Carcinogenesis Advance Access published online on April 15, 2009
Carcinogenesis, 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
1 Department of Biochemistry and Molecular Biology, University of Barcelona, Faculty of Biology, Av Diagonal 645, 08028 Barcelona, Spain
2 Biomed Division, Leitat Technological Center, Parc Científic Barcelona, C/ Baldiri i Reixach 15-21, 08028 Barcelona, Spain
3 Department of Pharmacology and Pharmaceutical Chemistry, University of Barcelona, Faculty of Pharmacy, Av. Diagonal 643, 08028-Barcelona, Spain
4 Department of Pediatrics, Research and Education Institute, UCLA School of Medicine, RB1, 1124 West Carson Street, Torrance, California 90502, USA
* To whom correspondence should be adressed. Tel: +34-93-402-1217; Fax: +34-93-402-1219; E-mail: 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 (HUVEC), [1,2-13C2]-glucose and mass isotopomer distribution analysis (MIDA). 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 (VEGFR-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 cell 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.
Key Words: Angiogenesis • Endothelial cells • Cancer • Central carbon metabolism • Glycogen
Received October 16, 2008; revised March 19, 2009; accepted April 4, 2009.