Profiling of high-grade central osteosarcoma and its putative progenitor cells identifies tumourigenic pathways.
Profiling of high-grade central osteosarcoma and its putative progenitor cells identifies tumourigenic pathways.
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DOI：
10.1038/sj.bjc.6605482
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发表时间：
2009-12-15
影响因子：
8.8
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中科院分区：
文献类型：
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背景：骨肉瘤是儿童和年轻人中最常见的原发性恶性骨肿瘤，40%的患者生存率低。为了确定参与肿瘤发生的信号通路，我们比较了基因表达在骨肉瘤与其假定的正常people.Methods：全基因组表达谱产生的25个高级中央骨肉瘤化疗前活检，5成骨细胞瘤，5间充质干细胞（MSC）的人口和这些相同的MSC分化成骨细胞。差异表达的基因进行了分析的背景下，他们的功能，使用GenMAPP programme.Results的途径：间充质干细胞，成骨细胞，成骨细胞瘤和成骨细胞瘤分别聚类和成千上万的差异表达的基因被确定。最显著改变的途径涉及细胞周期调节和DNA复制。Wnt信号通路的几个上游组分在骨肉瘤中下调。参与β-catenin蛋白降解的两个基因，Wnt信号传导的关键效应物Axin和GSK 3-β，显示表达降低，表明Wnt信号传导不再受常规信号的控制。比较良性成骨细胞瘤与骨肉瘤确定的细胞周期调控作为最显着的改变pathway.Conclusion：这些结果表明，上调的细胞周期和下调的Wnt信号传导有一个重要的作用，在骨肉瘤的发生。高度恶性骨肉瘤和良性成骨细胞瘤之间的基因表达差异涉及细胞周期调控。
Background:Osteosarcoma is the most prevalent primary malignant bone tumour in children and young adults, with poor survival in 40% of patients. To identify the signalling pathways involved in tumourigenesis, we compared gene expression in osteosarcoma with that in its presumed normal counterparts.Methods:Genome-wide expression profiles were generated from 25 high-grade central osteosarcoma prechemotherapy biopsies, 5 osteoblastomas, 5 mesenchymal stem cell (MSC) populations and these same MSCs differentiated into osteoblasts. Genes that were differentially expressed were analysed in the context of the pathways in which they function using the GenMAPP programme.Results:MSCs, osteoblasts, osteoblastomas and osteosarcomas clustered separately and thousands of differentially expressed genes were identified. The most significantly altered pathways are involved in cell cycle regulation and DNA replication. Several upstream components of the Wnt signalling pathway are downregulated in osteosarcoma. Two genes involved in degradation of β-catenin protein, the key effectors of Wnt signalling, Axin and GSK3-β, show decreased expression, suggesting that Wnt signalling is no longer under the control of regular signals. Comparing benign osteoblastomas with osteosarcomas identified cell cycle regulation as the most prominently changed pathway.Conclusion:These results show that upregulation of the cell cycle and downregulation of Wnt signalling have an important role in osteosarcoma genesis. Gene expression differences between highly malignant osteosarcoma and benign osteoblastoma involve cell cycle regulation.