Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force

Abstract

Abstract. Polet F, Feron O (Universit e catholique de Louvain (UCL), Brussels, Belgium) Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force (Review). J Intern Med 2013; 273: 156-165.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 respirationindependent 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 HIF1a and NFjB. 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.

The SIRT1/HIF2α Axis Drives Reductive Glutamine Metabolism under Chronic Acidosis and Alters Tumor Response to Therapy

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The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

“…Rather intriguingly, residues 41-48 of human CYP1B1 are part of a mitochondrial import signal and the cleavage of CYP1B1 by serine proteases results in its targeting to mitochondria, which is associated with oxidative stress and mitochondrial dysfunction (Bansal et al, 2014). Given that angiogenic endothelial cells undergo changes in metabolism (the so-called Warburg effect) (Polet and Feron, 2013), it will be interesting to determine whether CYP1B1 can also alter endothelial cell metabolism and mitochondrial function. Effects on CYP1B1 may also explain the antiangiogenic actions of the antidiabetic drug metformin, which prevents the tumor cell supernatantinduced upregulation of CYP1B1 in endothelial cells (Dallaglio et al, 2014).…”

Angiogenesis revisited – role and therapeutic potential of targeting endothelial metabolism

“…Reducing glycolytic activity by 80% with 2-deoxy-D-glucose (2DG) induces endothelial cell death, indicating the necessity of glycolysis for endothelial function (De Bock et al, 2013b;Merchan et al, 2010). Although endothelial cells rely mainly on glycolysis, they also reserve the capacity for oxidative metabolism and mitochondrial respiration under conditions of stress or when glycolysis is compromised (Dranka et al, 2010;Krützfeldt et al, 1990;Polet and Feron, 2013).…”