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

肿瘤细胞侵袭周围组织和穿透基底膜等屏障的能力是恶性表型的最重要特征之一。过去十年的研究表明，基质金属蛋白酶（MMPs），特别是明胶酶MMP-2和MMP-9，都能够降解基底膜中的IV型胶原，在这些过程中起着至关重要的作用。在正常条件下，MMP基因表达低或不存在，但在细胞-细胞和细胞-基质相互作用的改变下可迅速诱导。然而，肿瘤细胞中MMPs的诱导和激活机制尚不清楚。我们计划使用一个由非致瘤性、表皮HaCaT细胞和表现出不同致瘤表型的HaCaT变体组成的体外模型系统，分析基底膜及其成分如何调节这两种MMPs的表达和激活，以及肿瘤-宿主细胞相互作用如何影响这些过程。同时，将对人类肿瘤标本和实验诱导小鼠肿瘤进行体内研究，以验证我们体外数据的相关性。这种方法应该有助于阐明MMP-2和MMP-9可能促进表皮肿瘤进展的机制。

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.