title: Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis.
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.
authors.affiliation: Vascular Signaling Laboratory; and 2 Translational Research Laboratory, Catalan Institute of Oncology, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Adriana
authors.initials: A
authors.lastname: Soler
authors.forename: Helena
authors.initials: H
authors.lastname: Serra
authors.forename: Wayne
authors.initials: W
authors.lastname: Pearce
authors.forename: Ana
authors.initials: A
authors.lastname: Angulo
authors.forename: Julie
authors.initials: J
authors.lastname: Guillermet-Guibert
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.forename: Francesc
authors.initials: F
authors.lastname: Viñals
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
authors.forename: Oriol
authors.initials: O
authors.lastname: Casanovas
authors.forename: Mariona
authors.initials: M
authors.lastname: Graupera
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008546:Melanoma, Experimental; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C064045:delta protein; C421683:Pik3cd protein, mouse
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