Seyfried B Thomas N, Kiebish Michael, Marsh Jeremy, Mukherjee Purna
Department of Biology, Boston College, Chestnut Hill, MA 02467, USA.
J Cancer Res Ther. 2009 Sep;5 Suppl 1:S7-15. doi: 10.4103/0973-1482.55134.
Malignant brain tumors are a significant health problem in children and adults and are largely unmanageable. As a metabolic disorder involving the dysregulation of glycolysis and respiration (the Warburg effect), malignant brain cancer can be managed through changes in metabolic environment. In contrast to malignant brain tumors that are mostly dependent on glycolysis for energy, normal neurons and glia readily transition to ketone bodies (beta-hydroxybutyrate) for energy in vivo when glucose levels are reduced. The transition from glucose to ketone bodies as a major energy source is an evolutionary conserved adaptation to food deprivation that permits the survival of normal cells during extreme shifts in nutritional environment. Only those cells with a flexible genome, honed through millions of years of environmental forcing and variability selection, can transition from one energy state to another. We propose a different approach to brain cancer management that exploits the metabolic flexibility of normal cells at the expense of the genetically defective and less metabolically flexible tumor cells. This approach to brain cancer management is supported from recent studies in orthotopic mouse brain tumor models and in human pediatric astrocytoma treated with calorie restriction and the ketogenic diet. Issues of implementation and use protocols are discussed.
恶性脑肿瘤是儿童和成人面临的一个重大健康问题，且在很大程度上难以控制。作为一种涉及糖酵解和呼吸作用失调（瓦伯格效应）的代谢紊乱疾病，恶性脑癌可通过改变代谢环境来进行控制。与主要依赖糖酵解获取能量的恶性脑肿瘤不同，当葡萄糖水平降低时，正常神经元和神经胶质细胞在体内很容易转变为利用酮体（β-羟基丁酸）获取能量。从葡萄糖到酮体作为主要能量来源的转变是一种进化上保守的对食物匮乏的适应，它能使正常细胞在营养环境发生极端变化时存活下来。只有那些经过数百万年环境压力和变异性选择锤炼、具有灵活基因组的细胞，才能从一种能量状态转变为另一种能量状态。我们提出一种不同的脑癌治疗方法，即利用正常细胞的代谢灵活性，以牺牲基因缺陷且代谢灵活性较差的肿瘤细胞为代价。原位小鼠脑肿瘤模型以及采用热量限制和生酮饮食治疗的人类儿童星形细胞瘤的最新研究支持了这种脑癌治疗方法。文中还讨论了实施和使用方案的相关问题。
