Dr Paul Genever, University of York (£28,315)
Analysis of 3D mesenchymal stem cell-induced cytotoxicity in osteosarcoma and Ewing's sarcoma cell lines.
Mesenchymal stem cells (MSCs) are attractive candidates for cell-based therapies primarily aimed at skeletal tissues. MSCs are also able to home to tumour sites and inhibit tumour growth, but the molecular mechanisms involved are unclear. Using novel three-dimensional (3D) culture techniques for MSCs, we have identified unique characteristics that enable them to selectively induce cell death in cancer cells. For example, we have shown that conditioned medium from 3D MSCs causes a significant decrease in viability of different prostate cancer cell lines without affecting normal prostate cells, morover we have shown that the cancer-specific cytotoxic effects are mediated through the cytokine IL-24. The expression levels of IL-24 are elevated 300-fold in 3D MSCs compared to conventional 2D MSCs and this cytokine has previously been shown to have toxic effects in a wide range of tumours when delivered at supraphysiological levels by viral transduction. The proposed work will determine cytotoxic effects of 3D MSCs on different osteosarcoma and Ewing's sarcoma cell lines and we will confirm the mechanism of action. In anticipation of appropriate therapeutic routes, the work will include the analysis of 3D MSC conditioned medium and direct cell-cell contact in mixed MSC-tumour cell spheroids. This pump-priming proposal will determine the potential for 3D MSCs in primary bone cancer therapy using a simplified and inexpensive approach, without the need for viral gene transfer techniques.
