Non-invasive Investigation of Tumor Metabolism and Acidosis by MRI-CEST Imaging

Abstract

Altered metabolism is considered a core hallmark of cancer. By monitoring in vivo metabolites changes or characterizing the tumor microenvironment, non-invasive imaging approaches play a fundamental role in elucidating several aspects of tumor biology. Within the magnetic resonance imaging (MRI) modality, the chemical exchange saturation transfer (CEST) approach has emerged as a new technique that provides high spatial resolution and sensitivity for in vivo imaging of tumor metabolism and acidosis. This mini-review describes CEST-based methods to non-invasively investigate tumor metabolism and important metabolites involved, such as glucose and lactate, as well as measurement of tumor acidosis. Approaches that have been exploited to assess response to anticancer therapies will also be reported for each specific technique.

Keywords: CEST-MRI; imaging; therapy; tumor acidosis; tumor metabolism; tumor pH.

Figure 1

GlucoCEST imaging in human glioma tumor. (A) Anatomical (T2-weighted, left) and contrast-enhanced upon Gd-injection (T1-weighted, right) MR images in a glioma patient. (B) GlucoCEST contrast maps calculated as Area Under the Curve (AUC) showed at several time periods (0–110 s, left panel; 110–295 s, middle panel; 0295 s, right panel) indicate progressive accumulation of glucose inside tumor. (C) Dynamic glucoCEST contrast time curves for several brain regions (anterior cerebral artery, tumor core, lateral tumor rim, and contralateral vessel area). These curves show that glucose accumulation in lateral and medial tumor rim starts after 100 s of infusion, whereas the enhancement in the core area does not change over time. Reproduced with permission from Xu et al. (71).

Figure 2

MRI-CEST tumor pH imaging upon iopamidol injection in murine tumors. (A) CEST-MRI pHe maps of a breast cancer tumor overlaid on anatomical MRI image upon iopamidol injection (left) and FDG-PET image overlaid on CT image (middle) upon FDG injection in the same mouse. The tumor on the right side shows lower pHe values in the MRI-CEST pHe map corresponding to higher FDG uptake in the PET image. (B) Correlation plot between FDG-PET uptake and tumor pHe values shows a significant inverse correlation between FDG uptake (% ID/g) and tumor pH values. Reproduced with permission from Longo et al. (96). (C) Representative CEST-MRI tumor pHe maps overimposed on anatomical reference images before, 3 and 15 days after treatment with dichloroacetate for treated and untreated mice. Images show increased number of less acidic pixel in treated tumors upon dichloracetate therapy in comparison to control mates. (D) Bar graphs show a significant reduction in tumor acidosis after 3 days of treatment in treated tumors compared to untreated mates, whereas a restoration of tumor acidosis, likely reflecting the onset of tumor resistance is reported after 15 days of treatment (*P < 0.05, Student's t test). Reproduced with permission from Anemone et al. (97).