Rorie Checo J, Thomas Venetia D, Chen Pengchin, Pierce Heather Hanson, O'Bryan John P, Weissman Bernard E
Curriculum in Toxicology, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Cancer Res. 2004 Feb 15;64(4):1266-77. doi: 10.1158/0008-5472.can-03-3274.
Neuroblastoma (NB) and the Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumor (PNET) family are pediatric cancers derived from neural crest cells. Although NBs display features of the sympathetic nervous system, ES/PNETs express markers consistent with parasympathetic differentiation. To examine the control of these differentiation markers, we generated NB x ES/PNET somatic cell hybrids. NB-specific markers were suppressed in the hybrids, whereas ES/PNET-specific markers were unaffected. These results suggested that the Ews/Fli-1 fusion gene, resulting from a translocation unique to ES/PNETs, might account for the loss of NB-specific markers. To test this hypothesis, we generated two different NB cell lines that stably expressed the Ews/Fli-1 gene. We observed that heterologous expression of the Ews/Fli-1 protein led to the suppression of NB-specific markers and de novo expression of ES/PNET markers. To determine the extent of changes in differentiation, we used the Affymetrix GeneChip Array system to observe global transcriptional changes of genes. This analysis revealed that the gene expression pattern of the Ews/Fli-1-expressing NB cells resembled that observed in pooled ES/PNET cell lines and differed significantly from the NB parental cells. Therefore, we propose that Ews/Fli-1 contributes to the etiology of ES/PNET by subverting the differentiation program of its neural crest precursor cell to a less differentiated and more proliferative state.
神经母细胞瘤（NB）和尤因肉瘤（ES）/外周原始神经外胚层肿瘤（PNET）家族是源自神经嵴细胞的儿童癌症。尽管NB表现出交感神经系统的特征，但ES/PNET表达与副交感神经分化一致的标志物。为了研究这些分化标志物的调控机制，我们构建了NB×ES/PNET体细胞杂种。在杂种中，NB特异性标志物受到抑制，而ES/PNET特异性标志物未受影响。这些结果表明，ES/PNET特有的易位产生的Ews/Fli-1融合基因可能是NB特异性标志物丢失的原因。为了验证这一假设，我们构建了两种稳定表达Ews/Fli-1基因的不同NB细胞系。我们观察到Ews/Fli-1蛋白的异源表达导致NB特异性标志物的抑制和ES/PNET标志物的从头表达。为了确定分化变化的程度，我们使用Affymetrix基因芯片阵列系统观察基因的全局转录变化。该分析表明，表达Ews/Fli-1的NB细胞的基因表达模式类似于在合并的ES/PNET细胞系中观察到的模式，并且与NB亲代细胞有显著差异。因此，我们提出Ews/Fli-1通过将其神经嵴前体细胞的分化程序转变为分化程度较低且增殖性更强的状态，从而促进了ES/PNET的病因学发展。
