Characterization of Biomarkers of Tumorigenic and Chemoresistant Cancer Stem Cells in Human Gastric Carcinoma
Characterization of Biomarkers of Tumorigenic and Chemoresistant Cancer Stem Cells in Human Gastric Carcinoma
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DOI：
10.1158/1078-0432.ccr-15-2157
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发表时间：
2017-03-15
影响因子：
11.5
通讯作者：
Varon, Christine
中科院分区：
文献类型：
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作者：
Phu Hung Nguyen;Giraud, Julie;Varon, Christine
目的：胃癌是一种异质性肿瘤，目前的治疗主要以手术加常规化疗和放疗为主。本研究旨在表征可用于检测不同组织类型的人胃癌中的肿瘤干细胞(CSC)的生物标志物。实验设计：以37例肠型或弥漫型非贲门型胃癌患者的原发肿瘤为研究对象，建立免疫缺陷小鼠患者来源的肿瘤异种移植(PDX)模型。通过体外肿瘤球法和体内有限稀释法检测肿瘤细胞的致瘤性。结果：一批表达EpCAM、CD133、CD166、CD44的胃癌细胞亚群和高ALDH活性的胃癌细胞亚群具有在体外和体内形成新的异种肿瘤微球的特性。CD44和CD166共表达，占细胞总数的6.1%~37.5%；ALDH活性在1.6%~15.4%；ALDH(+)细胞是CD44(+)/CD166(+)亚群中的核心细胞，体内致瘤CSCs的频率最高。ALDH(+)细胞具有药物外排特性，对标准化疗的耐受性高于ALDH(+)细胞，这一过程可被维拉帕米部分逆转。结论：CD44和ALDH是检测和分离非贲门型胃癌中致瘤和耐药的最特异的生物标志物，与肿瘤的组织学分类无关。(C)2016年AACR。
Purpose: Gastric carcinomas are heterogeneous, and the current therapy remains essentially based on surgery with conventional chemotherapy and radiotherapy. This study aimed to characterize biomarkers allowing the detection of cancer stem cells (CSC) in human gastric carcinoma of different histologic types.Experimental Design: The primary tumors from 37 patients with intestinal- or diffuse-type noncardia gastric carcinoma were studied, and patient-derived tumor xenograft (PDX) models in immunodeficient mice were developed. The expressions of 10 putative cell surface markers of CSCs, as well as aldehyde dehydrogenase (ALDH) activity, were studied, and the tumorigenic properties of cells were evaluated by in vitro tumorsphere assays and in vivo xenografts by limiting dilution assays.Results: We found that a subpopulation of gastric carcinoma cells expressing EPCAM, CD133, CD166, CD44, and a highALDH activity presented the properties to generate new heterogeneous tumorspheres in vitro and tumors in vivo. CD44 and CD166 were coexpressed, representing 6.1% to 37.5% of the cells; ALDH activity was detected in 1.6% to 15.4% of the cells; and the ALDH(+) cells represented a core within the CD44(+)/CD166(+) subpopulation that contained the highest frequency of tumorigenic CSCs in vivo. The ALDH(+) cells possessed drug efflux properties and were more resistant to standard chemotherapy than the ALDH(+) cells, a process that was partially reversed by verapamil treatment.Conclusions: CD44 and ALDH are the most specific biomarkers to detect and isolate tumorigenic and chemoresistant gastric CSCs in noncardia gastric carcinomas independently of the histologic classification of the tumor. (C) 2016 AACR.