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.

RETRACTED ARTICLE: ω-3 free fatty acids and all-trans retinoic acid synergistically induce growth inhibition of three subtypes of breast cancer cell lines

“…Although all-trans retinoic acid has been widely used to treat several cancers, its antitumor effect is compromised due to intrinsic potential cytotoxicity and drug resistance when high dosage is applied in breast cancer 10, 33, 34 . Therefore, it is unlikely that ATRA will be an effective drug for triple negative breast cancer therapy when used as a single agent, and that the development of RA-based combination strategy is crucial to enhance ATRA chemopreventive efficacy for the treatment of breast cancer.…”

Screening the active compounds of Phellodendri Amurensis cortex for treating prostate cancer by high-throughput chinmedomics

“…It could promote cancer cell apoptosis, scavenging oxygen radicals, inhibit lipid peroxidation, and then as an antioxidant, prevent the deterioration of the tumour5657. All-trans-retinoic acid is involved in retinol metabolism, it could regulate cell proliferation, differentiation, apoptosis, and immune response, and then play an important role in the growth of cancer cells5859. Linoleic acid, as the main substance in arachidonic acid synthesis, is involved in linoleic acid metabolism.…”

Gastric Cancer: A Stem Cell Disease?

“…Determination of the signaling pathways controlling their properties is now instrumental to ind new targeted therapies for gastric cancer, for which there is a crucial unmet need to ind new eicient therapy. In this aim, we have shown by diferent strategies that the targeting of gastric CSCs expressing CD44 by blocking speciic microRNAs or by inducing their diferentiation by all-trans retinoic acid allows inhibition of tumor growth in vivo [58,83].…”

“…In vitro, under conditions in which cells are seeded at low-density in low-adherent plates, without serum and in the presence of some growth factors such as EGF, bFGF, and insulin, only GCSCs can survive, self-renew, and form tumorspheres [36,50,51,57]. Long self-renewal ability is evaluated after tumorsphere dissociation into single cells and several passages; indeed only GCSCs can generate tumorspheres after several passages [51,58]. In vivo, frequency of GCSCs in a given population is determined after subcutaneous xenograft in immunocompromised mice using diferent cell doses and an analysis of their ability to initiate a new heterogenous tumor after several weeks.…”