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

Abstract

Stratman et al. Page 2 PI recycling and angiogenesis SUMMARY STATEMENT: Targeting phosphoinositide recycling during tumor angiogenesis provides a potentially uniquely effective anti-cancer therapy. Stratman et al. Page 3 PI recycling and angiogenesis Anti-angiogenic therapies have generated significant interest for their potential to combat tumor growth (1-6). However, the ability of tumors to overproduce proangiogenic 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 proangiogenic 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 4,5bisphosphate (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.

Extracellular vesicles rich in HAX1 promote angiogenesis by modulating ITGB6 translation

“…Subsequent studies have shown that tumour‐associated vessels transport oxygen and nutrients and produce factors that can support the cancer microenvironment thus promoting tumour growth, progression and metastasis (Stuelten et al., 2018). Currently, vascular endothelial growth factor A (VEGFA) is considered the most predominant angiogenic factor, which initiates this process by engaging VEGF receptor 2 (VEGFR2) (Stratman et al., 2020; Wu et al., 2017). Therefore, VEGF is the most important therapeutic target for cancer angiogenesis (Lin et al., 2017).…”

Network pharmacology and molecular docking-based investigation on the mechanisms of action of Coptidis Rhizoma in the treatment of gastric precancerous lesions

“…TP53 mutations are often present in premalignant lesions and may precede morphologic changes from adenomas to carcinomas [45][46]. VEGFA is a key pro-angiogenic ligand, and highly expressed VEGFA often stimulates angiogenesis and growth and is involved in tumour angiogenesis and metastasis [47][48]. MYC is a well-established oncogene involved in cell cycle progression, apoptosis, and cell transformation [49].…”

Network pharmacology and molecular docking-based investigation on the mechanisms of action of Coptidis Rhizoma in the treatment of gastric precancerous lesions

“…VEGFA is a key pro-angiogenic ligand, and highly expressed VEGFA often stimulates angiogenesis and growth and is involved in tumour angiogenesis and metastasis [47][48]. MYC is a well-established oncogene involved in cell cycle progression, apoptosis, and cell transformation [49].…”