A self-renewal program controls the expansion of genetically unstable cancer stem cells in pluripotent stem cell-derived tumors.
A self-renewal program controls the expansion of genetically unstable cancer stem cells in pluripotent stem cell-derived tumors.
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DOI：
10.1634/stemcells.2008-0529
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发表时间：
2009-01
期刊：
影响因子：
--
通讯作者：
Clark AT
中科院分区：
文献类型：
--
作者：
Conway AE;Lindgren A;Galic Z;Pyle AD;Wu H;Zack JA;Pelligrini M;Teitell MA;Clark AT
人类生殖细胞肿瘤通常是转移性的，可能是由于癌症干细胞在肿瘤远端生长所致。为了确定在睾丸生殖细胞肿瘤移植模型中是否可以鉴定出癌症干细胞，我们将小鼠胚胎生殖细胞(EGCs)移植到成年严重联合免疫缺陷小鼠的睾丸中。移植导致局部侵袭性实体瘤，细胞成分在连续移植后产生继发性肿瘤。继发肿瘤总是转移性的，这一特征在来源于EGCs的原发肿瘤中没有观察到。为了鉴定EGCs和肿瘤干细胞之间的差异，我们进行了核型和微阵列分析。我们的结果表明，癌症干细胞的产生与原始种群中没有发现的非克隆性基因组重排的获得有关。此外，用一种有效的自我更新抑制剂维甲酸对EGCs进行预处理，可以防止肿瘤的形成和这些遗传不稳定的癌症干细胞的出现。微阵列分析显示，EGCs与第一代和第二代癌症干细胞高度相似；然而，可以识别出大约1000个差异表达的转录本，对应于癌基因和与运动和发育相关的基因的变化。综上所述，这些数据表明，在遗传不稳定的细胞背景下，致癌途径的激活，加上固有的自我更新能力，参与了从多潜能细胞来源的肿瘤的癌症干细胞群体中转移行为的获得。
Human germ cell tumors are often metastatic, presumably due to distal site tumor growth by cancer stem cells. To determine whether cancer stem cells can be identified in a transplantation model of testicular germ cell tumor, we transplanted murine embryonic germ cells (EGCs) into the testis of adult severe combined immunodeficient mice. Transplantation resulted in a locally invasive solid tumor, with a cellular component that generated secondary tumors upon serial transplantation. The secondary tumors were invariably metastatic, a feature not observed in the primary tumors derived from EGCs. To characterize the differences between EGCs and the tumor-derived stem cells, we performed karyotype and microarray analysis. Our results show that generation of cancer stem cells is associated with the acquisition of nonclonal genomic rearrangements not found in the originating population. Furthermore, pretreatment of EGCs with a potent inhibitor of self-renewal, retinoic acid, prevented tumor formation and the emergence of these genetically unstable cancer stem cells. Microarray analysis revealed that EGCs and first- and second-generation cancer stem cells were highly similar; however, approximately 1,000 differentially expressed transcripts could be identified corresponding to alterations in oncogenes and genes associated with motility and development. Combined, the data suggest that the activation of oncogenic pathways in a cellular background of genetic instability, coupled with an inherent ability to self-renew, is involved in the acquisition of metastatic behavior in the cancer stem cell population of tumors derived from pluripotent cells.
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影响因子：
37.8
作者：
Cao, F;Lin, S;Wu, JC
通讯作者：
Wu, JC
影响因子：
5.2
作者：
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通讯作者：
Benvenisty, Nissim
影响因子：
7.3
作者：
Gillis, A. J. M.;Stoop, H. J.;Looijenga, L. H. J.
通讯作者：
Looijenga, L. H. J.
影响因子：
5.1
作者：
Duester, G
通讯作者：
Duester, G
影响因子：
64.5
作者：
Hochedlinger, K;Yamada, Y;Jaenisch, R
通讯作者：
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