The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis

Hamada, Koichi; Sasaki, Takehiko; Koni, Pandelakis A.; Natsui, Miyuki; Kishimoto, Hiroyuki; Sasaki, Junko; Yajima, Nobuyuki; Horie, Yasuo; Hasegawa, Go; Naito, Makoto; Miyazaki, Jun‐ichi; Suda, Toshio; Itoh, Hiroshi; Nakao, Kazuwa; Mak, Tak W.; Nakano, Toru; Suzuki, Akira

doi:10.1101/gad.1308805

Cited by 258 publications

(220 citation statements)

References 54 publications

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“…These progenitor cells are distinct from VEGFR2 + vasculogenic progenitor cells present in hemangioblasts from the yolk sac (Iida et al, 2005;Kattman et al, 2006), thus raising the issue of how cardiomyogenesis and vasculogenesis are controlled during embryogenesis. PI3K signaling pathways are known to be regulated by VEGF (Hamada et al, 2005;Gliki et al, 2002;Gerber et al, 1998), suggesting the possibility that signaling pathways involved in embryonic vasculogenesis are diversifying downstream of PI3K. Hence, the present study was undertaken to evaluate the role of PI3K class IA (consisting of PI3Ka, PI3Kb and PI3K isoforms), their downstream effector pathways and their interrelation with the PKC family to dissect the mechanisms of cardiomyogenesis versus vasculogenesis in differentiating ES cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, relatively little is known about the involvement of distinct phosphoinositide 3-kinase (PI3K) catalytic subunits and protein kinase C (PKC) isoforms in VEGF action (Hamada et al, 2005;Gliki et al, 2002;Gerber et al, 1998). VEGF receptors (VEGFR1 and VEGFR2) are present on vascular endothelial cells and their signaling is mediated by receptor dimerization leading to autophosphorylation of the cytosolic domains of the receptors.…”

Section: Introductionmentioning

confidence: 99%

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

Bekhite

Finkensieper

Binas

et al. 2011

Journal of Cell Science

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SummaryVEGF-, phosphoinositide 3-kinase (PI3K)-and protein kinase C (PKC)-regulated signaling in cardiac and vascular differentiation was investigated in mouse ES cells and in ES cell-derived Flk-1 + cardiovascular progenitor cells. Inhibition of PI3K by wortmannin and LY294002, disruption of PI3K catalytic subunits p110a and p110 using short hairpin RNA (shRNA), or inhibition of p110a with compound 15e and of p110 with IC-87114 impaired cardiac and vascular differentiation. By contrast, TGX-221, an inhibitor of p110b, and shRNA knockdown of p110b were without significant effects. Antagonists of the PKC family, i.e. bisindolylmaleimide-1 (BIM-1), GÖ 6976 (targeting PKCa/bII) and rottlerin (targeting PKC) abolished vasculogenesis, but not cardiomyogenesis. Inhibition of Akt blunted cardiac as well as vascular differentiation. VEGF induced phosphorylation of PKCa/bII and PKC but not PKCz. This was abolished by PI3K inhibitors and the VEGFR-2 antagonist SU5614. Furthermore, phosphorylation of Akt and phosphoinositidedependent kinase-1 (PDK1) was blunted upon inhibition of PI3K, but not upon inhibition of PKC by BIM-1, suggesting that activation of Akt and PDK1 by VEGF required PI3K but not PKC. In summary, we demonstrate that PI3K catalytic subunits p110a and p110 are central to cardiovasculogenesis of ES cells. Akt downstream of PI3K is involved in both cardiomyogenesis and vasculogenesis, whereas PKC is involved only in vasculogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Bekhite

Finkensieper

Binas

et al. 2011

Journal of Cell Science

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“…Indeed, it has been shown that mTORC1 inhibitors can target tumour growth indirectly, by interacting with the maintenance of endothelial cells and pericytes that are required for tumour angiogenesis. Tumour angiogenesis relies on an intricate interplay between tumour cells, endothelial cells, and surrounding mesenchymal cells (pericytes in microvessels and vascular smooth-muscle cells in large vessels) to activate endothelial cell proliferation, to recruit migrating endothelial cells and pericytes, and to form new vessels through vascular remodelling and maturation (Hamada et al, 2005). At the molecular level, tumour angiogenesis depends on vascular growth factors such as VEGF, PDGF, basic fibroblast growth factor (bFGF), and members of the tumour growth factor-b (TGFb) superfamily.…”

Section: Do the Effects Of Rapalogues In Renal Cancer Rely On Antiangmentioning

confidence: 99%

mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work?

et al. 2008

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The proof of principle that a drug targeting mTOR can improve survival has been obtained recently from a large randomised trial using temsirolimus as a first-line therapy in patients with advanced poor prognostic renal cell carcinoma. Consistent data have recently shown the important role of the PI3K/AKT/mTOR signalling pathway in the regulation of crucial metabolic and mitotic functions of cancer cells and endothelial cells allowing a better understanding of the role of mTOR in controlling cancer cell proliferation and survival as well as tumour angiogenesis. As a result, rapamycin derivatives (rapalogues) that block mTOR/Raptor complex 1 were shown to exert direct antiproliferative effects against endometrial cancers, in which cancer cells frequently lose PTEN function as well as mantle cell lymphomas, in which cancer cell proliferation appears to be driven primarily by cyclin D1 overexpression. The overall antitumour effects of rapalogues in renal cell carcinoma appear to be more complex with tumour growth inhibition resulting from direct G1/S cell cycle blockage and/or apoptotic effects in carcinoma cells along with the inhibition of downstream signalling of the HIF1a-induced VEGF/VEGFR autocrine loop in endothelial cells shutting down the maintenance of tumour angiogenesis. Despite extensive cognitive researches, it is difficult to appraise which of those mechanisms is predominant in patients. This review focuses on mechanisms of action of rapalogues focusing on antitumour effects in patients with renal cell carcinoma.

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“…We generate mice with endothelial cell-specific loss of class 1A PI3K and show this class of PI3Ks is critical to the maintenance of vessel integrity. Recently, downstream effectors of the PI3K pathway such as AKT, FOXO1, and the lipid phosphatase PTEN, have been implicated in pathological angiogenesis (16)(17)(18)(19). Additionally, the mTOR inhibitor Rapamycin has been shown to decrease microvessel density in xenograft and in vitro models (17,(20)(21)(22).…”

mentioning

confidence: 99%

Class 1A PI3K regulates vessel integrity during development and tumorigenesis

Yuan¹,

Choi

Matsui

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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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...

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The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis

Cited by 258 publications

References 54 publications

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

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

mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work?

Class 1A PI3K regulates vessel integrity during development and tumorigenesis

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