Exploiting metabolic differences in glioma therapy

Abstract

Brain function depends upon complex metabolic interactions amongst only a few different cell types, with astrocytes providing critical support for neurons. Astrocyte functions include buffering the extracellular space, providing substrates to neurons, interchanging glutamate and glutamine for synaptic transmission with neurons, and facilitating access to blood vessels. Whereas neurons possess highly oxidative metabolism and easily succumb to ischemia, astrocytes rely more on glycolysis and metabolism associated with synthesis of critical intermediates, hence are less susceptible to lack of oxygen. Astrocytoma and higher grade glioma cells demonstrate both basic metabolic mechanisms of astrocytes as well as tumors in general, e.g. they show a high glycolytic rate, lactate extrusion, ability to proliferate even under hypoxia, and opportunistic use of mechanisms to enhance metabolism and blood vessel generation, and suppression of cell death pathways. There may be differences in metabolism between neurons, normal astrocytes and astrocytoma cells, providing therapeutic opportunities against astrocytomas, including a wide range of enzyme and transporter differences, regulation of hypoxia-inducible factor (HIF), glutamate uptake transporters and glutamine utilization, differential sensitivities of monocarboxylate transporters, presence of glycogen, high interlinking with gap junctions, use of NADPH for lipid synthesis, utilizing differential regulation of synthetic enzymes (e.g. isocitrate dehydrogenase, pyruvate carboxylase, pyruvate dehydrogenase, lactate dehydrogenase, malate-aspartate NADH shuttle) and different glucose uptake mechanisms. These unique metabolic susceptibilities may augment conventional therapeutic attacks based on cell division differences and surface receptors alone, and are starting to be implemented in clinical trials.

Fig. 1

This diagram shows the important metabolic interactions between the cellular elements of the brain: two neurons are shown on the left (orange), whereas the primary roles of astrocytes (green) are illustrated in terms of metabolic processing (center), as an interface to blood vessels and blood brain barrier (right). Neurons are shown to release glutamate, which is then transported into astrocytes, converted to glu-tamine and exported back for neuronal packaging back into glutamate (using glutamine synthetase, GS). Metabolites present in the extracellular space are shown (glucose: 0.5-1.5 mM concentration; brain lactate ∼ 2.5 mM; systemic lactate ∼ 0.75 mM) as well as transporters (glucose GLUT1 on endothelium and astrocytes, monocarboxylate transporter (MCT1) on endothelium and astrocytes). Astrocytes are net exporters of lactate, derived from glycolysis, maintaining a high extracellular level of lactate for neuronal uptake and metabolism. Oxygen is readily available in the extracellular space for both neuronal and astrocytic oxidative metabolism, even though considerable astrocytic ATP is derived from glycolysis.

Fig. 2

This diagram illustrates the subversion of normal cellular metabolic interactions for the maintenance and growth of glioma cells. Rapid astrocytoma tumor growth and expansion lead to additional glial cells (as shown by numerous green astrocytes), and neurons are dele-teriously affected by tumor growth, lack of oxygen, and extracellular toxicity. The rapid tumor growth leads to lack of blood vessels, hypoxia and depletion of extracellular glucose, causing a switch to the more sensitive GLUT3 glucose transporter, increases in extracellular lactate and promotion of migration. Upregulation of hypoxia inducible factor-1 HIF1signaling pathways results in the upregulation of various hypoxia regulated genes including vascular endothelial growth factor (VEGF) to enhance glycolysis, angiogenesis, glia proliferation, and blood-brain barrier breakdown. Due to rapid tumor growth and dependence on glycolysis extracellular lactate is enhanced and there is decreased oxidative phosphorylation present, even though the mitochondrial TCA cycle continues the synthesis of amino acids for cell growth and maintenance. Many ordinary characteristic astrocyte enzymatic and cellular processes are enhanced with this transformation into a tumor phenotype, yet still may provide susceptible points of metabolic treatments.