INSERM U935, Université de Poitiers, Poitiers F-86021, France.
Int J Cancer. 2011 Feb 15;128(4):826-38. doi: 10.1002/ijc.25416.
Glioblastoma (GBM), the highest-grade form of gliomas, is the most frequent and the most aggressive. Recently, a subpopulation of cells with stem cells characteristics, commonly named "tumor-initiating stem cells" (TISCs) or "cancer stem cells" (CSCs) were identified in GBM. These cells were shown to be highly resistant to chemotherapeutic drugs and to ionizing radiations. Consequently, the knowledge of the signals that regulate the functions and survival of TISCs is crucial. In our work, we describe a neurosphere-initiating cell (NS-IC) assay to quantify TISC/CSCs from patients with GBM and show that these cells are tumorigenic in vivo. We demonstrate that the intracellular signal transducer and activator of transcription STAT3 is constitutively activated by phosphorylation preferentially on serine 727 in these cells. Moreover, we demonstrate that the selective inhibition of STAT3 by the chemical compound Stattic or by siRNA STAT3 abrogates TISC/CSC proliferation and NS-IC suggesting that self-renewal of GBM "stem-like" cells depends on the presence of STAT3 for their maintenance. Finally, we show that inhibition of STAT3 by Stattic sensitizes TISC/CSCs to the inhibitory action of Temozolomide with a strong synergistic effect of both drugs. Overall, these results suggest that strategies focused on STAT3 inhibition are efficient at the level of "stem-like" cells and could be of interest for therapeutic purposes in patients with malignant GBM.
胶质母细胞瘤（GBM）是最高级别的神经胶质瘤，是最常见和最具侵袭性的肿瘤。最近，在 GBM 中发现了具有干细胞特征的细胞亚群，通常称为“肿瘤起始干细胞”（TISC）或“癌症干细胞”（CSC）。这些细胞被证明对化疗药物和电离辐射具有高度抗性。因此，了解调节 TISC 功能和存活的信号对于至关重要。在我们的工作中，我们描述了一种神经球起始细胞（NS-IC）测定法，用于从 GBM 患者中定量 TISC/CSC，并表明这些细胞在体内具有致瘤性。我们证明这些细胞中 STAT3 细胞内信号转导和转录激活物通过丝氨酸 727 的磷酸化优先被持续激活。此外，我们证明通过化学化合物 Stattic 或 siRNA STAT3 选择性抑制 STAT3 可阻断 TISC/CSC 的增殖和 NS-IC，表明 GBM“干细胞样”细胞的自我更新依赖于 STAT3 的存在来维持。最后，我们表明，Stattic 抑制 STAT3 可使 TISC/CSC 对替莫唑胺的抑制作用敏感，并具有两种药物的强烈协同作用。总的来说，这些结果表明，专注于 STAT3 抑制的策略在“干细胞样”细胞水平上是有效的，并且对于恶性 GBM 患者的治疗可能具有重要意义。
