Characterization of biomarkers of tumorigenic and chemoresistant cancer stem cells in human gastric carcinoma
A partir d'échantillons tumoraux prélevés sur 37 patients atteints d'un cancer de l'estomac, puis menée sur des modèles murins avec xénogreffes dérivées des tumeurs, cette étude suggère que la mesure d'une surexpression de CD44 et d'une activité ALDH permet de détecter et d'isoler des cellules souches cancéreuses résistantes à la chimiothérapie
Purpose: Gastric carcinomas (GC) are heterogeneous, and the current therapy remains essentially based on surgery with conventional chemo- and radiotherapy. This study aimed to characterize biomarkers allowing the detection of cancer stem cells (CSC) in human GC of different histological types.
Experimental Design: The primary tumors from thirty-seven patients with intestinal or diffuse type non-cardia GC were studied, and patient's derived tumor xenograft (PDX) models in immunodeficient mice were developed. The expression of ten putative cell surface markers of CSCs, as well as 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 GC 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 co-expressed, 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 which was partially reversed by verapamil treatment.
Conclusions: CD44 and ALDH activity are the most specific biomarkers to detect and isolate tumorigenic and chemoresistant gastric CSCs in non-cardia GCs independently of the histological classification of the tumor.
Clinical Cancer Research , résumé, 2015