Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects
Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects
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DOI：
10.1038/79075
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发表时间：
2000-09-01
期刊：
影响因子：
30.8
通讯作者：
Jacks, T
中科院分区：
文献类型：
--
作者：
Reilly, KM;Loisel, DA;Jacks, T
星形细胞瘤是人类脑癌的主要原因。由于这些肿瘤是高度浸润性的，目前依赖于靶向肿瘤肿块的治疗往往无效。星形细胞瘤的小鼠模型将是解剖肿瘤进展和测试治疗方法的有力工具。小鼠星形细胞瘤模型被设计为在星形胶质细胞中表达致癌蛋白，但由于肿瘤的低穿透性或肿瘤进展有限而取得的成功有限(1-3)。我们在这里提出了一个小鼠星形细胞瘤模型，涉及两个肿瘤抑制基因NF1和TrP53的突变。携带NF1基因突变的人会患上I型神经纤维瘤病(NF1)，并会增加患上视神经胶质瘤、星形细胞瘤和胶质母细胞瘤的风险(4，5)。TP53抑癌基因经常在一组星形细胞瘤中发生突变，这些星形细胞瘤在年轻时就发展起来，进展缓慢，发展成胶质母细胞瘤(称为继发性胶质母细胞瘤，与快速发展(6-10)的原发胶质母细胞瘤形成对比)。这个小鼠模型显示了从低级别星形细胞瘤到多形性胶质母细胞瘤的一系列星形细胞瘤阶段，并可能准确地模拟涉及TP53缺失的人类继发性胶质母细胞瘤。这是第一个报道的星形细胞瘤小鼠模型，由肿瘤抑制基因的缺失而不是转基因癌基因的过度表达引起。
Astrocytomas are the leading cause of brain cancer in humans. Because these tumours are highly infiltrative, current treatments that rely on targeting the tumour mass are often ineffective. A mouse model for astrocytoma would be a powerful tool for dissecting tumour progression and testing therapeutics. Mouse models of astrocytoma have been designed to express oncogenic proteins in astrocytes, but have had limited success due to low tumour penetrance or limited tumour progression(1-3). We present here a mouse model of astrocytomas involving mutation of two tumour-suppressor genes, Nf1 and Trp53. Humans with mutations in NF1 develop neurofibromatosis type I (NF1) and have increased risk of optic gliomas, astrocytomas and glioblastomas(4,5). The TP53 tumour suppressor is often mutated in a subset of astrocytomas that develop at a young age and progress slowly to glioblastoma (termed secondary glioblastomas, in contrast to primary glioblastomas that develop rapidly de novo(6-10)). This mouse model shows a range of astrocytoma stages, from low-grade astrocytoma to glioblastoma multiforme, and may accurately model human secondary glioblastoma involving TP53 loss. This is the first reported mouse model of astrocytoma initiated by loss of tumour suppressors, rather than overexpression of transgenic oncogenes.