P0024 IL-6 induces malignant transformation of rat mesenchymal stem cells in association with enhanced STAT3 signalling

Abstract

Background Mesenchymal stem cells (MSCs) have the potential to be a source for cell-based therapies. However, MSCs can undergo malignant transformation in the tumour microenvironment where a high level of IL-6 is present. In this study, we investigated the role of IL-6 and STAT3 signalling in malignant transformation of MSCs. Methods Rat MSCs were isolated and indirectly co-cultured with C6 glioma cells. Co-culture of MSCs with astrocytes was used as a control. After 7 days of culture, the cells were assessed for malignant transformation using MTT immunofluorescence staining. The levels of hepatocyte growth factor, IL-6, and basic fibroblast growth factor, and the expression of STAT3 and soluble IL-6 receptor (sIL-6R), in the cultured cells and the conditioned media were measured using RT-PCR, ELISA, and western blotting. The expression levels of STAT3 downstream targets, cyclin D1 and Bcl-xl, were determined as well. Findings Our data show that almost all of the MSCs became phenotypically malignant after indirect co-culture with glioma cells, which was confirmed by tumour formation assays when these cells were injected into nude mice. The expression of IL-6 was significantly increased in the MSCs co-cultured with glioma cells, which was associated with significantly increased expressions of sIL-6R, GP130, STAT3, phosphorylated STAT3, cyclin D1, and Bcl-xl. Similar results were obtained when the MSCs were treated with IL-6. Furthermore, by treating the co-cultured MSCs with glioma by STA-21 to block the constitutive STAT3 signalling, the risk of MSCs tumour-like transformation in the tumour microenvironment was reduced. Interpretation These data suggest that IL-6 plays a critical role in the malignant transformation of rat MSCs, which is associated with an enhancement of the STAT3 signalling pathway in the tumour microenvironment.