Format

Send to

Choose Destination
Cancer Lett. 2016 Jan 28;370(2):286-95. doi: 10.1016/j.canlet.2015.11.013. Epub 2015 Nov 11.

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

Author information

1
Pharmacology and Experimental Therapeutics, IBILI - Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal; Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Department of Pathology, Leiden University Medical Centre, Leiden, Netherlands.
2
Pharmacology and Experimental Therapeutics, IBILI - Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal.
3
Department of Pathology, Leiden University Medical Centre, Leiden, Netherlands.
4
CNC.IBILI, University of Coimbra, Coimbra, Portugal; Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal.
5
Pharmacology and Experimental Therapeutics, IBILI - Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
6
Pharmacology and Experimental Therapeutics, IBILI - Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal; Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address: cgomes@fmed.uc.pt.

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.

KEYWORDS:

Aldehyde dehydrogenase; Osteosarcoma; Pluripotency; Stemness; Wnt/β-catenin

PMID:
26577806
DOI:
10.1016/j.canlet.2015.11.013
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center