Université catholique de Louvain (UCL), Institut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology and Therapeutics (FATH), Brussels, Belgium.
J Intern Med. 2013 Feb;273(2):156-65. doi: 10.1111/joim.12016.
Angiogenic endothelial cells and tumour cells can survive under hypoxic conditions and even proliferate and migrate in a low-oxygen environment. In both cell types, high rates of glycolysis (i.e. conversion of glucose to lactate) and glutaminolysis provide most of the required biosynthetic intermediates and energy to support sprouting and cell division without coupling to oxidative phosphorylation. This metabolic preference is observed under hypoxic conditions, but also in situations in which oxygen is present. In the case of tumour cells, this is known as the Warburg effect and is largely governed by oncogenes. In endothelial cells lining tumour blood vessels, the option of respiration-independent metabolism allows the neovasculature to resist the hostile environment of fluctuating oxygen tension (ranging from severe hypoxia to quasi-normal levels of oxygen). In addition, accumulation in tumours of lactate, the end-product of glycolysis, largely contributes to the angiogenic phenotype through inhibition of prolyl hydroxylase 2 and the activation of HIF1α and NFκB. Activation of the latter in a hypoxia-independent manner leads to the increased production of interleukin-8/CXCL8 which drives the autocrine stimulation of endothelial cell proliferation and maturation of neovessels. In conclusion, the addiction of proliferating endothelial cells for glucose and glutamine as fuels and the driving force of lactate to promote angiogenesis provide novel potential treatment options without the disadvantages of conventional anti-angiogenic drugs.
血管生成的内皮细胞和肿瘤细胞可以在缺氧条件下存活，甚至在低氧环境中增殖和迁移。在这两种细胞类型中，糖酵解（即将葡萄糖转化为乳酸）和谷氨酰胺分解代谢的高速度提供了大部分所需的生物合成中间体和能量，以支持发芽和细胞分裂，而无需与氧化磷酸化偶联。这种代谢偏好不仅在缺氧条件下观察到，在氧气存在的情况下也观察到。在肿瘤细胞的情况下，这被称为沃伯格效应，主要由癌基因控制。在肿瘤血管内皮细胞中，不依赖呼吸的代谢选择允许新生血管抵抗氧张力波动的恶劣环境（从严重缺氧到几乎正常的氧水平）。此外，乳酸（糖酵解的终产物）在肿瘤中的积累，通过抑制脯氨酰羟化酶 2 和激活 HIF1α 和 NFκB，在很大程度上促成了血管生成表型。缺氧非依赖性激活后者会导致白细胞介素-8/CXCL8 的产生增加，从而驱动内皮细胞增殖的自分泌刺激和新生血管的成熟。总之，增殖的内皮细胞对葡萄糖和谷氨酰胺作为燃料的依赖以及乳酸促进血管生成的驱动力为提供了新的潜在治疗选择，而没有传统抗血管生成药物的缺点。
