Efficient Transformation of Primary Human Mesenchymal Stromal Cells by Adenovirus Early Region 1 Oncogenes
Efficient Transformation of Primary Human Mesenchymal Stromal Cells by Adenovirus Early Region 1 Oncogenes
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DOI：
10.1128/jvi.01782-16
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发表时间：
2017-01-01
影响因子：
5.4
通讯作者：
Dobner, Thomas
中科院分区：
文献类型：
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作者：
Speiseder, Thomas;Hofmann-Sieber, Helga;Dobner, Thomas
以前的观察，人羊水细胞（AFC）可以转化的人腺病毒5型（HAdV-5）E1 A/E1 B癌基因促使我们确定在AFC人口中的靶细胞是易受转化。我们的研究结果表明，一种细胞类型对应的间充质干/基质细胞（hMSCs）可以重复转化HAdV-5 E1 A/E1 B癌基因作为有效的原代啮齿类动物文化。HAdV-5 E1转化的hMSC表现出所有通常与高级别致癌转化相关的性质，包括增强的细胞增殖、锚定非依赖性生长、增加的生长速率和高端粒酶活性以及数目和结构染色体畸变。这些数据证实了先前的工作，表明HAdV优先转化啮齿动物间充质来源的细胞。更重要的是，他们首次证明了具有干细胞特征的人类细胞可以在组织培养中高效地被HAdV癌基因完全转化。我们的研究结果强烈支持这一假设，即未分化的祖细胞或具有干细胞样特性的细胞是HAdV介导的细胞转化的高度敏感靶点，并表明人类病毒相关肿瘤可能至少部分起源于这些细胞类型的感染。我们预计，主要的hMSCs将取代主要的啮齿类动物文化在HAdV病毒转化的研究，并有信心，这些调查将继续揭示病毒致癌的一般原则，可以扩展到人类DNA肿瘤病毒，以及。重要的是，一般认为，转化的主要人类细胞与HAdV-5 E1癌基因是非常低效的。然而，少数细胞系已经成功地用HAdV-5 E1 A和E1 B转化，表明存在对HAdV介导的转化敏感的某种细胞类型。有趣的是，所有这些细胞系都来自人类胚胎组织，尽管确切的细胞类型尚不清楚。我们第一次展示了HAdV-5 E1 A和E1 B对原代人间充质基质细胞（hMSCs）的成功转化。此外，我们表明，在HAdV-5 E1 A和E1 B表达后，这些原代祖细胞表现出肿瘤细胞的特征，并且不能再分化为成脂、成软骨或成骨谱系。因此，原代hMSCs代表了一个强大的和新的模型系统，以阐明腺病毒介导的多能人类祖细胞转化的潜在分子机制。
Previous observations that human amniotic fluid cells (AFC) can be transformed by human adenovirus type 5 (HAdV-5) E1A/E1B oncogenes prompted us to identify the target cells in the AFC population that are susceptible to transformation. Our results demonstrate that one cell type corresponding to mesenchymal stem/stroma cells (hMSCs) can be reproducibly transformed by HAdV-5 E1A/E1B oncogenes as efficiently as primary rodent cultures. HAdV-5 E1-transformed hMSCs exhibit all properties commonly associated with a high grade of oncogenic transformation, including enhanced cell proliferation, anchorage-independent growth, increased growth rate, and high telomerase activity as well as numerical and structural chromosomal aberrations. These data confirm previous work showing that HAdV preferentially transforms cells of mesenchymal origin in rodents. More importantly, they demonstrate for the first time that human cells with stem cell characteristics can be completely transformed by HAdV oncogenes in tissue culture with high efficiency. Our findings strongly support the hypothesis that undifferentiated progenitor cells or cells with stem cell-like properties are highly susceptible targets for HAdV-mediated cell transformation and suggest that virus-associated tumors in humans may originate, at least in part, from infections of these cell types. We expect that primary hMSCs will replace the primary rodent cultures in HAdV viral transformation studies and are confident that these investigations will continue to uncover general principles of viral oncogenesis that can be extended to human DNA tumor viruses as well.IMPORTANCE It is generally believed that transformation of primary human cells with HAdV-5 E1 oncogenes is very inefficient. However, a few cell lines have been successfully transformed with HAdV-5 E1A and E1B, indicating that there is a certain cell type which is susceptible to HAdV-mediated transformation. Interestingly, all those cell lines have been derived from human embryonic tissue, albeit the exact cell type is not known yet. We show for the first time the successful transformation of primary human mesenchymal stromal cells (hMSCs) by HAdV-5 E1A and E1B. Further, we show upon HAdV-5 E1A and E1B expression that these primary progenitor cells exhibit features of tumor cells and can no longer be differentiated into the adipogenic, chondrogenic, or osteogenic lineage. Hence, primary hMSCs represent a robust and novel model system to elucidate the underlying molecular mechanisms of adenovirus-mediated transformation of multipotent human progenitor cells.