A YKL-40-neutralizing antibody blocks tumor angiogenesis and progression: a potential therapeutic agent in cancers.
A YKL-40-neutralizing antibody blocks tumor angiogenesis and progression: a potential therapeutic agent in cancers.
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DOI：
10.1158/1535-7163.mct-10-0868
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发表时间：
2011-05
影响因子：
5.7
通讯作者：
Shao R
中科院分区：
文献类型：
--
作者：
Faibish M;Francescone R;Bentley B;Yan W;Shao R
越来越多的证据表明，YKL-40（一种分泌糖蛋白）的表达水平在多种晚期人类癌症中升高。最近，我们已经确定了YKL-40在癌症发展中的血管生成作用。然而，阻断YKL-40的功能，其潜在的治疗价值尚未被探索。我们目前的研究旨在建立一种单克隆抗ykl -40抗体作为阻断肿瘤血管生成和转移的中和抗体。小鼠单克隆抗YKL-40抗体（mAY）与重组YKL-40以及成骨细胞瘤细胞MG-63和脑肿瘤细胞U87分泌的YKL-40特异性结合。在功能分析中，我们发现mAY可以抑制MG-63和U87细胞以及重组YKL-40条件培养基诱导的基质微血管内皮细胞的管状形成。也可以消除ykl -40诱导的膜受体VEGF受体2 （Flk-1/KDR）和细胞内信号MAP激酶Erk 1和Erk 2的激活。此外，mAY通过降低pAKT和AKT的表达，增强了U87细胞系对γ辐照的细胞死亡反应，从而消除了γ辐照升高YKL-40水平的U87细胞条件培养基诱导的血管生成。此外，用mAY治疗异种移植肿瘤小鼠可以抑制肿瘤生长、血管生成和进展。综上所述，本研究证明了5在治疗肿瘤血管生成和转移中的治疗效用。
Accumulating evidence has indicated that expression levels of YKL-40, a secreted glycoprotein, were elevated in multiple advanced human cancers. Recently, we have identified an angiogenic role of YKL-40 in cancer development. However, blockade of the function of YKL-40, which implicates therapeutic value, has not been explored yet. Our current study sought to establish a monoclonal anti-YKL-40 antibody as a neutralizing antibody for the purpose of blocking tumor angiogenesis and metastasis. A mouse monoclonal anti-YKL-40 antibody (mAY) exhibited specific binding with recombinant YKL-40 and with YKL-40 secreted from osteoblastoma cells MG-63 and brain tumor cells U87. In the functional analysis, we found that mAY inhibited tube formation of microvascular endothelial cells in Matrigel induced by conditioned medium of MG-63 and U87 cells, as well as recombinant YKL-40. mAY also abolished YKL-40-induced activation of membrane receptor VEGF receptor 2 (Flk-1/KDR) and intracellular signaling MAP kinase Erk 1 and Erk 2. In addition, mAY enhanced cell death response of U87 line to γ-irradiation through decreased expression of pAKT and AKT, and accordingly abrogated angiogenesis induced by the conditioned medium of U87 cells in which YKL-40 levels were elevated by treatment with γ-irradiation. Furthermore, treatment of xenografted tumor mice with mAY restrained tumor growth, angiogenesis, and progression. Taken together, this study has demonstrated the therapeutic utility for the mAY in treatment of tumor angiogenesis and metastasis.