Lin Michelle I, Yu Jun, Murata Takahisa, Sessa William C
Department of Pharmacology, Boyer Center for Molecular Medicine, Yale University, New Haven, Connecticut 06536, USA.
Cancer Res. 2007 Mar 15;67(6):2849-56. doi: 10.1158/0008-5472.CAN-06-4082.
Caveolin-1 (Cav-1) is a major structural protein that is essential to the formation of the organelle, caveolae. Cav-1 knockout (KO) mice were observed to be completely devoid of caveolae yet they exhibit a hyperpermeable vasculature. Given the nature of the hyperpermeable Cav-1 KO endothelium, we sought to investigate if tumors grown in Cav-1 KO mice would be leaky and grow faster. Indeed, Lewis lung carcinoma cells implanted into Cav-1 KO mice had increased tumor vascular permeability, measured by Evans blue extravasation and fibrinogen deposition compared with tumors implanted into wild-type (WT) mice. Cav-1 KO mice also had significantly higher tumor growth rates, attributable to increased tumor angiogenesis and decreased tumor cell death. Furthermore, administration of an antipermeability peptide, cavtratin, was able to correct the tumor hyperpermeability as well as attenuate the increased tumor growth. Mechanistically, endothelial cells isolated from Cav-1 KO mice exhibited increased tyrosine phosphorylation on vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) and decreased association with the adherens junction protein, VE-cadherin. Thus, the loss of Cav-1 increases tumor permeability and growth and that may relate to enhanced VEGF signaling due to lack of Cav-1 inhibition of VEGFR-2 or decreased VE-cadherin mediated VEGFR-2 phosphorylation.
小窝蛋白-1(Cav-1)是一种主要的结构蛋白,对细胞器小窝的形成至关重要。观察到Cav-1基因敲除(KO)小鼠完全没有小窝,但它们的脉管系统具有高通透性。鉴于Cav-1基因敲除小鼠的高通透性内皮细胞的特性,我们试图研究在Cav-1基因敲除小鼠体内生长的肿瘤是否会渗漏并生长得更快。事实上,与植入野生型(WT)小鼠体内的肿瘤相比,植入Cav-1基因敲除小鼠体内的Lewis肺癌细胞具有更高的肿瘤血管通透性,这通过伊文思蓝外渗和纤维蛋白原沉积来测量。Cav-1基因敲除小鼠的肿瘤生长速率也显著更高,这归因于肿瘤血管生成增加和肿瘤细胞死亡减少。此外,给予抗通透性肽cavtratin能够纠正肿瘤的高通透性,并减弱肿瘤生长的增加。从机制上讲,从Cav-1基因敲除小鼠分离的内皮细胞在血管内皮生长因子(VEGF)受体-2(VEGFR-2)上表现出酪氨酸磷酸化增加,并且与黏附连接蛋白VE-钙黏蛋白的结合减少。因此,Cav-1的缺失增加了肿瘤的通透性和生长,这可能与由于缺乏Cav-1对VEGFR-2的抑制或VE-钙黏蛋白介导的VEGFR-2磷酸化减少而导致的VEGF信号增强有关。