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

Oncogene volume 35, pages 5619–5628 (2016)Cite this article

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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.

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Acknowledgements

The post-doctoral fellowship of Julie Giraud was granted by the French ‘Institut National du Cancer’ (grant 2014-152). We thank Vincent Pitard and Santiago Gonzalez (Flow Cytometry and FACS Platform, University of Bordeaux), Lamia Azzi-Martin and Jacky Ferrer (EA2406, University of Bordeaux), Elodie Siffre and Armelle Ménard (INSERM U853) for technical assistance and helpful advice. We thank the French ‘Association pour la Recherche contre le Cancer’ (grant number 8412), the ‘Institut National du Cancer’ (grant 07/3D1616/IABC-23-12/NC-NG and grant 2014-152), the ‘Conseil Regional d’Aquitaine’ (grant numbers 20071301017 and 20081302203) and the French National Society for Gastroenterology for financial support. This project is part of SIRIC BRIO (Site de Recherche Intégrée sur le Cancer – Bordeaux Recherche Intégrée Oncologie; grant INCa-DGOS-INSERM 6046).

Author information

Authors and Affiliations

  1. INSERM, U853, Bordeaux, France

    P H Nguyen, J Giraud, L Chambonnier, F Mégraud & C Varon

  2. University of Bordeaux, Bordeaux, France

    P H Nguyen, J Giraud, C Staedel, L Chambonnier, P Dubus, E Chevret, H Bœuf, X Gauthereau, B Rousseau, M Fevre, F Mégraud & C Varon

  3. ARNA Laboratory, INSERM, U869, Bordeaux, France

    C Staedel

  4. EA2406, University of Bordeaux, Bordeaux, France

    P Dubus & E Chevret

  5. University Hospital Center, Bordeaux, France

    P Dubus & F Mégraud

  6. UMR CNRS 5164 CIRID, Bordeaux, France

    H Bœuf & X Gauthereau

  7. Service Commun des Animaleries, University of Bordeaux, Bordeaux, France

    B Rousseau & M Fevre

  8. Department of Biopathology, Institut Bergonié, Bordeaux, France

    I Soubeyran

  9. Department of Histopathology of Tumors, Haut-Leveque Hospital, Bordeaux, France

    G Belleannée

  10. Department of Digestive Oncology, Institut Bergonié, Bordeaux, France

    S Evrard

  11. Department of Digestive Surgery, Haut-Leveque Hospital, Bordeaux, France

    D Collet

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  1. P H Nguyen
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Correspondence to C Varon.

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Nguyen, P., Giraud, J., Staedel, C. et al. All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth. Oncogene 35, 5619–5628 (2016). https://doi.org/10.1038/onc.2016.87

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