Han Yi-Peng, Enomoto Atsushi, Shiraki Yukihiro, Wang Shen-Qi, Wang Xiaoze, Toyokuni Shinya, Asai Naoya, Ushida Kaori, Ara Hosne, Ohka Fumiharu, Wakabayashi Toshihiko, Ma Jie, Natsume Atsushi, Takahashi Masahide
Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
Neuro Oncol. 2017 May 1;19(5):636-647. doi: 10.1093/neuonc/now237.
The significance of mammalian target of rapamycin complex 1 (mTORC1) activity in the maintenance of cancer stem cells (CSCs) remains controversial. Previous findings showed that mTORC1 activation depleted the population of leukemia stem cells in leukemia, while maintaining the stemness in pancreatic CSCs. The purpose of this study was to examine the currently unknown role and significance of mTORC1 activity in brain tumor stem cells (BTSCs).
Basal mTORC1 activity and its kinetics were investigated in BTSC clones isolated from patients with glioblastoma and their differentiated progenies (DIFFs). The effects of nutrient deprivation and the mTORC1 inhibitors on cell proliferation were compared between the BTSCs and DIFFs. Tissue sections from patients with brain gliomas were examined for expression of BTSC markers and mTORC1 activity by immunohistochemistry.
BTSCs presented lower basal mTORC1 activity under each culture condition tested and a more rapid decline of mTORC1 activity after nutrient deprivation than observed in DIFFs. The self-renewal capacity of BTSCs was unaffected by mTORC1 inhibition, whereas it effectively suppressed DIFF proliferation. In agreement, immunohistochemical staining of glioma tissues revealed low mTORC1 activity in tumor cells positive for BTSC markers. In in vitro culture, BTSCs exhibited resistance to the antitumor agent temozolomide.
Our findings indicated the importance of low mTORC1 activity in maintaining the undifferentiated state of BTSCs, implicating the relevance of manipulating mTORC1 activity when developing future strategies that target BTSCs.
雷帕霉素复合物1（mTORC1）活性在癌症干细胞（CSCs）维持中的意义仍存在争议。先前的研究结果表明，mTORC1激活可减少白血病中白血病干细胞的数量，同时维持胰腺CSCs的干性。本研究的目的是探讨mTORC1活性在脑肿瘤干细胞（BTSCs）中目前未知的作用和意义。
研究了从胶质母细胞瘤患者中分离出的BTSC克隆及其分化后代（DIFFs）的基础mTORC1活性及其动力学。比较了营养剥夺和mTORC1抑制剂对BTSCs和DIFFs细胞增殖的影响。通过免疫组织化学检查脑胶质瘤患者的组织切片中BTSC标志物的表达和mTORC1活性。
在每种测试的培养条件下，BTSCs的基础mTORC1活性较低，并且在营养剥夺后mTORC1活性的下降比DIFFs更快。BTSCs的自我更新能力不受mTORC1抑制的影响，而它有效地抑制了DIFF的增殖。同样，胶质瘤组织的免疫组织化学染色显示，BTSC标志物阳性的肿瘤细胞中mTORC1活性较低。在体外培养中，BTSCs表现出对抗肿瘤药物替莫唑胺的抗性。
我们的研究结果表明低mTORC1活性在维持BTSCs未分化状态中的重要性，这意味着在制定未来针对BTSCs的策略时，操纵mTORC1活性具有相关性。
