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

肿瘤细胞侵入周围组织和穿透屏障如基底膜的能力是恶性表型的最重要特征之一。在过去十年中进行的研究表明，基质金属蛋白酶（MMP），特别是明胶酶MMP-2和MMP-9，这两者都能够降解基底膜中的IV型胶原蛋白，在这些过程中起着至关重要的作用。MMP基因表达在正常条件下是低的或不存在的，但是通过改变的细胞-细胞和细胞-基质相互作用被快速诱导。然而，在肿瘤细胞中诱导和激活MMPs的潜在机制还不清楚。我们计划使用一个体外模型系统组成的非致瘤性，表皮HaCaT细胞和HaCaT变异体表现出不同的致瘤表型，分析基底膜及其组件如何调节这两个MMPs的表达和激活，以及肿瘤细胞-宿主细胞相互作用如何影响这些过程。同样，将进行对人肿瘤致癌物和实验诱导的小鼠肿瘤的体内研究，以验证我们的体外数据的相关性。这种方法将有助于阐明MMP-2和MMP-9可能有助于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.