Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma.
Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma.
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DOI：
10.1158/1078-0432.ccr-12-0370
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发表时间：
2013-04-15
期刊：
影响因子：
--
通讯作者：
Wicha MS
中科院分区：
文献类型：
--
作者：
Hassan KA;Wang L;Korkaya H;Chen G;Maillard I;Beer DG;Kalemkerian GP;Wicha MS
肿瘤干细胞理论假设肿瘤包含具有自我更新、分化和肿瘤启动等干细胞特性的细胞亚群。本研究的目的是确定Notch活性在肺癌干细胞鉴定中的作用。我们利用Notch GFP报告载体和抑制Notch途径活性的伽马分泌酶抑制剂(GSI)研究了Notch活性在肺腺癌中的作用。用Notch GFP-Report构建的肺癌细胞转导鉴定出一组具有高Notch活性的细胞(GFP-Bright)。GFP-Bright细胞能够在无血清培养中形成更多的肿瘤球体，并且能够同时产生GFP-Bright和GFP-DIM(Low Notch Activity)细胞群。在一系列异种移植试验中，GFP-Bright细胞对化疗耐药，并具有致瘤性。GSI治疗的小鼠肿瘤移植瘤中Notch途径下游效应分子的表达降低，并且在NOD/SCID小鼠重新种植时不能再生肿瘤。通过多因素分析，我们发现在441例肺腺癌患者中，临床预后差与Notch活性(表现为Notch配体表达增加或负调节因子表达减少)之间存在统计学上的显著相关性。这种相关性在89例腺癌患者中得到了进一步证实，其中Hes-1的过度表达与总体存活率较低相关。Notch活性可以识别肺癌干细胞样细胞群，其抑制作用可能是治疗肺腺癌的合适靶点。
The cancer stem cell theory postulates that tumors contain a subset of cells with stem cell properties of self-renewal, differentiation and tumor-initiation. The purpose of this study is to determine the role of Notch activity in identifying lung cancer stem cells. We investigated the role of Notch activity in lung adenocarcinoma utilizing a Notch GFP-reporter construct and a gamma-secretase inhibitor (GSI), which inhibits Notch pathway activity. Transduction of lung cancer cells with Notch GFP-reporter construct identified a subset of cells with high Notch activity (GFP-bright). GFP-bright cells had the ability to form more tumor spheres in serum-free media, and were able to generate both GFP-bright and GFP-dim (lower Notch activity) cell populations. GFP-bright cells were resistant to chemotherapy and were tumorigenic in serial xenotransplantation assays. Tumor xenografts of mice treated with GSI had decreased expression of downstream effectors of Notch pathway and failed to regenerate tumors upon reimplantation in NOD/SCID mice. Using multivariate analysis, we detected a statistically significant correlation between poor clinical outcome and Notch activity (reflected in increased Notch ligand expression or decreased expression of the negative modulators), in a group of 441 lung adenocarcinoma patients. This correlation was further confirmed in an independent group of 89 adenocarcinoma patients where Hes-1 overexpression correlated with poor overall survival. Notch activity can identify lung cancer stem cell-like population and its inhibition may be an appropriate target for treating lung adenocarcinoma.