Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells
Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells
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DOI：
10.1093/brain/awq128
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发表时间：
2010-07-01
期刊：
影响因子：
14.5
通讯作者：
Glass, Rainer
中科院分区：
文献类型：
--
作者：
Chirasani, Sridhar Reddy;Sternjak, Alexander;Glass, Rainer
具有干细胞样特性的胶质母细胞瘤细胞控制脑肿瘤的生长和复发。在这里，我们证明内源性神经前体细胞通过特异性靶向干细胞样脑肿瘤细胞来执行抗肿瘤反应。在体外，神经前体细胞主要表达骨形态发生蛋白7；骨形态发生蛋白-7 从神经球中组成型释放，并在干细胞样胶质母细胞瘤细胞中诱导典型的骨形态发生蛋白信号传导。将人类和小鼠干细胞样脑肿瘤细胞暴露于神经球来源的骨形态发生蛋白-7 中，会诱导肿瘤干细胞分化，减弱干细胞样标记物的表达，并降低自我更新和肿瘤发生的能力。神经球衍生或重组骨形态发生蛋白 7 通过下调转录因子 Olig2 来减少干细胞样细胞的胶质母细胞瘤扩张。在体内，大量表达骨形态发生蛋白7的神经前体细胞包围年轻小鼠的脑肿瘤，在干细胞样胶质母细胞瘤细胞中诱导典型的骨形态发生蛋白信号传导，从而减弱肿瘤的形成。这种抗肿瘤反应在老年小鼠中显着降低。我们的研究结果表明，内源性神经前体细胞通过释放骨形态发生蛋白-7来保护年轻大脑免受胶质母细胞瘤的侵害，骨形态发生蛋白7作为旁分泌肿瘤抑制因子，抑制干细胞样胶质母细胞瘤细胞的增殖、自我更新和肿瘤起始。
Glioblastoma cells with stem-like properties control brain tumour growth and recurrence. Here, we show that endogenous neural precursor cells perform an anti-tumour response by specifically targeting stem-like brain tumour cells. In vitro, neural precursor cells predominantly express bone morphogenetic protein-7; bone morphogenetic protein-7 is constitutively released from neurospheres and induces canonical bone morphogenetic protein signalling in stem-like glioblastoma cells. Exposure of human and murine stem-like brain tumour cells to neurosphere-derived bone morphogenetic protein-7 induces tumour stem cell differentiation, attenuates stem-like marker expression and reduces self-renewal and the ability for tumour initiation. Neurosphere-derived or recombinant bone morphogenetic protein-7 reduces glioblastoma expansion from stem-like cells by down-regulating the transcription factor Olig2. In vivo, large numbers of bone morphogenetic protein-7-expressing neural precursors encircle brain tumours in young mice, induce canonical bone morphogenetic protein signalling in stem-like glioblastoma cells and can thereby attenuate tumour formation. This anti-tumour response is strongly reduced in older mice. Our results indicate that endogenous neural precursor cells protect the young brain from glioblastoma by releasing bone morphogenetic protein-7, which acts as a paracrine tumour suppressor that represses proliferation, self-renewal and tumour-initiation of stem-like glioblastoma cells.