Real-time imaging of the dynamics of death receptors and therapeutics that overcome TRAIL resistance in tumors.
Real-time imaging of the dynamics of death receptors and therapeutics that overcome TRAIL resistance in tumors.
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DOI：
10.1038/onc.2012.304
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发表时间：
2013-06-06
期刊：
影响因子：
8
通讯作者：
Shah, K.
中科院分区：
文献类型：
--
作者：
Bagci-Onder, T.;Agarwal, A.;Flusberg, D.;Wanningen, S.;Sorger, P.;Shah, K.
肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 特异性诱导肿瘤细胞凋亡，其功效已通过将其作为纯化配体全身递送或通过工程干细胞 (SC) 在临床前模型中进行了测试。然而，约 50% 的肿瘤系对 TRAIL 具有耐药性，并克服侵袭性肿瘤（如多形性胶质母细胞瘤 (GBM)）中的 TRAIL 耐药性，了解基于 TRAIL 的联合疗法的分子动力学对于广泛使用 TRAIL 作为治疗剂至关重要。在这项研究中，我们开发了死亡受体 (DR)4/5 报告基因，它提供了一个基于成像的平台，通过监测 DR4/5 表达的变化来识别与 TRAIL 的有效分泌变体 (S-TRAIL) 协同作用的药物。利用这些报告基因，我们展示了当暴露于一组临床相关药物时 DR4/5 的差异调节。组蛋白脱乙酰酶抑制剂 MS-275 导致所有 GBM 细胞系中 DR4/5 上调，这些变化可以在荷瘤小鼠体内和体外实时追踪，并且与 TRAIL 敏感性的增加相关。为了进一步评估克服肿瘤对 SC 释放的 S-TRAIL 耐药性的组合策略的动态，我们还改造了肿瘤细胞以表达活细胞 caspase 报告基因，并改造 SC 来表达 S-TRAIL。并行利用 DR4/5 和 caspase 报告基因，我们发现 MS-275 通过改变体外和体内的死亡时间，使 TRAIL 抗性 GBM 细胞对干细胞 (SC) 传递的 S-TRAIL 敏感。这项研究证明了 TRAIL 诱导的细胞凋亡途径的实时报告基因组合在评估基于 SC-TRAIL 的疗法的功效方面的有效性，并且可能对针对广泛的癌症产生影响。
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induces apoptosis specifically in tumor cells and its efficacy has been tested in pre-clinical models by delivering it systemically as a purified ligand or via engineered stem cells (SC). However, about 50% of tumor lines are resistant to TRAIL and overcoming TRAIL resistance in aggressive tumors, such as glioblastoma-multiforme (GBM), and understanding the molecular dynamics of TRAIL-based combination therapies are critical to broadly use TRAIL as a therapeutic agent. In this study, we developed death receptor (DR)4/5-reporters that offer an imaging-based platform to identify agents that act in concert with a potent, secretable variant of TRAIL (S-TRAIL) by monitoring changes in DR4/5 expression. Utilizing these reporters, we show a differential regulation of DR4/5 when exposed to a panel of clinically relevant agents. A histone deacetylase inhibitor, MS-275, resulted in upregulation of DR4/5 in all GBM cell lines, and these changes could be followed in real time both in vitro and in vivo in mice bearing tumors and they correlated with increased TRAIL sensitivity. To further assess the dynamics of combinatorial strategies that overcome resistance of tumors to SC released S-TRAIL, we also engineered tumor cells to express live-cell caspase-reporters and SCs to express S-TRAIL. Utilizing DR4/5 and caspase reporters in parallel, we show that MS-275 sensitizes TRAIL-resistant GBM cells to stem cell (SC) delivered S-TRAIL by changing the time-to-death in vitro and in vivo. This study demonstrates the effectiveness of a combination of real-time reporters of TRAIL-induced apoptosis pathway in evaluating the efficacy of SC-TRAIL-based therapeutics and may have implications in targeting a broad range of cancers.
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影响因子：
9.8
作者：
Albeck JG;Burke JM;Spencer SL;Lauffenburger DA;Sorger PK
通讯作者：
Sorger PK
影响因子：
50.5
作者：
Neyns, B.;Sadones, J.;De Greve, J.
通讯作者：
De Greve, J.
影响因子：
5.7
作者：
Hingtgen S;Ren X;Terwilliger E;Classon M;Weissleder R;Shah K
通讯作者：
Shah K
影响因子：
5.7
作者：
Baritaki, Stavroula;Huerta-Yepez, Sara;Bonavida, Benjamin
通讯作者：
Bonavida, Benjamin
影响因子：
15.9
作者：
Raizer, Jeffrey J.;Abrey, Lauren E.;Prados, Michael D.
通讯作者：
Prados, Michael D.