Proliferation of Human Glioblastoma Stem Cells Occurs Independently of Exogenous Mitogens
Proliferation of Human Glioblastoma Stem Cells Occurs Independently of Exogenous Mitogens
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DOI：
10.1002/stem.98
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发表时间：
2009-08-01
期刊：
影响因子：
5.2
通讯作者：
Weiss, Samuel
中科院分区：
文献类型：
--
作者：
Kelly, John J. P.;Stechishin, Owen;Weiss, Samuel
中枢神经系统的原发性胶质瘤，最常见的是多形性胶质母细胞瘤（GBM），是侵袭性病变，预后不佳。尽管已经鉴定和分离了人脑肿瘤干细胞 (BTSC)，但区分 BTSC 和神经干细胞的特征仍有待阐明。我们使用神经球培养系统培养从神经胶质瘤中分离的细胞，以了解它们的生长要求。 CD133(+)和CD133(-)成体GBM BTSCs在没有外源有丝分裂刺激的情况下增殖，并产生能够自我更新的多能GBM球体。表皮生长因子 (EGF) 和成纤维细胞生长因子-2 增强 GBM BTSC 的存活、增殖和随后的球体大小。阻断 EGF 受体 (EGFR) 信号传导可减少外源性不依赖有丝分裂原的 GBM 球的生长。在免疫功能低下的小鼠中，植入仅仅 10 个不依赖有丝分裂原的外源性 GBM BTSC 就会导致高度侵袭性的颅内肿瘤的形成，该肿瘤与人类 GBM 非常相似。这些结果表明，部分通过 EGFR 信号介导的外源有丝分裂原独立性是区分 CD133(+) 和 CD133(-) GBM BTSC 与神经干细胞的特征之一。这个新颖的实验系统将允许阐明促进 GBM BTSC 存活、自我更新和增殖的其他组成性激活机制。干细胞2009； 27:1722-1733
Primary glial tumors of the central nervous system, most commonly glioblastoma multiforme (GBM), are aggressive lesions with a dismal prognosis. Despite identification and isolation of human brain tumor stem cells (BTSCs), characteristics that distinguish BTSCs from neural stem cells remain to be elucidated. We cultured cells isolated from gliomas, using the neurosphere culture system, to understand their growth requirements. Both CD133(+) and CD133(-) adult GBM BTSCs proliferated in the absence of exogenous mitogenic stimulation and gave rise to multipotent GBM spheres that were capable of self-renewal. Epidermal growth factor (EGF) and fibroblast growth factor-2 enhanced GBM BTSC survival, proliferation, and subsequent sphere size. Blockade of EGF receptor (EGFR) signaling reduced exogenous mitogen-independent GBM sphere growth. Implantation of as few as 10 exogenous mitogen-independent GBM BTSCs led to the formation of highly invasive intracranial tumors, which closely resembled human GBMs, in immunocompromised mice. These results demonstrate that exogenous mitogen independence, mediated in part through EGFR signaling, is one characteristic that distinguishes CD133(+) and CD133(-) GBM BTSCs from neural stem cells. This novel experimental system will permit the elucidation of additional constitutively activated mechanisms that promote GBM BTSC survival, self-renewal, and proliferation. STEM CELLS 2009; 27:1722-1733