title: All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth.
abstract: Gastric carcinoma is the third leading cause of cancer-related death worldwide. This cancer, most of the time metastatic, is essentially treated by surgery associated with conventional chemotherapy, and has a poor prognosis. The existence of cancer stem cells (CSC) expressing CD44 and a high aldehyde dehydrogenase (ALDH) activity has recently been demonstrated in gastric carcinoma and has opened new perspectives to develop targeted therapy. In this study, we evaluated the effects of all-trans-retinoic acid (ATRA) on CSCs in human gastric carcinoma. ATRA effects were evaluated on the proliferation and tumorigenic properties of gastric carcinoma cells from patient-derived tumors and cell lines in conventional 2D cultures, in 3D culture systems (tumorsphere assay) and in mouse xenograft models. ATRA inhibited both tumorspheres initiation and growth in vitro, which was associated with a cell-cycle arrest through the upregulation of cyclin-dependent kinase (CDK) inhibitors and the downregulation of cell-cycle progression activators. More importantly, ATRA downregulated the expression of the CSC markers CD44 and ALDH as well as stemness genes such as Klf4 and Sox2 and induced differentiation of tumorspheres. Finally, 2 weeks of daily ATRA treatment were sufficient to inhibit gastric tumor progression in vivo, which was associated with a decrease in CD44, ALDH1, Ki67 and PCNA expression in the remaining tumor cells. Administration of ATRA appears to be a potent strategy to efficiently inhibit tumor growth and more importantly to target gastric CSCs in both intestinal and diffuse types of gastric carcinoma.
authors.affiliation: INSERM, U853, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: P H
authors.initials: PH
authors.lastname: Nguyen
authors.affiliation: INSERM, U853, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: J
authors.initials: J
authors.lastname: Giraud
authors.affiliation: University of Bordeaux, Bordeaux, France.|ARNA Laboratory, INSERM, U869, Bordeaux, France.
authors.forename: C
authors.initials: C
authors.lastname: Staedel
authors.affiliation: INSERM, U853, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: L
authors.initials: L
authors.lastname: Chambonnier
authors.affiliation: University of Bordeaux, Bordeaux, France.|EA2406, University of Bordeaux, Bordeaux, France.|University Hospital Center, Bordeaux, France.
authors.forename: P
authors.initials: P
authors.lastname: Dubus
authors.affiliation: University of Bordeaux, Bordeaux, France.|EA2406, University of Bordeaux, Bordeaux, France.
authors.forename: E
authors.initials: E
authors.lastname: Chevret
authors.affiliation: University of Bordeaux, Bordeaux, France.|UMR CNRS 5164 CIRID, Bordeaux, France.
authors.forename: H
authors.initials: H
authors.lastname: Bœuf
authors.affiliation: University of Bordeaux, Bordeaux, France.|UMR CNRS 5164 CIRID, Bordeaux, France.
authors.forename: X
authors.initials: X
authors.lastname: Gauthereau
authors.affiliation: University of Bordeaux, Bordeaux, France.|Service Commun des Animaleries, University of Bordeaux, Bordeaux, France.
authors.forename: B
authors.initials: B
authors.lastname: Rousseau
authors.affiliation: University of Bordeaux, Bordeaux, France.|Service Commun des Animaleries, University of Bordeaux, Bordeaux, France.
authors.forename: M
authors.initials: M
authors.lastname: Fevre
authors.affiliation: Department of Biopathology, Institut Bergonié, Bordeaux, France.
authors.forename: I
authors.initials: I
authors.lastname: Soubeyran
authors.affiliation: Department of Histopathology of Tumors, Haut-Leveque Hospital, Bordeaux, France.
authors.forename: G
authors.initials: G
authors.lastname: Belleannée
authors.affiliation: Department of Digestive Oncology, Institut Bergonié, Bordeaux, France.
authors.forename: S
authors.initials: S
authors.lastname: Evrard
authors.affiliation: Department of Digestive Surgery, Haut-Leveque Hospital, Bordeaux, France.
authors.forename: D
authors.initials: D
authors.lastname: Collet
authors.affiliation: INSERM, U853, Bordeaux, France.|University of Bordeaux, Bordeaux, France.|University Hospital Center, Bordeaux, France.
authors.forename: F
authors.initials: F
authors.lastname: Mégraud
authors.affiliation: INSERM, U853, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: C
authors.initials: C
authors.lastname: Varon
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D016130:Immunophenotyping; D000090062:Kruppel-Like Factor 4; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D018874:Spheroids, Cellular; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D014212:Tretinoin; D000444:Aldehyde Dehydrogenase