic imaging, but separation of its different species is not possible [12,15]. The main different phosphorylated choline compounds can be detected via 31 P MR spectroscopic imaging employing 1 H decoupling or high magnetic fields (≥7T), although at a lower spatial resolution than total choline detection via 1 H MR spectroscopic imaging [12,16,17]. It is possible to obtain choline in which the nine protons at the methyl groups are replaced by deuterons which is favorable for a good SNR in DMI. ...
... To apply DMI of choline and glucose, separately or combined, to humans at lower field strengths (≤7T), it is necessary that their signals are resolved from HOD and from each other. The line width of HOD from DMI volumes in the tumor (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) was larger than that reported for the human brain at 4 and 7T [31], which is likely due to more difficult magnetic field shimming conditions. For choline, we found line widths of about 10 to 20 Hz. ...
Increased glucose and choline uptake are hallmarks of cancer. We investigated whether the uptake and conversion of [2H9]choline alone and together with that of [6,6′-2H2]glucose can be assessed in tumors via deuterium metabolic imaging (DMI) after administering these compounds. Therefore, tumors with human renal carcinoma cells were grown subcutaneously in mice. Isoflurane anesthetized mice were IV infused in the MR magnet for ~20 s with ~0.2 mL solutions containing either [2H9]choline (0.05 g/kg) alone or together with [6,6′-2H2]glucose (1.3 g/kg). 2H MR was performed on a 11.7T MR system with a home-built 2H/1H coil using a 90° excitation pulse and 400 ms repetition time. 3D DMI was recorded at high resolution (2 × 2 × 2 mm) in 37 min or at low resolution (3.7 × 3.7 × 3.7 mm) in 2:24 min. Absolute tissue concentrations were calculated assuming natural deuterated water [HOD] = 13.7 mM. Within 5 min after [2H9]choline infusion, its signal appeared in tumor spectra representing a concentration increase to 0.3–1.2 mM, which then slowly decreased or remained constant over 100 min. In plasma, [2H9]choline disappeared within 15 min post-infusion, implying that its signal arises from tumor tissue and not from blood. After infusing a mixture of [2H9]choline and [6,6′-2H2]glucose, their signals were observed separately in tumor 2H spectra. Over time, the [2H9]choline signal broadened, possibly due to conversion to other choline compounds, [[6,6′-2H2]glucose] declined, [HOD] increased and a lactate signal appeared, reflecting glycolysis. Metabolic maps of 2H compounds, reconstructed from high resolution DMIs, showed their spatial tumor accumulation. As choline infusion and glucose DMI is feasible in patients, their simultaneous detection has clinical potential for tumor characterization.
... Increased steady state levels of choline compounds in tumors can be mapped by 1 H MR spectroscopic imaging, but separation of its different species is not possible [12,15]. The main different phosphorylated choline compounds can be detected via 31 P MR spectroscopic imaging employing 1 H decoupling or high magnetic fields (≥7T), although at a lower spatial resolution than total choline detection via 1 H MR spectroscopic imaging [12,16,17]. It is possible to obtain choline in which the nine protons at the methyl groups are replaced by deuterons which is favorable for a good SNR in DMI. ...
... To apply DMI of choline and glucose, separately or combined, to humans at lower field strengths (≤7T), it is necessary that their signals are resolved from HOD and from each other. The line width of HOD from DMI volumes in the tumor (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) was larger than that reported for the human brain at 4 and 7T [31], which is likely due to more difficult magnetic field shimming conditions. For choline, we found line widths of about 10 to 20 Hz. ...
: Increased glucose and choline uptake are hallmarks of cancer. We investigated if the uptake and conversion of [2H9]choline alone and together with that of [6,6’ 2H2]glucose can be assessed in subcutaneous tumors by deuterium metabolic imaging (DMI) after bolus administration of these compounds. Therefore tumors with human renal carcinoma cells were grown subcutaneously in mice up to ~0.5 cm3. Mice were anesthetized with isoflurane and IV infused in the MR magnet for ~20 sec with ~0.2 ml solutions containing either [2H9]choline (0.05g/kg) alone or together with [6,6’ 2H2]glucose (1.3g/kg). 2H MR was performed on a 11.7T MR system with a home-built 2H/1H coil using a 900 excitation pulse and 400ms repetition time. 3D DMI was recorded at high resolution (2x2x2mm) in 37 min or at low resolution (3.7x3.7x3.7mm) in 2:24 min. Absolute tissue concentrations were calculate assuming initial [HOD]=13.7mM. Within 5 minutes after [2H9]choline infusion its signal appeared in tumor spectra representing concentration increasing up to 0.3–1.2 mM and then slowly decreased or remained constant over 100 minutes. In plasma [2H9]choline disappeared within 15 minutes post-infusion implying that its tumor signal arises from tissue and not blood. After infusing a mixture of [2H9]choline and [6,6’ 2H2]glucose their signals were observed separately in tumor 2H spectra. Over time the [2H9]choline signal broadened, possibly due to conversion to other choline compounds, [[6,6’ 2H2]glucose] declined, [HOD] increased and a lactate signal appeared, reflecting glycolysis. Metabolic maps of all 2H compounds were reconstructed from high resolution DMIs. As choline infusion and glucose DMI is feasible in patients, their simultaneous detection has clinical potential for tumor characterization.
... Phospholipid homeostasis has also been linked to IDH1 mutation; indeed, a dysregulation in phosphocholine/ethanolamine (PC and PE) and their adducts, GPC and glycerophosphorylethanolamine (GPE) was found in glioma xenografts harboring the IDH1 mutation by 31 P MRS, and was further confirmed in IDH1-R132H-expressing U251 glioma cell lines by HR-MAS [116]. 31 P NMR analysis of mouse xenografts revealed that NHA and U87 cell lines transduced with the mutant IDH1 R132H gene displayed lower levels of PC and PE in the polar extracts [117], and phosphatidylcholine (PtdC) and phosphatidylethanolamine (PtdE) were reduced in the lipid fraction [116,118]. ...
... Phospholipid homeostasis has also been linked to IDH1 mutation; indeed, a dysregulation in phosphocholine/ethanolamine (PC and PE) and their adducts, GPC and glycerophosphorylethanolamine (GPE) was found in glioma xenografts harboring the IDH1 mutation by 31 P MRS, and was further confirmed in IDH1-R132H-expressing U251 glioma cell lines by HR-MAS [116]. 31 P NMR analysis of mouse xenografts revealed that NHA and U87 cell lines transduced with the mutant IDH1 R132H gene displayed lower levels of PC and PE in the polar extracts [117], and phosphatidylcholine (PtdC) and phosphatidylethanolamine (PtdE) were reduced in the lipid fraction [116,118]. Wild type and IDH1 mutant cell lines were cultured in media containing either [1,2-13 C]-choline or [1,2-13 C]-ethanolamine to track their incorporation into the correspondent phospholipids by 13 C and 31 P NMR over time [119] in order to estimate choline kinase (CK) and ethanolamine kinase (EK) activities [118]. The decreased synthesis of these metabolites was validated by treating endogenously mutant IDH1 and wild type cell lines with the selective IDH1 inhibitor AGI-5198 [120] (Fig. 2D). ...
Despite intensive research, brain tumors are amongst the malignancies with the worst prognosis; therefore, a prompt diagnosis and thoughtful assessment of the disease is required. The resistance of brain tumors to most forms of conventional therapy has led researchers to explore the underlying biology in search of new vulnerabilities and biomarkers. The unique metabolism of brain tumors represents one potential vulnerability and the basis for a system of classification. Profiling this aberrant metabolism requires a method to accurately measure and report differences in metabolite concentrations. Magnetic resonance-based techniques provide a framework for examining tumor tissue and the evolution of disease. Nuclear Magnetic Resonance (NMR) analysis of biofluids collected from patients suffering from brain cancer can provide biological information about disease status. In particular, urine and plasma can serve to monitor the evolution of disease through the changes observed in the metabolic profiles. Moreover, cerebrospinal fluid can be utilized as a direct reporter of cerebral activity since it carries the chemicals exchanged with the brain tissue and the tumor mass. Metabolic reprogramming has recently been included as one of the hallmarks of cancer. Accordingly, the metabolic rewiring experienced by these tumors to sustain rapid growth and proliferation can also serve as a potential therapeutic target. The combination of ¹³C tracing approaches with the utilization of different NMR spectral modalities has allowed investigations of the upregulation of glycolysis in the aggressive forms of brain tumors, including glioblastomas, and the discovery of the utilization of acetate as an alternative cellular fuel in brain metastasis and gliomas. One of the major contributions of magnetic resonance to the assessment of brain tumors has been the non-invasive determination of 2-hydroxyglutarate (2HG) in tumors harboring a mutation in isocitrate dehydrogenase 1 (IDH1). The mutational status of this enzyme already serves as a key feature in the clinical classification of brain neoplasia in routine clinical practice and pilot studies have established the use of in vivo magnetic resonance spectroscopy (MRS) for monitoring disease progression and treatment response in IDH mutant gliomas. However, the development of bespoke methods for 2HG detection by MRS has been required, and this has prevented the wider implementation of MRS methodology into the clinic. One of the main challenges for improving the management of the disease is to obtain an accurate insight into the response to treatment, so that the patient can be promptly diverted into a new therapy if resistant or maintained on the original therapy if responsive. The implementation of ¹³C hyperpolarized magnetic resonance spectroscopic imaging (MRSI) has allowed detection of changes in tumor metabolism associated with a treatment, and as such has been revealed as a remarkable tool for monitoring response to therapeutic strategies. In summary, the application of magnetic resonance-based methodologies to the diagnosis and management of brain tumor patients, in addition to its utilization in the investigation of its tumor-associated metabolic rewiring, is helping to unravel the biological basis of malignancies of the central nervous system.
