Targeting endothelial connexin40 inhibits tumor growth by reducing angiogenesis and improving vessel perfusion.
Targeting endothelial connexin40 inhibits tumor growth by reducing angiogenesis and improving vessel perfusion.
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DOI：
10.18632/oncotarget.7370
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发表时间：
2016-03-22
期刊：
影响因子：
--
通讯作者：
Haefliger JA
中科院分区：
文献类型：
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作者：
Alonso F;Domingos-Pereira S;Le Gal L;Derré L;Meda P;Jichlinski P;Nardelli-Haefliger D;Haefliger JA
内皮细胞连接蛋白40(Cx40)参与调节血管的结构和功能。我们研究了在对照组小鼠(WT)、缺乏Cx40的小鼠(Cx40−/−)和仅在内皮细胞中表达该蛋白质的小鼠(Tie2-Cx40)建立的肿瘤模型中，该蛋白是否也调节血管的变化生长。Cx40−/−小鼠的肿瘤血管生成和生长减少，而血管灌注量、平滑肌细胞覆盖率和动物存活率增加，这表明内皮Cx40在转化组织中的关键参与与Cx40−/−小鼠的高血压状态无关。结果，携带肿瘤的Cx40−/−小鼠的存活时间显著长于相应的对照组，包括在给予细胞毒治疗后。在注射了针对Cx40的多肽的WT小鼠中也进行了类似的观察，支持Cx40的参与。在没有Cx40或在主动脉萌发、Matrigel Plug和SMC迁移试验中抑制这种连接蛋白的情况下，这种参与进一步得到证实，并与磷酸化形式的内皮型一氧化氮合酶的表达减少有关。这些数据表明，Cx40是癌症治疗的潜在新靶点。
Endothelial connexin40 (Cx40) contributes to regulate the structure and function of vessels. We have examined whether the protein also modulates the altered growth of vessels in tumor models established in control mice (WT), mice lacking Cx40 (Cx40−/−), and mice expressing the protein solely in endothelial cells (Tie2-Cx40). Tumoral angiogenesis and growth were reduced, whereas vessel perfusion, smooth muscle cell (SMC) coverage and animal survival were increased in Cx40−/− but not Tie2-Cx40 mice, revealing a critical involvement of endothelial Cx40 in transformed tissues independently of the hypertensive status of Cx40−/− mice. As a result, Cx40−/− mice bearing tumors survived significantly longer than corresponding controls, including after a cytotoxic administration. Comparable observations were made in WT mice injected with a peptide targeting Cx40, supporting the Cx40 involvement. This involvement was further confirmed in the absence of Cx40 or by peptide-inhibition of this connexin in aorta-sprouting, matrigel plug and SMC migration assays, and associated with a decreased expression of the phosphorylated form of endothelial nitric oxide synthase. The data identify Cx40 as a potential novel target in cancer treatment.