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Glucose Infusion Induced Change in Intracellular pH and Its Relationship with Tumor Glycolysis in a C6 Rat Model of Glioblastoma

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Abstract

Introduction

The reliance on glycolytic metabolism is a hallmark of tumor metabolism. Excess acid and protons are produced, leading to an acidic tumor environment. Therefore, we explored the relationship between the tumor glycolytic metabolism and tissue pH by comparing 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and hyperpolarized [1-13C]pyruvate MR spectroscopy imaging (MRSI) to chemical exchange saturation transfer (CEST) MRI measurements of tumor pH.

Methods

106 C6 glioma cells were implanted in the brains of male Wistar rats (N = 11) using stereotactic surgery. A 60-min PET acquisition after a bolus of FDG was performed at 11–13 days post implantation, and standardized uptake value (SUV) was calculated. CEST measurements were acquired the following day before and during constant infusion of glucose solution. Tumor intracellular pH (pHi) was evaluated using amine and amide concentration-independent detection (AACID) CEST MRI. The change of pHi (∆pHi) was calculated as the difference between pHi pre- and during glucose infusion. Rats were imaged immediately with hyperpolarized [1-13C]pyruvate MRSI. Regional maps of the ratio of Lac:Pyr were acquired. The correlations between SUV, Lac:Pyr ratio, and ∆pHi were evaluated using Pearson’s correlation.

Results

A decrease of 0.14 in pHi was found after glucose infusion in tumor region. Significant correlations between tumor glycolysis measurements of Lac:Pyr and ∆pHi within the tumor (ρ = 0.83, P = 0.01) and peritumoral region (ρ = 0.76, P = 0.028) were observed. No significant correlations were found between tumor SUV and ∆pHi within the tumor (ρ =  − 0.45, P = 0.17) and peritumor regions (ρ =  − 0.6, P = 0.051).

Conclusion

AACID detected the changes in pHi induced by glucose infusion. Significant correlations between tumor glycolytic measurement of Lac:Pyr and tumoral and peritumoral pHi and ∆pHi suggest the intrinsic relationship between tumor glycolytic metabolism and the tumor pH environment as well as the peritumor pH environment.

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Authors and Affiliations

  1. Department of Medical Biophysics, The University of Western Ontario, London, ON, N6A 3K7, Canada

    Qi Qi, Heeseung Lim, Andrew McClennan, Robert Bartha, Lisa Hoffman, Timothy J. Scholl, Ting-Yim Lee & Jonathan D. Thiessen

  2. Molecular Imaging Program, The University of Western Ontario, London, ON, N6A 3K7, Canada

    Qi Qi, Rebecca Sullivan, Robert Bartha, Lisa Hoffman, Timothy J. Scholl, Ting-Yim Lee & Jonathan D. Thiessen

  3. Department of Physics and Astronomy, The University of Western Ontario, London, ON, N6A 3K7, Canada

    Qi Qi & Matthew S. Fox

  4. Imaging Program, Lawson Health Research Institute, London, ON, N6A 4V2, Canada

    Matthew S. Fox, Rebecca Sullivan, Lise Desjardins, Andrew McClennan, Lisa Hoffman, Timothy J. Scholl, Ting-Yim Lee & Jonathan D. Thiessen

  5. Robarts Research Institute, The University of Western Ontario, London, ON, N6A 3K7, Canada

    Heeseung Lim, Alex Li, Miranda Bellyou, Robert Bartha & Ting-Yim Lee

  6. Department of Pathology, The University of Western Ontario, London, ON, N6A 3K7, Canada

    Rebecca Sullivan & Lisa Hoffman

  7. Department of Medical Imaging, The University of Western Ontario, London, ON, N6A 3K7, Canada

    Robert Bartha, Ting-Yim Lee & Jonathan D. Thiessen

  8. Department of Anatomy and Cell Biology, The University of Western Ontario, London, ON, N6A 3K7, Canada

    Lisa Hoffman

  9. Ontario Institute for Cancer Research, Toronto, ON, M5G 0A3, Canada

    Timothy J. Scholl

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  1. Qi Qi
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Correspondence to Jonathan D. Thiessen.

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Qi, Q., Fox, M.S., Lim, H. et al. Glucose Infusion Induced Change in Intracellular pH and Its Relationship with Tumor Glycolysis in a C6 Rat Model of Glioblastoma. Mol Imaging Biol 25, 271–282 (2023). https://doi.org/10.1007/s11307-022-01726-0

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