RT Journal Article
SR Electronic
T1 Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 402362
DO 10.1101/402362
A1 Amber N. Stratman
A1 Olivia M. Farrelly
A1 Constantinos M. Mikelis
A1 Mayumi F. Miller
A1 Zhiyong Wang
A1 Van N. Pham
A1 Andrew E. Davis
A1 Margaret C. Burns
A1 Sofia A. Pezoa
A1 Daniel Castranova
A1 Joseph J. Yano
A1 Tina M. Kilts
A1 George E. Davis
A1 J. Silvio Gutkind
A1 Brant M. Weinstein
YR 2019
UL http://biorxiv.org/content/early/2019/04/18/402362.abstract
AB Anti-angiogenic therapies have generated significant interest for their potential to combat tumor growth (1-6). However, the ability of tumors to overproduce pro-angiogenic ligands and overcome targeted inhibitory therapies has hampered this approach (7, 8). A novel way to circumvent this problem might be to target the resynthesis of critical substrates consumed during intracellular transduction of pro-angiogenic signals in endothelial cells, thus harnessing the tumor’s own production of excess stimulatory ligands to deplete adjacent host endothelial cells of the capacity to respond to these signals (9-12). Here we show using zebrafish and human endothelial cells in vitro that endothelial cells deficient in CDP-diacylglycerol synthase 2 are uniquely sensitive to increased VEGF stimulation due to a reduced capacity to re-synthesize phosphoinositides, including phosphatidylinositol 4,5-bisphosphate (PIP2) a key substrate for VEGF signal transduction, resulting in VEGF-exacerbated defects in angiogenesis and angiogenic signaling (9-22). Using murine tumor allograft models (23) we show that either systemic or endothelial cell specific suppression of phosphoinositide recycling results in reduced tumor growth and reduced tumor angiogenesis. Our results suggest that inhibition of phosphoinositide recycling may provide a useful anti-angiogenic approach, and highlights the general potential of targeting the resynthesis of rate limiting signaling substrates as a valuable therapeutic strategy.SUMMARY STATEMENT Targeting phosphoinositide recycling during tumor angiogenesis provides a potentially uniquely effective anti-cancer therapy.