Schwartz Laurent, Supuran Claudiu T, Alfarouk Khalid O
Assistance Publique des Hopitaux de Paris,France.
Al-Ghad International College for Applied Medical Sciences, Al-Madinah Al-Munawarah, KSA, Center for Evolution and Cancer, University of California San Francisco, San Francisco, CA,United States.
Anticancer Agents Med Chem. 2017;17(2):164-170. doi: 10.2174/1871520616666161031143301.
It is a longstanding debate whether cancer is one disease or a set of very diverse diseases. The goal of this paper is to suggest strongly that most of (if not all) the hallmarks of cancer could be the consequence of the Warburg's effect. As a result of the metabolic impairment of the oxidative phosphorylation, there is a decrease in ATP concentration. To compensate the reduced energy yield, there is massive glucose uptake, anaerobic glycolysis, with an up-regulation of the Pentose Phosphate Pathway resulting in increased biosynthesis leading to increased cell division and local pressure. This increased pressure is responsible for the fractal shape of the tumor, the secretion of collagen by the fibroblasts and plays a critical role in metastatic spread. The massive extrusion of lactic acid contributes to the extracellular acidity and the activation of the immune system. The decreased oxidative phosphorylation leads to impairment in CO2 levels inside and outside the cell, with increased intracellular alkalosis and contribution of carbonic acid to extracellular acidosis-mediated by at least two cancer-associated carbonic anhydrase isoforms. The increased intracellular alkalosis is a strong mitogenic signal, which bypasses most inhibitory signals. Mitochondrial disappearance (such as seen in very aggressive tumors) is a consequence of mitochondrial swelling, itself a result of decreased ATP concentration. The transmembrane pumps, which extrude, from the mitochondria, ions, and water, are ATP-dependant. Therapy aiming at increasing both the number and the efficacy of mitochondria could be very useful.
癌症是一种疾病还是一组极为多样的疾病，这是一个长期存在的争论。本文的目的是强烈表明，癌症的大多数（如果不是全部）特征可能是瓦伯格效应的结果。由于氧化磷酸化的代谢受损，ATP浓度降低。为了补偿能量产生的减少，会出现大量葡萄糖摄取、无氧糖酵解，同时戊糖磷酸途径上调，导致生物合成增加，进而导致细胞分裂增加和局部压力增大。这种增加的压力导致肿瘤呈分形形状、成纤维细胞分泌胶原蛋白，并在转移扩散中起关键作用。乳酸的大量排出导致细胞外酸度增加和免疫系统激活。氧化磷酸化减少导致细胞内外CO2水平受损，细胞内碱中毒增加，并且至少由两种癌症相关碳酸酐酶同工型介导碳酸对细胞外酸中毒有贡献。细胞内碱中毒增加是一个强大的促有丝分裂信号，它绕过了大多数抑制信号。线粒体消失（如在侵袭性很强的肿瘤中所见）是线粒体肿胀的结果，而线粒体肿胀本身是ATP浓度降低的结果。从线粒体中排出离子和水的跨膜泵依赖于ATP。旨在增加线粒体数量和功效的治疗可能非常有用。
