Calcein-effluxing human colon cancer cells are enriched for self-renewal capacity and depend on β-catenin.
Calcein-effluxing human colon cancer cells are enriched for self-renewal capacity and depend on β-catenin.
复制标题
DOI：
10.18632/oncotarget.883
复制
发表时间：
2013-02
期刊：
影响因子：
--
通讯作者：
El-Deiry WS
中科院分区：
文献类型：
--
作者：
Allen JE;El-Deiry WS
推定的癌症干细胞是引起化疗耐药性的癌细胞亚群，因此具有预后和治疗意义，尽管由于缺乏可靠和准确的标记物，它们的鉴定在结肠癌中仍然难以捉摸。我们以前确定了一个p53依赖性推定的癌症干细胞群体，钙黄绿素低群体（CloP），基于他们的独家流出的荧光染料钙黄绿素。这种功能鉴定方法能够对亚群进行比较性活细胞研究，而不会出现传统Hoechst方法所出现的差异毒性，这混淆了结论并限制了这种癌症干细胞标志物的实用性。在这项研究中，我们检查了体内CloP群体与人结肠癌异种移植物中的亲本和钙黄绿素高群体（ChiP）相比的癌症干细胞样性质。在NOD/SCID小鼠中的连续稀释异种移植物实验揭示，与ChiP或亲本细胞相比，CloP仅略微更具致瘤性。然而，这些肿瘤的连续传代揭示了与其他群体相比，CloP在体内独特地富集了自我更新能力。这些肿瘤的免疫组织化学分析显示，CloP具有增加的核β-连环蛋白水平，此外，siRNA介导的β-连环蛋白敲低显著减少了CloP群体。这些发现突出了CloP作为肿瘤细胞的重要亚群，其专门具有自我更新和增殖肿瘤的能力。CloP对β-连环蛋白的依赖性为这种能力提供了分子解释，并表明该群体可以并且应该通过抑制Wnt信号传导来治疗靶向。
Putative cancer stem cells are a subpopulation of cancer cells that give rise to chemotherapy resistance and are therefore of prognostic and therapeutic interest, though their identification remains elusive in colon cancer due to lack of reliable and accurate markers. We previously identified a p53-dependent putative cancer stem cell population, the calcein low population (CloP), based on their exclusive efflux of the fluorescent dye Calcein. This functional identification method enables comparative live cell studies of subpopulations without differential toxicity that occurs with traditional Hoechst methods, which has confounded conclusions and limited the utility of this cancer stem cell marker. In this study, we examined the cancer stem cell-like properties of the CloP population in vivo in comparison with the parental and calcein-high population (ChiP) in human colon cancer xenografts. Serial dilution xenograft experiments in NOD/SCID mice revealed that the CloP is only marginally more tumorigenic compared to the ChiP or parental cells. However, serial passage of these tumors revealed that the CloP is uniquely enriched for self-renewal capacity in vivo compared to the other populations. Immunohistochemical analysis of these tumors revealed that the CloP possesses increased levels of nuclear β-catenin and furthermore, siRNA-mediated knockdown of β-catenin significantly reduced the CloP population. These findings highlight the CloP as an important subpopulation of tumor cells that are exclusively endowed with the ability to self-renew and propagate tumors. The dependency of the CloP on β-catenin provides a molecular explanation for this ability and suggests that this population can and should be therapeutically targeted by inhibition of Wnt signaling.
登录
查看更多内容
影响因子：
11.2
作者：
Huang EH;Hynes MJ;Zhang T;Ginestier C;Dontu G;Appelman H;Fields JZ;Wicha MS;Boman BM
通讯作者：
Boman BM
影响因子：
2.8
作者：
Brabletz, T;Jung, A;Kirchner, T
通讯作者：
Kirchner, T
影响因子：
6.2
作者：
Horst, David;Reu, Simone;Jung, Andreas
通讯作者：
Jung, Andreas
影响因子：
21.3
作者：
Vermeulen, Louis;Melo, Felipe De Sousa E.;Medema, Jan Paul
通讯作者：
Medema, Jan Paul
影响因子：
23.9
作者：
Pang, Roberta;Law, Wai Lun;Wong, Benjamin C. Y.
通讯作者：
Wong, Benjamin C. Y.