Analysis of gene expression and chemoresistance of CDI33+ cancer stem cells in glioblastoma
Analysis of gene expression and chemoresistance of CDI33+ cancer stem cells in glioblastoma
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DOI：
10.1186/1476-4598-5-67
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发表时间：
2006-12-02
期刊：
影响因子：
37.3
通讯作者：
Yu, John S.
中科院分区：
文献类型：
--
作者：
Liu, Gentao;Yuan, Xiangpeng;Yu, John S.
背景：最近，在成人和儿童脑肿瘤中发现了一小部分癌症干细胞。一些证据表明 CD133 是白血病和胶质母细胞瘤干细胞亚群的标记物。特别是，从人胶质母细胞瘤中分离出的 CD133 阳性细胞可能引发肿瘤并代表新的治疗靶点。然而，CD133阳性癌症干细胞的基因表达和耐药特性仍然未知。 结果：在本研究中，通过FACS分析，我们确定了从胶质母细胞瘤患者建立的三个原代培养细胞系中CD133阳性细胞的百分比分别为10.2％、69.7％和27.5％。我们还测定了与神经前体相关的标记物的平均 mRNA 水平。例如，与源自细胞系66的自体CD133阴性细胞相比，CD133阳性细胞上的CD90、CD44、CXCR4、Nestin、Msil和MELK mRNA分别增加至15.6、5.7、337.8、21.4、84和1351倍。此外，CD133阳性细胞表达更高水平的BCRPI和MGMT mRNA，如以及抑制细胞凋亡的基因的 mRNA 水平较高。此外，与自体 CD133 阴性细胞相比，CD133 阳性细胞对替莫唑胺、卡铂、紫杉醇 (Taxol) 和依托泊苷 (VP16) 等化疗药物显着耐药。最后，与新诊断的肿瘤相比，从五名患者获得的复发性GBM组织中CD133的表达显着升高。结论：我们的研究首次提供了CD133阳性癌症干细胞对肿瘤化疗具有强大抵抗能力的证据。这种抵抗可能是由BCRP1和MGMT表达较高的CD133阳性细胞以及抗凋亡蛋白和凋亡蛋白家族抑制剂所致。未来的治疗应该针对肿瘤中这一小群 CD133 阳性癌症干细胞，以提高脑肿瘤患者的生存率。
Background: Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been identified. Some evidence has suggested that CD133 is a marker for a subset of leukemia and glioblastoma cancer stem cells. Especially, CD133 positive cells isolated from human glioblastoma may initiate tumors and represent novel targets for therapeutics. The gene expression and the drug resistance property of CD133 positive cancer stem cells, however, are still unknown.Results: In this study, by FACS analysis we determined the percentage of CD133 positive cells in three primary cultured cell lines established from glioblastoma patients 10.2%, 69.7% and 27.5%, respectively. We also determined the average mRNA levels of markers associated with neural precursors. For example, CD90, CD44, CXCR4, Nestin, Msil and MELK mRNA on CD133 positive cells increased to 15.6, 5.7, 337.8, 21.4, 84 and 1351 times, respectively, compared to autologous CD133 negative cells derived from cell line No. 66. Additionally, CD133 positive cells express higher levels of BCRPI and MGMT mRNA, as well as higher mRNA levels of genes that inhibit apoptosis. Furthermore, CD133 positive cells were significantly resistant to chemotherapeutic agents including temozolomide, carboplatin, paclitaxel (Taxol) and etoposide ( VP16) compared to autologous CD133 negative cells. Finally, CD133 expression was significantly higher in recurrent GBM tissue obtained from five patients as compared to their respective newly diagnosed tumors.Conclusion: Our study for the first time provided evidence that CD133 positive cancer stem cells display strong capability on tumor's resistance to chemotherapy. This resistance is probably contributed by the CD133 positive cell with higher expression of on BCRP1 and MGMT, as well as the anti-apoptosis protein and inhibitors of apoptosis protein families. Future treatment should target this small population of CD133 positive cancer stem cells in tumors to improve the survival of brain tumor patients.