Diamandis Phedias, Wildenhain Jan, Clarke Ian D, Sacher Adrian G, Graham Jeremy, Bellows David S, Ling Erick K M, Ward Ryan J, Jamieson Leanne G, Tyers Mike, Dirks Peter B
The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto M5G 1X8, Canada.
Nat Chem Biol. 2007 May;3(5):268-73. doi: 10.1038/nchembio873. Epub 2007 Apr 8.
The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.
在哺乳动物大脑中鉴定自我更新和多能神经干细胞（NSCs）为治疗神经疾病带来了希望，并为脑癌研究提供了新的见解。然而，控制NSCs增殖和自我更新的信号通路的完整组合，即我们所说的“基态”，在很大程度上仍未得到充分表征。尽管候选基因方法已经揭示了NSC生物学中的重要通路，但到目前为止，仅对少数经过深入研究的通路进行了调查。基于NSC自我更新与神经球增殖之间的密切关系，我们进行了一项化学遗传学筛选，以寻找神经球增殖的抑制剂，从而探究NSC的运作机制。筛选过程中发现了一些已知会影响先前认为主要在成熟中枢神经系统中起作用的神经传递途径的小分子；这些化合物对富含脑癌干细胞的培养物也有强大的抑制作用。这些结果表明，临床批准的神经调节剂可能会重塑成熟的中枢神经系统，并在脑癌治疗中找到应用。
