Wu Anhua, Oh Seunguk, Wiesner Stephen M, Ericson Katya, Chen Lisa, Hall Walter A, Champoux Paul E, Low Walter C, Ohlfest John R
Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Stem Cells Dev. 2008 Feb;17(1):173-84. doi: 10.1089/scd.2007.0133.
The concept of cancer stem cells suggests that there are malignant stem-like cells within a tumor that are responsible for tumor renewal and resistance to cytotoxic therapies. Studies have identified glioma stem-like cells that extrude Hoechst 33342 dye, representing a double-negative "side population" (SP) thought to be selectively resistant to drug therapy. A CD133+ stem cell-like subpopulation has been isolated from a human glioma that was enriched for tumor-initiating cells. It is unknown whether CD133+ cells with similar phenotype persist in established glioma cell lines, or if CD133 is a marker of glioma stem-like cells in rodents. We investigated whether CD133+ and SP cells existed in the GL261 cell line, a syngeneic mouse glioma model that is widely used for preclinical and translational research. Intracerebral injection of less than 100 CD133+ GL261 cells formed tumors, whereas it required 10,000 CD133(-) cells to initiate a tumor. CD133+ GL261 cells expressed nestin, formed tumor spheres with high frequency, and differentiated into glial and neuronal-like cells. Similar to GL261, seven human glioma cell lines analyzed also contained a rare CD133+ population. Surprisingly, we found that CD133+ GL261 cells did not reside in the SP, nor did the majority ( approximately 94%) of CD133+ human glioma cells. These results demonstrate that the expression of CD133 in murine glioma cells is associated with enhanced tumorigenicity and a stem-like phenotype. This study also reveals a previously unrecognized level of heterogeneity in glioma cell lines, exposing several populations of cells that have characteristics of cancer stem cells.
癌症干细胞的概念表明，肿瘤内存在恶性干细胞样细胞，它们负责肿瘤的更新以及对细胞毒性疗法的抗性。研究已鉴定出能排出Hoechst 33342染料的胶质瘤干细胞样细胞，代表一个双阴性的“侧群”（SP），被认为对药物治疗具有选择性抗性。已从富含肿瘤起始细胞的人胶质瘤中分离出CD133 +干细胞样亚群。尚不清楚具有相似表型的CD133 +细胞是否存在于已建立的胶质瘤细胞系中，或者CD133是否为啮齿动物中胶质瘤干细胞样细胞的标志物。我们研究了GL261细胞系中是否存在CD133 +和SP细胞，GL261细胞系是一种同基因小鼠胶质瘤模型，广泛用于临床前和转化研究。脑内注射少于100个CD133 + GL261细胞可形成肿瘤，而启动肿瘤则需要10,000个CD133（-）细胞。CD133 + GL261细胞表达巢蛋白，高频形成肿瘤球，并分化为神经胶质样和神经元样细胞。与GL261相似，分析的7种人类胶质瘤细胞系也含有罕见的CD133 +群体。令人惊讶的是，我们发现CD133 + GL261细胞并不存在于SP中，大多数（约94％）的CD133 +人类胶质瘤细胞也不存在于SP中。这些结果表明，小鼠胶质瘤细胞中CD133的表达与增强的致瘤性和干细胞样表型相关。这项研究还揭示了胶质瘤细胞系中以前未被认识到的异质性水平，揭示了几个具有癌症干细胞特征的细胞群体。
