Chemotherapy induces stemness in osteosarcoma cells through activation of Wnt/β-catenin signaling.

Abstract

Development of resistance represents a major drawback in osteosarcoma treatment, despite improvements in overall survival. Treatment failure and tumor progression have been attributed to pre-existing drug-resistant clones commonly assigned to a cancer stem-like phenotype. Evidence suggests that non stem-like cells, when submitted to certain microenvironmental stimuli, can acquire a stemness phenotype thereby strengthening their capacity to handle with stressful conditions. Here, using osteosarcoma cell lines and a mouse xenograft model, we show that exposure to conventional chemotherapeutics induces a phenotypic cell transition toward a stem-like phenotype. This associates with activation of Wnt/β-catenin signaling, up-regulation of pluripotency factors and detoxification systems (ABC transporters and Aldefluor activity) that ultimately leads to chemotherapy failure. Wnt/β-catenin inhibition combined with doxorubicin, in the MNNG-HOS cells, prevented the up-regulation of factors linked to transition into a stem-like state and can be envisaged as a way to overcome adaptive resistance. Finally, the analysis of the public R2 database, containing microarray data information from diverse osteosarcoma tissues, revealed a correlation between expression of stemness markers and a worse response to chemotherapy, which provides evidence for drug-induced phenotypic stem cell state transitions in osteosarcoma.

• Authors: Sara R Martins-Neves, Daniela I Paiva-Oliveira, Pauline M Wijers-Koster, Antero J Abrunhosa, Carlos Fontes-Ribeiro, Judith V M G Bovée, Anne-Marie Cleton-Jansen, Célia M F Gomes
• Journal: Cancer letters (Cancer Lett) Vol. 370 Issue 2 Pg. 286-95 (Jan 28 2016) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 26577806 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• ABCB1 protein, human
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• CTNNB1 protein, human
• Neoplasm Proteins
• beta Catenin
• Aldehyde Dehydrogenase

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (genetics)
• Aldehyde Dehydrogenase (analysis, physiology)
• Animals
• Bone Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Humans
• Mice
• Neoplasm Proteins (genetics)
• Osteosarcoma (drug therapy, pathology)
• Signal Transduction
• Wnt Signaling Pathway (physiology)
• beta Catenin (physiology)