β-Catenin Does Not Confer Tumorigenicity When Introduced into Partially Transformed Human Mesenchymal Stem Cells

Abstract

Although osteosarcoma is the most common primary malignant bone tumor in children and adolescents, its cell of origin and the genetic alterations are unclear. Previous studies have shown that serially introducing hTERT, SV40 large TAg, and H-Ras transforms human mesenchymal stem cells into two distinct sarcomas cell populations, but they do not form osteoid. In this study, β-catenin was introduced into mesenchymal stem cells already containing hTERT and SV40 large TAg to analyze if this resulted in a model which more closely recapitulated osteosarcoma. Results. Regardless of the level of induced β-catenin expression in the stable transfectants, there were no marked differences induced in their phenotype or invasion and migration capacity. Perhaps more importantly, none of them formed tumors when injected into immunocompromised mice. Moreover, the resulting transformed cells could be induced to osteogenic and chondrogenic differentiation but not to adipogenic differentiation. Conclusions. β-catenin, although fostering osteogenic differentiation, does not induce the malignant features and tumorigenicity conveyed by oncogenic H-RAS when introduced into partly transformed mesenchymal stem cells. This may have implications for the role of β-catenin in osteosarcoma pathogenesis. It also may suggest that adipogenesis is an earlier branch point than osteogenesis and chondrogenesis in normal mesenchymal differentiation.

Genetically transforming human osteoblasts to sarcoma: development of an osteosarcoma model

“…While the stages of osteoblast differentiation have not been clearly delineated, it is known that early progenitor cells have tri-lineage differentiation capacity. As the progenitor cells mature, experiments suggest the cells first lose adipogenic differentiation capacity, and subsequently lose chondrogenic differentiation capacity (Figure 5 ) [ 19 , 20 , 30 ]. This theory is supported by studies demonstrating hMSCs transformed with hTERT, SV40, and β-catenin lose the capacity to be induced towards adipogenic differentiation; while the capacity to induce osteogenic differentiation in the transformed cells remain, and the capacity to induce chondrogenic differentiation is delayed [ 30 ].…”

“…Subsequently, with the hypothesis that introducing a genetic alteration inducing osteogenic differentiation may result in the desired phenotype, β-catenin, which may be involved in both tumor development and osteogenic differentiation, was introduced instead of H-Ras into partially transformed hMSC. The resulting cells did not produce tumors in mice and lacked the phenotype of fully malignant cells [ 20 ]. It remained unclear whether the failure to produce an osteosarcoma model was the result of MSC not being the cell of origin or once again incorrect selection of genes for cellular transformation.…”

Multifunctional 3D-printed bioceramic scaffolds: Recent strategies for osteosarcoma treatment

“… 30 Chondrocytes, fibroblasts, osteoblasts, and telangiectatic tumors are the four subtypes of osteosarcoma that can be distinguished based on the primary matrix produced. 31 Osteosarcomas can also be classified into three groups, low, intermediate, and high grade, as relative indicators of the danger of developing metastases. 32 Low-grade OS is typically inert and can only be removed surgically.…”

The canonical Wnt-beta-catenin pathway in development and chemotherapy of osteosarcoma

“…Targeting the canonical Wnt-β-catenin pathway may thus lead to promising new modalities for early prevention or therapy of OS. However, β-catenin cannot induce the malignant features and tumorigenicity conveyed by oncogenic H-RAS when introduced into partly transformed mesenchymal stem cells, even though it can foster osteogenic differentiation (23).…”