Targeting a glioblastoma cancer stem-cell population defined by EGF receptor variant III.
Targeting a glioblastoma cancer stem-cell population defined by EGF receptor variant III.
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DOI：
10.1158/0008-5472.can-13-1407
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发表时间：
2014-02-15
期刊：
影响因子：
11.2
通讯作者：
Wong AJ
中科院分区：
文献类型：
--
作者：
Emlet DR;Gupta P;Holgado-Madruga M;Del Vecchio CA;Mitra SS;Han SY;Li G;Jensen KC;Vogel H;Xu LW;Skirboll SS;Wong AJ
突变蛋白与癌症干细胞群体之间的关系尚不清楚。胶质母细胞瘤肿瘤经常表达EGFRvIII，这是一种通过基因重排和扩增产生的EGFR变体。然而，EGFRvIII的表达受到限制，尽管改变的流行。在这里，我们发现EGFRvIII与CD 133高度共表达，并且EGFRvIII+/CD 133+定义了具有最高程度自我更新和肿瘤起始能力的癌症干细胞群体。EGFRvIII+细胞与其他干/祖细胞标志物相关，而分化标志物在EGFRvIII−细胞中发现。EGFRvIII表达在标准细胞培养中丧失，但其表达在肿瘤球培养中得以维持，并且培养的细胞还保留了EGFRvIII+/CD 133+共表达和自我更新以及肿瘤起始能力。使用双特异性抗体消除EGFRvIII+/CD 133+群体比针对单一表位的任何试剂更好地降低了植入肿瘤细胞的致瘤性。这项工作表明，突变的癌基因可以具有CSC特异性表达，并用于特异性靶向该人群。
The relationship between mutated proteins and the cancer stem cell population is unclear. Glioblastoma tumors frequently express EGFRvIII, an EGFR variant that arises via gene rearrangement and amplification. However, expression of EGFRvIII is restricted despite the prevalence of the alteration. Here we show that EGFRvIII is highly co-expressed with CD133 and that EGFRvIII+/CD133+ defines the population of cancer stem cells with the highest degree of self-renewal and tumor initiating ability. EGFRvIII+ cells are associated with other stem/progenitor markers while markers of differentiation are found in EGFRvIII− cells. EGFRvIII expression is lost in standard cell culture but its expression is maintained in tumor sphere culture, and cultured cells also retain the EGFRvIII+/CD133+ co-expression and self-renewal and tumor initiating abilities. Elimination of the EGFRvIII+/CD133+ population using a bispecific antibody reduced tumorigenicity of implanted tumor cells better than any reagent directed against a single epitope. This work demonstrates that a mutated oncogene can have CSC specific expression and be used to specifically target this population.