Circulating oncometabolite D-2-hydroxyglutarate enantiomer is a surrogate marker of isocitrate dehydrogenase–mutated intrahepatic cholangiocarcinomas

Delahousse, J; Verlingue, Loïc; Broutin, Sophie; Legoupil, Colette; Touat, Mehdi; Doucet, Ludovic; Ammari, Samy; Lacroix, Ludovic; Ducreux, Michel; Scoazec, Jean‐Yves; Malka, David; Paci, Angélo; Hollebecque, Antoine

doi:10.1016/j.ejca.2017.11.024

Cited by 29 publications

(17 citation statements)

References 38 publications

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“…d-2HG exhibited cytotoxicity at concentrations >5 mM in vascular endothelial cells; this concentration was lower than that used in other reports, i.e., 50 mM, for the analysis of metabolites in cancer cells (14), suggesting that vascular endothelial cells are more susceptible to higher concentrations of d-2HG. The serum levels of d-2HG in patients with IDH1/2-mutated biliary tract cancer have been shown to be approximately 11 µM (median value) (36). Therefore, 250 µM d-2HG was sufficient to observe the angiogenic activity in endothelial cells.…”

Section: Discussionmentioning

confidence: 96%

The oncometabolite d‑2‑hydroxyglutarate induces angiogenic activity through the vascular endothelial growth factor receptor 2 signaling pathway

et al. 2018

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The mutation of isocitrate dehydrogenase (IDH)1 (R132H) and IDH2 (R172K) and the induction of hypoxia in various solid tumors results in alterations in metabolic profiles, including the production of the d-or l-forms of 2-hydroxyglutarate (2HG) from α-ketoglutarate in aerobic metabolism in the tricarboxylic acid (TCA) cycle. However, it is unclear whether the oncometabolite d-2HG increases angiogenesis in endothelial cells. Therefore, in this study, we analyzed the levels of various metabolites, including d-2HG, under hypoxic conditions and in IDH2R172K mutant breast cancer cells by mass spectrometry. We then further evaluated the effects of this metabolite on angiogenesis in breast cancer cells. The results revealed that treatment with d-2HG increased the levels of secreted vascular endothelial growth factor (VEGF) in cancer cells and enhanced endothelial cell proliferation in a concentration-dependent manner. Wound healing and cell migration (examined by Transwell assay) were significantly increased by d-2HG to a level similar to that induced by VEGF. Tube formation was significantly stimulated by d-2HG, and chick chorioallantoic membrane angiogenesis was also enhanced by d-2HG. d-2HG activated VEGF receptor (VEGFR)2 and VEGFR2 downstream signaling, extracellular signal-regulated kinase 1/2, focal adhesion kinase, AKT and matrix metalloproteinase (MMP)2. Taken together, the findings of this study suggested that d-2HG induced angiogenic activity via VEGFR2 signaling and increased MMP2 activity.

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Section: Discussionmentioning

confidence: 96%

The oncometabolite d‑2‑hydroxyglutarate induces angiogenic activity through the vascular endothelial growth factor receptor 2 signaling pathway

et al. 2018

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“…2-HG is normally present as two enantiomers, dextrogyre (D) and laevogyre (L). Interestingly mIDH preferably provokes an increase in the D-enantiomer of 2-HG rather than the L-enantiomer and these forms can be measured in the serum by gas chromatography coupled to mass spectrometry [158] or liquid chromatography combined with mass spectrometry [159,160].…”

Section: Isocitrate Dehidrogenase (Idh)mentioning

confidence: 99%

Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives

Pastore

Lori

Gentilini

et al. 2020

Cells

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Cholangiocarcinoma (CCA) is a deadly tumor without an effective therapy. Unique metabolic and bioenergetics features are important hallmarks of tumor cells. Metabolic plasticity allows cancer cells to survive in poor nutrient environments and maximize cell growth by sustaining survival, proliferation, and metastasis. In recent years, an increasing number of studies have shown that specific signaling networks contribute to malignant tumor onset by reprogramming metabolic traits. Several evidences demonstrate that numerous metabolic mediators represent key-players of CCA progression by regulating many signaling pathways. Besides the well-known Warburg effect, several other different pathways involving carbohydrates, proteins, lipids, and nucleic acids metabolism are altered in CCA. The goal of this review is to highlight the main metabolic processes involved in the cholangio-carcinogeneis that might be considered as potential novel druggable candidates for this disease.

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“…2‐HG exists in two forms, D‐ 2‐hydroxyglutarate (D‐2‐HG) and L ‐2‐hydroxyglutarate (L‐2‐HG) (Nowicki & Gottlieb, ; Dang & Su, ). D‐2‐HG is mainly produced by mutated IDH in cancer cells, and the detection of this molecule in blood or urine samples can be used as a clinical marker to identify tumours with IDH mutation and monitor tumour burden, as has been proposed for acute myeloid leukemia and intrahepatic cholangiocarcinomas (Collins et al , ; Delahousse et al , ). By contrast, L‐2‐HG is produced by a different mechanism involving the activity of malate dehydrogenase (Collins et al , ), although it has been reported to accumulate even under hypoxic conditions (Intlekofer et al , ; Sciacovelli & Frezza, ).…”

Section: Oncometabolites and Their Related Metabolic Enzymesmentioning

confidence: 99%

“…It has been shown recently that in patients with cholangiocarcinoma, 2‐HG is secreted by tumour cells and can be detected at significant levels in patient serum (Delahousse et al , ). This observation suggests that 2‐HG may be present within exosomes released by therapy‐killed tumour cells, as has been found for succinate and fumarate.…”

Section: Oncometabolites and Tumour Repopulationmentioning

confidence: 99%

Oncometabolites in cancer aggressiveness and tumour repopulation

et al. 2019

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Tumour repopulation is recognized as a crucial event in tumour relapse where therapy-sensitive dying cancer cells influence the tumour microenvironment to sustain therapy-resistant cancer cell growth. Recent studies highlight the role of the oncometabolites succinate, fumarate, and 2-hydroxyglutarate in the aggressiveness of cancer cells and in the worsening of the patient's clinical outcome. These oncometabolites can be produced and secreted by cancer and/or surrounding cells, modifying the tumour microenvironment and sustaining an invasive neoplastic phenotype. In this review, we report recent findings concerning the role in cancer development of succinate, fumarate, and 2-hydroxyglutarate and the regulation of their related enzymes succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. We propose that oncometabolites are crucially involved in tumour repopulation. The study of the mechanisms underlying the relationship between oncometabolites and tumour repopulation is fundamental for identifying efficient anti-cancer therapeutic strategies and novel serum biomarkers in order to overcome cancer relapse.

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Circulating oncometabolite D-2-hydroxyglutarate enantiomer is a surrogate marker of isocitrate dehydrogenase–mutated intrahepatic cholangiocarcinomas

Cited by 29 publications

References 38 publications

The oncometabolite d‑2‑hydroxyglutarate induces angiogenic activity through the vascular endothelial growth factor receptor 2 signaling pathway

The oncometabolite d‑2‑hydroxyglutarate induces angiogenic activity through the vascular endothelial growth factor receptor 2 signaling pathway

Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives

Oncometabolites in cancer aggressiveness and tumour repopulation

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