A new role for hypoxia in tumor progression: Induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRs
A new role for hypoxia in tumor progression: Induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRs
复制标题
DOI：
10.1016/s1097-2765(00)80137-9
复制
发表时间：
1998-08-01
期刊：
影响因子：
16
通讯作者：
Debatisse, M
中科院分区：
文献类型：
--
作者：
Coquelle, A;Toledo, F;Debatisse, M
包括基因扩增在内的基因组重排是肿瘤细胞的常见特性，但它们与肿瘤微环境的关系尚不清楚。在这里，我们报告的直接证据之间的因果关系缺氧，诱导脆性位点，和基因扩增。最近，我们发现脆性位点的断裂启动了染色体内扩增。我们在这里证明，缺氧是一种有效的脆性位点诱导剂，并且像脆性位点诱导药物一样，它驱动双分钟（DM）的融合及其靶向重返染色体脆性位点，产生均匀染色区域（HSR）。这一途径有效地运作的DM轴承不同的序列，表明低氧驱动的模型的形成的HSR含有nonsyntenic序列经常在实体瘤中观察到。
Genome rearrangements including gene amplification are frequent properties of tumor cells, but how they are related to the tumor microenvironment is unknown. Here, we report direct evidence for a causal relationship between hypoxia, induction of fragile sites, and gene amplification. Recently, we showed that breaks at fragile sites initiate intrachromosomal amplification. We demonstrate here that hypoxia is a potent fragile site inducer and that, like fragile sites inducing drugs, it drives fusion of double minutes (DMs) and their targeted reintegration into chromosomal fragile sites, generating homogeneously staining regions (HSRs). This pathway operates efficiently for DMs bearing different sequences, suggesting a model of hypoxia-driven formation of the HSRs containing nonsyntenic sequences frequently observed in solid tumors.