1. Identification of RSK and TTK as Modulators of Blood Vessel Morphogenesis Using an Embryonic Stem Cell-Based Vascular Differentiation Assay.
- Author
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Hammoud L, Adams JR, Loch AJ, Marcellus RC, Uehling DE, Aman A, Fladd C, McKee TD, Jo CEB, Al-Awar R, Egan SE, and Rossant J
- Subjects
- Angiogenesis Inhibitors pharmacology, Animals, Cell Cycle Proteins antagonists & inhibitors, Cell Line, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Discovery, Female, Humans, Mice, Morphogenesis, Neoplasms drug therapy, Neoplasms genetics, Neoplasms metabolism, Neoplasms pathology, Neovascularization, Pathologic, Neovascularization, Physiologic drug effects, Neovascularization, Physiologic genetics, Organogenesis, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases antagonists & inhibitors, Ribosomal Protein S6 Kinases antagonists & inhibitors, Blood Vessels embryology, Blood Vessels metabolism, Cell Cycle Proteins metabolism, Cell Differentiation, Embryonic Stem Cells cytology, Embryonic Stem Cells metabolism, Protein Serine-Threonine Kinases metabolism, Protein-Tyrosine Kinases metabolism, Ribosomal Protein S6 Kinases metabolism
- Abstract
Blood vessels are formed through vasculogenesis, followed by remodeling of the endothelial network through angiogenesis. Many events that occur during embryonic vascular development are recapitulated during adult neoangiogenesis, which is critical to tumor growth and metastasis. Current antiangiogenic tumor therapies, based largely on targeting the vascular endothelial growth factor pathway, show limited clinical benefits, thus necessitating the discovery of alternative targets. Here we report the development of a robust embryonic stem cell-based vascular differentiation assay amenable to small-molecule screens to identify novel modulators of angiogenesis. In this context, RSK and TTK were identified as angiogenic modulators. Inhibition of these pathways inhibited angiogenesis in embryoid bodies and human umbilical vein endothelial cells. Furthermore, inhibition of RSK and TTK reduced tumor growth, vascular density, and improved survival in an in vivo Lewis lung carcinoma mouse model. Our study suggests that RSK and TTK are potential targets for antiangiogenic therapy, and provides an assay system for further pathway screens., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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