Identification and Expansion of Human Osteosarcoma-Cancer-Stem Cells by Long-Term 3-Aminobenzamide Treatment
Identification and Expansion of Human Osteosarcoma-Cancer-Stem Cells by Long-Term 3-Aminobenzamide Treatment
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DOI：
10.1002/jcp.21667
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发表时间：
2009-05-01
影响因子：
5.6
通讯作者：
Vento, Renza
中科院分区：
文献类型：
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作者：
Di Fiore, Riccardo;Santulli, Andrea;Vento, Renza
用3-氨基苯甲酰胺(3AB)从人骨肉瘤MG-63细胞中不可逆地筛选出一株表达多种多能干细胞标志物的新型肿瘤干细胞系(3AB-OS)。3AB-OS细胞是由梭形、多边形和圆形三种类型的成纤维细胞组成的稳定的异质性细胞群。与MG-63细胞相比，3AB-OS细胞体积极小，具有更强的球体形成能力、更强的自我更新能力和更高水平的细胞周期标志物，可解释G1-S/G2-M期的进展。与MG-63细胞不同的是，3AB-OS细胞可以无限制地重复种植，而不会失去其增殖能力。它们表现为依赖于ATP结合盒转运体ABCG2的表型，具有高药物外排能力，并且对多能干细胞的标志CD133呈强阳性，而在MG-63细胞中几乎无法检测到CD133。3AB-CS细胞向成骨和成脂分化的能力远低于MG-63细胞，并且高度表达维持干细胞状态所需的基因(Oct3/4、端粒酶逆转录酶、核干蛋白、Nanog)和抑制细胞凋亡所需的基因(HIF-1α、flip-L、Bcl2、XIAP、IAPs和Survivin)。3AB-OS可能是一种新的肿瘤细胞系，可用于研究在肿瘤细胞系中诱导干细胞浓缩的机制。确定在骨肉瘤中驱动肿瘤发生和化疗耐药的肿瘤干细胞亚群可能会导致预后和最佳治疗决定。干细胞标记物，尤其是CD133和ABCG2的表达模式可能反映骨肉瘤的未分化状态，并可能与临床上的不良预后相关。
A novel cancer stem-like cell line (3AB-OS), expressing a number of pluripotent stem cell markers, was irreversibly selected from human osteosarcoma MG-63 cells by long-term treatment (100 days) with 3-aminobenzamide (3AB). 3AB-OS cells are a heterogeneous and stable cell population composed by three types of fibroblastoid cells, spindle-shaped, polygonal-shaped, and rounded-shaped. With respect to MG-63 cells, 3AB-OS cells are extremely smaller, possess a much greater capacity to form spheres, a stronger self-renewal ability and much higher levels of cell cycle markers which account for G1-S/G2-M phases progression. Differently from MG-63 cells, 3AB-OS cells can be reseeded unlimitedly without losing their proliferative potential. They show an ATP-binding cassette transporter ABCG2-dependent phenotype with high drug efflux capacity, and a strong positivity for CD133, marker for pluripotent stem cells, which are almost unmeasurable in MG-63 cells. 3AB-CS cells are much less committed to osteogenic and adipogenic differentiation than MG-63 cells and highly express genes required for maintaining stem cell state (Oct3/4, hTERT, nucleostemin, Nanog) and for inhibiting apoptosis (HIF-1 alpha, FLIP-L, Bcl-2, XIAP, IAPs, and survivin). 3AB-OS may be a novel tumor cell line useful for investigating the mechanisms by which stem cells enrichment may be induced in a tumor cell line. The identification of a subpopulation of cancer stem cells that drives tumorigenesis and chemoresistance in osteosarcoma may lead to prognosis and optimal therapy determination. Expression patterns of stem cell markers, especially CD133 and ABCG2, may indicate the undifferentiated state of osteosarcoma tumors, and may correlate with unfavorable prognosis in the clinical setting.