Pten haploinsufficiency accelerates formation of high-grade astrocytomas
Pten haploinsufficiency accelerates formation of high-grade astrocytomas
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DOI：
10.1158/0008-5472.can-07-6867
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发表时间：
2008-05-01
期刊：
影响因子：
11.2
通讯作者：
Parada, Luis F.
中科院分区：
文献类型：
--
作者：
Kwon, Chang-Hyuk;Zhao, Dawen;Parada, Luis F.
我们先前报道了小鼠中枢神经系统（CNS）Nf 1和p53肿瘤抑制基因的失活导致低级别至高级别进行性星形细胞瘤的发展。当肿瘤达到高级别时，它们经常伴随着Akt激活，这让人想起人类高级别胶质瘤中PTEN突变的频繁关联。在本研究中，我们将Pten的CNS杂合性引入Nf 1/p53星形细胞瘤模型。结果小鼠的发病率加快，生存期缩短，高级别星形细胞瘤完全消失。Pten单倍不足加速了3级星形细胞瘤的形成，而Pten杂合性缺失和Akt激活与进展为4级肿瘤一致。这些数据表明，每个Pten等位基因的连续丢失可能分别导致高级别星形细胞瘤的从头形成和进展为胶质母细胞瘤，从而提供了对原发性胶质母细胞瘤病因的深入了解。异位迁移的神经干/祖细胞谱系细胞的存在下，在presymptosis Pten缺陷突变体的大脑支持的概念，这些肿瘤可能产生的干/祖细胞。
We previously reported that central nervous system (CNS) inactivation of Nf1 and p53 tumor suppressor genes in mice results in the development of low-grade to high-grade progressive astrocytomas. When the tumors achieve high grade, they are frequently accompanied by Akt activation, reminiscent of the frequent association of PTEN mutations in human high-grade glioma. In the present study, we introduced CNS heterozygosity of Pten into the Nf1/p53 astrocytoma model. Resulting mice had accelerated morbidity, shortened survival, and full penetrance of high-grade astrocytomas. Haploinsufficiency of Pten accelerated formation of grade 3 astrocytomas, whereas loss of Pten heterozygosity and Akt activation coincided with progression into grade 4 tumors. These data suggest that successive loss of each Pten allele may contribute to de novo formation of high-grade astrocytoma and progression into glioblastoma, respectively, thus providing insight into the etiology of primary glioblastoma. The presence of ectopically migrating neural stem/progenitor lineage cells in presymptomatic Pten-deficient mutant brains supports the notion that these tumors may arise from stem/progenitor cells.