Molecular heterogeneity in a patient-derived glioblastoma xenoline is regulated by different cancer stem cell populations.
Molecular heterogeneity in a patient-derived glioblastoma xenoline is regulated by different cancer stem cell populations.
复制标题
DOI：
10.1371/journal.pone.0125838
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Pfeffer LM
中科院分区：
文献类型：
--
作者：
Garner JM;Ellison DW;Finkelstein D;Ganguly D;Du Z;Sims M;Yang CH;Interiano RB;Davidoff AM;Pfeffer LM
恶性胶质母细胞瘤（GBM）是一种高度侵袭性的脑肿瘤，预后不良，治疗选择有限。GBM样品的基因组分析已经鉴定了四种分子亚型（前神经、神经、经典和间充质），其可能来自不同的胶质母细胞瘤干细胞样细胞（GSC）群体。我们以前的研究表明，在层粘连蛋白包被的平板上生长的GSC贴壁培养物（Ad-GSC）和GSC球状体培养物（Sp-GSC）具有干细胞标志物（CD 133、Sox 2和Nestin）的高表达，但分化标志物（β III-微管蛋白和胶质细胞酸性蛋白）的低表达。在本研究中，我们的特点是GBM肿瘤产生的皮下和颅内注射的Ad-GSC和Sp-GSC分离自患者来源的xenoline。虽然它们形成具有相同组织学特征的肿瘤，但基因表达分析显示Sp-GSC的异种移植物具有与大量肿瘤细胞相似的经典分子亚型。相反，Ad-GSC的异种移植物表达间充质基因签名。贴壁GSC衍生的异种移植物具有高STAT 3和ANGPTL 4表达，以及间充质亚型特征性的干细胞标志物、转录网络和促血管生成标志物的富集。对GBM患者的临床样本的检查显示，STAT 3表达与ANGPTL 4表达直接相关，并且这些基因的表达增加与患者的生存率和表现差相关。药理学STAT 3抑制剂消除STAT 3与ANGPTL 4启动子的结合，并在体内表现出抗癌活性。因此，Ad-GSC和Sp-GSC产生了具有不同基因表达模式的组织学上相同的肿瘤，并且在胶质母细胞瘤中鉴定了STAT 3/ANGPTL 4途径，其可以作为治疗干预的靶点。
Malignant glioblastoma (GBM) is a highly aggressive brain tumor with a dismal prognosis and limited therapeutic options. Genomic profiling of GBM samples has identified four molecular subtypes (Proneural, Neural, Classical and Mesenchymal), which may arise from different glioblastoma stem-like cell (GSC) populations. We previously showed that adherent cultures of GSCs grown on laminin-coated plates (Ad-GSCs) and spheroid cultures of GSCs (Sp-GSCs) had high expression of stem cell markers (CD133, Sox2 and Nestin), but low expression of differentiation markers (βIII-tubulin and glial fibrillary acid protein). In the present study, we characterized GBM tumors produced by subcutaneous and intracranial injection of Ad-GSCs and Sp-GSCs isolated from a patient-derived xenoline. Although they formed tumors with identical histological features, gene expression analysis revealed that xenografts of Sp-GSCs had a Classical molecular subtype similar to that of bulk tumor cells. In contrast xenografts of Ad-GSCs expressed a Mesenchymal gene signature. Adherent GSC-derived xenografts had high STAT3 and ANGPTL4 expression, and enrichment for stem cell markers, transcriptional networks and pro-angiogenic markers characteristic of the Mesenchymal subtype. Examination of clinical samples from GBM patients showed that STAT3 expression was directly correlated with ANGPTL4 expression, and that increased expression of these genes correlated with poor patient survival and performance. A pharmacological STAT3 inhibitor abrogated STAT3 binding to the ANGPTL4 promoter and exhibited anticancer activity in vivo. Therefore, Ad-GSCs and Sp-GSCs produced histologically identical tumors with different gene expression patterns, and a STAT3/ANGPTL4 pathway is identified in glioblastoma that may serve as a target for therapeutic intervention.
登录
查看更多内容
影响因子：
37.3
作者：
Katanasaka Y;Kodera Y;Kitamura Y;Morimoto T;Tamura T;Koizumi F
通讯作者：
Koizumi F
影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
8
作者：
Niu, GL;Wright, KL;Yu, H
通讯作者：
Yu, H
影响因子：
11.2
作者：
Bonavia R;Inda MM;Cavenee WK;Furnari FB
通讯作者：
Furnari FB
影响因子：
3.5
作者：
KAHN, HJ;MARKS, A;BAUMAL, R
通讯作者：
BAUMAL, R