Blood：阎锡蕴等发现肿瘤血管生成新机制

6月20日，Blood杂志在线发表了中国科学院生物物理研究所阎锡蕴课题组在肿瘤血管生成方面的最新研究成果。这是该课题组继发现CD146是肿瘤血管新靶标之后的又一重大突破。

此项研究揭示了肿瘤血管内皮标志分子CD146作为细胞表面受体促进血管生成的最新分子机制，是CD146作为肿瘤血管生成标志分子的最直接证据。这一发现最重要的意义是其提供了一种更加有效的治疗肿瘤的新策略，即靶向CD146作为VEGFR-2共受体这一角色进行抗体联合治疗。

血管内皮细胞生长VEGF是肿瘤血管生成过程中最重要的调控因子，因此，靶向VEGF治疗已经成为靶向肿瘤血管治疗的热点，其中最有效的抗体药物是贝伐单抗(Bevacizumab)，即抗VEGF的单克隆抗体，它通过阻断VEGF与其受体VEGFR-2的结合，阻断VEGF引起的内皮细胞活化和血管生成，从而抑制肿瘤生长。自2004年作为第一个有效抑制肿瘤血管生成的抗体药物被美国FDA批准上市后，贝伐单抗已经被批准应用于治疗结直肠癌、乳腺癌、非小细胞肺癌、肾癌等癌症，年产值约为60亿美元。

阎锡蕴课题组研究发现，CD146是血管内皮细胞生长因子受体VEGFR-2的共受体，调节VEGF诱导的VEGFR-2的活化及下游信号的传递，进而促进肿瘤血管生成。基于CD146是VEGFR-2共受体这一分子机制，研究人员利用抗CD146单克隆抗体AA98及抗VEGF单克隆抗体Bevacizumab，建立了靶向血管生成的抗体联合治疗模型，该联合策略的有效性在接种人胰腺癌细胞和人黑素瘤细胞的裸鼠荷瘤模型中得到验证，即与单一抗体给药相比，AA98及Bevacizumab联合给药具有协同效应，其抑瘤率是Bevacizumab单独给药组1.5倍。

上述研究成果不仅揭示了CD146作为内皮细胞受体促进肿瘤血管生成的新机制，同时也为临床靶向血管新生治疗肿瘤提供了新思路和新策略，这种联合治疗策略的高效性为更多癌症患者带来了曙光。

该项研究得到科技部、自然科学基金委和中国科学院的资助。

doi:10.1182/blood-2012-01-406108
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CD146 is a co-receptor for VEGFR-2 in tumor angiogenesis

Tianxia Jiang, Jie Zhuang, Hongxia Duan, Yongting Luo, Qiqun Zeng, Kelong Fan, Huiwen Yan, Di Lu, Zhongde Ye, Junfeng Hao, Jing Feng, Dongling Yang, and Xiyun Yan*

CD146 is a novel endothelial biomarker and plays an essential role in angiogenesis. However, its role in the molecular mechanism underlying angiogenesis still remains poorly understood. Here, we show that CD146 directly interacts with VEGFR-2 on endothelial cells as well as at the molecular level. The detail structural basis of CD146 binding to VEGFR-2 is identified. In addition, we show that CD146 is required in VEGF-induced VEGFR-2 phosphorylation, AKT/p38 MAPKs/NF-κB activation and thus promotion of endothelial cell migration as well as microvascular formation. Furthermore, anti-CD146 AA98 or CD146 siRNA abrogated all VEGFR-2 activation induced by VEGF. An in vivo angiogenesis assay showed that VEGF-promoted microvascular formation was impaired in the endothelial conditional knockout of CD146 (CD146EC-KO). Importantly, our animal experiments demonstrated that anti-CD146 (AA98) and anti-VEGF (Bevacizumab) play an additive inhibitory effect on xenografted human pancreatic and melanoma tumor. Our findings suggest that CD146 is a new co-receptor for VEGFR-2 and a promising target for blocking tumor-related angiogenesis.