All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth

• Published in: Oncogene 2016-10, Vol.35 (43), p.5619-5628
• Main Authors: Nguyen, P H, Giraud, J, Staedel, C, Chambonnier, L, Dubus, P, Chevret, E, Bœuf, H, Gauthereau, X, Rousseau, B, Fevre, M, Soubeyran, I, Belleannée, G, Evrard, S, Collet, D, Mégraud, F, Varon, C
• Format: Article
• Language: English
• Subjects: 13; 13/100; 13/2; 13/51; 14/63; 631/532/71; 631/67/1504/1829; 82/80; Aldehyde dehydrogenase; Aldehyde Dehydrogenase - metabolism; Animal models; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Biomarkers; Cancer therapies; Care and treatment; CD44 antigen; Cell Biology; Cell culture; Cell Cycle Checkpoints - drug effects; Cell Cycle Checkpoints - genetics; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Chemotherapy; Cyclin-dependent kinase; Cyclin-dependent kinases; Development and progression; Disease Models, Animal; Female; Gastric cancer; Gastrointestinal diseases; Health aspects; Human Genetics; Humans; Hyaluronan Receptors - metabolism; Immunophenotyping; Innovations; Internal Medicine; KLF4 protein; Medicine; Medicine & Public Health; Metastases; Mice; Molecular targeted therapy; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Oncology; original-article; Patients; Retinoic acid; Spheroids, Cellular; Stem cell transplantation; Stem cells; Stomach cancer; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Tretinoin; Tretinoin - pharmacology; Tumor cells; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.87

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.