Simultaneous characterization of tumor cellularity and the Warburg effect with PET, MRI and hyperpolarized ¹³C-MRSI

Abstract

Modern oncology aims at patient-specific therapy approaches, which triggered the development of biomedical imaging techniques to synergistically address tumor biology at the cellular and molecular level. PET/MR is a new hybrid modality that allows acquisition of high-resolution anatomic images and quantification of functional and metabolic information at the same time. Key steps of the Warburg effect-one of the hallmarks of tumors-can be measured non-invasively with this emerging technique. The aim of this study was to quantify and compare simultaneously imaged augmented glucose uptake and LDH activity in a subcutaneous breast cancer model in rats (MAT-B-III) and to study the effect of varying tumor cellularity on image-derived metabolic information.Methods: For this purpose, we established and validated a multimodal imaging workflow for a clinical PET/MR system including proton magnetic resonance (MR) imaging to acquire accurate morphologic information and diffusion-weighted imaging (DWI) to address tumor cellularity. Metabolic data were measured with dynamic [18F]FDG-PET and hyperpolarized (HP) 13C-pyruvate MR spectroscopic imaging (MRSI). We applied our workflow in a longitudinal study and analyzed the effect of growth dependent variations of cellular density on glycolytic parameters.Results: Tumors of similar cellularity with similar apparent diffusion coefficients (ADC) showed a significant positive correlation of FDG uptake and pyruvate-to-lactate exchange. Longitudinal DWI data indicated a decreasing tumor cellularity with tumor growth, while ADCs exhibited a significant inverse correlation with PET standard uptake values (SUV). Similar but not significant trends were observed with HP-13C-MRSI, but we found that partial volume effects and point spread function artifacts are major confounders for the quantification of 13C-data when the spatial resolution is limited and major blood vessels are close to the tumor. Nevertheless, analysis of longitudinal data with varying tumor cellularity further detected a positive correlation between quantitative PET and 13C-data.Conclusions: Our workflow allows the quantification of simultaneously acquired PET, MRSI and DWI data in rodents on a clinical PET/MR scanner. The correlations and findings suggest that a major portion of consumed glucose is metabolized by aerobic glycolysis in the investigated tumor model. Furthermore, we conclude that variations in cell density affect PET and 13C-data in a similar manner and correlations of longitudinal metabolic data appear to reflect both biochemical processes and tumor cellularity.

Pyruvate‐lactate exchange and glucose uptake in human prostate cancer cell models. A study in xenografts and suspensions by hyperpolarized [1‐13C]pyruvate MRS and [18F]FDG‐PET

“…These k pl values are in the range of k pl values that have been reported for subcutaneous tumors and relative standard deviations per tumor group are comparable. 33,[41][42][43] In another model of prostate cancer, the TRAMP transgenic mouse, a significantly higher pyruvate-to-lactate k pl was observed for tumors defined as high grade compared with those defined as low grade. 44 A couple of factors may have influenced the k pl values in our study.…”

“…This suggests that glucose and/or pyruvate metabolism is different from that observed in other tumor types for which combined [ 18 F]FDG-PET and hyperpolarized [1- 13 C] pyruvate MRS revealed a positive correlation between measures of pyruvate to lactate conversion and glucose uptake, or no correlation at all. 41,[59][60][61] For example, in a subcutaneous rat breast cancer model, tumors with similar apparent diffusion coefficients (ADCs) showed a significant positive correlation between the label exchange rate k pl between pyruvate and lactate and [ 18 F]FDG standard uptake values. 41 A (significant) weak negative correlation was found between ADC values and SUV mean and a trend towards a weak negative correlation between ADC values and k pl .…”

“…41,[59][60][61] For example, in a subcutaneous rat breast cancer model, tumors with similar apparent diffusion coefficients (ADCs) showed a significant positive correlation between the label exchange rate k pl between pyruvate and lactate and [ 18 F]FDG standard uptake values. 41 A (significant) weak negative correlation was found between ADC values and SUV mean and a trend towards a weak negative correlation between ADC values and k pl . This suggests an effect of tumor cellularity on both measures of energy metabolism.…”

Influence of pre-operative oral carbohydrate loading vs. standard fasting procedure on tumor proliferation and clinical outcome in breast cancer patients — a randomized trial

“…The present study supports the hypothesis that adjuvant metformin or other insulinlowering therapeutic interactions may have their largest effect in breast cancer patients with ERpositive T2 tumors. In addition, the greatly increased glucose consumption of cancer cells measured by positron emission tomography (PET) with 18 F-deoxy-glucose (FDG) as tracer [62] identifies patients with an inferior clinical outcome [63]. This may also serve as a promising proxy for becoming an insulin / metformin responder.…”

Influence of pre-operative oral carbohydrate loading vs. standard fasting procedure on tumor proliferation and clinical outcome in breast cancer patients — a randomized trial

“…The present study supports the hypothesis that adjuvant metformin or other insulinlowering therapeutic interactions may have their largest effect in breast cancer patients with ERpositive T2 tumors. In addition, the greatly increased glucose consumption of cancer cells measured by positron emission tomography (PET) with 18 F-deoxy-glucose (FDG) as tracer [62] identifies patients with an inferior clinical outcome [63]. This may also serve as a promising proxy for becoming an insulin / metformin responder.…”