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

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

doi:10.1101/gad.1308805

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

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

Research output: Contribution to journal › Article › peer-review

246 Scopus citations

Abstract

PTEN is an important tumor suppressor gene. Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePten^flox/+ mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85α and p110γ. In vitro, Tie2CrePten^flox/+ endothelial cells showed enhanced proliferation/migration. Tie2CrePten^flox/flox mice died before embryonic day 11.5 (E11.5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes depend strongly on p110γ rather than on p85α and were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2. Pten is thus indispensable for normal cardiovascular morphogenesis and post-natal angiogenesis, including tumor angiogenesis.

Original language	English (US)
Pages (from-to)	2054-2065
Number of pages	12
Journal	Genes and Development
Volume	19
Issue number	17
DOIs	https://doi.org/10.1101/gad.1308805
State	Published - Sep 1 2005
Externally published	Yes

Keywords

Cardiovasculogenesis
Endothelial cells
PI3K
PTEN
Tumor angiogenesis

ASJC Scopus subject areas

General Medicine

Access to Document

10.1101/gad.1308805

Cite this

Hamada, K., Sasaki, T., Koni, P. A., Natsui, M., Kishimoto, H., Sasaki, J., Yajima, N., Horie, Y., Hasegawa, G., Naito, M., Miyazaki, J. I., Suda, T., Itoh, H., Nakao, K., Tak, W. M., Nakano, T., & Suzuki, A. (2005). The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. Genes and Development, 19(17), 2054-2065. https://doi.org/10.1101/gad.1308805

@article{7cce3699ce1c44d7befe4e7384923902,

title = "The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis",

abstract = "PTEN is an important tumor suppressor gene. Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePtenflox/+ mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85α and p110γ. In vitro, Tie2CrePtenflox/+ endothelial cells showed enhanced proliferation/migration. Tie2CrePtenflox/flox mice died before embryonic day 11.5 (E11.5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes depend strongly on p110γ rather than on p85α and were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2. Pten is thus indispensable for normal cardiovascular morphogenesis and post-natal angiogenesis, including tumor angiogenesis.",

keywords = "Cardiovasculogenesis, Endothelial cells, PI3K, PTEN, Tumor angiogenesis",

author = "Koichi Hamada and Takehiko Sasaki and Koni, {Pandelakis A.} and Miyuki Natsui and Hiroyuki Kishimoto and Junko Sasaki and Nobuyuki Yajima and Yasuo Horie and Go Hasegawa and Makoto Naito and Miyazaki, {Jun Ichi} and Toshio Suda and Hiroshi Itoh and Kazuwa Nakao and Tak, {Wah Mak} and Toru Nakano and Akira Suzuki",

year = "2005",

month = sep,

day = "1",

doi = "10.1101/gad.1308805",

language = "English (US)",

volume = "19",

pages = "2054--2065",

journal = "Genes and Development",

issn = "0890-9369",

publisher = "Cold Spring Harbor Laboratory Press",

number = "17",

}

TY - JOUR

T1 - The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis

AU - Hamada, Koichi

AU - Sasaki, Takehiko

AU - Koni, Pandelakis A.

AU - Natsui, Miyuki

AU - Kishimoto, Hiroyuki

AU - Sasaki, Junko

AU - Yajima, Nobuyuki

AU - Horie, Yasuo

AU - Hasegawa, Go

AU - Naito, Makoto

AU - Miyazaki, Jun Ichi

AU - Suda, Toshio

AU - Itoh, Hiroshi

AU - Nakao, Kazuwa

AU - Tak, Wah Mak

AU - Nakano, Toru

AU - Suzuki, Akira

PY - 2005/9/1

Y1 - 2005/9/1

N2 - PTEN is an important tumor suppressor gene. Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePtenflox/+ mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85α and p110γ. In vitro, Tie2CrePtenflox/+ endothelial cells showed enhanced proliferation/migration. Tie2CrePtenflox/flox mice died before embryonic day 11.5 (E11.5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes depend strongly on p110γ rather than on p85α and were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2. Pten is thus indispensable for normal cardiovascular morphogenesis and post-natal angiogenesis, including tumor angiogenesis.

AB - PTEN is an important tumor suppressor gene. Hereditary mutation of PTEN causes tumor-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of Pten (Tie2CrePten) in mice. Tie2CrePtenflox/+ mice displayed enhanced tumorigenesis due to an increase in angiogenesis driven by vascular growth factors. This effect was partially dependent on the PI3K subunits p85α and p110γ. In vitro, Tie2CrePtenflox/+ endothelial cells showed enhanced proliferation/migration. Tie2CrePtenflox/flox mice died before embryonic day 11.5 (E11.5) due to bleeding and cardiac failure caused by impaired recruitment of pericytes and vascular smooth muscle cells to blood vessels, and of cardiomyocytes to the endocardium. These phenotypes depend strongly on p110γ rather than on p85α and were associated with decreased expression of Ang-1, VCAM-1, connexin 40, and ephrinB2 but increased expression of Ang-2, VEGF-A, VEGFR1, and VEGFR2. Pten is thus indispensable for normal cardiovascular morphogenesis and post-natal angiogenesis, including tumor angiogenesis.

KW - Cardiovasculogenesis

KW - Endothelial cells

KW - PI3K

KW - PTEN

KW - Tumor angiogenesis

UR - http://www.scopus.com/inward/record.url?scp=24344446438&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24344446438&partnerID=8YFLogxK

U2 - 10.1101/gad.1308805

DO - 10.1101/gad.1308805

M3 - Article

C2 - 16107612

AN - SCOPUS:24344446438

SN - 0890-9369

VL - 19

SP - 2054

EP - 2065

JO - Genes and Development

JF - Genes and Development

IS - 17

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this