Published in

Rockefeller University Press, Journal of Experimental Medicine, 10(210), p. 1937-1945, 2013

DOI: 10.1084/jem.20121571

Rockefeller University Press, Journal of Cell Biology, 7(202), p. 2027OIA99

DOI: 10.1083/jcb.2027oia99

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

Journal article published in 2013 by Adriana Soler, Helena Serra, Wayne Pearce, Ana Angulo ORCID, Julie Guillermet-Guibert, Ls Friedman, Francesc Viñals, Holger Gerhardt, Oriol Casanovas, Mariona Graupera, Bart Vanhaesebroeck
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.