Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling

Authors

• AN Stratman
• OM Farrelly
• MF Miller
• VN Pham
• D Castranova
• AE Davis
• Z Wang
• CM Mikelis
• JS Gutkind
• BM Weinstein

Abstract

Anti-angiogenic therapies to “starve” tumors of their host blood vessel supply have been regarded as one of the most promising new approaches for combating cancer, but they have yet to fulfill their full potential. In large part, this is because of the ability of tumors to evade or overcome these therapies by up-regulating production of pro-angiogenic cytokines, such as VEGF. We report a new approach to inhibit angiogenesis - targeting recycling of the rate-limiting substrate used for intracellular transduction of VEGF-dependent pro-angiogenic signaling in endothelial cells. Beginning with zebrafish mutants identified in a genetic screen and using zebrafish, cell culture, and mouse tumor models, we show that this new approach has the potential to result in uniquely effective inhibition of tumor angiogenesis- as increased VEGF production by tumors, rather than overcoming therapies, only results in faster consumption of the limiting substrate in host endothelial cells leading to a more rapid and complete inhibition of angiogenesis. In addition to uncovering a novel and potentially valuable anti-cancer approach, our findings also highlight an important new general therapeutic paradigm - targeting rate-limiting substrates promoting intracellular signal transduction.

Scientific Focus Area: Cancer Biology

This page was last updated on Friday, March 26, 2021