CD133+ anaplastic thyroid cancer cells initiate tumors in immunodeficient mice and are regulated by thyrotropin.
CD133+ anaplastic thyroid cancer cells initiate tumors in immunodeficient mice and are regulated by thyrotropin.
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DOI：
10.1371/journal.pone.0005395
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Lin RY
中科院分区：
文献类型：
--
作者：
Friedman S;Lu M;Schultz A;Thomas D;Lin RY
间变性甲状腺癌(ATC)是人类最致命的恶性肿瘤之一。它的快速发病和对传统疗法的抵抗力有助于在诊断后平均存活6个月，并使识别甲状腺癌启动细胞变得越来越重要。在以往对ATC细胞株的研究中，CD133+细胞在体外表现出高增殖、自我更新和集落形成能力等干细胞样特性。在这里，我们表明，将CD133+细胞移植到免疫缺陷的NOD/SCID小鼠中足以诱导体内肿瘤的生长，而不是CD133−细胞。我们还描述了在三个月的培养过程中，CD133+的ATC细胞的比例如何急剧增加，从7%增加到80%以上。这个CD133+细胞池可以通过流式细胞术进一步分为两个不同的群体：CD133+/高和CD133+/低。虽然这两个亚群都能够长期发生肿瘤，但快速增殖的CD133+/高表达细胞是目前为止最有效的。它们还表达高水平的干细胞抗原Oct4和促甲状腺激素受体TSHR。用TSH处理ATC细胞后，CD133+细胞数量增加三倍，TSHR和Oct4的表达呈剂量依赖性上调。更重要的是，对ATC患者组织标本的免疫组织化学分析表明，CD133在肿瘤细胞上高表达，而在邻近的正常甲状腺细胞上不表达。据我们所知，这是第一个表明CD133+ATC细胞是免疫缺陷小鼠肿瘤生长的唯一原因的报告。我们的数据也为TSH对CD133的调控提供了独特的见解。这些高致瘤性的CD133+细胞和激活的TSH信号通路可能是未来ATC治疗的有用靶点。
Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies. Its rapid onset and resistance to conventional therapeutics contribute to a mean survival of six months after diagnosis and make the identification of thyroid-cancer-initiating cells increasingly important. In prior studies of ATC cell lines, CD133+ cells exhibited stem-cell-like features such as high proliferation, self-renewal and colony-forming ability in vitro. Here we show that transplantation of CD133+ cells, but not CD133− cells, into immunodeficient NOD/SCID mice is sufficient to induce growth of tumors in vivo. We also describe how the proportion of ATC cells that are CD133+ increases dramatically over three months of culture, from 7% to more than 80% of the total. This CD133+ cell pool can be further separated by flow cytometry into two distinct populations: CD133+/high and CD133+/low. Although both subsets are capable of long-term tumorigenesis, the rapidly proliferating CD133+/high cells are by far the most efficient. They also express high levels of the stem cell antigen Oct4 and the receptor for thyroid stimulating hormone, TSHR. Treating ATC cells with TSH causes a three-fold increase in the numbers of CD133+ cells and elicits a dose-dependent up-regulation of the expression of TSHR and Oct4 in these cells. More importantly, immunohistochemical analysis of tissue specimens from ATC patients indicates that CD133 is highly expressed on tumor cells but not on neighboring normal thyroid cells. To our knowledge, this is the first report indicating that CD133+ ATC cells are solely responsible for tumor growth in immunodeficient mice. Our data also give a unique insight into the regulation of CD133 by TSH. These highly tumorigenic CD133+ cells and the activated TSH signaling pathway may be useful targets for future ATC therapies.
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影响因子：
8.4
作者：
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通讯作者：
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通讯作者：
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