Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands
Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands
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DOI：
10.1016/j.ccr.2004.08.018
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发表时间：
2004-09-01
期刊：
影响因子：
50.3
通讯作者：
Pasqualini, R
中科院分区：
文献类型：
--
作者：
Arap, MA;Lahdenranta, J;Pasqualini, R
我们最近发现葡萄糖调节蛋白-78 （GRP78）是转移性肿瘤中表达的相关分子靶点，通过指纹识别来自癌症患者的循环抗体库。在此，我们设计并评估了基于GRP78肿瘤细胞膜表达的配体-受体系统。我们发现GRP78结合肽基序在体内和离体人类癌症标本中特异性靶向肿瘤细胞。此外，合成的由GRP78结合基序融合到程序性细胞死亡诱导序列的嵌合肽可以抑制前列腺癌和乳腺癌异种移植和等基因小鼠模型中的肿瘤生长。总之，这些临床前数据验证了肿瘤细胞表面的GRP78作为一个功能性分子靶点，可能被证明对转化为临床应用有用。
We have recently identified glucose-regulated protein-78 (GRP78) as a relevant molecular target expressed in metastatic tumors by fingerprinting the circulating repertoire of antibodies from cancer patients. Here we design and evaluate a ligand-receptor system based on the tumor cell membrane expression of GRP78. We show that GRP78 binding peptide motifs target tumor cells specifically in vivo and in human cancer specimens ex vivo. Moreover, synthetic chimeric peptides composed of GRP78 binding motifs fused to a programmed cell death-inducing sequence can suppress tumor growth in xenograft and isogenic mouse models of prostate and breast cancer. Together, these preclinical data validate GRP78 on the tumor cell surface as a functional molecular target that may prove useful for translation into clinical applications.