c-Myc is required for maintenance of glioma cancer stem cells.
c-Myc is required for maintenance of glioma cancer stem cells.
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DOI：
10.1371/journal.pone.0003769
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Rich JN
中科院分区：
文献类型：
--
作者：
Wang J;Wang H;Li Z;Wu Q;Lathia JD;McLendon RE;Hjelmeland AB;Rich JN
恶性神经胶质瘤是最致命的癌症之一。神经胶质瘤表现出惊人的细胞异质性和分化状态的层次结构。最近的研究支持神经胶质瘤中存在癌症干细胞，其功能是通过其广泛的自我更新和形成继发性肿瘤（其表型与原始肿瘤相似）的能力来定义的。由于 c-Myc 癌蛋白在正常干细胞生物学中具有公认的作用，我们假设 c-Myc 可能有助于癌症干细胞生物学，因为这些细胞与正常干细胞具有相同的特征。根据我们和其他人之前采用的方法，使用干细胞标记物 CD133 (Prominin-1) 富集或去除肿瘤细胞群中的癌症干细胞。我们使用实时 PCR、免疫印迹、免疫荧光和流式细胞术表征了匹配肿瘤细胞群中的 c-Myc 表达。在这里，我们报告相对于非干胶质瘤细胞，c-Myc 在胶质瘤干细胞中高表达。为了探究 c-Myc 在神经胶质瘤干细胞中表达的意义，我们使用慢病毒转导的短发夹 RNA (shRNA) 来靶向其表达。胶质瘤干细胞中 c-Myc 的敲低可减少增殖，同时细胞周期停滞在 G0/G1 期，并增加细胞凋亡。非干胶质瘤细胞的生存和增殖对 c-Myc 表达的依赖性有限。此外，c-Myc 水平降低的神经胶质瘤干细胞在体外无法形成神经球，也无法在异种移植到免疫受损小鼠的大脑中时形成肿瘤。这些发现支持 c-Myc 在调节神经胶质瘤干细胞增殖和存活中的核心作用。针对核心干细胞途径可能为晚期癌症提供改进的治疗方法。
Malignant gliomas rank among the most lethal cancers. Gliomas display a striking cellular heterogeneity with a hierarchy of differentiation states. Recent studies support the existence of cancer stem cells in gliomas that are functionally defined by their capacity for extensive self-renewal and formation of secondary tumors that phenocopy the original tumors. As the c-Myc oncoprotein has recognized roles in normal stem cell biology, we hypothesized that c-Myc may contribute to cancer stem cell biology as these cells share characteristics with normal stem cells. Based on previous methods that we and others have employed, tumor cell populations were enriched or depleted for cancer stem cells using the stem cell marker CD133 (Prominin-1). We characterized c-Myc expression in matched tumor cell populations using real time PCR, immunoblotting, immunofluorescence and flow cytometry. Here we report that c-Myc is highly expressed in glioma cancer stem cells relative to non-stem glioma cells. To interrogate the significance of c-Myc expression in glioma cancer stem cells, we targeted its expression using lentivirally transduced short hairpin RNA (shRNA). Knockdown of c-Myc in glioma cancer stem cells reduced proliferation with concomitant cell cycle arrest in the G0/G1 phase and increased apoptosis. Non-stem glioma cells displayed limited dependence on c-Myc expression for survival and proliferation. Further, glioma cancer stem cells with decreased c-Myc levels failed to form neurospheres in vitro or tumors when xenotransplanted into the brains of immunocompromised mice. These findings support a central role of c-Myc in regulating proliferation and survival of glioma cancer stem cells. Targeting core stem cell pathways may offer improved therapeutic approaches for advanced cancers.
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