Metabolic Syndromes and Malignant Transformation: Where the Twain Shall Meet
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Science translational medicine
(Impact Factor: 15.84).
10/2010; 2(54):54ps50. DOI: 10.1126/scitranslmed.3001669
Recurrent somatic mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes that result in the accumulation of D-2-hydroxyglutarate (D-2-HG) have been identified in malignant gliomas and in acute myeloid leukemia (AML). However, the function of this metabolite in normal and malignant tissues remains uncertain. A report in the current issue of Science describes a germline IDH2 mutation in a subset of patients with a rare metabolic disorder--D-2-hydroxyglutaric aciduria-that is similar to mutations seen in cancer patients. These observations further elucidate the effects of IDH mutations on normal and malignant cells.
Available from: Timothy P Kegelman
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ABSTRACT: Despite an increased emphasis on developing new therapies for malignant gliomas, they remain among the most intractable tumors faced today as they demonstrate a remarkable ability to evade current treatment strategies. Numerous candidate treatments fail at late stages, often after showing promising preclinical results. This disconnect highlights the continued need for improved animal models of glioma, which can be used to both screen potential targets and authentically recapitulate the human condition. This review examines recent developments in the animal modeling of glioma, from more established rat models to intriguing new systems using Drosophila and zebrafish that set the stage for higher throughput studies of potentially useful targets. It also addresses the versatility of mouse modeling using newly developed techniques recreating human protocols and sophisticated genetically engineered approaches that aim to characterize the biology of gliomagenesis. The use of these and future models will elucidate both new targets and effective combination therapies that will impact on disease management.
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ABSTRACT: FOXO transcription factors are considered bona fide tumor suppressors; however, recent studies showed FOXOs are also required for tumor survival. Here, we identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. In cancer cells carrying mutant IDH1, FOXOs likewise stimulate mutant IDH1 expression and maintain the levels of the oncometabolite 2-hydroxyglutarate, which stimulates cancer cell proliferation and inhibits TET enzymes and histone demethylases. Combined, our data provide a new paradigm for the paradoxical role of FOXOs in both tumor suppression and promotion.
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