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

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...

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Bibliographic Details
Published in:Genes & development 2005-09, Vol.19 (17), p.2054-2065
Main Authors: 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 Wah, Nakano, Toru, Suzuki, Akira
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Cells, Cultured
Female
Fetal Heart - embryology
Fetal Heart - metabolism
Genes, Tumor Suppressor
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Mutant Strains
Mice, Transgenic
Mutation
Neoplasms, Experimental - blood supply
Neoplasms, Experimental - genetics
Neovascularization, Pathologic
Neovascularization, Physiologic
Phosphatidylinositol 3-Kinases - deficiency
Phosphatidylinositol 3-Kinases - genetics
Phosphatidylinositol 3-Kinases - physiology
Protein Tyrosine Phosphatases - deficiency
Protein Tyrosine Phosphatases - genetics
Protein Tyrosine Phosphatases - physiology
PTEN Phosphohydrolase
Research Papers
RNA, Small Interfering - genetics
Tumor Suppressor Proteins - deficiency
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - physiology
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Summary: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 p85alpha and p110gamma. 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 p110gamma rather than on p85alpha 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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.1308805