PgmNr Z642: A story in translation: Phosphoinositide signaling and angiogenesis.
Authors:
B. M. Weinstein
1 ; A. N. Stratman
1 ; C. M. Mikelis
3 ; Z. Wang
3 ; O. M. Farrelly
1 ; M. F. Miller
1 ; S. A. Pezoa
1 ; V. N. Pham
1 ; D. Castranova
1 ; A. E. Davis
1 ; T. M. Kilts
4 ; G. E. Davis
5 ; J. S. Gutkind
3 ; W. Pan
1,2
Institutes
1) Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892; 2) Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China, 200031; 3) Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; 4) Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892; 5) Department of Medical Pharmacology and Physiology, School of Medicine, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65212. Abstract: Anti-angiogenic therapies have been regarded as one of the most promising new approaches for combating cancer, but they have yet to fulfill this promise. In large part, this is because of the ability of tumors to evade or overcome these therapies by up-regulating pro-angiogenic cytokines. We report a new approach to inhibit angiogenesis - targeting recycling of the rate-limiting substrate used for transduction of VEGF-dependent angiogenic signaling. 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 a uniquely effective inhibition of tumor angiogenesis, since increased VEGF stimulation, rather than overcoming the inhibition, only results in faster consumption of the limiting substrate and more rapid and complete inhibition of angiogenesis.