The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis
The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis
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DOI：
10.1101/gad.1308805
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发表时间：
2005-09-01
影响因子：
10.5
通讯作者：
Suzuki, A
中科院分区：
文献类型：
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作者：
Hamada, K;Sasaki, T;Suzuki, A
PTEN是一种重要的抑癌基因。PTEN基因的遗传性突变导致肿瘤易感性疾病，如Cowden病。我们使用Cre-loxP系统在小鼠中产生Pten的内皮细胞特异性突变（Tie 2CrePten）。Tie 2CrePten（flox/+）小鼠由于血管生长因子驱动的血管生成增加而显示出增强的肿瘤发生。这种作用部分依赖于PI 3 K亚基p85 α和p110 γ。在体外，Tie 2CrePten（flox/+）内皮细胞显示增强的增殖/迁移。Tie 2CrePten（flox/flox）小鼠在胚胎第11.5天（E11.5）之前由于周细胞和血管平滑肌细胞向血管的募集受损以及心肌细胞向内皮细胞的募集受损引起的出血和心力衰竭而死亡。这些表型强烈依赖于p110 γ，而不是p85 α，并与Ang-1，VCAM-1，连接蛋白40和ephrinB 2的表达减少，但Ang-2，VEGF-A，VEGFR 1和VEGFR 2的表达增加有关。因此Pten对于正常心血管形态发生和出生后血管生成，包括肿瘤血管生成是不可或缺的。
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 p85 alpha and p110 gamma. 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 p110 gamma rather than on p85 alpha 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.