5月14日,，國際腫瘤學(xué)著名雜志Cancer Cell發(fā)表了加州大學(xué)舊金山分校William A. Weiss領(lǐng)導(dǎo)的研究小組的研究論文“Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC”。首次闡明時空性轉(zhuǎn)錄差異導(dǎo)致神經(jīng)干細(xì)胞對癌基因MYCN信號不同的反應(yīng)可引發(fā)不同類型的腦瘤。
以往研究表明在許多類型的人類腦瘤中原癌基因MYCN都呈現(xiàn)異常的表達(dá),。為了闡明MYCN基因的發(fā)育和區(qū)域性表達(dá)差異對于正常神經(jīng)細(xì)胞向癌細(xì)胞轉(zhuǎn)化的影響,，William A. Weiss研究組將野生型和突變型（N-mycT58A）小鼠N-myc基因轉(zhuǎn)入來源于圍產(chǎn)期小鼠小腦,、腦干及前腦的神經(jīng)干細(xì)胞（NSCs）,。
結(jié)果發(fā)現(xiàn)，轉(zhuǎn)入了野生型N-myc神經(jīng)干細(xì)胞不能通過移植形成腫瘤,。轉(zhuǎn)入了突變型（N-mycT58A）小鼠N-myc基因的小腦和腦干NSCs形成成神經(jīng)管細(xì)胞瘤和原始神經(jīng)外胚層瘤,，而N-mycT58A前腦NSCs則形成擴(kuò)散性膠質(zhì)細(xì)胞瘤。
分析表明上述來源于不同區(qū)域的腫瘤表達(dá)譜是不同的,。胚胎期小腦NSCs的腫瘤表現(xiàn)為Sonic Hedgehog (SHH) 依賴性,，而來源于出生后小鼠小腦NSCs的腫瘤表現(xiàn)為SHH非依賴性。這種差異部分受到轉(zhuǎn)錄因子SOX9的調(diào)節(jié),。該因子在人成神經(jīng)管細(xì)胞瘤SHH亞型中呈激活狀態(tài),。該研究證明對于同一原癌基因激活信號，NSCs可以因?yàn)榘l(fā)育階段和區(qū)域位置的不同而做出不同的反應(yīng),，發(fā)生不同的轉(zhuǎn)化,。（生物谷Bioon.com）
doi:10.1016/j.cell.2011.10.017
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Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC
Fredrik J. Swartling1, 2, , , Vasil Savov2, 5, Anders I. Persson1, 5, Justin Chen1, Christopher S. Hackett1, Paul A. Northcott3, Matthew R. Grimmer1, Jasmine Lau1, Louis Chesler4, Arie Perry1, Joanna J. Phillips1, Michael D. Taylor3 and William A. Weiss
The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally stabilized murine N-mycT58A into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem, and forebrain. Transplantation of N-mycWT NSCs was insufficient for tumor formation. N-mycT58A cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating Sonic Hedgehog (SHH) dependence and SHH independence, respectively. These differences were regulated in part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal.
