Jiang Hong, Gomez-Manzano Candelaria, Aoki Hiroshi, Alonso Marta M, Kondo Seiji, McCormick Frank, Xu Jing, Kondo Yasuko, Bekele B Nebiyou, Colman Howard, Lang Frederick F, Fueyo Juan
Brain Tumor Center, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
J Natl Cancer Inst. 2007 Sep 19;99(18):1410-4. doi: 10.1093/jnci/djm102. Epub 2007 Sep 11.
The eradication of brain tumor stem cells is essential for long-term brain tumor remission after treatment. In this study, we examined the therapeutic potential of an oncolytic adenovirus, Delta-24-RGD, targeted to the abnormal p16INK4/Rb pathway in brain tumor stem cells. Four brain tumor stem cell lines from surgical glioblastoma specimens expressed high levels of adenoviral receptors and allowed for efficient viral infection, replication, and oncolysis in an Rb-dependent manner. Delta-24-RGD induced autophagic cell death, as indicated by accumulation of Atg5 and LC3-II protein and autophagic vacuoles. Treatment of xenografts derived from brain tumor stem cells with Delta-24-RGD statistically significantly improved the survival of glioma-bearing mice (means: 38.5 versus 66.3 days, difference = 27.8 days, 95% confidence interval = 19.5 to 35.9 days, P <.001). Analyses of treated tumors showed that Atg5 expression colocalized with viral fiber protein and delineated a wave front of autophagic cells that circumscribed areas of virally induced necrosis. Our results show for the first time that brain tumor stem cells are susceptible to adenovirus-mediated cell death via autophagy in vitro and in vivo.
根除脑肿瘤干细胞对于治疗后实现脑肿瘤的长期缓解至关重要。在本研究中，我们检测了一种溶瘤腺病毒Delta-24-RGD针对脑肿瘤干细胞中异常的p16INK4/Rb通路的治疗潜力。来自手术切除的胶质母细胞瘤标本的四种脑肿瘤干细胞系表达高水平的腺病毒受体，并允许以Rb依赖的方式进行有效的病毒感染、复制和溶瘤。Delta-24-RGD诱导自噬性细胞死亡，表现为Atg5和LC3-II蛋白以及自噬泡的积累。用Delta-24-RGD处理源自脑肿瘤干细胞的异种移植瘤，在统计学上显著提高了荷胶质瘤小鼠的生存率（平均值：38.5天对66.3天，差异=27.8天，95%置信区间=19.5至35.9天，P<.001）。对治疗后的肿瘤分析表明，Atg5表达与病毒纤维蛋白共定位，并勾勒出一个自噬细胞的波前，该波前围绕着病毒诱导坏死的区域。我们的结果首次表明，脑肿瘤干细胞在体外和体内均易受腺病毒介导的通过自噬的细胞死亡的影响。
