Class 1A PI3K regulates vessel integrity during development and tumorigenesis

Abstract

PI3K is important in the regulation of growth, proliferation, and survival of tumor cells. We show that class 1A PI3K is also critical in the tumor microenvironment by regulating the integrity of the tumor vasculature. Using Tie2Cre-mediated deletion of the PI3K regulatory subunits (p85␣, p55␣, p50␣, and p85␤), we generated mice with endothelial cell-specific loss of class 1A PI3K. Complete loss of all subunits caused acute embryonic lethality at E11.5 due to hemorrhaging, whereas retention of a single p85␣ allele yielded viable mice that survived to adulthood. These heterozygous mice exhibited no vascular defects until challenged with a pathological insult, such as tumor cells or high levels of VEGF. Under these pathological conditions, heterozygous mice exhibited localized vascular abnormalities, including vessel leakage and the inability to maintain large vessels, which caused a deceleration of tumorigenesis. Furthermore, we show that a PI3K inhibitor can mimic the effects of class 1A PI3K loss, which suggests that targeting class 1A PI3K may be a promising therapy for blocking tumor angiogenesis.angiogenesis ͉ neovasculature ͉ endothelium A ctivating mutations in PIK3CA, the gene encoding the p110␣ catalytic subunit of PI3K, were recently identified as mechanisms of inducing oncogenic PI3K signaling (1). These mutations join PIK3CA amplification, PTEN loss, and AKT mutations in a broad class of genomic aberrations that promote tumorigenesis through up-regulation of the PI3K/AKT pathway (reviewed in refs. 2, 3). Somatic missense mutations in PIK3CA are the drivers of over 25% of breast and colorectal carcinomas, where they confer constitutive kinase activity through release from inhibitory interactions with its binding partner, p85, and other yet unknown mechanisms (4,5). This has been shown to lead to growth factor independence, elevated AKT activity, and transforming potential (6, 7). p110␣ has therefore become an attractive target for therapeutic intervention, with numerous isoform-specific inhibitors of the enzyme in development for the ablation of cancer cells (2,8,9).We investigate the possibility that an additional benefit to the development of p110␣ inhibitors is the ability to treat cancer through perturbation of the tumor vasculature. As tumors grow larger, it is essential that de novo blood vessel formation occurs to maintain oxygen and nutrient exchange between the tumor periphery and the hypoxic core (10). These vessels are also used by metastatic cells, which intravasate into the lumen and are carried to distant sites for secondary site engraftment (11). Blood vessel formation is regulated by vascular growth factors that are secreted by the tumor and its microenvironment. The primary recipient of these signals is the endothelial cell, which coordinates these signals through activation of growth factor receptors, including VEGFR1-3, TIE-1/2, FGFR1-2, PDGFR-␤, and ERBB1-4. Signaling through these receptors regulates endothelial cell proliferation and survival, angiogenic sprouting, and vessel grow...

VEGF-mediated PI3K class IA and PKC signaling in cardiomyogenesis and vasculogenesis of mouse embryonic stem cells

“…These data were consistent with previously published data demonstrating that PI3K determines heart size in mice (Shioi et al, 2000). Furthermore, the data corroborated studies of others demonstrating that PI3K class IA was required for cardiovascular differentiation in mouse embryos in the presence of VEGF (Luo et al, 2005;Yuan et al, 2008), and in differentiating ES cells where VEGF was found to significantly 1826 Journal of Cell Science 124 (11) enhance a-MHC, cardiac troponin I and Nkx2.5 expression (Chen et al, 2006).…”

PDK1 Regulates Vascular Remodeling and Promotes Epithelial-Mesenchymal Transition in Cardiac Development

“…It was shown that PDK1 plays an essential role in regulating endothelial cell migration in response to VEGF-A stimulation (34). Recently, it was shown that PI3K KO mice displayed defects in angiogenesis and vascular integrity (19,44). In these mice, the activation of Akt was impaired, which is the possible cause for vascular abnormalities (19,44).…”

“…Recently, it was shown that PI3K KO mice displayed defects in angiogenesis and vascular integrity (19,44). In these mice, the activation of Akt was impaired, which is the possible cause for vascular abnormalities (19,44). Previously, we studied the Akt1 and Akt3 double knockout (DKO) mice (41,43).…”

Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor

“…PI3K can be actively recruited and activated by angiogenic factors (35,36). PI3K inhibitors are, therefore, expected to display some degree of antiangiogenic activity.…”