Epidermal growth factor plays a crucial role in mitogenic regulation of human brain tumor stem cells
Epidermal growth factor plays a crucial role in mitogenic regulation of human brain tumor stem cells
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DOI：
10.1074/jbc.m704205200
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发表时间：
2008-04-18
影响因子：
4.8
通讯作者：
Iwama, Toru
中科院分区：
文献类型：
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作者：
Soeda, Akio;Inagaki, Akihito;Iwama, Toru
恶性脑肿瘤中的癌症干细胞群在脑肿瘤的发生、生长和复发中起重要作用。生长因子，如表皮生长因子、成纤维细胞生长因子-2、血管内皮生长因子、血小板衍生生长因子和肝细胞生长因子，被证明支持神经干细胞的增殖，并且也可能在胶质瘤形成中发挥关键作用。然而，负责控制脑肿瘤干细胞维持的生长因子尚未发现。我们已经建立了三种来自人类神经胶质瘤的癌症干细胞系。这些细胞与神经元祖细胞标记物巢蛋白和CD 133呈免疫反应性，并在移植到小鼠脑中后建立了与原始肿瘤特征非常相似的肿瘤。三种细胞系仅在表皮生长因子（> 2.5ng/ml）存在下保持其自我更新能力和增殖。与此形成鲜明对比的是，其他生长因子，包括成纤维细胞生长因子-2，未能支持这些细胞的维持。表皮生长因子信号的酪氨酸激酶抑制剂（AG 1478和吉非替尼）抑制这些细胞的增殖和自我更新。吉非替尼抑制表皮生长因子受体以及Akt激酶和细胞外信号调节激酶1/2的磷酸化。流式细胞仪分析显示，表皮生长因子浓度依赖性增加的CD 133阳性细胞的人口。吉非替尼显着减少CD 133阳性分数，也诱导其凋亡。这些结果表明，人类脑肿瘤干细胞的维持绝对需要表皮生长因子，并且表皮生长因子信号传导的酪氨酸激酶抑制剂可能抑制这些细胞的增殖并诱导凋亡。
A cancer stem cell population in malignant brain tumors takes an essential part in brain tumor initiation, growth, and recurrence. Growth factors, such as epidermal growth factor, fibroblast growth factor-2, vascular endothelial growth factor, platelet-derived growth factor, and hepatocyte growth factor, are shown to support the proliferation of neural stem cells and also may play key roles in gliomagenesis. However, the responsible growth factor(s), which controls maintenance of brain tumor stem cells, is not yet uncovered. We have established three cancer stem cell lines from human gliomas. These cells were immunoreactive with the neuronal progenitor markers, nestin and CD133, and established tumors that closely resembled the features of original tumor upon transplantation into mouse brain. Three cell lines retained their self-renewal ability and proliferation only in the presence of epidermal growth factor (>2.5 ng/ml). In sharp contrast, other growth factors, including fibroblast growth factor-2, failed to support maintenance of these cells. The tyrosine kinase inhibitors of epidermal growth factor signaling (AG1478 and gefitinib) suppressed the proliferation and self-renewal of these cells. Gefitinib inhibited phosphorylation of epidermal growth factor receptor as well as Akt kinase and extracellular signal-regulated kinase 1/2. Flow cytometric analysis revealed that epidermal growth factor concentration-dependently increased the population of CD133-positive cells. Gefitinib significantly reduced CD133-positive fractions and also induced their apoptosis. These results indicate that maintenance of human brain tumor stem cells absolutely requires epidermal growth factor and that tyrosine kinase inhibitors of epidermal growth factor signaling potentially inhibit proliferation and induce apoptosis of these cells.