Combination of a Ptgs2 Inhibitor and an Epidermal Growth Factor Receptor-Signaling Inhibitor Prevents Tumorigenesis of Oligodendrocyte Lineage-Derived Glioma-Initiating Cells
Combination of a Ptgs2 Inhibitor and an Epidermal Growth Factor Receptor-Signaling Inhibitor Prevents Tumorigenesis of Oligodendrocyte Lineage-Derived Glioma-Initiating Cells
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DOI：
10.1002/stem.618
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发表时间：
2011-04-01
期刊：
影响因子：
5.2
通讯作者：
Kondo, Toru
中科院分区：
文献类型：
--
作者：
Hide, Takuichiro;Takezaki, Tatsuya;Kondo, Toru
最近的研究结果表明，恶性肿瘤，包括多形性胶质母细胞瘤（GBM），含有癌症起始细胞（CIC;也称为癌症干细胞），其自我更新并且是恶性的。然而，它仍然是有争议的，这样的CIC是否来自组织特异性干细胞，定向前体细胞，或分化的细胞。在这里，我们试图研究GBM中CIC的起源。我们首先发现，致癌HRas（L 61）的过度表达转化p53缺陷的少突胶质细胞前体细胞（OPC）和神经干细胞（NSC）成胶质瘤起始细胞（GIC）样细胞在小鼠。当这些GIC样细胞中的少至10个被体内移植时，它们形成具有人GBM特征的可移植GBM，这表明这些GIC样细胞富集在CIC中。DNA微阵列分析表明，在OPCs的转化过程中发生了广泛的遗传重编程：它们在很大程度上失去了OPC特征，并获得了NSC特征，包括表达p53蛋白1，hmga 2，ptgs 2和epiregulin。此外，Ptgs 2抑制剂和表皮生长因子受体（EGFR）信号传导抑制剂的组合防止了从间变性少突胶质细胞瘤获得的转化的OPC和人GIC（hGIC）的肿瘤发生，但不能防止从GBM获得的转化的NSC或hGIC的肿瘤发生。总之，这些发现表明GBM可以来自OPCs或NSC，并且GBM的治疗靶点可能不同，这取决于每个GIC的起源细胞。干细胞2011; 29：590-599
Recent findings have demonstrated that malignant tumors, including glioblastoma multiforme (GBM), contain cancer-initiating cells (CICs; also known as cancer stem cells), which self-renew and are malignant. However, it remains controversial whether such CICs arise from tissue-specific stem cells, committed precursor cells, or differentiated cells. Here, we sought to examine the origin of the CICs in GBM. We first showed that the overexpression of oncogenic HRas(L61) transformed p53-deficient oligodendrocyte precursor cells (OPCs) and neural stem cells (NSCs) into glioma-initiating cell (GIC)-like cells in mice. When as few as 10 of these GIC-like cells were transplanted in vivo, they formed a transplantable GBM with features of human GBM, suggesting that these GIC-like cells were enriched in CICs. DNA microarray analysis showed that widespread genetic reprogramming occurred during the OPCs' transformation: they largely lost their OPC characteristics and acquired NSC ones, including the expression of prominin1, hmga2, ptgs2, and epiregulin. In addition, the combination of a Ptgs2 inhibitor and an epidermal growth factor receptor (EGFR)-signaling inhibitor prevented the tumorigenesis of transformed OPCs and human GICs (hGICs) obtained from anaplastic oligodendroglioma, but not of transformed NSCs or hGICs obtained from GBM. Together, these findings suggest that GBM can arise from either OPCs or NSCs and that the therapeutic targets for GBM might be different, depending on each GIC's cell-of-origin. STEM CELLS 2011; 29: 590-599