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

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, i...

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Detalles Bibliográficos
Autores: Soler, Adriana, Serra, Helena, Pearce, Wayne, Angulo Aguado, Ana, Guillermet-Guibert, Julie, Friedman, Lori S., Viñals Canals, Francesc, Gerhardt, Holger, Casanovas i Casanovas, Oriol, Graupera i Garcia-Milà, Mariona, Vanhaesebroeck, Bart
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2013
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/68399
Acceso en línea:https://hdl.handle.net/2445/68399
Access Level:acceso abierto
Palabra clave:Angiogènesi
Càncer
Neovascularization
Cancer
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spelling Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesisSoler, AdrianaSerra, HelenaPearce, WayneAngulo Aguado, AnaGuillermet-Guibert, JulieFriedman, Lori S.Viñals Canals, FrancescGerhardt, HolgerCasanovas i Casanovas, OriolGraupera i Garcia-Milà, MarionaVanhaesebroeck, BartAngiogènesiCàncerNeovascularizationCancerUnderstanding 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.Rockefeller University Press2013info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/68399Articles publicats en revistes (Ciències Fisiològiques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: http://dx.doi.org/10.1084/jem.20121571Journal of Experimental Medicine, 2013, vol. 210, num. 10, p. 1937-1945http://dx.doi.org/10.1084/jem.20121571(c) Rockefeller University Press, 2013info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/683992026-05-27T06:46:51Z
dc.title.none.fl_str_mv Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis
title Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis
spellingShingle Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis
Soler, Adriana
Angiogènesi
Càncer
Neovascularization
Cancer
title_short Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis
title_full Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis
title_fullStr Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis
title_full_unstemmed Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis
title_sort Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis
dc.creator.none.fl_str_mv Soler, Adriana
Serra, Helena
Pearce, Wayne
Angulo Aguado, Ana
Guillermet-Guibert, Julie
Friedman, Lori S.
Viñals Canals, Francesc
Gerhardt, Holger
Casanovas i Casanovas, Oriol
Graupera i Garcia-Milà, Mariona
Vanhaesebroeck, Bart
author Soler, Adriana
author_facet Soler, Adriana
Serra, Helena
Pearce, Wayne
Angulo Aguado, Ana
Guillermet-Guibert, Julie
Friedman, Lori S.
Viñals Canals, Francesc
Gerhardt, Holger
Casanovas i Casanovas, Oriol
Graupera i Garcia-Milà, Mariona
Vanhaesebroeck, Bart
author_role author
author2 Serra, Helena
Pearce, Wayne
Angulo Aguado, Ana
Guillermet-Guibert, Julie
Friedman, Lori S.
Viñals Canals, Francesc
Gerhardt, Holger
Casanovas i Casanovas, Oriol
Graupera i Garcia-Milà, Mariona
Vanhaesebroeck, Bart
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Angiogènesi
Càncer
Neovascularization
Cancer
topic Angiogènesi
Càncer
Neovascularization
Cancer
description 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.
publishDate 2013
dc.date.none.fl_str_mv 2013
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/68399
url https://hdl.handle.net/2445/68399
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: http://dx.doi.org/10.1084/jem.20121571
Journal of Experimental Medicine, 2013, vol. 210, num. 10, p. 1937-1945
http://dx.doi.org/10.1084/jem.20121571
dc.rights.none.fl_str_mv (c) Rockefeller University Press, 2013
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Rockefeller University Press, 2013
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Rockefeller University Press
publisher.none.fl_str_mv Rockefeller University Press
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.301603

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