DNER, an epigenetically modulated gene, regulates glioblastoma-derived neurosphere cell differentiation and tumor propagation.
DNER, an epigenetically modulated gene, regulates glioblastoma-derived neurosphere cell differentiation and tumor propagation.
复制标题
DOI：
10.1002/stem.89
复制
发表时间：
2009-07
期刊：
影响因子：
5.2
通讯作者：
Laterra, John
中科院分区：
文献类型：
--
作者：
Sun, Peng;Xia, Shuli;Lal, Bachchu;Eberhart, Charles G.;Quinones-Hinojosa, Alfredo;Maciaczyk, Jarek;Matsui, William;DiMeco, Francesco;Piccirillo, Sara M.;Vescovi, Angelo L.;Laterra, John
来源于胶质母细胞瘤（GBM）和其他实体恶性肿瘤的神经球含有肿瘤干细胞样细胞，其有效地繁殖肿瘤生长并抵抗细胞毒性治疗。本研究的主要目的是使用组蛋白修饰剂来阐明GBM衍生的肿瘤干细胞样细胞的表型和促肿瘤能力受到调节的机制。使用已建立的GBM衍生神经球系和低传代原代GBM衍生神经球，我们表明组蛋白脱乙酰酶（HDAC）抑制剂抑制肿瘤性神经球细胞的生长，诱导分化和诱导凋亡。HDAC抑制诱导的特异性基因产物Delta/Notch样表皮生长因子相关受体（DNER）抑制GBM衍生的神经球的生长，在体内和体外诱导其分化，并抑制其作为肿瘤异种移植物的植入和生长。DNER（一种非经典Notch配体）的分化和肿瘤抑制作用与先前建立的脑癌干细胞样细胞中经典Notch信号传导的肿瘤促进作用形成对比。我们的研究结果是第一个涉及非经典Notch信号在调节肿瘤干细胞样细胞，并提出新的肿瘤干细胞靶向治疗GBM和潜在的其他实体恶性肿瘤的策略。
Neurospheres derived from glioblastoma (GBM) and other solid malignancies contain neoplastic stem-like cells that efficiently propagate tumor growth and resist cytotoxic therapeutics. The primary objective of this study was to use histone-modifying agents to elucidate mechanisms by which the phenotype and tumor-promoting capacity of GBM-derived neoplastic stem-like cells are regulated. Using established GBM-derived neurosphere lines and low passage primary GBM-derived neurospheres, we show that histone deacetylase (HDAC) inhibitors inhibit growth, induce differentiation, and induce apoptosis of neoplastic neurosphere cells. A specific gene product induced by HDAC inhibition, Delta/Notch-like epidermal growth factor-related receptor (DNER), inhibited the growth of GBM-derived neurospheres, induced their differentiation in vivo and in vitro, and inhibited their engraftment and growth as tumor xenografts. The differentiating and tumor suppressive effects of DNER, a noncanonical Notch ligand, contrast with the previously established tumor-promoting effects of canonical Notch signaling in brain cancer stem-like cells. Our findings are the first to implicate noncanonical Notch signaling in the regulation of neoplastic stem-like cells and suggest novel neoplastic stem cell targeting treatment strategies for GBM and potentially other solid malignancies.
登录
查看更多内容
影响因子：
5.2
作者：
Bar, Eli E.;Chaudhry, Aneeka;Eberharta, Charles G.
通讯作者：
Eberharta, Charles G.
影响因子：
10.5
作者：
Dai, C;Celestino, JC;Holland, EC
通讯作者：
Holland, EC
影响因子：
11.2
作者：
Galli, R;Binda, E;Vescovi, A
通讯作者：
Vescovi, A
影响因子：
3.3
作者：
Balasubramaniyan, V.;Boddeke, E.;Copray, S.
通讯作者：
Copray, S.
DOI：
10.1073/pnas.0407643101
发表时间：
2004-11-23
影响因子：
11.1
作者：
Hsieh, J;Nakashima, K;Gage, FH
通讯作者：
Gage, FH