Characterization of Biomarkers of Tumorigenic and Chemoresistant Cancer Stem Cells in Human Gastric Carcinoma.
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 byin vitrotumorsphere assays andin vivoxenografts 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 tumorspheresin vitroand tumorsin vivoCD44 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 CSCsin vivoThe 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.Clin Cancer Res; 23(6); 1586-97. ©2016 AACR.
INSERM, U853 Helicobacter Infection, Inflammation and Cancer, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
Phu Hung
PH
Nguyen
INSERM, U853 Helicobacter Infection, Inflammation and Cancer, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
Julie
J
Giraud
INSERM, U853 Helicobacter Infection, Inflammation and Cancer, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
Lucie
L
Chambonnier
University of Bordeaux, Bordeaux, France.|EA 2406, University of Bordeaux, Bordeaux, France.|University Hospital Center of Bordeaux, Bordeaux, France.
Pierre
P
Dubus
University of Bordeaux, Bordeaux, France.|INSERM, ISPED, Centre INSERM U1219 Bordeaux Population Health, Bordeaux, France.|Pôle de Santé Publique, Service d'information médicale, University Hospital Center of Bordeaux, Bordeaux, France.
Linda
L
Wittkop
University Hospital Center of Bordeaux, Bordeaux, France.
Geneviève
G
Belleannée
University Hospital Center of Bordeaux, Bordeaux, France.
Denis
D
Collet
Institut Bergonié, Bordeaux, France.|INSERM, U1012 Actions for onCogenesis understanding and Target Identification in Oncology (ACTION), Bordeaux, France.
Isabelle
I
Soubeyran
University of Bordeaux, Bordeaux, France.|Institut Bergonié, Bordeaux, France.|INSERM, U1012 Actions for onCogenesis understanding and Target Identification in Oncology (ACTION), Bordeaux, France.
Serge
S
Evrard
University of Bordeaux, Bordeaux, France.|Service Commun des Animaleries, Animalerie A2, Bordeaux, France.
Benoit
B
Rousseau
University of Bordeaux, Bordeaux, France.|SFR TransBioMed, Bordeaux, France.
Nathalie
N
Senant-Dugot
INSERM, U853 Helicobacter Infection, Inflammation and Cancer, Bordeaux, France.|University of Bordeaux, Bordeaux, France.|University Hospital Center of Bordeaux, Bordeaux, France.
Francis
F
Mégraud
CNRS UMR 7292, GICC LNOx, Tours, France.
Frédéric
F
Mazurier
INSERM, U853 Helicobacter Infection, Inflammation and Cancer, Bordeaux, France. christine.varon@u-bordeaux.fr.|University of Bordeaux, Bordeaux, France.
Christine
C
Varon
D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D000444:Aldehyde Dehydrogenase