Fig. 1. Glucose metabolism in cancer and its relevance for metabolic imaging.

Cancer cells frequently demonstrate increased levels of glycolysis including conversion of glucose into pyruvate and subsequently into lactate (the Warburg effect). Consequently, increased import of glucose into tumour cells is maintained by increased expression of glucose transporters (GLUT). The intravenously injected positron emission tomography (PET) tracer [¹⁸F]2-fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) is similarly taken up via the same transporter and also undergoes subsequent phosphorylation catalysed by hexokinase; this phosphorylation prevents its subsequent export from the cell. Hyperpolarised [1-¹³C]pyruvate can be used to image metabolic alterations further down the glycolytic pathway. Monocarboxylate transporters (MCTs) mediate its uptake into cancer cells, where it undergoes reduction to [1-¹³C]lactate catalysed by lactate dehydrogenase (LDH), transamination to [1-¹³C]alanine by alanine-aminotransferase (ALT), or irreversible oxidative decarboxylation to acetyl Co-A, a reaction catalysed by pyruvate dehydrogenase (PDH). During the latter oxidation, the hyperpolarised ¹³C-label is transferred from the carboxyl (C1) position of pyruvate to ¹³CO₂ and is detectable on spectroscopic imaging as bicarbonate (H¹³CO₃⁻). An alternative fate of [1-¹³C]pyruvate is carboxylation via pyruvate carboxylase (PC) to [1-¹³C]oxaloacetic acid, which can then be metabolised to [1-¹³C]malate. Any fumarate that is formed through the reverse fumarase reaction is symmetrical and therefore any subsequent forward exchange via fumarase results in the production of four-carbon intermediates with the ¹³C-labelling also present at C4 ([4-¹³C]malate and [4-¹³C]oxalacetic acid). The metabolites of this pathway have been detected using hyperpolarised ¹³C-MRI in preclinical liver studies;^110,111 increased conversion of pyruvate into oxaloacetic acid has been demonstrated in lung and breast cancer using non-imaging studies, which raises important applications for detecting this reaction more generally within tumours.¹¹² However, none of these four-carbon intermediates have been detected in cancer using clinical hyperpolarised ¹³C-MRI. The ¹³C-label in the C1 position is shown as yellow circles and in the C4 position as red circles. For clarity, enzymatic cofactors and some of the additional substrates and products have been omitted. Other metabolic alterations relevant for cancer imaging are accumulation of 2-hydroxyglutarate (2HG) due to mutated isocitrate dehydrogenase (IDH) in the tricarboxylic acid cycle and accumulation of succinate due to succinate dehydrogenase (SDH) deficiency.