Metabolic Imaging of Glutamine in Cancer

Zhu, Lin; Plöessl, Karl; Zhou, Rong; Mankoff, David A.; Kung, Hank F.

doi:10.2967/jnumed.116.182345

Cited by 70 publications

(63 citation statements)

References 31 publications

(52 reference statements)

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“…In many cases, tumors become glucose-and glutamine-addicted and deplete these substrates in their microenvironment. [326][327][328][329][330] We found IAV induced similar regulatory events, ultimately leading to epithelial cells depending on glucose and glutamine for survival while DCs were resistant.…”

Section: Con Clus Ionsmentioning

confidence: 69%

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

Bahadoran

Bezavada

Smallwood

2020

Immunological Reviews

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The metabolic impact of influenza A virus (IAV) infections on immune cells remains largely uncharacterized. However, much is known about the metabolism of IAV infection and immunometabolism. Thus, we will consider four main factors: the metabolic requirements of influenza virus, metabolic reprogramming of immune cells that are mobilized to fight IAV infection, the impact of systemic or local metabolism on the infection and immune response, and vice versa. We will also address the interplay of metabolism and cytokines with a focus on those relevant to IAV infections. Finally, we will limit information on immunometabolism to key cell types critical to fighting IAV infection. We will relate this information to the unique metabolic demands on immune cells and discuss how their translocation through nutrient diverse and changing environments may affect their functions in IAV infection. | ME TABOLIS M AND THE LUNG MICROENVIRONMENT | Steady-state metabolismUnder aerobic conditions, cells sustain themselves catabolically using glycolytic carbons to fuel the tricarboxylic acid (TCA) cycle. AbstractRecent studies support the notion that glycolysis and oxidative phosphorylation are rheostats in immune cells whose bioenergetics have functional outputs in terms of their biology. Specific intrinsic and extrinsic molecular factors function as molecular potentiometers to adjust and control glycolytic to respiratory power output. In many cases, these potentiometers are used by influenza viruses and immune cells to support pathogenesis and the host immune response, respectively. Influenza virus infects the respiratory tract, providing a specific environmental niche, while immune cells encounter variable nutrient concentrations as they migrate in response to infection. Immune cell subsets have distinct metabolic programs that adjust to meet energetic and biosynthetic requirements to support effector functions, differentiation, and longevity in their ever-changing microenvironments. This review details how influenza coopts the host cell for metabolic reprogramming and describes the overlap of these regulatory controls in immune cells whose function and fate are dictated by metabolism. These details are contextualized with emerging evidence of the consequences of influenzainduced changes in metabolic homeostasis on disease progression. K E Y W O R D Shost pathogen, immune response, Immunometabolism, Influenza, metabolism, viral infection, virus | 141 BAHADORAN et Al.

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Section: Con Clus Ionsmentioning

confidence: 69%

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

Bahadoran

Bezavada

Smallwood

2020

Immunological Reviews

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“…It is our hope that with the low-dose capability of a totalbody system, PET will once again become more widely used to study normal biology, metabolism, and physiology, but this time addressing different sets of questions that are not amenable to study with existing tools. New metabolic tracers are becoming available, such as the recent introduction of 18 F-fluoroglutamine for imaging of glutamine metabolism (52). There are a broad range of studies that could be conducted to study the role of nutrition and exercise and their impact on metabolism, inflammation, the immune system, the cardiovascular system, the endocrine system, and the microbiome.…”

Section: Applications For Total-body Pet Human Researchmentioning

confidence: 99%

Total-Body PET: Maximizing Sensitivity to Create New Opportunities for Clinical Research and Patient Care

et al. 2017

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PET is widely considered the most sensitive technique available for noninvasively studying physiology, metabolism, and molecular pathways in the living human being. However, the utility of PET, being a photon-deficient modality, remains constrained by factors including low signal-to-noise ratio, long imaging times, and concerns about radiation dose. Two developments offer the potential to dramatically increase the effective sensitivity of PET. First by increasing the geometric coverage to encompass the entire body, sensitivity can be increased by a factor of about 40 for total-body imaging or a factor of about 4-5 for imaging a single organ such as the brain or heart. The world's first total-body PET/CT scanner is currently under construction to demonstrate how this step change in sensitivity affects the way PET is used both in clinical research and in patient care. Second, there is the future prospect of significant improvements in timing resolution that could lead to further effective sensitivity gains. When combined with total-body PET, this could produce overall sensitivity gains of more than 2 orders of magnitude compared with existing state-of-the-art systems. In this article, we discuss the benefits of increasing body coverage, describe our efforts to develop a first-generation total-body PET/CT scanner, discuss selected application areas for total-body PET, and project the impact of further improvements in time-of-flight PET.Key Words: instrumentation; molecular imaging; PET/CT; instrumentation; PET; total-body imaging J Nucl Med 2018; 59:3-12 DOI: 10.2967/jnumed.116.184028Al l nuclear medicine studies in humans are limited by the trade-offs between the number of detected decay events, imaging time, and absorbed dose. The number of detected events determines the signal-to-noise ratio (SNR) in the final image, but constraints on administered activity, as well as high random event rates and dead time that occur at high activities, currently prevent acquisition of high-SNR images in short times. This in turn limits the ability to perform high-resolution, dynamic imaging studies with tracer kinetic modeling, because short-time-frame datasets are always noisy. A further limitation is that although the tracer injection is systemic and radiotracer is present in the entire body, current imaging systems contain only a small portion of the body within the field of view (FOV). For applications in which the distribution of radiotracer in the entire body or multiple organ systems is of interest, this limitation leads to further inefficiencies and makes it difficult to acquire dynamic data from all the tissues of interest. If one takes whole-body PET scanning with 18 F-FDG as an example, the total efficiency with which pairs of coincidence photons that escape the body are detected is well under 1% even on today's best scanners. Simplistically, this number can be derived by considering that the average geometric sensitivity within the FOV of a typical clinical PET scanner is under 5% and that with an axial coverage of ...

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“…Cancer-related metabolic alterations, adaptations and their role in tumourigenesis and progression are extensively studied in many cancers. The metabolic characterisation of human gliomas started with the reinterpretation of Warburg effect suggesting that other substrates than glucose can also be oxidised by glioma cells [ 12 , 16 , 17 ], such as glutamine and acetate [ 18 – 20 ].…”

Section: Introductionmentioning

confidence: 99%

GABA, glutamine, glutamate oxidation and succinic semialdehyde dehydrogenase expression in human gliomas

Hujber

Horváth

Petővári

et al. 2018

J Exp Clin Cancer Res

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BackgroundBioenergetic characterisation of malignant tissues revealed that different tumour cells can catabolise multiple substrates as salvage pathways, in response to metabolic stress. Altered metabolism in gliomas has received a lot of attention, especially in relation to IDH mutations, and the associated oncometabolite D-2-hydroxyglutarate (2-HG) that impact on metabolism, epigenetics and redox status. Astrocytomas and oligodendrogliomas, collectively called diffuse gliomas, are derived from astrocytes and oligodendrocytes that are in metabolic symbiosis with neurons; astrocytes can catabolise neuron-derived glutamate and gamma-aminobutyric acid (GABA) for supporting and regulating neuronal functions.MethodsMetabolic characteristics of human glioma cell models – including mitochondrial function, glycolytic pathway and energy substrate oxidation – in relation to IDH mutation status and after 2-HG incubation were studied to understand the Janus-faced role of IDH1 mutations in the progression of gliomas/astrocytomas. The metabolic and bioenergetic features were identified in glioma cells using wild-type and genetically engineered IDH1-mutant glioblastoma cell lines by metabolic analyses with Seahorse, protein expression studies and liquid chromatography-mass spectrometry.ResultsU251 glioma cells were characterised by high levels of glutamine, glutamate and GABA oxidation. Succinic semialdehyde dehydrogenase (SSADH) expression was correlated to GABA oxidation. GABA addition to glioma cells increased proliferation rates. Expression of mutated IDH1 and treatment with 2-HG reduced glutamine and GABA oxidation, diminished the pro-proliferative effect of GABA in SSADH expressing cells. SSADH protein overexpression was found in almost all studied human cases with no significant association between SSADH expression and clinicopathological parameters (e.g. IDH mutation).ConclusionsOur findings demonstrate that SSADH expression may participate in the oxidation and/or consumption of GABA in gliomas, furthermore, GABA oxidation capacity may contribute to proliferation and worse prognosis of gliomas. Moreover, IDH mutation and 2-HG production inhibit GABA oxidation in glioma cells. Based on these data, GABA oxidation and SSADH activity could be additional therapeutic targets in gliomas/glioblastomas.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0946-5) contains supplementary material, which is available to authorized users.

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Metabolic Imaging of Glutamine in Cancer

Cited by 70 publications

References 31 publications

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

Total-Body PET: Maximizing Sensitivity to Create New Opportunities for Clinical Research and Patient Care

GABA, glutamine, glutamate oxidation and succinic semialdehyde dehydrogenase expression in human gliomas

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