Paradoxic Effects of Metformin on Endothelial Cells and Angiogenesis
Menée in vitro et in vivo, cette étude met en évidence divers effets de la metformine sur l'angiogenèse et sur les cellules endothéliales
The biguanide metformin is used in type 2 diabetes management and has gained significant attention as a potential cancer preventive agent. Angioprevention represents a mechanism of cancer prevention, yet conflicting data concerning the anti-angiogenic action of metformin have emerged. Here we clarify some of the contradictory effects of metformin on endothelial cells and angiogenesis, using in vitro and in vivo assays combined with transcriptomic and protein array approaches. Metformin inhibits formation of capillary-like networks by endothelial cells; this effect is partially dependent on the energy sensor AMPK as shown by siRNA knock-down. Gene expression profiling of HUVEC revealed a paradoxical modulation of several angiogenesis-associated genes and proteins by metformin, with short term induction of VEGF, COX2 and CXCR4 at mRNA levels and down-regulation of ADAMTS1. Antibody array analysis shows an essentially opposite regulation of numerous angiogenesis-associated proteins in endothelial and breast cancer cells. Endothelial production of the cytochrome P450 member CYP1B1 is up-regulated by tumor cell supernatants in an AMPK dependent manner, metformin blocks this effect. Metformin inhibits VEGF-dependent activation of ERK1/2, and the inhibition of AMPK activity abrogates this event. Metformin hinders angiogenesis in matrigel pellets in vivo, contrasts the microvessel density increase observed in obese mice on a high fat diet, down-regulating the number of white adipose tissue endothelial precursor cells. Our data show that metformin has an anti-angiogenic activity in vitro and in vivo associated with a contradictory short-term enhancement of pro-angiogenic mediators, as well as with a differential regulation in endothelial and breast cancer cells.
http://carcin.oxfordjournals.org/content/early/2014/01/13/carcin.bgu001.abstract