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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.
AuthorsSara 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
JournalCancer letters (Cancer Lett) Vol. 370 Issue 2 Pg. 286-95 (Jan 28 2016) ISSN: 1872-7980 [Electronic] Ireland
PMID26577806 (Publication Type: Journal Article)
CopyrightCopyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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