HIF-2α maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells
HIF-2α maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells
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DOI：
10.1073/pnas.0904606106
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发表时间：
2009-09-29
影响因子：
11.1
通讯作者：
Pahlman, Sven
中科院分区：
文献类型：
--
作者：
Pietras, Alexander;Hansford, Loen M.;Pahlman, Sven
在神经母细胞瘤中，高水平的低氧诱导因子-2α(HIF-2α)蛋白水平预示着不良的预后，低氧使培养的神经母细胞瘤细胞去分化为神经峰样表型。在这里，我们确认HIF-2α是从患者骨髓分离的常氧神经峰样神经母细胞瘤肿瘤起始/干细胞(TICS)的标志。当这些TIC在干细胞促进的条件下体外培养时，HIF-2α的敲除减少了VEGF的表达，并诱导了部分交感神经元的分化。HIF-2α沉默细胞的异种移植瘤广泛坏死，血运不良，与临床神经母细胞瘤中的大部分肿瘤细胞相似，表达额外的交感神经元标记物，而对照肿瘤不成熟，血运良好，基质丰富。因此，HIF-2α维持神经母细胞瘤抽搐的未分化状态。由于低分化与不良预后相关，而血管生成对肿瘤生长至关重要，因此HIF-2α是神经母细胞瘤治疗的一个有吸引力的靶点。
High hypoxia-inducible factor-2 alpha (HIF-2 alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2 alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2 alpha reduced VEGF expression and induced partial sympathetic neuronal differentiation when these TICs were grown in vitro under stem cell-promoting conditions. Xenograft tumors of HIF-2 alpha-silenced cells were widely necrotic, poorly vascularized, and resembled the bulk of tumor cells in clinical neuroblastomas by expressing additional sympathetic neuronal markers, whereas control tumors were immature, well-vascularized, and stroma-rich. Thus, HIF-2 alpha maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2 alpha is an attractive target for neuroblastoma therapy.