University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Mol Carcinog. 2013 May;52(5):329-37. doi: 10.1002/mc.21863. Epub 2012 Jan 6.
Using relatively primitive tools in the 1920s, Otto Warburg demonstrated that tumor cells show an increased dependence on glycolysis to meet their energy needs, regardless of whether they were well-oxygenated or not. High rates of glucose uptake, fueling glycolysis, are now used clinically to identify cancer cells. However, the Warburg effect does not account for the metabolic diversity that has been observed amongst cancer cells nor the influences that might direct such diversity. Modern tools have shown that the oncogenes, variable hypoxia levels, and the utilization of different carbon sources affect tumor evolution. These influences may produce metabolic symbiosis, in which lactate from a hypoxic, glycolytic tumor cell population fuels ATP production in the oxygenated region of a tumor. Lactate, once considered a waste product of glycolysis, is an important metabolite for oxidative phosphorylation in many tissues. While much is known about how muscle and the brain use lactate in oxidative phosphorylation, the contribution of lactate in tumor bioenergetics is less defined. A refocused perspective of cancer metabolism that recognizes metabolic diversity within a tumor offers novel therapeutic targets by which cancer cells may be starved from their fuel sources, and thereby become more sensitive to traditional cancer treatments.
在 20 世纪 20 年代，奥托·瓦尔堡（Otto Warburg）使用相对原始的工具证明，肿瘤细胞表现出对糖酵解的依赖性增加，以满足其能量需求，无论它们是否得到充分氧合。现在，葡萄糖摄取率高，促进糖酵解，临床上用于识别癌细胞。然而，Warburg 效应并不能解释在癌细胞中观察到的代谢多样性，也不能解释可能影响这种多样性的因素。现代工具表明，致癌基因、可变的缺氧水平和不同碳源的利用会影响肿瘤的进化。这些影响可能产生代谢共生关系，其中缺氧、糖酵解的肿瘤细胞群中的乳酸为肿瘤中氧气充足区域的 ATP 产生提供燃料。乳酸曾经被认为是糖酵解的废物产物，在许多组织中是氧化磷酸化的重要代谢物。虽然人们已经了解肌肉和大脑如何在氧化磷酸化中使用乳酸，但乳酸在肿瘤生物能量学中的作用还不太明确。重新聚焦于癌症代谢，可以认识到肿瘤内的代谢多样性，为提供了新的治疗靶点，通过这些靶点可以从肿瘤细胞的燃料来源中饿死它们，从而使它们对传统癌症治疗更敏感。
