Multimodal Elucidation of Choline Metabolism in a Murine Glioma Model Using Magnetic Resonance Spectroscopy and 11C-Choline Positron Emission Tomography

Abstract

The metabolites, transporters, and enzymes involved in choline metabolism are regarded as biomarkers for disease progression in a variety of cancers, but their in vivo detection is not ideal. Both magnetic resonance spectroscopy [MRS using chemical shift imaging (CSI) total choline (tCho)] and 11 C-choline positron emission tomography (PET) can probe this pathway, but they have not been compared side by side. In this study, we used the spontaneous murine astrocytoma model SMA560 injected intracranially into syngeneic VM/Dk mice, analyzing animals at various postimplantation time points using dynamic microPET imaging and CSI MRS. We observed an increase in tumor volume and 11 C-choline uptake between days 5 and 18. Similarly, tCho levels decreased at days 5 to 18. We found a negative correlation between the tCho and PET results in the tumor and a positive correlation between the tCho tumor-to-brain ratio and choline uptake in the tumor. PCR results confirmed expected increases in expression levels for most of the transporters and enzymes. Using MRS quantification, a good agreement was found between CSI and 11 C-choline PET data, whereas a negative correlation occurred when CSI was not referenced. Thus, 11 C-choline PET and MRS methods seemed to be complementary in strengths. While advancing tumor proliferation caused an increasing 11 C-choline uptake, gliosis and inflammation potentially accounted for a high peritumoral tCho signal in CSI, as supported by histology and secondary ion mass spectrometry imaging. Our findings provide definitive evidence of the use of MRS, CSI, and PET for imaging tumors in vivo. Cancer Res; 73(5);

Preclinical and Translational PET/MR Imaging

“…Many preclinical imaging sites around the world perform PET/MR imaging studies, but only a small number are simultaneous or from integrated systems. Until now, preclinical PET/MR imaging has mainly operated at a proofof-concept level (2,12,13), but first studies showing the value of combined acquisitions have been published (7,9).…”

“…Wehrl et al (9) used PET/MR imaging to compare 11 C-choline uptake with MR spectroscopy chemical shift imaging of choline metabolism in a murine orthotopic glioma model. Imaging findings were validated by ex vivo immunohistology and also by ex vivo secondary ion mass spectrometry imaging.…”

“…First, in vivo preclinical and clinical studies impressively show the power of this new imaging device, which without doubt will cause a paradigm shift in the realm of imaging science (2,3,(5)(6)(7)(8)(9).…”

Principles of PET/MR Imaging

“…Both PET and MR provide information on equivalent or similar physiologic parameters, but the 2 modalities complement each other. Discrepancies can still be seen in direct comparisons, for example, between MR spectroscopy of endogenous choline and 11 C-choline PET (77).…”

Glutaraldehyde fixation method for single‐cell lipid analysis by time‐of‐flight secondary ion‐mass spectrometry

“…[1][2][3][4] Recently, a relationship between tumor progression and alteration in lipid metabolisms was reported. [5][6][7] In tumor cells, the fatty acid synthesis pathway is activated constitutively to sustain the increasing demand of new membrane phospholipids. [8][9][10] The development of imaging mass spectrometry (IMS) involving matrix-assisted laser desorption/ionization (MALDI)-IMS has contributed to these findings.…”