Vivek Tiwari1, Elena V Daoud2, Kimmo J Hatanpaa2,3,4, Ang Gao5, Song Zhang5, Zhongxu An1, Sandeep K Ganji6,7, Jack M Raisanen2,3,4, Cheryl M Lewis3, Pegah Askari1, Jeannie Baxter1, Michael Levy8, Ivan Dimitrov1,9, Binu P Thomas1, Marco C Pinho1,7, Christopher J Madden3,4,8, Edward Pan3,8,10, Toral R Patel8,10,11, Ralph J DeBerardinis12,13,14,15, A Dean Sherry1,7,16, Bruce E Mickey3,4,8, Craig R Malloy1,7,17,18, Elizabeth A Maher3,4,10,17, Changho Choi1,3,7. 1. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas. 2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas. 3. Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas. 4. Annette Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, Texas. 5. Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas. 6. Philips Healthcare, Andover, Massachusetts. 7. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas. 8. Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas. 9. Philips Medical Systems, Cleveland, Ohio. 10. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas. 11. Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas. 12. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas. 13. Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas. 14. McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas. 15. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas. 16. Department of Chemistry, University of Texas at Dallas, Dallas, Texas. 17. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. 18. Veterans Affairs North Texas Health Care System, Dallas, Texas.
Abstract
BACKGROUND: High-grade gliomas likely remodel the metabolic machinery to meet the increased demands for amino acids and nucleotides during rapid cell proliferation. Glycine, a non-essential amino acid and intermediate of nucleotide biosynthesis, may increase with proliferation. Non-invasive measurement of glycine by magnetic resonance spectroscopy (MRS) was evaluated as an imaging biomarker for assessment of tumor aggressiveness. METHODS: We measured glycine, 2-hydroxyglutarate (2HG), and other tumor-related metabolites in 35 glioma patients using an MRS sequence tailored for co-detection of glycine and 2HG in gadolinium-enhancing and non-enhancing tumor regions on 3T MRI. Glycine and 2HG concentrations as measured by MRS were correlated with tumor cell proliferation (MIB-1 labeling index), expression of mitochondrial serine hydroxymethyltransferase (SHMT2), and glycine decarboxylase (GLDC) enzymes, and patient overall survival. RESULTS: Elevated glycine was strongly associated with presence of gadolinium enhancement, indicating more rapidly proliferative disease. Glycine concentration was positively correlated with MIB-1, and levels higher than 2.5 mM showed significant association with shorter patient survival, irrespective of isocitrate dehydrogenase status. Concentration of 2HG did not correlate with MIB-1 index. A high glycine/2HG concentration ratio, >2.5, was strongly associated with shorter survival (P < 0.0001). GLDC and SHMT2 expression were detectable in all tumors with glycine concentration, demonstrating an inverse correlation with GLDC. CONCLUSIONS: The data suggest that aggressive gliomas reprogram glycine-mediated one-carbon metabolism to meet the biosynthetic demands for rapid cell proliferation. MRS evaluation of glycine provides a non-invasive metabolic imaging biomarker that is predictive of tumor progression and clinical outcome. KEY POINTS: 1. Glycine and 2-hydroxyglutarate in glioma patients are precisely co-detected using MRS at 3T.2. Tumors with elevated glycine proliferate and progress rapidly.3. A high glycine/2HG ratio is predictive of shortened patient survival.
BACKGROUND: High-grade gliomas likely remodel the metabolic machinery to meet the increased demands for amino acids and nucleotides during rapid cell proliferation. Glycine, a non-essential amino acid and intermediate of nucleotide biosynthesis, may increase with proliferation. Non-invasive measurement of glycine by magnetic resonance spectroscopy (MRS) was evaluated as an imaging biomarker for assessment of tumor aggressiveness. METHODS: We measured glycine, 2-hydroxyglutarate (2HG), and other tumor-related metabolites in 35 gliomapatients using an MRS sequence tailored for co-detection of glycine and 2HG in gadolinium-enhancing and non-enhancing tumor regions on 3T MRI. Glycine and 2HG concentrations as measured by MRS were correlated with tumor cell proliferation (MIB-1 labeling index), expression of mitochondrial serine hydroxymethyltransferase (SHMT2), and glycine decarboxylase (GLDC) enzymes, and patient overall survival. RESULTS: Elevated glycine was strongly associated with presence of gadolinium enhancement, indicating more rapidly proliferative disease. Glycine concentration was positively correlated with MIB-1, and levels higher than 2.5 mM showed significant association with shorter patient survival, irrespective of isocitrate dehydrogenase status. Concentration of 2HG did not correlate with MIB-1 index. A high glycine/2HG concentration ratio, >2.5, was strongly associated with shorter survival (P < 0.0001). GLDC and SHMT2 expression were detectable in all tumors with glycine concentration, demonstrating an inverse correlation with GLDC. CONCLUSIONS: The data suggest that aggressive gliomas reprogram glycine-mediated one-carbon metabolism to meet the biosynthetic demands for rapid cell proliferation. MRS evaluation of glycine provides a non-invasive metabolic imaging biomarker that is predictive of tumor progression and clinical outcome. KEY POINTS: 1. Glycine and 2-hydroxyglutarate in gliomapatients are precisely co-detected using MRS at 3T.2. Tumors with elevated glycine proliferate and progress rapidly.3. A high glycine/2HG ratio is predictive of shortened patient survival.
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