Osteosarcoma originates from mesenchymal stem cells in consequence of aneuploidization and genomic loss of Cdkn2
Osteosarcoma originates from mesenchymal stem cells in consequence of aneuploidization and genomic loss of Cdkn2
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DOI：
10.1002/path.2603
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发表时间：
2009-11-01
影响因子：
7.3
通讯作者：
Hogendoorn, Pancras C. W.
中科院分区：
文献类型：
--
作者：
Mohseny, Alexander B.;Szuhai, Karoly;Hogendoorn, Pancras C. W.
高度恶性骨肉瘤的特征是广泛的遗传不稳定性，从而阻碍了致病基因突变的鉴定和对潜在病理过程的理解。它缺乏良性的前驱病变，尽管发病年龄较早，但与遗传易感性或生殖系突变相关的报道并不常见。在这里，我们展示了一种新的综合方法，用于研究在移植后形成骨肉瘤的小鼠间充质干细胞（MSC）系统中骨肉瘤发展的癌前阶段。通过对正常骨髓间充质干细胞、转化骨髓间充质干细胞和骨肉瘤细胞的功能和表型分析，我们为骨肉瘤的骨髓间充质干细胞起源提供了大量证据。在一个逐步的方法，使用COBRA-FISH核型分析和阵列CGH在不同代的MSC，我们确定了非整倍化，易位和纯合丢失的cdkn 2区域的MSC恶性转化的关键介质。然后，我们确定了CDKN 2A/p16蛋白在88例骨肉瘤患者中的表达作为敏感的预后标志物，从而将鼠MSC模型与人骨肉瘤连接起来。此外，偶尔有患者报告提到骨髓移植治疗无关恶性肿瘤后骨肉瘤形成。我们的研究结果表明，MSC的临床应用可能存在危险;然而，它们也提供了新的机会来研究骨肉瘤发生中的早期遗传事件，更重要的是，调节这些事件并记录对肿瘤进展的影响。这可能有助于识别新的治疗策略，因为目前的治疗方法的成功已经达到了平台期。版权所有（C）2009大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
High-grade osteosarcoma is characterized by extensive genetic instability, thereby hampering the identification of causative gene mutations and understanding of the underlying pathological processes. It lacks a benign precursor lesion and reports on associations with hereditary predisposition or germline mutations are uncommon, despite the early age of onset. Here we demonstrate a novel comprehensive approach for the study of premalignant stages of osteosarcoma development in a murine mesenchymal stem cell (MSC) system that formed osteosarcomas upon grafting. By parallel functional and phenotypic analysis of normal MSCs, transformed MSCs and derived osteosarcoma cells, we provide substantial evidence for a MSC origin of osteosarcoma. In a stepwise approach, using COBRA-FISH karyotyping and array CGH in different passages of MSCs, we identified aneuploidization, translocations and homozygous loss of the cdkn2 region as the key mediators of MSC malignant transformation. We then identified CDKN2A/p16 protein expression in 88 osteosarcoma patients as a sensitive prognostic marker, thereby bridging the murine MSCs model to human osteosarcoma. Moreover, occasional reports in patients mention osteosarcoma formation following bone marrow transplantation for an unrelated malignancy. Our findings suggest a possible hazard for the clinical use of MSCs; however, they also offer new opportunities to study early genetic events in osteosarcoma genesis and, more importantly, to modulate these events and record the effect on tumour progression. This could be instrumental for the identification of novel therapeutic strategies, since the success of the current therapies has reached a plateau phase. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.