Targeted Inhibition of CD133+ Cells in Oral Cancer Cell Lines
Targeted Inhibition of CD133+ Cells in Oral Cancer Cell Lines
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DOI：
10.1177/0022034510393511
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发表时间：
2011-05-01
影响因子：
7.6
通讯作者：
DiRienzo, J. M.
中科院分区：
文献类型：
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作者：
Damek-Poprawa, M.;Volgina, A.;DiRienzo, J. M.
头颈部鳞状细胞癌（HNSCC）的治疗抵抗和继发性肿瘤的出现归因于病变部位上皮基底层具有干细胞样特性的细胞的存在。在这项研究中，我们验证了HNSCC中这些假定的癌症干细胞（CSC）可以被特异性靶向和抑制的假设。我们发现10例头颈部肿瘤活检中有9例含有表达CD133的细胞亚群，CD133是一种与CSC相关的不寻常的表面暴露膜跨越糖蛋白。将一种来自牙周病原体放线菌聚集杆菌的基因修饰的细胞致死膨胀毒素（Cdt）与一种抗人CD133单克隆抗体（MAb）结合。Cdt-MAb复合物在HNSCC细胞系培养物中优先抑制CD133（+）细胞的增殖。CD133（+）细胞的抑制是速率和剂量依赖性的。饱和动力学表明对Cdt-MAb复合物的反应是特异性的。健康的原代牙龈上皮细胞是野生型Cdt的天然靶点，不受影响。这些数据的分析为未来开发针对HNSCC早期治疗CSC的新疗法提供了基础。缩写：Cdt，细胞致死膨胀毒素；CSC，癌症干细胞；HNSCC、头颈部鳞状细胞癌；单克隆抗体。
Resistance to treatment and the appearance of secondary tumors in head and neck squamous cell carcinomas (HNSCC) have been attributed to the presence of cells with stem-cell-like properties in the basal layer of the epithelium at the site of the lesion. In this study, we tested the hypothesis that these putative cancer stem cells (CSC) in HNSCC could be specifically targeted and inhibited. We found that 9 of 10 head and neck tumor biopsies contained a subpopulation of cells that expressed CD133, an unusual surface-exposed membrane-spanning glycoprotein associated with CSC. A genetically modified cytolethal distending toxin (Cdt), from the periodontal pathogen Aggregatibacter actinomycetemcomitans, was conjugated to an anti-human CD133 monoclonal antibody (MAb). The Cdt-MAb complex preferentially inhibited the proliferation of CD133(+) cells in cultures of established cell lines derived from HNSCC. Inhibition of the CD133(+) cells was rate-and dose-dependent. Saturation kinetics indicated that the response to the Cdt-MAb complex was specific. Healthy primary gingival epithelial cells that are native targets of the wild-type Cdt were not affected. Analysis of these data provides a foundation for the future development of new therapies to target CSC in the early treatment of HNSCC. Abbreviations: Cdt, cytolethal distending toxin; CSC, cancer stem cells; HNSCC, head and neck squamous cell carcinoma; MAb, monoclonal antibody.