Hyperdiploid tumor cells increase phenotypic heterogeneity within Glioblastoma tumors
Hyperdiploid tumor cells increase phenotypic heterogeneity within Glioblastoma tumors
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DOI：
10.1039/c3mb70484j
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发表时间：
2014-01-01
影响因子：
--
通讯作者：
Harding, Angus
中科院分区：
文献类型：
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作者：
Donovan, Prudence;Cato, Kathleen;Harding, Angus
在这里，我们报告了胶质母细胞瘤（GB）患者肿瘤中存在的增殖性、存活性和超二倍体肿瘤细胞亚群的鉴定。使用异种移植肿瘤模型，我们证明超二倍体细胞群在异种移植肿瘤中得以维持，并且克隆扩增的超二倍体细胞支持体内肿瘤的形成和进展。在一些患者肿瘤球系中，超二倍体在长期培养期间和体内异种移植肿瘤模型中得以维持，表明超二倍体可以是稳定的细胞状态。在其他患者系中，超二倍体细胞在体外和体内表现出遗传漂移，这表明在这些患者中，超二倍体是一种短暂的细胞状态，可产生新的表型，可能促进肿瘤的快速进化。我们发现超二倍体细胞对常规疗法具有抵抗力，部分原因是由于细胞周期的 G(0)/G(1) 期延迟而导致细胞分裂不频繁。超二倍体肿瘤细胞比整倍体癌细胞明显更大且代谢活性更高，这与对糖酵解抑制作用的敏感性增加相关。这些数据共同表明 GB 超二倍体肿瘤细胞是一个潜在的重要细胞亚群，能够很好地促进成年脑癌患者的肿瘤进化和疾病复发，并表明肿瘤代谢是针对该亚群的治疗干预的一个有希望的点。
Here we report the identification of a proliferative, viable, and hyperdiploid tumor cell subpopulation present within Glioblastoma (GB) patient tumors. Using xenograft tumor models, we demonstrate that hyperdiploid cell populations are maintained in xenograft tumors and that clonally expanded hyperdiploid cells support tumor formation and progression in vivo. In some patient tumorsphere lines, hyperdiploidy is maintained during long-term culture and in vivo within xenograft tumor models, suggesting that hyperdiploidy can be a stable cell state. In other patient lines hyperdiploid cells display genetic drift in vitro and in vivo, suggesting that in these patients hyperdiploidy is a transient cell state that generates novel phenotypes, potentially facilitating rapid tumor evolution. We show that the hyperdiploid cells are resistant to conventional therapy, in part due to infrequent cell division due to a delay in the G(0)/G(1) phase of the cell cycle. Hyperdiploid tumor cells are significantly larger and more metabolically active than euploid cancer cells, and this correlates to an increased sensitivity to the effects of glycolysis inhibition. Together these data identify GB hyperdiploid tumor cells as a potentially important subpopulation of cells that are well positioned to contribute to tumor evolution and disease recurrence in adult brain cancer patients, and suggest tumor metabolism as a promising point of therapeutic intervention against this subpopulation.