Efficacy of rapamycin against glioblastoma cancer stem cells
Efficacy of rapamycin against glioblastoma cancer stem cells
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DOI：
10.1007/s12094-013-1109-y
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发表时间：
2014-05-01
影响因子：
3.4
通讯作者：
Izquierdo, M.
中科院分区：
文献类型：
--
作者：
Mendiburu-Elicable, M.;Gil-Ranedo, J.;Izquierdo, M.
癌症干细胞（CSC）假说表明肿瘤内细胞的分层组织，其中只有干细胞样细胞的亚群负责肿瘤的发生和进展。胶质母细胞瘤（GBM）是一种致命的脑肿瘤，可能含有不同比例的活性CSC。另一方面，磷脂酰肌醇3-激酶（PI 3 K）/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）途径在高达70%的GBM中具有高度活性。激酶mTOR是PI 3 K通路的关键组分，其介导生长和细胞存活信号的调节。然而，雷帕霉素（一种有效的mTOR抑制剂）的临床试验尚未达到预期，并且缺乏合理的解释。在这项工作中，我们分析了雷帕霉素对GBM-CSC群体的影响。雷帕霉素在体外对两种来源于人GBM手术切除的原代细胞系进行了测试，这些细胞系符合被认为是CSC的标准。我们通过分析mTOR直接靶向核糖体蛋白S6，确认了PI 3 K/Akt/mTOR通路的抑制状态。检测不同剂量雷帕霉素作用下CSCs的生长速度、CD 133表达及软琼脂集落形成能力。雷帕霉素在体内的疗效是在CSCs为基础的原位异种移植。我们报告雷帕霉素的疗效，通过减少CSCs的增殖和体外致瘤潜力。尽管有这些令人鼓舞的结果，但体内疗效非常差。这一发现证实了雷帕霉素作为胶质母细胞瘤单一疗法的有限用途。
The cancer stem cell (CSC) hypothesis suggests a hierarchical organization of cells within the tumor, in which only a subpopulation of stem-like cells is responsible for the rise and progression of the tumor. Glioblastomas (GBM), a lethal brain tumor, may contain a variable proportion of active CSCs. On the other hand, the phosphatidylinositol 3-kinase (PI3 K)/Akt/mammalian target of rapamycin (mTOR) pathway is highly active in up to 70 % of GBM. The kinase mTOR is a key component of the PI3K pathway that mediates the regulation of growth and cell survival signaling. However, clinical trials with rapamycin, an effective inhibitor of mTOR, have not been up to the created expectations and a plausible explanation is missing. In this work, we analyze the effect of rapamycin on the GBM-CSC population.The efficacy of rapamycin in vitro was tested on two primary cell lines derived from human GBM surgical resections that fulfill the criteria to be considered as CSCs. We confirmed the inhibition state of the PI3K/Akt/mTOR pathway analyzing the mTOR direct target ribosomal protein S6. We assayed the growth rate, CD133 expression and ability of forming colonies in soft agar of the CSCs under different doses of rapamycin. The efficacy of rapamycin in vivo was assayed in a CSCs-based orthotopic xenograft.We report the efficacy of rapamycin by reducing CSCs proliferation and tumorigenic potential in vitro. Despite these encouraging results, the efficacy in vivo was very poor. This finding confirms the limited use of rapamycin as a monotherapy for glioblastomas.