Wirkung und Wirkungsweise von Insulin-like Growth-factor-I auf das proliferative Wachstum neuroendokriner Tumorzellen am Beispiel der humanen Karzinoidzelllinie BON

Carcinoids are neuroendocrine tumours developed throughout the gastrointestinal tract. There is no effective curative therapeutic strategy apart from surgery. The expression of the IGF-I-receptor and IGF-I secretion had already been shown in this type of tumours. Both parts of the IGF-System are well documented to be very important for development and maintenance of a malignant phenotype. Recently, the IGF-System was suggestet to be a new and promising target for anticancer strategies. The aim of this study was to characterize the role of IGF-I and its signal transduction pathways in growth regulation of human carcinoid BON cells. The expression of the IGF-receptor had been shown by receptor binding studies. The secretion of IGF-I was messured by radioimmunoassay. Treatment of BON cells with IGF-I increases significantly cell proliferation. It had been found, that PD 98059, a specific inhibitor of ERK 1 and 2, and LY 294002, a specific inhibitor of PI3-kinase, are important for basal and IGF-I induced cell proliferation. Moreover, there is every indication that those two signalling cascades are linked. The effects on map-kinase was visualised by map-kinase assay. Finally it had been demonstrated by transfection of an IGF-I-promotor-plasmid, that both signal transducing pathways influence IGF-I gene expression. In connection with the presence of IGF-receptor-I and the proven IGF-I secretion, it might be concluded, that IGF-I act on BON cells in an autocrine way. Consequently, the IGF-I system may represent an attractive and new therapeutic target for the treatment of human endocrine GEP tumours. Several strategies seem possible: hitting (1) the IGF-I-receptor, (2) its signal transduction machinery or (3) the expression of IGF-I.