Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis.
Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis.
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DOI：
10.18632/oncotarget.6842
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发表时间：
2016-02-02
期刊：
影响因子：
--
通讯作者：
Liebl J
中科院分区：
文献类型：
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作者：
Merk H;Zhang S;Lehr T;Müller C;Ulrich M;Bibb JA;Adams RH;Bracher F;Zahler S;Vollmar AM;Liebl J
基于VEGF的抗血管生成肿瘤疗法的治疗成功由于耐药性而受到限制。因此，迫切需要基于新靶点的抗血管生成癌症治疗的新策略。我们以前的体外研究表明，小分子Cdk 5抑制剂影响血管生成过程，如内皮细胞迁移和增殖。此外，我们最近发现了Cdk 5在淋巴管发育中的重要作用。在这里，我们钉在血管生成中的内皮Cdk 5抑制的体内影响，并阐明了潜在的机制，以判断Cdk 5作为一种新的抗血管生成和抗癌靶点的潜力。通过使用内皮特异性Cdk 5敲除小鼠模型和各种基于内皮和肿瘤细胞的测定，包括人肿瘤异种移植模型，我们表明，内皮特异性敲除Cdk 5导致过度但非生产性的血管生成在发展过程中，但也在肿瘤中，这随后导致抑制肿瘤生长。由于Cdk 5抑制通过减少活性Notch胞内结构域（NICD）的产生而破坏Notch功能，并且Cdk 5调节Notch依赖性内皮细胞增殖和出芽，因此我们提出Dll 4/Notch驱动的血管生成信号枢纽是Cdk 5的重要且有前途的机制靶点。事实上，Cdk 5抑制可以使肿瘤对常规抗血管生成治疗敏感，如肿瘤异种移植模型中所示。总之，我们的数据为Cdk 5作为抑制Notch驱动的血管生成的药物靶点奠定了基础，从而浓缩了Cdk 5是癌症治疗的有希望的靶点的观点。
Therapeutic success of VEGF-based anti-angiogenic tumor therapy is limited due to resistance. Thus, new strategies for anti-angiogenic cancer therapy based on novel targets are urgently required. Our previous in vitro work suggested that small molecule Cdk5 inhibitors affect angiogenic processes such as endothelial migration and proliferation. Moreover, we recently uncovered a substantial role of Cdk5 in the development of lymphatic vessels. Here we pin down the in vivo impact of endothelial Cdk5 inhibition in angiogenesis and elucidate the underlying mechanism in order to judge the potential of Cdk5 as a novel anti-angiogenic and anti-cancer target. By the use of endothelial-specific Cdk5 knockout mouse models and various endothelial and tumor cell based assays including human tumor xenograft models, we show that endothelial-specific knockdown of Cdk5 results in excessive but non-productive angiogenesis during development but also in tumors, which subsequently leads to inhibition of tumor growth. As Cdk5 inhibition disrupted Notch function by reducing the generation of the active Notch intracellular domain (NICD) and Cdk5 modulates Notch-dependent endothelial cell proliferation and sprouting, we propose that the Dll4/Notch driven angiogenic signaling hub is an important and promising mechanistic target of Cdk5. In fact, Cdk5 inhibition can sensitize tumors to conventional anti-angiogenic treatment as shown in tumor xenograft models. In summary our data set the stage for Cdk5 as a drugable target to inhibit Notch-driven angiogenesis condensing the view that Cdk5 is a promising target for cancer therapy.