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 b1 (TGF-b1) signaling and a hypoxic environment dramatically induced selfrenewal capacity in non-stem osteosarcoma cells, which in turn promoted chemoresistance, tumorigenicity, neovasculogenesis, and metastatic potential. Furthermore, blocking the TGF-b1 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. STEM CELLS 2013;31:433-446 Disclosure of potential conflicts of interest is found at the end of this article.

Cancer stem cells in osteosarcoma

“…The potential plasticity of the CSC phenotype in osteosarcoma was shown by Zhang et al (39). The authors presented that MNNG/HOS, Saos2 and MG63 cells readily formed spheres and that treatment with TGFβ1 or application of hypoxic conditions (both abundant in the bone microenvironment) significantly increased sphere formation suggesting an induction of CSCs through environmental factors.…”

Microenvironment Signals and Mechanisms in the Regulation of Osteosarcoma

“…Notably, unlike the typical CD31⁻/CD34⁻/PAS⁺ VM, our group found that osteosarcoma stem cells (OSCs) had the capability to construct a CD31-positive vascular network de novo either under hypoxia or upon VEGFA induction [5]. This neo-VM subtype was formed by a type of vascular endothelial cell-like cells that transdiferentiated from OSCs as shown in Figure 3. …”

“…These cells could also form lipid droplets in an adipogenic diferentiation medium. Gene set enrichment analysis (GSEA) revealed that gene alterations during the process of dediferentiation are closely correlated with chemoresistance and metastasis in OS patients [5].…”

“…The activation of TGF-β1 signaling triggers the epithelial-mesenchymal transition (EMT) and ensures that the transformed cancer cells possess a stronger capacity of self-renewal, tumorigenesis, and chemo-/radioresistance [52]. In OS or other tumor types, solid evidence suggests that TGF-β1 is responsible for promoting stemness [5,53]. The TGF-β1 inhibitor SB525334 signiicantly inhibited the migration and invasion of sphere-forming stemlike cells [54].…”

“…Importantly, the OS microenvironment is characterized by abundant transforming growth factor-β1 (TGF-β1) and hypoxia. These conditions induce non-stem-like OS cells to adopt cancer stem cell characteristics, which in turn promote tumorigenesis and chemoresistance [5]. In addition, identifying distinct metabolic paterns and vascularization in OS should be considered in more detail and could provide a potential framework for clinical applications.…”