Title:Exploiting Metabolic Differences in Glioma Therapy
VOLUME: 9 ISSUE: 4
Author(s):Francesca Galeffi and Dennis A. Turner
Affiliation:Neurosurgery, Box 3807, Duke University Medical Center, Durham, NC 27710, USA.
Keywords:Astrocyte, glycolysis, hypoxia-inducible factor, lactate, metabolism, mitochondria, Glioma, neurons, astrocytoma cells, glutamine
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.
