title: 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.affiliation: 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.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Martins-Neves
authors.affiliation: Pharmacology and Experimental Therapeutics, IBILI - Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal.
authors.forename: Daniela I
authors.initials: DI
authors.lastname: Paiva-Oliveira
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Wijers-Koster
authors.affiliation: CNC.IBILI, University of Coimbra, Coimbra, Portugal; Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal.
authors.forename: Antero J
authors.initials: AJ
authors.lastname: Abrunhosa
authors.affiliation: Pharmacology and Experimental Therapeutics, IBILI - Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fontes-Ribeiro
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Judith V M G
authors.initials: JV
authors.lastname: Bovée
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cleton-Jansen
authors.affiliation: 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.
authors.forename: Célia M F
authors.initials: CM
authors.lastname: Gomes
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000444:Aldehyde Dehydrogenase / Q000032:analysis / Q000502:physiology; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C495270:CTNNB1 protein, human; D009363:Neoplasm Proteins; D051176:beta Catenin; D000444:Aldehyde Dehydrogenase
keywords: Aldehyde dehydrogenase; Osteosarcoma; Pluripotency; Stemness; Wnt/β-catenin