Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice
Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice
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DOI：
10.1038/75596
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发表时间：
2000-05-01
期刊：
影响因子：
30.8
通讯作者：
Fuller, GN
中科院分区：
文献类型：
--
作者：
Holland, EC;Celestino, J;Fuller, GN
胶质瘤是最常见的原发恶性脑肿瘤，可分为四个临床级别，其中最具侵袭性的是4级星形细胞瘤(又称多形性胶质母细胞瘤；GBM)。基底膜频繁的遗传改变(参考文献2-5)导致了涉及RAS、Akt和其他蛋白质的常见信号转导通路的刺激(6-10)。目前尚不清楚这些途径中的哪些足以诱导GBM的形成，在这里，我们以组织特异性的方式，将编码激活形式的RAS和Akt的基因转移到小鼠的星形胶质细胞和神经前体细胞中。我们发现，虽然激活的RAS或Akt单独不足以诱导GBM的形成，但激活的RAS和Akt联合诱导具有人GBM的组织学特征的高级别胶质瘤。这些肿瘤似乎是在将基因转移到神经前体细胞后出现的，而不是在转移到分化的星形胶质细胞后出现的。在许多人类GBM中发现RAS活性增加(参考文献)。11)，我们在这里表明，在大多数这些肿瘤中，Akt活性增加，这意味着这两个途径的联合激活准确地模拟了这种疾病的生物学。
Gliomas are the most common primary malignant brain tumours and are classified into four clinical grades', with the most aggressive tumours being grade 4 astrocytomas (also known as glioblastoma multiforme; GBM). Frequent genetic alterations in GBMs (refs 2-5) result in stimulation of common signal transduction pathways involving Ras, Akt and other proteins(6-10). It is not known which of these pathways, if any, are sufficient to induce GBM formation, Here we transfer, in a tissue-specific manner, genes encoding activated forms of Ras and Akt to astrocytes and neural progenitors in mice. We found that although neither activated Ras nor Akt alone is sufficient to induce GBM formation, the combination of activated Ras and Akt induces high-grade gliomas with the histological features of human GBMs. These tumours appear to arise after gene transfer to neural progenitors, but not after transfer to differentiated astrocytes. Increased activity of RAS is found in many human GBMs (ref. 11), and we show here that Akt activity is increased in most of these tumours, implying that combined activation of these two pathways accurately models the biology of this disease.