Mesenchymal stem cells (MSCs) have the potential to be the source for cell-based
therapies. However, MSCs can undergo malignant transformation in a tumor microenvironment where a high level of
interleukin (IL)-6 is present. In this study, we investigated the role of
IL-6 and
signal transducer and activator of transcription 3 (STAT3) signaling in malignant transformation of MSCs. Rat MSCs were isolated and indirectly cocultured with C6
glioma cells. Coculture of MSCs with astrocytes was used as a control. After 7 days of culture, the cells were assessed for malignant transformation using MTT assay and 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 in the cultured cells and
conditioned media were measured using RT-PCR, ELISA, and Western blot analysis. The expression levels of STAT3 downstream targets, CyclinD1 and Bcl-xl, were determined as well. Our data showed that almost all of the MSCs became phenotypically malignant after indirect coculture with
glioma cells, which was confirmed by
tumor formation assays when these cells were injected into nude mice. The expression of
IL-6 was significantly increased in MSCs cocultured with
glioma cells, which was associated with significantly increased expressions of soluble
IL-6 receptor, transmembrane
glycoprotein GP130, STAT3, phosphorylated STAT3, CyclinD1, and Bcl-xl. Similar results were obtained when the MSCs were treated with
IL-6. Treatment of the cocultured MSCs and
glioma cells with
STA-21, to block the constitutive STAT3 signaling, reduced the risk of MSC
tumor-like transformation in the tumor microenvironment. These data suggest that
IL-6 plays a critical role in malignant transformation of rat MSCs, which is associated with an enhancement of the STAT3 signaling pathway in the tumor microenvironment.