Perturbation of the processes that control normal cell growth and survival often lead to cancer. Osteosarcoma is one example of a cancer that is caused by the abnormal behaviour of the cells which form bone, called osteoblasts. Our bone mass is normally maintained in homeostasis because the amount of bone made by osteoblasts is under very tight control. One of the factors which controls the amount of bone that osteoblasts synthesise are members of the family of growth factors, called Fibroblast Growth Factors (FGFs). FGFs work by attaching to and activating specific "receptors" on osteoblasts, which transmit the signal into the osteoblasts and instruct them to carry out their function. Aberrant signalling therefore leads to abnormal cell activity, such as that seen in cancers like osteosarcoma.

We have recently found using an animal model for osteosarcoma, that the cells that form osteosarcomas are characterised by abnormal FGF receptor signalling pathways. With the generous help of the BCRT, we have begun to demonstrate that human osteosarcoma cells also have similar abnormal signalling mechanisms that are different to normal bone cells, and which might explain why osteosarcomas arise and grow. These are novel findings that must be followed up in order to provide a basis for proposing that FGF signalling is a useful target for therapeutic intervention. The FGF-FGF receptor system is very complex, with 22 different FGFs signalling through 4 receptors, and it is not kwown which combination is responsible for bone tumour growth. In this proposal, we will identify the key signalling components which make osteosarcoma cells as well as whole tumour explants grow, and we will provide evidence that blocking the action of these specific components will block tumour growth. These experiments will provide for the first time an underlying mechanistic basis for the cause of osteosarcoma which will underpin future work and pre-clinical trials in targeting FGF signalling pathways as a potential cure for this skeletal malignancy.

Dr Agamemnon Grigoriadis