PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo
PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo
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DOI：
10.1101/gad.1627008
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发表时间：
2008-02-15
影响因子：
10.5
通讯作者：
Holland, Eric C.
中科院分区：
文献类型：
--
作者：
Hambardzumyan, Dolores;Becher, Oren J.;Holland, Eric C.
髓母细胞瘤是一种发生在儿童小脑的脑肿瘤，在血管周围的壁龛中含有干细胞，被认为在放疗后会引起复发。我们平行使用了几种成神经管细胞瘤小鼠模型，以更好地了解这些肿瘤中的关键细胞类型对治疗的反应。在我们的模型中，肿瘤体中的增殖细胞经历辐射诱导的p53依赖性凋亡细胞死亡。通过PTEN缺失激活Akt信号将这些细胞转变为非增殖的广泛结节状形态。相比之下，表达巢蛋白的血管周围干细胞在辐射中存活，激活PI3K/Akt通路，经历p53依赖的细胞周期阻滞，并在72小时后重新进入细胞周期。此外，这些细胞诱导p53的能力依赖于PTEN的存在。这些细胞特征与人髓母细胞瘤相似。最后，Akt信号的抑制使血管周围区域的细胞对辐射诱导的凋亡敏感。
Medulloblastomas are brain tumors that arise in the cerebellum of children and contain stem cells in a perivascular niche thought to give rise to recurrence following radiation. We used several mouse models of medulloblastomas in parallel to better understand how the critical cell types in these tumors respond to therapy. In our models, the proliferating cells in the tumor bulk undergo radiation-induced, p53-dependent apoptotic cell death. Activation of Akt signaling via PTEN loss transforms these cells to a nonproliferating extensive nodularity morphology. By contrast, the nestin-expressing perivascular stem cells survive radiation, activate PI3K/Akt pathway, undergo p53-dependent cell cycle arrest, and re-enter the cell cycle at 72 h. Furthermore, the ability of these cells to induce p53 is dependent on the presence of PTEN. These cellular characteristics are similar to human medulloblastomas. Finally, inhibition of Akt signaling sensitizes cells in the perivascular region to radiation-induced apoptosis.