Non-small cell lung cancer cells survived ionizing radiation treatment display cancer stem cell and epithelial-mesenchymal transition phenotypes.
Non-small cell lung cancer cells survived ionizing radiation treatment display cancer stem cell and epithelial-mesenchymal transition phenotypes.
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DOI：
10.1186/1476-4598-12-94
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发表时间：
2013-08-16
期刊：
影响因子：
37.3
通讯作者：
Levina V
中科院分区：
文献类型：
--
作者：
Gomez-Casal R;Bhattacharya C;Ganesh N;Bailey L;Basse P;Gibson M;Epperly M;Levina V
电离辐射（IR）用于诊断为不可切除的非小细胞肺癌（NSCLC）的患者，但由于放射耐药，放疗在很大程度上仍然是姑息性的。肿瘤干细胞（CSCs）以及上皮-间质转化（EMT）可能有助于实体瘤的药物和辐射耐药机制。在这里，我们研究了A549和H460 NSCLC细胞的分子表型，这些细胞在接受IR （5Gy）治疗后存活，并以漂浮肿瘤球的形式生长，并在照射后维持在单层细胞中。一周后收集未照射和照射过的细胞，接种于超低附着板上，培养成肿瘤球。在辐射中存活并在球体中生长的大量非小细胞肺癌细胞表达癌症干细胞表面和胚胎干细胞标记物，能够自我更新并产生分化的后代。这些细胞也具有间充质表型。特别是，与未放疗的肺肿瘤球细胞相比，放疗后存活的球细胞表达的CSC标记物（CD24和CD44）、核β-catenin和EMT标记物（Snail1、Vimentin和N-cadherin）水平明显更高。在辐照后维持单层的H460细胞中检测到Oct-4、Sox2和β -catenin水平上调，而在辐照后存活的A459细胞中检测到Oct-4、Sox2和β -catenin水平上调。pdgfr - β在A549和H460细胞系辐射存活球形细胞和辐射存活贴壁细胞中表达上调。IR治疗联合抗pdfgr抑制剂阿西替尼或达沙替尼可增强NSCLC放射治疗的体外疗效。我们的研究结果表明，辐射存活细胞具有复杂的表型，结合了CSCs和EMT的特性。CD44、SNAIL和pdgfr - β在辐射存活细胞中显著上调，可能被认为是NSCLC放疗反应的标志物。
Ionizing radiation (IR) is used for patients diagnosed with unresectable non small cell lung cancer (NSCLC), however radiotherapy remains largely palliative due to radioresistance. Cancer stem cells (CSCs), as well as epithelial-mesenchymal transition (EMT), may contribute to drug and radiation resistance mechanisms in solid tumors. Here we investigated the molecular phenotype of A549 and H460 NSCLC cells that survived treatment with IR (5Gy) and are growing as floating tumor spheres and cells that are maintained in a monolayer after irradiation. Non-irradiated and irradiated cells were collected after one week, seeded onto ultra low attachment plates and propagated as tumor spheres. Bulk NSCLC cells which survived radiation and grew in spheres express cancer stem cell surface and embryonic stem cell markers and are able to self-renew, and generate differentiated progeny. These cells also have a mesenchymal phenotype. Particularly, the radiation survived sphere cells express significantly higher levels of CSC markers (CD24 and CD44), nuclear β-catenin and EMT markers (Snail1, Vimentin, and N-cadherin) than non-irradiated lung tumor sphere cells. Upregulated levels of Oct-4, Sox2 and beta-catenin were detected in H460 cells maintained in a monolayer after irradiation, but not in radiation survived adherent A459 cells. PDGFR-beta was upregulated in radiation survived sphere cells and in radiation survived adherent cells in both A549 and H460 cell lines. Combining IR treatment with axitinib or dasatinib, inhibitors with anti-PDFGR activity, potentiates the efficacy of NSCLC radiotherapy in vitro. Our findings suggest that radiation survived cells have a complex phenotype combining the properties of CSCs and EMT. CD44, SNAIL and PDGFR-beta are dramatically upregulated in radiation survived cells and might be considered as markers of radiotherapy response in NSCLC.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
DOI：
10.4161/cc.8.20.9701
发表时间：
2009-10-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Heddleston JM;Li Z;McLendon RE;Hjelmeland AB;Rich JN
通讯作者：
Rich JN
DOI：
10.1387/ijdb.082747rb
发表时间：
2009
期刊：
The International journal of developmental biology
影响因子：
--
作者：
Barnes RM;Firulli AB
通讯作者：
Firulli AB
影响因子：
12.4
作者：
Eramo, A.;Lotti, F.;De Maria, R.
通讯作者：
De Maria, R.
影响因子：
11.5
作者：
Carlos Montero, Juan;Seoane, Samuel;Pandiella, Atanasio
通讯作者：
Pandiella, Atanasio