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Keywords:

  • angiogenesis;
  • endothelial cell;
  • glucose;
  • glutamine;
  • hypoxia;
  • lactate;
  • metabolism;
  • metabolism-targeting drugs;
  • prolyl hydroxylase

Abstract

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.