Patient-Specific Screening Using High-Grade Glioma Explants to Determine Potential Radiosensitization by a TGF-β Small Molecule Inhibitor.
Patient-Specific Screening Using High-Grade Glioma Explants to Determine Potential Radiosensitization by a TGF-β Small Molecule Inhibitor.
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DOI：
10.1016/j.neo.2016.08.008
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发表时间：
2016-12
期刊：
影响因子：
4.8
通讯作者：
Placantonakis, Dimitris
中科院分区：
文献类型：
--
作者：
Bayin, N. Sumru;Ma, Lin;Thomas, Cheddhi;Baitalmal, Rabaa;Sure, Akhila;Fansiwala, Kush;Bustoros, Mark;Golfinos, John G.;Pacione, Donato;Snuderl, Matija;Zagzag, David;Barcellos-Hoff, Mary Helen;Placantonakis, Dimitris
高级别胶质瘤（High-grade glioma， HGG）是一种致命的原发性脑恶性肿瘤，表现出由细胞内在和微环境机制介导的放射耐药。HGG中高水平的细胞因子转化生长因子-β (TGF-β)通过加强有效的DNA损伤反应和支持胶质瘤干细胞自我更新来促进辐射抵抗。我们对HGG TCGA数据和磷酸化Smad2（典型TGF-β信号的主要换能器）的免疫组织化学染色分析表明，TGF-β通路在HGG肿瘤中的激活水平是不同的。这些数据表明，评估在放疗期间抑制TGF-β的推定益处需要个性化筛查。因此，我们使用7个HGG标本的外植体培养作为快速的、患者特异性的离体平台，来验证TGF-β I型受体的小分子抑制剂LY364947在HGG中作为放射增敏剂的假设。免疫荧光检测和图像分析γ-H2AX焦点（辐射诱导DNA损伤的细胞识别标记）和Sox2（辐射后增加的干细胞标记）表明，LY364947阻断了7个样本中5个样本的这些辐射反应。总的来说，我们的研究结果表明，TGF-β信号增加了大多数（但不是全部）hgg的辐射抗性。我们建议，HGG外植体的短期培养提供了一个灵活而快速的平台，可以根据患者的具体情况筛选放射增敏剂的相关疗效。这种既省时又经济的方法可用于HGG患者的个性化治疗方案。
High-grade glioma (HGG), a deadly primary brain malignancy, manifests radioresistance mediated by cell-intrinsic and microenvironmental mechanisms. High levels of the cytokine transforming growth factor-β (TGF-β) in HGG promote radioresistance by enforcing an effective DNA damage response and supporting glioma stem cell self-renewal. Our analysis of HGG TCGA data and immunohistochemical staining of phosphorylated Smad2, which is the main transducer of canonical TGF-β signaling, indicated variable levels of TGF-β pathway activation across HGG tumors. These data suggest that evaluating the putative benefit of inhibiting TGF-β during radiotherapy requires personalized screening. Thus, we used explant cultures of seven HGG specimens as a rapid, patient-specific ex vivo platform to test the hypothesis that LY364947, a small molecule inhibitor of the TGF-β type I receptor, acts as a radiosensitizer in HGG. Immunofluorescence detection and image analysis of γ-H2AX foci, a marker of cellular recognition of radiation-induced DNA damage, and Sox2, a stem cell marker that increases post-radiation, indicated that LY364947 blocked these radiation responses in five of seven specimens. Collectively, our findings suggest that TGF-β signaling increases radioresistance in most, but not all, HGGs. We propose that short-term culture of HGG explants provides a flexible and rapid platform for screening context-dependent efficacy of radiosensitizing agents in patient-specific fashion. This time- and cost-effective approach could be used to personalize treatment plans in HGG patients.
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影响因子：
11.2
作者：
Hardee ME;Marciscano AE;Medina-Ramirez CM;Zagzag D;Narayana A;Lonning SM;Barcellos-Hoff MH
通讯作者：
Barcellos-Hoff MH
DOI：
10.1056/nejmoa1407279
发表时间：
2015-06-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Eckel-Passow JE;Lachance DH;Molinaro AM;Walsh KM;Decker PA;Sicotte H;Pekmezci M;Rice T;Kosel ML;Smirnov IV;Sarkar G;Caron AA;Kollmeyer TM;Praska CE;Chada AR;Halder C;Hansen HM;McCoy LS;Bracci PM;Marshall R;Zheng S;Reis GF;Pico AR;O'Neill BP;Buckner JC;Giannini C;Huse JT;Perry A;Tihan T;Berger MS;Chang SM;Prados MD;Wiemels J;Wiencke JK;Wrensch MR;Jenkins RB
通讯作者：
Jenkins RB
影响因子：
15.9
作者：
Hussain, S. Farzana;Yang, David;Heimberger, Amy B.
通讯作者：
Heimberger, Amy B.
影响因子：
3.4
作者：
Costes, SV;Boissière, A;Barcellos-Hoff, MH
通讯作者：
Barcellos-Hoff, MH
影响因子：
1.7
作者：
Jaskova, Katarina;Pavlovicova, Michaela;Jurkovicova, Dana
通讯作者：
Jurkovicova, Dana