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

Qi Qi; Matthew S Fox; Heeseung Lim; Rebecca Sullivan; Alex Li; Miranda Bellyou; Lise Desjardins; Andrew McClennan; Robert Bartha; Lisa Hoffman; Timothy J Scholl; Ting-Yim Lee; Jonathan D Thiessen

doi:10.1007/s11307-022-01726-0

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

Mol Imaging Biol. 2023 Apr;25(2):271-282. doi: 10.1007/s11307-022-01726-0. Epub 2022 Nov 23.

Authors

Qi Qi^{1

2

3}, Matthew S Fox^{3

4}, Heeseung Lim^{1

5}, Rebecca Sullivan^{2

4

6}, Alex Li⁵, Miranda Bellyou⁵, Lise Desjardins⁴, Andrew McClennan^{1

4}, Robert Bartha^{1

2

5

7}, Lisa Hoffman^{1

2

4

6

8}, Timothy J Scholl^{1

2

4

9}, Ting-Yim Lee^{1

2

4

5

7}, Jonathan D Thiessen^{10

11

12

13}

Affiliations

¹ Department of Medical Biophysics, The University of Western Ontario, London, ON, N6A 3K7, Canada.
² Molecular Imaging Program, The University of Western Ontario, London, ON, N6A 3K7, Canada.
³ Department of Physics and Astronomy, The University of Western Ontario, London, ON, N6A 3K7, Canada.
⁴ Imaging Program, Lawson Health Research Institute, London, ON, N6A 4V2, Canada.
⁵ Robarts Research Institute, The University of Western Ontario, London, ON, N6A 3K7, Canada.
⁶ Department of Pathology, The University of Western Ontario, London, ON, N6A 3K7, Canada.
⁷ Department of Medical Imaging, The University of Western Ontario, London, ON, N6A 3K7, Canada.
⁸ Department of Anatomy and Cell Biology, The University of Western Ontario, London, ON, N6A 3K7, Canada.
⁹ Ontario Institute for Cancer Research, Toronto, ON, M5G 0A3, Canada.
¹⁰ Department of Medical Biophysics, The University of Western Ontario, London, ON, N6A 3K7, Canada. jthiessen@lawsonimaging.ca.
¹¹ Molecular Imaging Program, The University of Western Ontario, London, ON, N6A 3K7, Canada. jthiessen@lawsonimaging.ca.
¹² Imaging Program, Lawson Health Research Institute, London, ON, N6A 4V2, Canada. jthiessen@lawsonimaging.ca.
¹³ Department of Medical Imaging, The University of Western Ontario, London, ON, N6A 3K7, Canada. jthiessen@lawsonimaging.ca.

PMID: 36418769
DOI: 10.1007/s11307-022-01726-0

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 pH_i (∆pH_i) was calculated as the difference between pH_i 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 ∆pH_i were evaluated using Pearson's correlation.

Results: A decrease of 0.14 in pH_i was found after glucose infusion in tumor region. Significant correlations between tumor glycolysis measurements of Lac:Pyr and ∆pH_i 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 ∆pH_i within the tumor (ρ = - 0.45, P = 0.17) and peritumor regions (ρ = - 0.6, P = 0.051).

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

Keywords: Glucose solution; Tissue pH; Tumor glycolytic metabolism.

MeSH terms

Animals
Brain Neoplasms* / pathology
Fluorodeoxyglucose F18
Glioblastoma* / pathology
Glucose
Glycolysis
Hydrogen-Ion Concentration
Magnetic Resonance Imaging / methods
Male
Pyruvates
Rats
Rats, Wistar

Substances

Fluorodeoxyglucose F18
Glucose
Pyruvates