The influence of ionising radiation on intracellular pathways of the mitogen activated protein kinase (MAPK) family

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For radiotherapists, it is well known that different tumour types have different radiosensitivities. It is believed that a cross talk between tumour and endothelial cells have an impact on the radiosensitivity of solid tumours. Ionising radiation modulates signaling pathways in tumour cells. In this context, the mitogen activated protein kinase (MAPK) pathways play a major role. There are two key players of MAPK pathways in tumour cells that are activated by ionising radiation known to influence survival or apoptosis of tumour cells. In addition, the activation of these pathways can lead to overexpression of the vascular endothelial growth factor (VEGF). VEGF is then released from tumour cells and it protects endothelial cells from radiation induced apoptosis. The aim of this study is to first investigate the influence of ionising radiation on VEGF release from tumour cells, second, to analyse the influence of VEGF on intracellular MAPK signalling pathways in endothelial cells and third, to evaluate the direct influence of ionising radiation on MAPK pathways by blocking the signal transduction of VEGF with a specific VEGF receptor tyrosin kinase inhibitor (PTK787). Cell line studies are already under investigation. Part of this study will be a tumour xenograft model. The mice will be treated with fractionated radiation therapy alone or in combination with PTK787. At the same time canine patients with spontaneous oral SCC, FSA will be included in the study. For detection of active and inactive signalling proteins immunofluorescence and immunoblotting will be used. This study will give more insights in the mechanisms of radioresistance in tumours by showing a ratio between active and inactive MAPK signalling pathways in vitro and in vivo. This study will prove the efficacy of combined treatment of radiation therapy and specific blockage of survival pathways.