Kerationcyte growth factor and cell-extracellular matrix interactions in normal and neoplastic epithelia of the upper aerodivestive tract

In malignant tumors cells have escaped normal control mechanisms enabling them to overgrow normal cells and invade other tissues. This results in local tumors and/or distant metastasis, often killing the patient. In some types of cancer, especially in childhood leukemias, the basic molecular events causing malignant transformation have been identified and successful treatment regimens could be designed. In head and neck cancer, which is increasing in incidence partly due to smoking and drinking habits, hardly any progress has been made in this respect. The treatment still mainly consists of surgery and postoperative irradiation resulting in severe speech and swallowing disabilities. In the proposed project we want to investigate the mechanisms by which the normal epithelial structure of the upper aerodigestive tract is established and maintained, and how these mechanisms are disturbed in head and neck cancer. It is known, that in normal squamous epithelium the basal and suprabasal epithelial cells (keratinocytes) proliferate, and that they undergo programmed cell death as they move to the surface. Obviously this does not happen in malignant tumors. The tissue below the epithelial layer, and the interaction of the keratinocytes with this tissue are essential for establishing and maintaining normal mucosa. The interaction of keratinocytes with the surrounding tissue via so-called integrin receptors will be investigated in normal mucosa and in head and neck tumors. The effect of growth factors produced by the subepithelial tissue - especially of keratinocyte growth factor (KGF) - on these interactions will be examined. The results of the proposed study will provide new information about local tumor spread and tumor invasion and potentially lead to new strategies for tumor control in head and neck cancer.