title: Transforming growth factor β1 signal is crucial for dedifferentiation of cancer cells to cancer stem cells in osteosarcoma.
abstract: Human osteosarcoma harbors a small subpopulation of cancer stem cells (CSCs) that is believed to be associated with tumor metastasis, radioresistance/chemoresistance, local invasion, and poor clinical outcome. In this study, we found that transforming growth factor β1 (TGF-β1) signaling and a hypoxic environment dramatically induced self-renewal capacity in non-stem osteosarcoma cells, which in turn promoted chemoresistance, tumorigenicity, neovasculogenesis, and metastatic potential. Furthermore, blocking the TGF-β1 signaling pathway resulted in the inhibition of the dedifferentiation and clonogenicity of osteosarcoma cells, and the reduction of CSC self-renewal capacity and hypoxia-mediated dedifferentiation. These findings demonstrate that stem cells and non-stem cells exist in a dynamic equilibrium within the osteosarcoma cell population, and that CSCs may develop de novo from differentiated cancer cells. Hierarchical models of mammalian CSCs, therefore, should be considered to serve as bidirectional interconversion between the stem and non-stem cell components of the tumor.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Haixia
authors.initials: H
authors.lastname: Zhang
authors.forename: Haotong
authors.initials: H
authors.lastname: Wu
authors.forename: Junheng
authors.initials: J
authors.lastname: Zheng
authors.forename: Pei
authors.initials: P
authors.lastname: Yu
authors.forename: Lixiao
authors.initials: L
authors.lastname: Xu
authors.forename: Pan
authors.initials: P
authors.lastname: Jiang
authors.forename: Jin
authors.initials: J
authors.lastname: Gao
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015197:Carcinogenicity Tests; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D018874:Spheroids, Cellular; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D053773:Transforming Growth Factor beta1