Carcinogenesis Advance Access originally published online on April 15, 2009
Carcinogenesis 2009 30(6):946-952; doi:10.1093/carcin/bgp083
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Characterization of the metabolic changes underlying growth factor angiogenic activation: identification of new potential therapeutic targets
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Avenue Diagonal 645, 08028 Barcelona, Spain
1 Biomed Division, Leitat Technological Center, Parc Científic Barcelona, C/Baldiri i Reixach, 15-21, 08028 Barcelona, Spain
2 Department of Pharmacology and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Barcelona, Avenue Diagonal 643, 08028 Barcelona, Spain
3 Department of Pediatrics, Research and Education Institute, UCLA School of Medicine, 1124 West Carson Street, RB1, Torrance, CA 90502, USA
4 Present address: Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
5 Present address: Cancer Biology and Epigenetics Program (PEBC), Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, Avinguda Gran Via de L'Hospitalet, 199-203, 08907 1'Hospitalet de Llobregat, Spain
* To whom correspondence should be addressed. Tel: +34 93 402 1217; Fax: +34 93 402 1219; Email: martacascante{at}ub.edu
Angiogenesis is a fundamental process to normal and abnormal tissue growth and repair, which consists of recruiting endothelial cells toward an angiogenic stimulus. The cells subsequently proliferate and differentiate to form endothelial tubes and capillary-like structures. Little is known about the metabolic adaptation of endothelial cells through such a transformation. We studied the metabolic changes of endothelial cell activation by growth factors using human umbilical vein endothelial cells (HUVECs), [1,2-13C2]-glucose and mass isotopomer distribution analysis. The metabolism of [1,2-13C2]-glucose by HUVEC allows us to trace many of the main glucose metabolic pathways, including glycogen synthesis, the pentose cycle and the glycolytic pathways. So we established that these pathways were crucial to endothelial cell proliferation under vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) stimulation. A specific VEGF receptor-2 inhibitor demonstrated the importance of glycogen metabolism and pentose cycle pathway. Furthermore, we showed that glycogen was depleted in a low glucose medium, but conserved under hypoxic conditions. Finally, we demonstrated that direct inhibition of key enzymes to glycogen metabolism and pentose phosphate pathways reduced HUVEC viability and migration. In this regard, inhibitors of these pathways have been shown to be effective antitumoral agents. To sum up, our data suggest that the inhibition of metabolic pathways offers a novel and powerful therapeutic approach, which simultaneously inhibits tumor cell proliferation and tumor-induced angiogenesis.
Abbreviations: DMEM, Dulbecco's modified Eagle's medium; EBM, endothelial cell basal medium; EGM, endothelial cell growth medium; FCS, fetal calf serum; FGF, fibroblast growth factor; HUVEC, human umbilical vein endothelial cell; PPP, pentose phosphate pathway; VEGF, vascular endothelial growth factor; VEGFR-2, vascular endothelial growth factor receptor-2
Received October 16, 2008; revised March 19, 2009; accepted April 4, 2009.