Die Rolle von Zell-Zell- und Zell-Matrix-Interaktionen bei der Synthese und Aktivierung von MMP-2 und MMP-9 in epidermalen Tumorzellen in vitro und in vivo

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The ability of tumor cells to invade surrounding tissue and to penetrate barriers such as basement membranes is one of the most important feature of the malignant phenotype. Studies performed over the last decade revealed that matrix metalloproteinases (MMPs) and in particular the gelatinases MMP-2 and MMP-9, which both are capable of degrading collagen type IV in basement membranes, play a crucial role during these processes. MMP gene expression is low or absent under normal conditions but is rapidly induced by altered cell-cell and cell-matrix interactions. However, the mechanisms underlying induction and activation of MMPs in tumor cells is not well understood. We plan to use an in vitro model system consisting of non-tumorigenic, epidermal HaCaT cells and HaCaT variants exhibiting different tumorigenic phenotypes, to analyse how basement membranes and their components regulate the expression and activation of these two MMPs and how tumor cell-host cell interactions influence these processes. Parallely, in vivo studies on human tumor speciments and experimental induced mouse tumors will be performed to verify the relevance of our in vitro data. This approach should be helpful to elucidate the mechanisms by which MMP-2 and MMP-9 might contribute to epidermal tumor progression.