R132H-mutation of isocitrate dehydrogenase-1 is not sufficient for HIF-1α upregulation in adult glioma

Williams, Susan; Karajannis, Matthias A.; Chiriboga, Luis; Golfinos, John G.; Deimling, Andreas von; Zagzag, David

doi:10.1007/s00401-010-0790-y

Cited by 70 publications

(54 citation statements)

References 10 publications

(14 reference statements)

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“…Actually, the possibility that IDH-mutated glioma cells could have developed alternative molecular pathways or adaptative mechanisms to overcome the pseudo-hypoxic condition induced acutely and in vitro by IDH reduced activity should be envisioned. A pioneering work by Williams and colleagues recently provided the first evidence that HIF-1a expression in gliomas was not associated with R132H-mutated IDH1 expression [23]. These findings are in good agreement with our results.…”

Section: Discussionsupporting

confidence: 93%

IDH mutation status impact on in vivo hypoxia biomarkers expression: new insights from a clinical, nuclear imaging and immunohistochemical study in 33 glioma patients

et al. 2011

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Mutations in the gene encoding isocitrate dehydrogenase enzyme isoforms 1 (IDH1) and 2 (IDH2) have recently been identified in a large proportion of glial tumors of the CNS, but their mechanistic role in tumor development remains unclear. Here, we assessed the actual impact of IDH1 and IDH2 mutations in patients harboring WHO grade II and III gliomas. We sequenced IDH1 at codon 132 and IDH2 at codon 172 in 33 patients with WHO grade II and III gliomas who benefited from a preoperative (18)F-FDG positron emission tomography (PET). Immunohistochemical expression of Hypoxia Inducible Factor-1alpha (HIF-1α), Carbonic Anhydrase IX (CAIX), Glucose Transporter 1 (GLUT1) and Caspase 3 active form (CASP3) along with the R132HIDH1 mutation was assessed in all cases as well as 1p/19q deletion status and p53 expression. HIF-1α expression was found in 15% of IDH-mutated compared to 7.7% of IDH-nonmutated tumors (P = 0.954). Also, GLUT-1 positive staining was found in 5% of IDH-mutated and in 7.1% of IDH-nonmutated tumors (P = 0.794). Finally, CA-IX expression was found in 15% of IDH-mutated and in 7.7% of IDH-nonmutated tumors (P = 0.484). The combined expression of these three hypoxic markers was found in two WHO grade III tumors, one of which was IDH-mutated whereas the other was IDH-nonmutated (P = 0.794). In IDH-mutated tumors, the median SUVmax ratio was 2.24 versus 2.15 in IDH-nonmutated tumors (P = 0.775). Together, these data question the actual relationship between IDH mutation status and in vivo hypoxic biomarkers expression in WHO grade II and III gliomas.

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Section: Discussionsupporting

confidence: 93%

IDH mutation status impact on in vivo hypoxia biomarkers expression: new insights from a clinical, nuclear imaging and immunohistochemical study in 33 glioma patients

et al. 2011

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“…However, further study has shown that, on the contrary, (R)-2HG potentiates EglN activity in vitro and in vivo and blunts the induction of HIFa in response to hypoxia in cell culture models (Koivunen et al 2012;Losman et al 2013). Consistent with this observation, IDH mutant brain tumors display decreased HIF activation compared with their wild-type counterparts (Williams et al 2011;Koivunen et al 2012). It should be noted that HIFa levels are elevated in the brains of the brain-specific IDH1 R132H knock-in mice (Sasaki et al 2012a).…”

Section: Egln Prolyl-4-hydroxylasesmentioning

confidence: 75%

What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

2013

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Mutations in metabolic enzymes, including isocitrate dehydrogenase 1 (IDH1) and IDH2, in cancer strongly implicate altered metabolism in tumorigenesis. IDH1 and IDH2 catalyze the interconversion of isocitrate and 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate and an essential cofactor for many enzymes, including JmjC domain-containing histone demethylases, TET 5-methylcytosine hydroxylases, and EglN prolyl-4-hydroxylases. Cancer-associated IDH mutations alter the enzymes such that they reduce 2OG to the structurally similarHere we review what is known about the molecular mechanisms of transformation by mutant IDH and discuss their implications for the development of targeted therapies to treat IDH mutant malignancies.Cellular metabolism has been hypothesized to play a central role in cancer since the observation made almost a century ago by Otto Warburg (Warburg 1956) that cancer cells preferentially generate energy by metabolizing glucose to lactate. Even in the presence of oxygen, cancer cells switch from generating ATP by the highly energy-efficient process of oxidative phosphorylation to the much less efficient process of glycolysis (Vander Heiden et al. 2009;Dang 2012). Why this switch occurs has long been a mystery, although the observation that normal cells use ''aerobic glycolysis'' during periods of increased proliferation supports the hypothesis that this metabolic switch is an important feature of rapidly dividing cells (Locasale and Cantley 2011;Lunt and Vander Heiden 2011). Recent work suggests that aerobic glycolysis facilitates cellular transformation by producing the high levels of glycolytic intermediates that proliferating cells need for the biosynthesis of lipids, amino acids, and nucleic acids. Moreover, metabolic reprogramming appears to be sufficient to mediate tumorigenesis in some systems (Lyssiotis and Cantley 2012;Sebastian et al. 2012). Nevertheless, whether altered cellular metabolism is a cause of cancer or merely an adaptive response of cancer cells in the face of accelerated cell proliferation is still a topic of some debate.The recent identification of cancer-associated mutations in three metabolic enzymes suggests that altered cellular metabolism can indeed be a cause of some cancers (Pollard et al. 2003;King et al. 2006;Raimundo et al. 2011). Two of these enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are bone fide tumor suppressors, and loss-of-function mutations in FH and SDH have been identified in various cancers, including renal cell carcinomas and paragangliomas. The third mutated enzyme, isocitrate dehydrogenase (IDH), is a more complicated case. Mutations in two isoforms of IDH, IDH1 and IDH2, are common in a diverse array of cancers, including gliomas and acute myelogenous leukemia (AML) (Dang et al. 2010). The mutant enzymes are not catalytically inactive. Rather, the cancer-associated mutations alter the catalytic activity of the enzymes such that they produce high levels of a metabolite, (R)-2-hydroxyglutarate [(R)-2HG], which is normally ...

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“…IDH1mut related to a significantly lower expression of both receptors, CXCR4 and CXCR7, but presented no significant impact on the expression of HIF1α corroborating previous observations by others. [54] , [55] In fact, it have been demonstrated that 2HG, the oncometabolite generated by IDH1 mutation, inhibits α-KG-dependent dioxygenases. These enzymes modulate several pathways, including sensitization to hypoxia, demethylation of histones and DNA, fatty acid metabolism and modifications of collagen, contributing to tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

CXCR7 and CXCR4 Expressions in Infiltrative Astrocytomas and Their Interactions with HIF1α Expression and IDH1 Mutation

Bianco

Uno

Oba-Shinjo

et al. 2014

Pathol. Oncol. Res.

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The CXCR7, a new receptor for CXCL12 with higher affinity than CXCR4 has raised key issues on glioma cell migration. The aim of this study is to investigate the CXCR7 mRNA expression in diffuse astrocytomas tissues and to evaluate its interactions with CXCR4 and HIF1α expression and IDH1 mutation. CXCR7, CXCR4 and HIF1α mRNA expression were evaluated in 129 frozen samples of astrocytomas. IDH1 mutation status was analyzed with gene expressions, matched with clinicopathological parameters and overall survival time. Protein expression was analyzed by immunohistochemistry in different grades of astrocytoma and in glioma cell line (U87MG) by confocal microscopy. There was significant difference in the expression levels of the genes studied between astrocytomas and non-neoplasic (NN) controls (p < 0.001). AGII showed no significant correlation between CXCR7/HIF1α (p = 0.548); there was significant correlation between CXCR7/CXCR4 (p = 0.042) and CXCR7/IDH1 (p = 0.008). GBM showed significant correlations between CXCR7/CXCR4 (p = 0.002), CXCR7/IDH1 (p < 0.001) and CXCR7/HIF1α (p = 0.008). HIF1α overexpression was associated with higher expressions of CXCR7 (p = 0.01) and CXCR4 (p < 0.0001), while IDH1 mutation was associated with lower CXCR7 (p = 0.009) and CXCR4 (p = 0.0005) mRNA expressions. Protein expression increased with malignancy and in U87MG cell line was mainly localized in the cellular membrane. CXCR7 was overexpressed in astrocytoma and correlates with CXCR4 and IDH1 in AGII and CXCR4, IDH1 and HIF1α in GBM. Overexpression HIF1α was related with higher expressions of CXCR7 and CXCR4, otherwise IDH1 mutation related with lower expression of both genes. No association between CXCR7 and CXCR4 expression and survival data was related.

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R132H-mutation of isocitrate dehydrogenase-1 is not sufficient for HIF-1α upregulation in adult glioma

Cited by 70 publications

References 10 publications

IDH mutation status impact on in vivo hypoxia biomarkers expression: new insights from a clinical, nuclear imaging and immunohistochemical study in 33 glioma patients

IDH mutation status impact on in vivo hypoxia biomarkers expression: new insights from a clinical, nuclear imaging and immunohistochemical study in 33 glioma patients

What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

CXCR7 and CXCR4 Expressions in Infiltrative Astrocytomas and Their Interactions with HIF1α Expression and IDH1 Mutation

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