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 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.
Hamada
Koichi
K
Department of Molecular Biology, Department of Microbiology, Department of Gastroenterology, Akita University School of Medicine, Akita 010-8543, Japan.
Sasaki
Takehiko
T
Koni
Pandelakis A
PA
Natsui
Miyuki
M
Kishimoto
Hiroyuki
H
Sasaki
Junko
J
Yajima
Nobuyuki
N
Horie
Yasuo
Y
Hasegawa
Go
G
Naito
Makoto
M
Miyazaki
Jun-Ichi
J
Suda
Toshio
T
Itoh
Hiroshi
H
Nakao
Kazuwa
K
Mak
Tak Wah
TW
Nakano
Toru
T
Suzuki
Akira
A
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D005260:Female; D005318:Fetal Heart / Q000196:embryology / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D019869:Phosphatidylinositol 3-Kinases; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse