6月20日,，Blood雜志在線發(fā)表了中國科學(xué)院生物物理研究所閻錫蘊課題組在腫瘤血管生成方面的最新研究成果,。這是該課題組繼發(fā)現(xiàn)CD146是腫瘤血管新靶標之后的又一重大突破。
此項研究揭示了腫瘤血管內(nèi)皮標志分子CD146作為細胞表面受體促進血管生成的最新分子機制,，是CD146作為腫瘤血管生成標志分子的最直接證據(jù),。這一發(fā)現(xiàn)最重要的意義是其提供了一種更加有效的治療腫瘤的新策略，即靶向CD146作為VEGFR-2共受體這一角色進行抗體聯(lián)合治療,。
血管內(nèi)皮細胞生長VEGF是腫瘤血管生成過程中最重要的調(diào)控因子,，因此，靶向VEGF治療已經(jīng)成為靶向腫瘤血管治療的熱點,，其中最有效的抗體藥物是貝伐單抗(Bevacizumab),，即抗VEGF的單克隆抗體，它通過阻斷VEGF與其受體VEGFR-2的結(jié)合,，阻斷VEGF引起的內(nèi)皮細胞活化和血管生成,，從而抑制腫瘤生長。自2004年作為第一個有效抑制腫瘤血管生成的抗體藥物被美國FDA批準上市后,，貝伐單抗已經(jīng)被批準應(yīng)用于治療結(jié)直腸癌,、乳腺癌、非小細胞肺癌,、腎癌等癌癥,，年產(chǎn)值約為60億美元。
閻錫蘊課題組研究發(fā)現(xiàn),，CD146是血管內(nèi)皮細胞生長因子受體VEGFR-2的共受體,，調(diào)節(jié)VEGF誘導(dǎo)的VEGFR-2的活化及下游信號的傳遞，進而促進腫瘤血管生成?；贑D146是VEGFR-2共受體這一分子機制,，研究人員利用抗CD146單克隆抗體AA98及抗VEGF單克隆抗體Bevacizumab，建立了靶向血管生成的抗體聯(lián)合治療模型,，該聯(lián)合策略的有效性在接種人胰腺癌細胞和人黑素瘤細胞的裸鼠荷瘤模型中得到驗證,，即與單一抗體給藥相比，AA98及Bevacizumab聯(lián)合給藥具有協(xié)同效應(yīng),，其抑瘤率是Bevacizumab單獨給藥組1.5倍,。
上述研究成果不僅揭示了CD146作為內(nèi)皮細胞受體促進腫瘤血管生成的新機制，同時也為臨床靶向血管新生治療腫瘤提供了新思路和新策略,，這種聯(lián)合治療策略的高效性為更多癌癥患者帶來了曙光,。
該項研究得到科技部、自然科學(xué)基金委和中國科學(xué)院的資助,。（生物谷Bioon.com）
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.
