Radiation-induced Notch signaling in breast cancer stem cells.
Radiation-induced Notch signaling in breast cancer stem cells.
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DOI：
10.1016/j.ijrobp.2013.06.2064
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发表时间：
2013-11-01
影响因子：
7
通讯作者：
Pajonk, Frank
中科院分区：
文献类型：
--
作者：
Lagadec, Chann;Vlashi, Erina;Alhiyari, Yazeed;Phillips, Tiffany M.;Dratver, Milana Bochkur;Pajonk, Frank
乳腺癌被认为是由少数能够自我更新并使整个肿瘤再生的乳腺癌干细胞分层组织而成。重要的是，乳腺癌干细胞对现有的化疗药物有抵抗力，对辐射也有相对的抵抗力。乳腺癌干细胞的自我更新受到Notch信号通路的控制，这表明靶向Notch信号通路可能是一种消除乳腺癌干细胞的新方法。γ-分泌酶复合物控制最后的膜内裂解步骤，该步骤在与配体结合后激活Notch受体，γ-分泌酶的特异性抑制剂可阻止Notch激活，目前正在临床试验中联合放疗治疗实体癌。辐射激活Notch信号，因此，我们试图探索Notch受体和配体在辐射响应中的表达模式，这可能是确定γ-分泌酶抑制剂与辐射联合使用的最佳剂量方案的关键。以MCF-7和T47D乳腺癌细胞系为研究对象，采用实时RT-PCR技术研究Notch通路对辐射的响应。我们发现，Notch受体和配体在照射后48小时内的表达遵循复杂的辐射剂量依赖模式，在乳腺癌干细胞富集的乳房微球中表达最为明显。此外，辐射激活了Notch通路。用γ-分泌酶抑制剂治疗可以阻止辐射诱导的Notch家族基因表达，并导致乳腺癌干细胞池的大小显著减少。我们的研究结果表明，如果与辐射联合使用，γ-分泌酶抑制剂可能会阻止Notch受体和配体家族成员的上调，从而减少乳腺癌干细胞的存活数量。
Breast cancers are thought to be organized hierarchically with a small number of breast cancer stem cells able to self-renew and to regrow the entire tumor. Importantly, breast cancer stem cells are resistant to established chemotherapeutic agents and relatively resistant to radiation. Self-renewal of breast cancer stem cells is under control of the Notch signaling pathway, which suggests that targeting this pathway could be a novel way of eliminating breast cancer stem cells. The γ-secretase complex controls the final intramembranous cleavage step that activates Notch receptors upon binding of its ligands and specific inhibitors of γ-secretase, which prevent Notch activation, are currently clinically tested against solid cancers in combination with radiotherapy. Radiation activates Notch signaling and therefore, we sought to explore patterns of Notch receptor and ligand expression in response to radiation that could be crucial in defining optimal dosing schemes for γ-secretase inhibitors if combined with radiation. Using MCF-7 and T47D breast cancer cell lines we used realtime RT-PCR to study the Notch pathway in response to radiation. We show that Notch receptor and ligand expression during the first 48 hours after irradiation followed a complex radiation dose-dependent pattern and was most pronounced in mammospheres, enriched for breast cancer stem cells. Additionally, radiation activated the Notch pathway. Treatment with a γ-secretase inhibitor prevented radiation-induced Notch family gene expression and led to a significant reduction in the size of the breast cancer stem cell pool. Our results indicate that, if combined with radiation, γ-secretase inhibitors may prevent up-regulation of Notch receptor and ligand family members and thus reduce the number of surviving breast cancer stem cells.
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DOI：
10.1186/bcr920
发表时间：
2004
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dontu G;Jackson KW;McNicholas E;Kawamura MJ;Abdallah WM;Wicha MS
通讯作者：
Wicha MS
影响因子：
7.4
作者：
Fillmore, Christine M.;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
DOI：
10.1158/1541-7786.mcr-10-0457
发表时间：
2011-07
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
McGowan PM;Simedrea C;Ribot EJ;Foster PJ;Palmieri D;Steeg PS;Allan AL;Chambers AF
通讯作者：
Chambers AF
影响因子：
14.5
作者：
Politi, K;Feirt, N;Kitajewski, J
通讯作者：
Kitajewski, J
影响因子：
11.5
作者：
Debucquoy, Annelies;Machiels, Jean-Pascal;Haustermans, Karin
通讯作者：
Haustermans, Karin