Laboratory for Cell Lineage Modulation, RIKEN Center for Developmental Biology, Kobe, Japan.
Cancer Sci. 2011 Jul;102(7):1306-12. doi: 10.1111/j.1349-7006.2011.01943.x. Epub 2011 May 3.
Recent findings have demonstrated that malignant tumors, including glioblastoma multiforme, contain cancer-initiating cells (also known as cancer stem cells), which self-renew and are malignant, with features of tissue-specific stem cells. As these cells are resistant to irradiation and anti-cancer drugs, it is important to characterize them and find targeting therapies. In this study, we established two primary human glioma cell lines from anaplastic oligodendroglioma and glioblastoma multiforme. These lines were enriched in glioma-initiating cells, as just 10 cells formed malignant glioma when injected into mouse brain. We used these cell lines to examine the roles of the Notch, Hedgehog and Wnt signaling pathways, which are involved in stem-cell maintenance and tumorigenesis, to determine which of these pathways are crucial to glioma-initiating cells and their regulation. Here we show that the Hedgehog pathway is indispensable for glioma-initiating cell proliferation and tumorigenesis; the Hedgehog signaling inhibitors prevented glioma-initiating cell proliferation, while signaling inhibitors for Notch or Wnt did not. Overexpression of Gli2ΔC, a C-terminal-truncated form of Gli2 that antagonizes Gli transcription factor functions, blocked glioma-initiating cell proliferation in culture and tumorigenesis in vivo. Knockdown of the Gli downstream factor Cdc2 also prevented glioma-initiating cell proliferation. Taken together, these results show that the Hedgehog→ Gli→Cdc2 signaling cascade plays a role in the proliferation and malignancy of glioma-initiating cells.
最近的研究结果表明，包括多形性胶质母细胞瘤在内的恶性肿瘤中存在着肿瘤起始细胞（也称为癌症干细胞），这些细胞具有自我更新和恶性的特性，同时具有组织特异性干细胞的特征。由于这些细胞对辐射和抗癌药物具有抗性，因此对其进行特征描述并寻找靶向治疗方法非常重要。在本研究中，我们从间变性少突胶质细胞瘤和多形性胶质母细胞瘤中建立了两个原发性人胶质母细胞瘤细胞系。这些细胞系富含胶质瘤起始细胞，因为仅 10 个细胞注射到小鼠脑内就可形成恶性胶质瘤。我们使用这些细胞系来研究 Notch、Hedgehog 和 Wnt 信号通路的作用，这些信号通路参与干细胞维持和肿瘤发生，以确定这些通路中哪些对胶质瘤起始细胞及其调节至关重要。我们的研究结果表明 Hedgehog 信号通路对于胶质瘤起始细胞的增殖和肿瘤发生是不可或缺的；Hedgehog 信号通路抑制剂可阻止胶质瘤起始细胞的增殖，而 Notch 或 Wnt 的信号通路抑制剂则没有这种作用。Gli2ΔC 的过表达，一种拮抗 Gli 转录因子功能的 C 端截断形式的 Gli2，可阻断体外培养中的胶质瘤起始细胞增殖和体内肿瘤发生。下调 Gli 下游因子 Cdc2 也可阻止胶质瘤起始细胞的增殖。综上所述，这些结果表明 Hedgehog→Gli→Cdc2 信号级联在胶质瘤起始细胞的增殖和恶性转化中发挥作用。
