Highly aneuploid zebrafish malignant peripheral nerve sheath tumors have genetic alterations similar to human cancers.
Highly aneuploid zebrafish malignant peripheral nerve sheath tumors have genetic alterations similar to human cancers.
复制标题
高度非整倍体斑马鱼恶性周围神经鞘瘤具有与人类癌症相似的遗传改变。
DOI：
10.1073/pnas.1011548107
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发表时间：
2010
影响因子：
11.1
通讯作者：
Hopkins,Nancy
中科院分区：
文献类型：
--
作者：
Zhang,Guangjun;Hoersch,Sebastian;Amsterdam,Adam;Whittaker,CharlesA;Lees,JacquelineA;Hopkins,Nancy
非整倍性是人类癌症的一个标志，但大多数小鼠癌症模型缺乏许多人类肿瘤中所见的广泛非整倍性。斑马鱼正在成为研究癌症的越来越流行的模型。在此，我们报道斑马鱼中由于核糖体蛋白（rp）基因或 inp53 突变而产生的恶性周围神经鞘瘤（MPNST）是高度非整倍体。核型分析显示，这些肿瘤经常含有接近三倍体的染色体数量，并且单个肿瘤内不同细胞的染色体数量有所不同。使用阵列比较基因组杂交，我们发现，就像在人类癌症中一样，某些鱼类染色体在许多 MPNST 中优先代表性过高，而其他染色体则代表性不足。此外，我们还获得了反复出现的亚染色体扩增和缺失的证据，这些扩增和缺失可能包含与癌症发生或进展有关的基因。这些局部扩增涵盖了在人类肿瘤中观察到扩增的几个基因，包括met、cyclinD2、slc45a3和cdk6。一种焦点放大包括fgf6a。通过过度表达 fgf8 的突变增加 fgf 信号传导，加速了 p53 突变鱼中 MPNST 的发生，表明 fgf6a 本身可能是 MPNST 的驱动因素。我们的研究结果表明，斑马鱼是研究人类癌症非整倍性的有用模型，并可用于识别可能在鱼类和人类肿瘤中充当驱动因素的候选基因。
Aneuploidy is a hallmark of human cancers, but most mouse cancer models lack the extensive aneuploidy seen in many human tumors. The zebrafish is becoming an increasingly popular model for studying cancer. Here we report that malignant peripheral nerve sheath tumors (MPNSTs) that arise in zebrafish as a result of mutations in either ribosomal protein (rp) genes or inp53are highly aneuploid. Karyotyping reveals that these tumors frequently harbor near-triploid numbers of chromosomes, and they vary in chromosome number from cell to cell within a single tumor. Using array comparative genomic hybridization, we found that, as in human cancers, certain fish chromosomes are preferentially overrepresented, whereas others are underrepresented in many MPNSTs. In addition, we obtained evidence for recurrent subchromosomal amplifications and deletions that may contain genes involved in cancer initiation or progression. These focal amplifications encompassed several genes whose amplification is observed in human tumors, includingmet,cyclinD2,slc45a3, andcdk6. One focal amplification includedfgf6a. Increasing fgf signaling via a mutation that overexpressesfgf8accelerated the onset of MPNSTs in fish bearing a mutation inp53, suggesting thatfgf6aitself may be a driver of MPNSTs. Our results suggest that the zebrafish is a useful model in which to study aneuploidy in human cancer and in which to identify candidate genes that may act as drivers in fish and potentially also in human tumors.