Cellular Neuroscience, Max Delbrück Center for Molecular Medicine, Robert Rössle Strasse 10, 13125 Berlin, Germany.
Brain. 2010 Jul;133(Pt 7):1961-72. doi: 10.1093/brain/awq128. Epub 2010 May 30.
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.
具有干细胞样特性的神经胶质母细胞瘤细胞控制着脑瘤的生长和复发。在这里，我们发现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发挥抗肿瘤反应。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 从神经球中持续释放，并在干细胞样神经母细胞瘤细胞中诱导经典的骨形态发生蛋白信号。将人源和鼠源干细胞样脑肿瘤细胞暴露于神经球衍生的骨形态发生蛋白-7 中，可诱导肿瘤干细胞分化，减弱干细胞样标志物的表达，并降低自我更新和肿瘤起始能力。神经球衍生的或重组的骨形态发生蛋白-7 通过下调转录因子 Olig2 来减少由干细胞样细胞引起的神经母细胞瘤的扩增。在体内，大量表达骨形态发生蛋白-7 的神经前体细胞在幼鼠的脑瘤周围环绕，在干细胞样神经母细胞瘤细胞中诱导经典的骨形态发生蛋白信号，从而减轻肿瘤的形成。这种抗肿瘤反应在老年小鼠中大大减弱。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 来保护幼脑免受神经母细胞瘤的侵害，骨形态发生蛋白-7 作为一种旁分泌肿瘤抑制因子，抑制干细胞样神经母细胞瘤细胞的增殖、自我更新和肿瘤起始。
