Chemotherapy induces stemness in osteosarcoma cells through activation of Wnt/[beta]-catenin signaling

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...

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Bibliographic Details
Published in:Cancer letters 2016-01, Vol.370 (2), p.286
Main Authors: Martins-Neves, Sara R, Paiva-Oliveira, Daniela I, Wijers-Koster, Pauline M, Abrunhosa, Antero J, Fontes-Ribeiro, Carlos, Bovée, Judith VMG, Cleton-Jansen, Anne-Marie, Gomes, Célia MF
Format: Article
Language:English
Subjects:
Binding sites
Cancer therapies
Chemotherapy
Gene expression
Genomics
Genotype & phenotype
Hypotheses
Medical prognosis
Metastasis
Software
Stem cells
Survival analysis
Tumors
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Summary: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.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2015.11.013