In Vivo Metabolic Evaluation of Breast Tumor Mouse Xenografts for Predicting Aggressiveness Using the Hyperpolarized 13C-NMR Technique

Xu, He N.; Kadlececk, Stephen; Pullinger, B. D.; Profka, Harrila; Cai, Kejia; Hariharan, Hari; Rizi, Rahim R.; Li, Lin Z.

doi:10.1007/978-1-4614-7411-1_32

Cited by 3 publications

(4 citation statements)

References 21 publications

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“…All NMR experiments were performed with a 1.1-cm or 1.4-cm 1 H/ 13 C dual-tuned home-made surface coil in a 9.4-T Varian vertical bore NMR spectrometer as previously described (32, 33). The tumor-bearing mice were anesthetized by administering oxygen doped with 1% isofluorane while the body temperature was maintained at ~35.0±2.5 °C with heated air.…”

Section: Methodsmentioning

confidence: 99%

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Is Higher Lactate an Indicator of Tumor Metastatic Risk? A Pilot MRS Study Using Hyperpolarized 13C-Pyruvate

Kadlececk

Profka

et al. 2014

Academic Radiology

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Rationale and Objectives Cancer cells generate more lactate than normal cells under aerobic and hypoxic conditions – exhibiting the so-called Warburg effect. However, the relationship between the Warburg effect and tumor metastatic potential remains controversial. We intend to investigate whether the higher lactate reflects higher tumor metastatic potential. Materials and Methods We employed hyperpolarized 13C-pyruvate magnetic resonance spectroscopy (MRS) to compare lactate 13C-labeling in vivo in breast cancer mouse xenografts of highly metastatic (MDA-MB-231) and relatively indolent (MCF-7) human cell lines. We obtained the kinetic parameters of the lactate dehydrogenase (LDH)-catalyzed reaction by three methods of analysis including the differential equation (DE) fit, q-ratio (qR) fit, and ratio fit (RF) methods. Results Consistent results from the three methods showed that the highly metastatic breast tumors exhibited a smaller apparent forward rate constant (k+ = 0.060 ± .004 s−1) than the relatively indolent tumors (k+ = 0.097 ± .013 s−1). The RF fit generates the highest statistical significance for the difference (p=0.02). No significant difference is found for the reverse rate constant. Conclusion The result indicates that the less metastatic breast tumors may produce more lactate than the highly metastatic ones from the injected 13C-pyruvate, and supports the viewpoint that breast tumor metastatic risk is not necessarily associated with the high levels of glycolysis and lactate production. More studies are needed to confirm whether and how much the measured apparent rate constants are affected by the membrane transporter activity and whether they are primarily determined by the LDH activity or not.

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Section: Methodsmentioning

confidence: 99%

“…the reaction rate constants of the lactate dehydrogenase-catalyzed reaction as described by Li et al (32, 33). The principles of the analysis are briefly summarized as follows.…”

Section: Methodsmentioning

confidence: 99%

Is Higher Lactate an Indicator of Tumor Metastatic Risk? A Pilot MRS Study Using Hyperpolarized 13C-Pyruvate

Kadlececk

Profka

et al. 2014

Academic Radiology

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“…13 C MRI. HP [1-13 C] pyruvate has been used to test the degree of aerobic glycolysis versus tumor progression in breast cancer cell xenografts in mice, with higher conversion rates observed for more indolent xenografts (Xu et al 2013(Xu et al , 2014. Several studies have also looked at biologic factors modulating the observed metabolic signals in breast cancer studies, including perfusion (Lau et al 2016c), cellular transport (Harris et al 2009), and endogenous lactate and lactate dehydrogenase (LDH) concentrations (Lodi et al 2013).…”

Section: Diffusion Weighted Imaging (Dwi)mentioning

confidence: 99%

Magnetic resonance imaging with hyperpolarized agents: methods and applications

et al. 2017

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In the past decade, hyperpolarized (HP) contrast agents have been under active development for MRI applications to address the twin challenges of functional and quantitative imaging. Both HP helium (3He) and xenon (129Xe) gases have reached the stage where they are under study in clinical research. HP 129Xe, in particular, is poised for larger scale clinical research to investigate asthma, chronic obstructive pulmonary disease, and fibrotic lung diseases. With advances in polarizer technology and unique capabilities for imaging of 129Xe gas exchange into lung tissue and blood, HP 129Xe MRI is attracting new attention. In parallel, HP 13C and 15N MRI methods have steadily advanced in a wide range of pre-clinical research applications for imaging metabolism in various cancers and cardiac disease. The HP [1-13C] pyruvate MRI technique, in particular, has undergone phase I trials in prostate cancer and is poised for investigational new drug trials at multiple institutions in cancer and cardiac applications. This review treats the methodology behind both HP gases and HP 13C and 15N liquid state agents. Gas and liquid phase HP agents share similar technologies for achieving non-equilibrium polarization outside the field of the MRI scanner, strategies for image data acquisition, and translational challenges in moving from pre-clinical to clinical research. To cover the wide array of methods and applications, this review is organized by numerical section into 1) a brief introduction, 2) the physical and biological properties of the most common polarized agents with a brief summary of applications and methods of polarization, 3) methods for image acquisition and reconstruction specific to improving data acquisition efficiency for HP MRI, 4) the main physical properties that enable unique measures of physiology or metabolic pathways, followed by a more detailed review of the literature describing the use of HP agents to study 5) metabolic pathways in cancer and cardiac disease and 6) lung function in both pre-clinical and clinical research studies, 7) some future directions and challenges, and 8) an overall summary.

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“…Hyperpolarized 13 C MRS/MRSI has specific applications in breast cancer but with sometimes unexpected results. For example, Xu et al explored differences in the apparent conversion rate of pyruvate-to-lactate (k PL ) in mouse xenograft models of breast cancer with different levels of aggressiveness and found that more indolent tumors exhibited higher k PL values, contrary to the conventional model of upregulated aerobic glycolysis predicted by the Warburg hypothesis [ 9 , 10 ]. In contrast, Ward et al demonstrated the sensitivity of hyperpolarized pyruvate-to-lactate conversion to LDH modulation by inhibiting phosphoinositide 3-kinases (PI3K), a key enzyme implicated in cancer development and involved in regulating LDH concentrations [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Hyperpolarized 13C Magnetic Resonance Spectroscopic Imaging of Pyruvate Metabolism in Murine Breast Cancer Models of Different Metastatic Potential

et al. 2021

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This study uses dynamic hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopic imaging (MRSI) to estimate differences in glycolytic metabolism between highly metastatic (4T1, n = 7) and metastatically dormant (4T07, n = 7) murine breast cancer models. The apparent conversion rate of pyruvate-to-lactate (kPL) and lactate-to-pyruvate area-under-the-curve ratio (AUCL/P) were estimated from the metabolite images and compared with biochemical metabolic measures and immunohistochemistry (IHC). A non-significant trend of increasing kPL (p = 0.17) and AUCL/P (p = 0.11) from 4T07 to 4T1 tumors was observed. No significant differences in tumor IHC lactate dehydrogenase-A (LDHA), monocarboxylate transporter-1 (MCT1), cluster of differentiation 31 (CD31), and hypoxia inducible factor-α (HIF-1α), tumor lactate-dehydrogenase (LDH) activity, or blood lactate or glucose levels were found between the two tumor lines. However, AUCL/P was significantly correlated with tumor LDH activity (ρspearman = 0.621, p = 0.027) and blood glucose levels (ρspearman = −0.474, p = 0.042). kPL displayed a similar, non-significant trend for LDH activity (ρspearman = 0.480, p = 0.114) and blood glucose levels (ρspearman = −0.414, p = 0.088). Neither kPL nor AUCL/P were significantly correlated with blood lactate levels or tumor LDHA or MCT1. The significant positive correlation between AUCL/P and tumor LDH activity indicates the potential of AUCL/P as a biomarker of glycolytic metabolism in breast cancer models. However, the lack of a significant difference between in vivo tumor metabolism for the two models suggest similar pyruvate-to-lactate conversion despite differing metastatic potential.

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In Vivo Metabolic Evaluation of Breast Tumor Mouse Xenografts for Predicting Aggressiveness Using the Hyperpolarized 13C-NMR Technique

Cited by 3 publications

References 21 publications

Is Higher Lactate an Indicator of Tumor Metastatic Risk? A Pilot MRS Study Using Hyperpolarized 13C-Pyruvate

Is Higher Lactate an Indicator of Tumor Metastatic Risk? A Pilot MRS Study Using Hyperpolarized 13C-Pyruvate

Magnetic resonance imaging with hyperpolarized agents: methods and applications

Hyperpolarized 13C Magnetic Resonance Spectroscopic Imaging of Pyruvate Metabolism in Murine Breast Cancer Models of Different Metastatic Potential

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