Immunometabolic profiles in glioma studied with 1H HRMAS NMR Open Access

Abstract

Gliomas are one of the most common types of brain tumors, with 20,000 cases diagnosed every year in the United States alone. Developing specific imaging biomarkers may aid in noninvasively diagnosing and monitoring treatment response in order to improve the prognosis of gliomas. A common property of cancer is the Warburg effect, in which cancer cells use aerobic glycolysis over oxidative phosphorylation, enabling glycolytic byproducts to serve as the precursors for the synthetic biomass needed for cancer proliferation. The precursors for the synthetic biomass arise from glutamine metabolism, which provides nitrogen for the biomass that supports the Warburg effect and enables rapid cancer growth. Moreover, inflammation in the tumor microenvironment increases the expression of enzymes that metabolize glutamine. As glutamine is one of the main substrates for cellular growth in gliomas, it may be a potential imaging biomarker for prognosis and treatment monitoring. The goal of this study was to investigate the relationship between glutamine and inflammation in the tumor microenvironment. 1H high-resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectra were acquired from 16 histologically-confirmed ex vivo human glioma samples (World Health Organization grade II=5; grade III=6; grade IV=5) and metabolites were quantified using LCModel. Concentrations of interleukin (IL)-1A, IL-1B, IL-8, IL-6, tumor necrosis factor a (TNF-a), and C-reactive protein (CRP) in glioma samples were quantified using electrochemiluminescence assays. Principal component analysis (PCA) was performed to limit multiple comparisons of the inflammatory markers. Glutamine, glutamate glutathione, lactate, and alanine increased significantly with tumor grade (p<.05). Concentrations of inflammatory markers IL-1A, IL-1B, IL-6, and IL-8 also increased with tumor grade (p<.05). Glutamine, alanine, glutathione, and lactate were positively associated with the first inflammatory marker PC, and myo-inositol was positively associated with the second PC. Our findings indicate that inflammation is associated with metabolic reprogramming and identifies glutamine as a potential biomarker for metabolic reprogramming in gliomas. Future work will translate the investigation of glutamine as an imaging biomarker to in vivo studies.

Table of Contents

1.     Introduction……………………………………………………………………….…...........……...........1

2.     Methods………………………………………………………………….......…...................................4

2.1    Human Glioma Tissue Samples………………………………………………………………….........4

2.2    Electrochemiluminescence Assays…………………………………………………………………....5

2.3    HRMAS NMR spectroscopy………………………………………………………………….......…......6

2.4    Statistical analysis………………………………………………………………….......…...................6

3.     Results………………………………………………………………….......….....................................7

4.     Discussion………………………………………………………………….......…...............................15

5.     References………………………………………………………………….......…...............................18

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Biochemistry Chemistry, Physical
Keyword	Glioma Cancer MRS Biochemistry NMR Physical chemistry
Committee Chair / Thesis Advisor	Candace C. Fleischer, Emory University
Committee Members	Michael McCormick, Emory University Jeremy Weaver, Emory University

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