The role of host cell-tumor cell interaction for beta-catenin mediated tumor cell invasion in colorectal liver metastases

成功的转移需要侵袭性和无限的生长潜能，这是分别与上皮间充质转化(EMT)和干细胞特性相关的肿瘤细胞特性。间质来源的微环境似乎通过对肿瘤细胞的旁分泌方式参与了这两种特性。β-连环蛋白是EMT和茎的关键分子。到目前为止，已经描述了近百个核β-连环蛋白的结合伙伴，其中一些是由宿主细胞调控的。在这个项目中，我们打算研究肿瘤细胞/宿主细胞相互作用对结直肠癌肝转移侵袭前沿的EMT和干性的影响。我们对这些过程的主要指示分子是？-catenin，它位于侵袭前沿的肿瘤细胞中，我们已经发现它在转录上被激活。在这项申请的第二个资助期内，我们将继续鉴定和进一步鉴定宿主细胞分泌的分子，作用于肿瘤细胞，最终导致？连环蛋白启动子的激活。在第一个资助期确定的候选分子将在体外试验中得到验证，新的候选分子将通过显微解剖和基质成分的差异基因表达来确定。此外，我们还将继续研究β-Catenin基因和蛋白的空间分布和细胞内分布与临床预后参数的关系。这些数据将有助于进一步阐明β-连环蛋白在侵袭和转移中的作用，并确定参与宿主细胞和肿瘤细胞各自的信号级联反应的新的候选分子。

Successful metastasis requires invasion and unlimited growth potential, which are tumor cell properties associated with epithelial mesenchymal transition (EMT) and stemness, respectively. The stromal derived microenvironment seems to be involved in both properties by acting in a paracrine fashion on the tumor cells. Beta-catenin is a crucial molecule in EMT and stemness. So far, nearly 100 binding partners of nuclear β-catenin have been described, some of which are regulated by host cells. In this project we propose to examine the influence of tumor cell/host cell interaction on EMT and stemness in the invasion front of colorectal liver metastases. Our main indicator molecule for these processes is ß-catenin which is nuclearly localized in the tumor cells of the invasion front and has been found by us to be transcriptionally activated. Within this application for a second funding period, we will continue our identification and further characterization of molecules secreted by host cells, acting on tumor cells finally leading to activation of the ß-catenin promoter. Candidate molecules determined during the first funding period will be validated in ex vivo assays and new candidates will be determined by microdissection and differential gene expression of stromal components. In addition, we will continue our correlation of the spatial and intracellular distribution of β-catenin mRNA and protein with clinical prognostic parameters. These data will help further elucidating the role of β-catenin in invasion and metastasis and determine new candidate molecules involved in the respective signalling cascades in host cells and tumor cells.