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Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis

Item Type:Article
Title:Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis
Creators Name:Soler, A. and Serra, H. and Pearce, W. and Angulo, A. and Guillermet-Guibert, J. and Friedman, L.S. and Viñals, F. and Gerhardt, H. and Casanovas, O. and Graupera, M. and Vanhaesebroeck, B.
Abstract:Understanding the direct, tumor cell-intrinsic effects of PI 3-kinase (PI3K) has been a key focus of research to date. Here, we report that cancer cell-extrinsic PI3K activity, mediated by the p110α isoform of PI3K, contributes in an unexpected way to tumor angiogenesis. In syngeneic mouse models, inactivation of stromal p110α led to increased vascular density, reduced vessel size, and altered pericyte coverage. This increased vascularity lacked functionality, correlating with enhanced tumor hypoxia and necrosis, and reduced tumor growth. The role of p110α in tumor angiogenesis is multifactorial, and includes regulation of proliferation and DLL4 expression in endothelial cells. p110α in the tumor stroma is thus a regulator of vessel formation, with p110α inactivation giving rise to nonfunctional angiogenesis, which can stunt tumor growth. This type of vascular aberration differs from vascular endothelial growth factor-centered antiangiogenesis therapies, which mainly lead to vascular pruning. Inhibition of p110α may thus offer a new antiangiogenic therapeutic opportunity in cancer.
Keywords:Tumor Cell Line, Cell Proliferation, Class Ia Phosphatidylinositol 3-Kinase, Endothelial Cells, Enzyme Activation, Enzyme Inhibitors, Experimental Melanoma, Intracellular Signaling Peptides And Proteins, Membrane Proteins, Neoplasms, Pathologic Neovascularization, Phosphatidylinositol 3-Kinases, Stromal Cells, Animals, Mice
Source:Journal of Experimental Medicine
Publisher:Rockefeller University Press
Page Range:1937-1945
Date:23 September 2013
Official Publication:https://doi.org/10.1084/jem.20121571
PubMed:View item in PubMed

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