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Effect of injection of a gadolinium chelate (Prohance) on the tumor lactate signal intensity. The contrast agent was injected ~35 s after injection of hyperpolarized [1-13 C]pyruvate at t = 0. The full line shows a fit to Equation 1. The broken line shows the expected lactate signal intensity if the gadolinium (Gd) chelate had not been injected. 4-CIN, α-cyano-4-hydroxycinnamate TABLE 3 Analysis of exchange rate constants and lactate polarization decay rates in tumors of untreated mice and mice treated with a monocarboxylate transporter (MCT) inhibitor (4-CIN, α-cyano-4-hydroxycinnamate). The animals were injected with a gadolinium chelate 35 s after injection of hyperpolarized [1-13 C]pyruvate k P (s-1 ) R 1 (s-1 ) R 1,Gd (s-1 ) Control (n = 9) 0.153 ± 0.03 0.056 ± 0.004 0.091 ± 0.011 b 4-CIN (n = 6) 0.102 ± 0.014* 0.041 ± 0.003 a 0.084 ± 0.005 The control group includes animals with (n = 4) and without (n = 5) gadolinium chelate injection. Lactate peak intensities were fitted to Equation 1. a Different from control, p < 0.05 (Student's t-test). b
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![FIGURE 1 Biodistribution [percentage of injected dose (ID%)/g] of [1-14...](publication/323290726/figure/fig1/AS:613929583669253@1523383627242/Biodistribution-percentage-of-injected-dose-ID-g-of-1-14-C-pyruvate-injected_Q320.jpg)
Measurements of hyperpolarized13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool can give an apparent first-order rate constant for the exchange. The determination of the isotope flux, however, requires an estimate of the labeled pyruvate concentration in the tumor. This was achieved here by measurement of the...
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... Previous reports have indicated that the rate of lactate transport to the extracellular compartment is only slightly slower than the rate of labeled lactate formation, 19 and we have shown previously in EL4 tumor cells that transport and LDH activity have similar flux control coefficients for the exchange of hyperpolarized 13 C label. 24 Injection of the gadolinium chelate resulted in an increased rate of decay of the lactate signal, which could not be explained simply by the accelerated loss of pyruvate polarization (Figure 3). The broken lines in Figure 3 show the lactate signal that would have been observed based on the observed pyruvate signal and assuming that k P does not change following the injection of the gadolinium chelate. ...
Context 2
... Injection of the gadolinium chelate resulted in an increased rate of decay of the lactate signal, which could not be explained simply by the accelerated loss of pyruvate polarization (Figure 3). The broken lines in Figure 3 show the lactate signal that would have been observed based on the observed pyruvate signal and assuming that k P does not change following the injection of the gadolinium chelate. This is consistent with some fraction of the lactate signal coming from the extracellular compartment, which will be predominantly the interstitial space, given the low blood volume. ...
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This study shows the use of hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) to assess therapeutic efficacy in a preclinical tumor model. 13C-labeled pyruvate was used to monitor early changes in tumor metabolism based on the Warburg effect. High-grade malignant tumors exhibit increased glycolytic activity and lactate production t...
Citations
... Oxidative substrate pyruvate in vitro enhances the oxidative and ATP-productive capacity of mitochondria and protects pancreatic acinar cells from toxic substances (Peng et al. 2018;Manko et al. 2019Manko et al. , 2021. It is interesting that substantial levels of pyruvate are quickly accumulated in the pancreas among other organs after intravenous administration (Serrao et al. 2018), making this substance a very attractive choice for acute pancreatitis management. Indeed, intravenous sodium pyruvate has a positive effect on acute cerulein-induced pancreatitis in rats (Ziolkowski et al. 2008). ...
Plasma amino acid levels are altered upon many pathological conditions including acute pancreatitis. It is unclear whether amino acids can be used as specific biomarker of acute pancreatitis severity or recovery. Development of acute pancreatitis is associated with mitochondrial dysfunction and decreased cytosolic ATP level. Sodium pyruvate is considered as a potential treatment of pancreatitis due to its ability to sustain mitochondrial oxidative and ATP-productive capacity in vitro. This study investigated the effect of sodium pyruvate on pancreatic morphology and plasma amino acid levels in rats with acute pancreatitis. Acute pancreatitis in rats was induced by administration of l-arginine (5 g/kg) Experimental treatment group received sodium pyruvate (1 g/kg) for 4 days. On day 8 of the experiment, animals were killed, blood was collected and plasma amino acid concentration was determined with high-performance liquid chromatography. Histological examination showed large areas of fibrosis in the pancreas of animals treated with l-arginine irrespectively of sodium pyruvate administration. Sodium pyruvate improved the plasma amino acid levels. Rats with acute pancreatitis had significantly lower levels of most essential and non-essential amino acids and increased glutamate and aspartate in plasma. Administration of sodium pyruvate completely or partially restored the levels of methionine, phenylalanine, tryptophan, leucine, isoleucine, aspartate, asparagine and ornithine levels, while increasing glutamine and serine to levels significantly higher than control. Plasma lysine, alanine, arginine and taurine remained unaffected in all experimental groups. Sodium pyruvate may be considered for use as a maintenance therapy in acute pancreatitis.
... There may be several reasons for the reduction in flux, such as loss of cell enzymes, reduced tumor cellularity, or reduced concentrations of lactate and NAD(H) in the tumor. Therefore, it is important to compare these results with FDG-PET to improve the value of FDG-PET in its current board-certified clinical application [47]. ...
Cellular metabolism governs the signaling that supports physiological mechanisms and homeostasis in an individual, including neuronal transmission, wound healing, and circadian clock manipulation. Various factors have been linked to abnormal metabolic reprogramming, including gene mutations, epigenetic modifications, altered protein epitopes, and their involvement in the development of disease, including cancer. The presence of multiple distinct hallmarks and the resulting cellular reprogramming process have gradually revealed that these metabolism-related molecules may be able to be used to track or prevent the progression of cancer. Consequently, translational medicines have been developed using metabolic substrates, precursors, and other products depending on their biochemical mechanism of action. It is important to note that these metabolic analogs can also be used for imaging and therapeutic purposes in addition to competing for metabolic functions. In particular, due to their isotopic labeling, these compounds may also be used to localize and visualize tumor cells after uptake. In this review, the current development status, applicability, and limitations of compounds targeting metabolic reprogramming are described, as well as the imaging platforms that are most suitable for each compound and the types of cancer to which they are most appropriate.
... It is also important to note that studies with hyperpolarized [1-13 C]pyruvate are translational as it is the lead agent for clinical use [13]. One of the most observed metabolic conversions when administering hyperpolarized [1-13 C]pyruvate to mammalian tissues in vivo or ex vivo is the production of hyperpolarized [1-13 C]lactate, which is due to the incell activity of lactate dehydrogenase (LDH) [14][15][16][17][18][19][20][21][22]. Previously, the metabolic properties of organoids were studied mostly by mass spectroscopy-based methods [23][24][25]. ...
Organoids are a powerful tool in the quest to understand human diseases. As the developing brain is extremely inaccessible in mammals, cerebral organoids (COs) provide a unique way to investigate neural development and related disorders. The aim of this study was to utilize hyperpolarized 13C NMR to investigate the metabolism of COs in real-time, in a non-destructive manner. The enzymatic activity of lactate dehydrogenase (LDH) was determined by quantifying the rate of [1-13C]lactate production from hyperpolarized [1-13C]pyruvate. Organoid development was assessed by immunofluorescence imaging. Organoid viability was confirmed using 31P NMR spectroscopy. A total of 15 organoids collated into 3 groups with a group total weight of 20–77 mg were used in this study. Two groups were at the age of 10 weeks and one was at the age of 33 weeks. The feasibility of this approach was demonstrated in both age groups, and the LDH activity rate was found to be 1.32 ± 0.75 nmol/s (n = 3 organoid batches). These results suggest that hyperpolarized NMR can be used to characterize the metabolism of brain organoids with a total tissue wet weight of as low as 20 mg (<3 mm3) and a diameter ranging from 3 to 6 mm.
... Measurements included hyperpolarized urea, revealing information about tumor perfusion (measured as tumor-tomuscle and tumor-to-liver ratios of urea), pyruvate and its metabolic conversion, as well as fumarate conversion to malate, providing insight into the levels of necrosis [49]. However, due to the cellular export and re-circulation of lactate, systemic lactate levels should be taken into account when modelling local conversion rates [50]. ...
With the increasing understanding of resistance mechanisms mediated by the metabolic reprogramming in cancer cells, there is a growing clinical interest in imaging technologies that allow for the non-invasive characterization of tumor metabolism and the interactions of cancer cells with the tumor microenvironment (TME) mediated through tumor metabolism. Specifically, tumor glycolysis and subsequent tissue acidosis in the realms of the Warburg effect may promote an immunosuppressive TME, causing a substantial barrier to the clinical efficacy of numerous immuno-oncologic treatments. Thus, imaging the varying individual compositions of the TME may provide a more accurate characterization of the individual tumor. This approach can help to identify the most suitable therapy for each individual patient and design new targeted treatment strategies that disable resistance mechanisms in liver cancer. This review article focuses on non-invasive positron-emission tomography (PET)- and MR-based imaging techniques that aim to visualize the crosstalk between tumor cells and their microenvironment in liver cancer mediated by tumor metabolism.
... Our imaging experiments show clearly and reproducibly the appearance of [1-13 C]pyruvate in the great vessels on both sides of the rat head and neck, illustrating that the receive profile of the RF coil array would not be limiting for the detection of metabolites within the brain parenchyma. In naïve rats, we apparently observed lactate production within the great vessels also, which may reflect either the glycolytic nature of red blood cells, or alternatively the efflux of hyperpolarised [1-13 C]lactate from other organs, such as the liver 91 . We note that while we detected bicarbonate spectroscopically, we were not able to image its production. ...
Hyperpolarised MRI with Dynamic Nuclear Polarisation overcomes the fundamental thermodynamic limitations of conventional magnetic resonance, and is translating to human studies with several early-phase clinical trials in progress including early reports that demonstrate the utility of the technique to observe lactate production in human brain cancer patients. Owing to the fundamental coupling of metabolism and tissue function, metabolic neuroimaging with hyperpolarised [1-¹³C]pyruvate has the potential to be revolutionary in numerous neurological disorders (e.g. brain tumour, ischemic stroke, and multiple sclerosis). Through the use of [1-¹³C]pyruvate and ethyl-[1-¹³C]pyruvate in naïve brain, a rodent model of metastasis to the brain, or porcine brain subjected to mannitol osmotic shock, we show that pyruvate transport across the blood-brain barrier of anaesthetised animals is rate-limiting. We show through use of a well-characterised rat model of brain metastasis that the appearance of hyperpolarized [1-¹³C]lactate production corresponds to the point of blood-brain barrier breakdown in the disease. With the more lipophilic ethyl-[1-¹³C]pyruvate, we observe pyruvate production endogenously throughout the entire brain and lactate production only in the region of disease. In the in vivo porcine brain we show that mannitol shock permeabilises the blood-brain barrier sufficiently for a dramatic 90-fold increase in pyruvate transport and conversion to lactate in the brain, which is otherwise not resolvable. This suggests that earlier reports of whole-brain metabolism in anaesthetised animals may be confounded by partial volume effects and not informative enough for translational studies. Issues relating to pyruvate transport and partial volume effects must therefore be considered in pre-clinical studies investigating neuro-metabolism in anaesthetised animals, and we additionally note that these same techniques may provide a distinct biomarker of blood-brain barrier permeability in future studies.
... Our imaging experiments show clearly and reproducibly the appearance of [1-13 C]pyruvate in the great vessels on both sides of the rat head and neck, illustrating that the receive profile of the RF coil array would not be limiting for the detection of metabolites within the brain parenchyma. In naïve rats, we apparently observed lactate production within the great vessels also, which may reflect either the glycolytic nature of red blood cells, or alternatively the efflux of hyperpolarised [1-13 C]lactate from other organs, such as the liver 91 . We note that while we detected bicarbonate spectroscopically, we were not able to image its production. ...
Hyperpolarised MRI with Dynamic Nuclear Polarisation overcomes the fundamental thermodynamic limitations of conventional
magnetic resonance, and is translating to human studies with several early-phase clinical trials in progress including early
reports that demonstrate the utility of the technique to observe lactate production in human brain cancer patients. Owing to
the fundamental coupling of metabolism and tissue function, metabolic neuroimaging with hyperpolarised [1-13C]pyruvate
has the potential to be revolutionary in numerous neurological disorders (e.g. brain tumour, ischemic stroke, and multiple
sclerosis). Through the use of [1-13C]pyruvate and ethyl-[1-13C]pyruvate in na¨ıve brain, a rodent model of metastasis to the
brain, or porcine brain subjected to mannitol osmotic shock, we show that pyruvate transport across the blood-brain barrier
of anaesthetised animals is rate-limiting. We show through use of a well-characterised rat model of brain metastasis that
the appearance of hyperpolarized [1-13C]lactate production corresponds to the point of blood-brain barrier breakdown in the
disease. With the more lipophilic ethyl-[1-13C]pyruvate, we observe pyruvate production endogenously throughout the entire
brain and lactate production only in the region of disease. In the in vivo porcine brain we show that mannitol shock permeabilises
the blood-brain barrier sufficiently for a dramatic 90-fold increase in pyruvate transport and conversion to lactate in the brain,
which is otherwise not resolvable. This suggests that earlier reports of whole-brain metabolism in anaesthetised animals
may be confounded by partial volume effects and not informative enough for translational studies. Issues relating to pyruvate
transport and partial volume effects must therefore be considered in pre-clinical studies investigating neuro-metabolism in
anaesthetised animals, and we additionally note that these same techniques may provide a distinct biomarker of blood-brain
barrier permeability in future studies.
... A recent study showed that, in tumor-bearing mice, following injection of hyperpolarized [1-13 C]pyruvate, there were high levels of labeled lactate in the blood, which was assumed to come from other tissues, including the blood pool. However, this labeled lactate had lost most of its polarization and therefore ''wash-in'' of this material into the tumor did not compromise the measurements of tumor pyruvate-lactate exchange (Serrao et al., 2018). The first-order rate constant describing this exchange is typically calculated by fitting the pyruvate and lactate signal intensities to a two-site exchange model (Day et al., 2007) or, more simply, by taking the ratio of the area under the lactate and pyruvate labeling curves (Hill et al., 2013). ...
... A recent study using 14 C-and 13 C-labeled pyruvate showed that only $1%-2% of the labeled pyruvate reached the tumor site, but from this concentration a metabolic flux could be calculated using the hyperpolarized 13 C label exchange data obtained in vivo. This calculated flux showed good agreement with a flux determined directly from measurements of 13 C-labeled lactate in tumor extracts (Serrao et al., 2018). ...
Due to the implication of altered metabolism in a large spectrum of tissue function and disease, assessment of metabolic processes becomes essential in managing health. In this regard, imaging can play a critical role in allowing observation of biochemical and physiological processes. Nuclear imaging methods, in particular positron emission tomography, have been widely employed for imaging metabolism but are mainly limited by the use of ionizing radiation and the sensing of only one parameter at each scanning session. Observations in healthy individuals or longitudinal studies of disease could markedly benefit from non-ionizing, multi-parameter imaging methods. We therefore focus this review on progress with the non-ionizing radiation methods of MRI, hyperpolarized magnetic resonance and magnetic resonance spectroscopy, chemical exchange saturation transfer, and emerging optoacoustic (photoacoustic) imaging. We also briefly discuss the role of nuclear and optical imaging methods for research and clinical protocols.
Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1α acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find that, unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1α-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD⁺ ratio that suppresses the activity of the NADH-sensitive GAPDH glycolytic enzyme. This is manifested when pyruvate supply is limited, since pyruvate acts as an electron acceptor that prevents the increment of the NADH/NAD⁺ ratio. Furthermore, this anti-glycolytic function provides a molecular basis to explain how HIF1α can suppress tumor cell proliferation by increasing the NADH/NAD⁺ ratio.
Hyperpolarized carbon 13 MRI (13C MRI) is a novel imaging approach that can noninvasively probe tissue metabolism in both normal and pathologic tissues. The process of hyperpolarization increases the signal acquired by several orders of magnitude, allowing injected 13C-labeled molecules and their downstream metabolites to be imaged in vivo, thus providing real-time information on kinetics. To date, the most important reaction studied with hyperpolarized 13C MRI is exchange of the hyperpolarized 13C signal from injected [1-13C]pyruvate with the resident tissue lactate pool. Recent preclinical and human studies have shown the role of several biologic factors such as the lactate dehydrogenase enzyme, pyruvate transporter expression, and tissue hypoxia in generating the MRI signal from this reaction. Potential clinical applications of hyperpolarized 13C MRI in oncology include using metabolism to stratify tumors by grade, selecting therapeutic pathways based on tumor metabolic profiles, and detecting early treatment response through the imaging of shifts in metabolism that precede tumor structural changes. This review summarizes the foundations of hyperpolarized 13C MRI, presents key findings from human cancer studies, and explores the future clinical directions of the technique in oncology. Keywords: Hyperpolarized Carbon 13 MRI, Molecular Imaging, Cancer, Tissue Metabolism © RSNA, 2023.
From basic principles to insights into pioneering research, this introductory textbook provides the fundamentals of cancer biology that will enable students of biology and medicine to enter the field with confidence. It opens with a discussion of global cancer patterns, how cancers arise, and the risk factors involved. A description of the normal signalling pathways within cells then explains how DNA mutations affect proteins and what this means for the development and behaviour of tumours. Later chapters discuss methods for tumour detection, biomarker identification and the impact of genome sequencing, before reviewing the development of anti-cancer drugs and exciting current advances in treatment. With 50% new material, including two new chapters on genetic analysis of cancer and cancer chemotherapy, improved pedagogy, examples of revolutionising technologies in drug design and delivery, and useful online resources, this textbook offers an accessible and engaging account of cancer biology for undergraduate and graduate students.
