Galeffi Francesca, Turner Dennis A
Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA.
Curr Drug Discov Technol. 2012 Dec;9(4):280-93. doi: 10.2174/157016312803305906.
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.
脑功能依赖于仅几种不同细胞类型之间复杂的代谢相互作用，星形胶质细胞为神经元提供关键支持。星形胶质细胞的功能包括缓冲细胞外空间、为神经元提供底物、与神经元交换谷氨酸和谷氨酰胺以进行突触传递，以及促进与血管的接触。神经元具有高度氧化代谢，容易死于缺血，而星形胶质细胞更多地依赖糖酵解和与关键中间体合成相关的代谢，因此对缺氧不太敏感。星形细胞瘤和高级别胶质瘤细胞既表现出星形胶质细胞的基本代谢机制，也表现出一般肿瘤的代谢机制，例如它们显示出高糖酵解率、乳酸外排、即使在缺氧条件下也能增殖的能力，以及利用机制增强代谢和血管生成并抑制细胞死亡途径的机会主义行为。神经元、正常星形胶质细胞和星形细胞瘤细胞之间的代谢可能存在差异，这为针对星形细胞瘤提供了治疗机会，包括广泛的酶和转运体差异、缺氧诱导因子（HIF）的调节、谷氨酸摄取转运体和谷氨酰胺利用、单羧酸转运体的不同敏感性、糖原的存在、与缝隙连接的高度相互连接、利用NADPH进行脂质合成、利用合成酶（如异柠檬酸脱氢酶、丙酮酸羧化酶、丙酮酸脱氢酶、乳酸脱氢酶、苹果酸-天冬氨酸NADH穿梭）的差异调节以及不同的葡萄糖摄取机制。这些独特的代谢易感性可能会增强仅基于细胞分裂差异和表面受体的传统治疗攻击，并且已开始在临床试验中实施。
