Centro de Biología Molecular Severo Ochoa (CSIC), Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid, Spain.
Clin Transl Oncol. 2014 May;16(5):495-502. doi: 10.1007/s12094-013-1109-y. Epub 2013 Sep 17.
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.
癌症干细胞（CSC）假说表明，肿瘤内的细胞存在一个层次结构，只有一小部分干细胞样细胞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，可能含有一定比例的活跃 CSC。另一方面，磷酸肌醇 3-激酶（PI3K）/Akt/雷帕霉素靶蛋白（mTOR）途径在高达 70%的 GBM 中高度活跃。激酶 mTOR 是介导生长和细胞存活信号调节的 PI3K 途径的关键组成部分。然而，雷帕霉素（mTOR 的有效抑制剂）的临床试验并未达到预期效果，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。
我们在两个源自人类 GBM 手术切除的原代细胞系中测试了雷帕霉素的体外疗效，这些细胞系符合被认为是 CSC 的标准。我们通过分析 mTOR 的直接靶标核糖体蛋白 S6 来确认 PI3K/Akt/mTOR 途径的抑制状态。我们在不同剂量的雷帕霉素下检测 CSC 的生长速度、CD133 表达和软琼脂集落形成能力。我们在基于 CSC 的原位异种移植模型中检测了雷帕霉素的体内疗效。
我们通过减少 CSC 的增殖和体外致瘤潜力报告了雷帕霉素的疗效。尽管这些结果令人鼓舞，但体内疗效却非常差。这一发现证实了雷帕霉素作为胶质母细胞瘤单一疗法的应用有限。
