Notch signaling contributes to the maintenance of both normal neural stem cells and patient-derived glioma stem cells.
Notch signaling contributes to the maintenance of both normal neural stem cells and patient-derived glioma stem cells.
复制标题
Notch信号传导有助于维持正常神经干细胞和患者来源的神经胶质瘤干细胞
DOI：
10.1186/1471-2407-11-82
复制
发表时间：
2011-02-22
期刊：
影响因子：
3.8
通讯作者：
Han H
中科院分区：
文献类型：
--
作者：
Hu YY;Zheng MH;Cheng G;Li L;Liang L;Gao F;Wei YN;Fu LA;Han H
背景肿瘤干细胞（Cancer stem cells，CSCs）在恶性肿瘤包括胶质瘤的发生、发展和复发中起着重要作用。Notch信号通路是一种进化上保守的直接介导细胞间相互作用的信号通路，在神经干细胞（NSC）和胶质瘤干细胞（GSC）的正常神经发生和病理性癌变过程中分别起调控作用。然而，Notch信号如何调节GSCs的增殖和分化尚未得到很好的阐明。MethodsWe分离和培养人GSCs从胶质瘤患者标本。与NSCs平行比较，我们用γ-分泌酶抑制剂（GSI）抑制Notch信号并评估Notch信号在人GSCs. ResultsGSI处理的NSCs中的潜在功能，GSI处理的GSCs的原发性和继发性肿瘤球的数量显著减少，表明GSI处理的GSCs的增殖和自我更新能力减弱。GSI处理的GSC在分化培养基中表现出向成熟神经细胞类型的分化增加，类似于GSI处理的NSC。接下来，我们发现与对照组相比，GSI处理的肿瘤球由更多的中间祖细胞而不是CSC组成。有趣的是，尽管Notch信号的抑制降低了长期培养中增殖的NSC的比例，但我们发现G2+M期GSC的比例在GSI处理72小时内几乎不受干扰。结论这些数据表明，与NSC一样，Notch信号通过促进其自我更新和抑制其分化来维持患者来源的GSC，支持Notch信号抑制剂GSI可能是靶向胶质瘤干细胞治疗的一个有前景的候选药物，但GSI在胶质瘤干细胞周期的早期阶段具有抵抗性。
BackgroundCancer stem cells (CSCs) play an important role in the development and recurrence of malignant tumors including glioma. Notch signaling, an evolutionarily conserved pathway mediating direct cell-cell interaction, has been shown to regulate neural stem cells (NSCs) and glioma stem cells (GSCs) in normal neurogenesis and pathological carcinogenesis, respectively. However, how Notch signaling regulates the proliferation and differentiation of GSCs has not been well elucidated.MethodsWe isolated and cultivate human GSCs from glioma patient specimens. Then on parallel comparison with NSCs, we inhibited Notch signaling using γ-secretase inhibitors (GSI) and assessed the potential functions of Notch signaling in human GSCs.ResultsSimilar to the GSI-treated NSCs, the number of the primary and secondary tumor spheres from GSI-treated GSCs decreased significantly, suggesting that the proliferation and self-renewal ability of GSI-treated GSCs were attenuated. GSI-treated GSCs showed increased differentiation into mature neural cell types in differentiation medium, similar to GSI-treated NSCs. Next, we found that GSI-treated tumor spheres were composed of more intermediate progenitors instead of CSCs, compared with the controls. Interestingly, although inhibition of Notch signaling decreased the ratio of proliferating NSCs in long term culture, we found that the ratio of G2+M phase-GSCs were almost undisturbed on GSI treatment within 72 h.ConclusionsThese data indicate that like NSCs, Notch signaling maintains the patient-derived GSCs by promoting their self-renewal and inhibiting their differentiation, and support that Notch signal inhibitor GSI might be a prosperous candidate of the treatment targeting CSCs for gliomas, however, with GSI-resistance at the early stage of GSCs cell cycle.
登录
查看更多内容
影响因子：
50.3
作者：
Chen, Ruihuan;Nishimura, Merry C.;Phillips, Heidi S.
通讯作者：
Phillips, Heidi S.
影响因子：
11.2
作者：
Purow, BW;Haque, RM;Fine, HA
通讯作者：
Fine, HA
影响因子：
4.8
作者：
Shih, Alan H.;Holland, Eric C.
通讯作者：
Holland, Eric C.
影响因子：
64.8
作者：
JARRIAULT, S;BROU, C;ISRAEL, A
通讯作者：
ISRAEL, A
影响因子：
11.2
作者：
Galli, R;Binda, E;Vescovi, A
通讯作者：
Vescovi, A