Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage
Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage
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DOI：
10.1073/pnas.0805462105
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发表时间：
2008-08-19
影响因子：
11.1
通讯作者：
Lees, Jacqueline A.
中科院分区：
文献类型：
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作者：
Berman, Seth D.;Calo, Eliezer;Lees, Jacqueline A.
RB-1 和 p53 肿瘤抑制因子的突变与人类骨肉瘤的发展有关。为了建立这种疾病的小鼠模型，我们使用条件转基因小鼠品系来灭活成骨细胞前体中的 Rb 和/或 p53。由此产生的 Rb;p53 双突变 (DKO) 动物是可行的，但会发展为完全外显的早发性骨肉瘤。这些肿瘤表现出人类骨肉瘤的许多特征，包括高度转移。我们建立了 DKO 骨肉瘤细胞系，以进一步研究其特性。这些永生化细胞系具有高度增殖性，并且根据它们在免疫功能低下的小鼠中形成转移性肿瘤的能力来判断，它们保留了致瘤潜力。此外，它们可以被诱导分化，并且根据诱导信号，它们将采取成骨或脂肪形成的命运。与这种多能性一致，这些肿瘤细胞的很大一部分表达 Sca-1，这是一种通常与干细胞/未定型祖细胞相关的标记物。通过在移植试验中分析分选的细胞，我们证明骨肉瘤细胞系的致瘤性与 Sca-1 标记物的存在相关。最后，我们表明，Sca-1 阳性间充质干细胞/祖细胞中 Rb 和 p53 的缺失足以产生可在体内引发骨肉瘤形成的转化细胞。
Mutation of the RB-1 and p53 tumor suppressors is associated with the development of human osteosarcoma. With the goal of generating a mouse model of this disease, we used conditional and transgenic mouse strains to inactivate Rb and/or p53 specifically in osteoblast precursors. The resulting Rb;p53 double mutant (DKO) animals are viable but develop early onset osteosarcomas with complete penetrance. These tumors display many of the characteristics of human osteosarcomas, including being highly metastatic. We established cell lines from the DKO osteosarcomas to further investigate their properties. These immortalized cell lines are highly proliferative and they retain their tumorigenic potential, as judged by their ability to form metastatic tumors in immunocompromised mice. Moreover, they can be induced to differentiate and, depending on the inductive signal, will adopt either the osteogenic or adipogenic fate. Consistent with this multipotency, a significant portion of these tumor cells express Sca-1, a marker that is typically associated with stem cells/uncommitted progenitors. By assaying sorted cells in transplant assays, we demonstrate that the tumorigenicity of the osteosarcoma cell lines correlates with the presence of the Sca-1 marker. Finally, we show that loss of Rb and p53 in Sca-1-positive mesenchymal stem/progenitor cells is sufficient to yield transformed cells that can initiate osteosarcoma formation in vivo.