Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas.
Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas.
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DOI：
10.1038/onc.2011.405
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发表时间：
2012-05-03
期刊：
影响因子：
8
通讯作者：
Basilico, C.
中科院分区：
文献类型：
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作者：
Basu-Roy, U.;Seo, E.;Ramanathapuram, L.;Rapp, T. B.;Perry, J. A.;Orkin, S. H.;Mansukhani, A.;Basilico, C.
肿瘤被认为是由一个自我更新的细胞库维持的，称为肿瘤起始细胞或癌症干细胞。骨肉瘤是由成骨细胞祖细胞分化而来的高级别肉瘤，是最常见的小儿骨恶性肿瘤。在这份报告中，我们表明，干细胞转录因子Sox 2在人类和小鼠骨肉瘤细胞系以及肿瘤样本中高度表达。骨肉瘤细胞在悬浮液中作为骨球生长的能力增加，骨球在Sox 2和干细胞标志物Sca-1的表达中大大富集。在独立的鼠骨肉瘤衍生细胞中，Sox 2被shRNA耗尽显著降低了它们的体外转化特性和它们形成肿瘤的能力。Sox 2缺失的骨肉瘤细胞不能再形成骨球，并分化为成熟的成骨细胞。同时，它们表现出Sca-1表达降低和Wnt信号通路上调。因此，尽管有其他突变，这些肿瘤细胞仍维持对Sox 2的增殖需求。我们的数据表明，Sox 2是骨肉瘤细胞自我更新所必需的，并且Sox 2拮抗促分化Wnt通路，这反过来可以降低Sox 2的表达。这些研究将Sox 2定义为骨肉瘤中的生存因子和自我更新的新型生物标志物，并支持Wnt途径在间充质来源的肿瘤中的肿瘤抑制作用。我们的研究结果可能为基于抑制Sox 2或增强Wnt信号转导治疗骨肉瘤的新治疗策略提供基础。
Tumors are thought to be sustained by a reservoir of self-renewing cells, termed tumor initiating cells or cancer stem cells. Osteosarcomas are high-grade sarcomas derived from osteoblast progenitor cells and are the most common pediatric bone malignancy. In this report we show that the stem cell transcription factor Sox2 is highly expressed in human and murine osteosarcoma cell lines as well as in tumor samples. Osteosarcoma cells have increased ability to grow in suspension as osteospheres, that are greatly enriched in expression of Sox2 and the stem cell marker, Sca-1. Depletion of Sox2 by shRNAs in independent murine osteosarcoma-derived cells drastically reduces their transformed properties in vitro and their ability to form tumors. Sox2-depleted osteosarcoma cells can no longer form osteospheres, and differentiate into mature osteoblasts. Concomitantly, they exhibit decreased Sca-1 expression and upregulation of the Wnt signaling pathway. Thus, despite other mutations, these tumor cells maintain a proliferative requirement for Sox2. Our data indicate that Sox2 is required for osteosarcoma cell self-renewal, and that Sox2 antagonizes the pro-differentiation Wnt pathway, that can in turn reduce Sox2 expression. These studies define Sox2 as a survival factor and a novel biomarker of self-renewal in osteosarcomas, and support a tumor suppressive role for the Wnt pathway in tumors of mesenchymal origin. Our findings could provide the basis for novel therapeutic strategies based on inhibiting Sox2 or enhancing Wnt signaling for the treatment of osteosarcomas.
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影响因子：
5.2
作者：
Fujii, Hiromasa;Honoki, Kanya;Takakura, Yoshinori
通讯作者：
Takakura, Yoshinori
DOI：
10.1073/pnas.0805462105
发表时间：
2008-08-19
影响因子：
11.1
作者：
Berman, Seth D.;Calo, Eliezer;Lees, Jacqueline A.
通讯作者：
Lees, Jacqueline A.
影响因子：
15.9
作者：
Kansara, Maya;Tsang, Michael;Thomas, David M.
通讯作者：
Thomas, David M.
影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.8
作者：
通讯作者：
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