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Characterization of Biomarkers of Tumorigenic and Chemoresistant Cancer Stem Cells in Human Gastric Carcinoma

Abstract : 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 dehy-drogenase (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 high ALDH 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 þ cells represented a core within the CD44 þ /CD166 þ subpopulation that contained the highest frequency of tumori-genic CSCs in vivo. The ALDH þ 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 chemore-sistant gastric CSCs in noncardia gastric carcinomas independently of the histologic classification of the tumor. Clin Cancer Res; 23(6); 1586-97. Ó2016 AACR.
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Phu Nguyen, Julie Giraud, Lucie Chambonnier, Pierre Dubus, Linda Wittkop, et al.. Characterization of Biomarkers of Tumorigenic and Chemoresistant Cancer Stem Cells in Human Gastric Carcinoma. Clinical Cancer Research, American Association for Cancer Research, 2017, 23 (6), pp.1586-1597. ⟨10.1158/1078-0432.CCR-15-2157⟩. ⟨inserm-03004874⟩

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