CD44细胞
癌症研究
生物
癌症干细胞
癌症
SOX2
细胞周期
分化疗法
醛脱氢酶
下调和上调
维甲酸
癌细胞
干细胞
细胞生长
细胞培养
细胞
急性早幼粒细胞白血病
细胞生物学
转录因子
生物化学
基因
遗传学
作者
Phu Hung Nguyen,Julie Giraud,Cathy Staedel,Lucie Chambonnier,Pierre Dubus,Edith Chevret,Hélène Bœuf,Xavier Gauthereau,Benoı̂t Rousseau,M Fèvre,Isabelle Soubeyran,Geneviève Belleannée,Serge Évrard,Denis Collet,Françis Mégraud,Christine Varon
出处
期刊:Oncogene
[Springer Nature]
日期:2016-05-09
卷期号:35 (43): 5619-5628
被引量:106
摘要
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.
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