Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling.
Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling.
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DOI：
10.1158/0008-5472.can-10-0881
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发表时间：
2010-12-01
期刊：
影响因子：
11.2
通讯作者：
Minna JD
中科院分区：
文献类型：
--
作者：
Sullivan JP;Spinola M;Dodge M;Raso MG;Behrens C;Gao B;Schuster K;Shao C;Larsen JE;Sullivan LA;Honorio S;Xie Y;Scaglioni PP;DiMaio JM;Gazdar AF;Shay JW;Wistuba II;Minna JD
乙醛脱氢酶(ALDH)是具有干细胞样特性的肺癌细胞的候选标志物。大量原发非小细胞肺癌(NSCLC)标本ALDH1A1、ALDH3A1和CD133的免疫组织化学染色显示，ALDH1A1的表达(而不是ALDH3A1或CD133)的表达与包括I期和N0期在内的患者的不良预后显著相关。对一组肺癌细胞系和患者肿瘤的流式细胞仪分析显示，大多数NSCLC含有ALDH活性升高的细胞亚群，这种活性与ALDH1A1的表达有关。与ALDH−相比，分离的ALDH+肺癌细胞具有高度的致瘤性和克隆性以及自我更新的能力。分选细胞的表达分析显示，Notch途径在ALDH+细胞中的转录水平升高。通过伽玛分泌酶抑制剂或针对NOTCH3的shRNA稳定表达抑制Notch途径，导致ALDH+肺癌细胞显著减少，与肿瘤细胞增殖和克隆性降低相适应。综上所述，这些发现表明，ALDH选择具有更高致瘤潜能的自我更新的NSCLC干细胞亚群，携带ALDH1A1表达的肿瘤细胞的NSCLC预后较差，ALDH1A1和CD133识别不同的肿瘤亚群。针对Notch通路的治疗靶向减少了这种ALDH+成分，暗示了Notch信号在肺癌干细胞维持中的作用。
Aldehyde dehydrogenase (ALDH) is a candidate marker for lung cancer cells with stem cell-like properties. Immunohistochemical staining of a large panel of primary non-small cell lung cancer (NSCLC) samples for the ALDH1A1, ALDH3A1 and CD133 revealed a significant correlation between ALDH1A1 (but not ALDH3A1 or CD133) expression and poor prognosis in patients including those with stage I and N0 disease. Flow cytometric analysis of a panel of lung cancer cell lines and patient tumors revealed most NSCLCs contain a subpopulation of cells with elevated ALDH activity, and that this activity is associated with ALDH1A1 expression. Isolated ALDH+ lung cancer cells were observed to be highly tumorigenic and clonogenic as well as capable of self-renewal compared to their ALDH− counterparts. Expression analysis of sorted cells revealed elevated Notch pathway transcript expression in ALDH+ cells. Suppression of the Notch pathway by treatment with either a gamma-secretase inhibitor or stable expression of shRNA against NOTCH3 resulted in a significant decrease in ALDH+ lung cancer cells, commensurate with a reduction in tumor cell proliferation and clonogenicity. Taken together, these findings indicate that ALDH selects for a subpopulation of self-renewing NSCLC stem-like cells with increased tumorigenic potential, that NSCLCs harboring tumor cells with ALDH1A1 expression have inferior prognosis, and that ALDH1A1 and CD133 identify different tumor subpopulations. Therapeutic targeting of the Notch pathway reduces this ALDH+ component, implicating Notch signaling in lung cancer stem cell maintenance.