Metabolic Portraits of Breast Cancer by HR MAS MR Spectroscopy of Intact Tissue Samples

Abstract

Despite progress in early detection and therapeutic strategies, breast cancer remains the second leading cause of cancer-related death among women globally. Due to the heterogeneity and complexity of tumor biology, breast cancer patients with similar diagnosis might have different prognosis and response to treatment. Thus, deeper understanding of individual tumor properties is necessary. Cancer cells must be able to convert nutrients to biomass while maintaining energy production, which requires reprogramming of central metabolic processes in the cells. This phenomenon is increasingly recognized as a potential target for treatment, but also as a source for biomarkers that can be used for prognosis, risk stratification and therapy monitoring. Magnetic resonance (MR) metabolomics is a widely used approach in translational research, aiming to identify clinically relevant metabolic biomarkers or generate novel understanding of the molecular biology in tumors. Ex vivo proton high-resolution magic angle spinning (HR MAS) MR spectroscopy is widely used to study central metabolic processes in a non-destructive manner. Here we review the current status for HR MAS MR spectroscopy findings in breast cancer in relation to glucose, amino acid and choline metabolism.

Keywords: HR MAS MR spectroscopy; amino acid metabolism; breast cancer; choline phospholipids; glycolysis.

Figure 1

The omics cascade. Metabolomics is the final step in the cascade, and thus studies information closer to the phenotype than the preceding omics.

Figure 2

A representative proton HR MAS MR breast tumor tissue spectrum acquired using a Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence on a 600 MHz spectrometer. Black bars represent excluded lipid regions. The spectral region shown excludes the water signal and above (>4.7 ppm) and regions with characteristically high and broad lipid signals (<1.4 ppm).

Figure 3

Overview of cellular glucose and glutamine metabolism. Glucose can undergo three fates: glycolysis (dark blue), glycogen synthesis (brown), or the pentose phosphate pathway (PPP), which has an oxidative (dark orange) and non-oxidative (light orange) phase. The TCA cycle (black) reactions that are recruited by glutaminolysis (gray) are marked ◊. Enzymes are shown in red. ADP: adenosine diphosphate; ATP: adenosine triphosphate; CoA: coenzyme A; FAD: oxidized flavin adenine dinucleotide; FADH₂: reduced flavin adenine dinucleotide; NAD⁺: oxidized nicotinamide adenine dinucleotide; NADH: reduced nicotinamide adenine dinucleotide; NADP⁺: oxidized nicotinamide adenine dinucleotide phosphate; NADPH: reduced nicotinamide adenine dinucleotide phosphate; P_i: inorganic phosphate; ROS: reactive oxygen species.

Figure 4

Choline phospholipid metabolism. Enzymes are shown in red. ADP: adenosine diphosphate; ATP: adenosine triphosphate; CMP: cytidine monophosphate; CTP: cytidine triphosphate; PPi: inorganic pyrophosphate.