Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9133, USA.
Nature. 2012 Aug 23;488(7412):522-6. doi: 10.1038/nature11287.
Glioblastoma multiforme is the most common primary malignant brain tumour, with a median survival of about one year. This poor prognosis is due to therapeutic resistance and tumour recurrence after surgical removal. Precisely how recurrence occurs is unknown. Using a genetically engineered mouse model of glioma, here we identify a subset of endogenous tumour cells that are the source of new tumour cells after the drug temozolomide (TMZ) is administered to transiently arrest tumour growth. A nestin-ΔTK-IRES-GFP (Nes-ΔTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumour cells. On arrest of tumour cell proliferation with TMZ, pulse-chase experiments demonstrate a tumour re-growth cell hierarchy originating with the Nes-ΔTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumour growth, and combined TMZ and ganciclovir treatment impeded tumour development. Thus, a relatively quiescent subset of endogenous glioma cells, with properties similar to those proposed for cancer stem cells, is responsible for sustaining long-term tumour growth through the production of transient populations of highly proliferative cells.
多形性胶质母细胞瘤是最常见的原发性恶性脑肿瘤，中位生存期约为一年。这种不良预后是由于治疗耐药和手术切除后的肿瘤复发。确切的复发机制尚不清楚。本研究使用一种胶质母细胞瘤的基因工程小鼠模型，鉴定出一小部分内源性肿瘤细胞，这些细胞是替莫唑胺（TMZ）给药后短暂抑制肿瘤生长时新肿瘤细胞的来源。一种巢蛋白-ΔTK-IRES-GFP（Nes-ΔTK-GFP）转基因可标记静息的侧脑室下区成体神经干细胞，也可标记一小部分内源性胶质母细胞瘤肿瘤细胞。用 TMZ 抑制肿瘤细胞增殖后，脉冲追踪实验表明，肿瘤再生长的细胞层次起源于 Nes-ΔTK-GFP 转基因亚群。用更昔洛韦慢性给药清除 GFP+细胞可显著抑制肿瘤生长，联合 TMZ 和更昔洛韦治疗可阻碍肿瘤的发展。因此，具有类似于癌症干细胞特性的相对静止的内源性胶质母细胞瘤亚群通过产生短暂的高增殖细胞群体，负责维持长期的肿瘤生长。
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