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和无限的生长潜力，这是肿瘤细胞的特性，分别与上皮间充质转化（EMT）和干性相关。基质来源的微环境似乎以旁分泌的方式作用于肿瘤细胞，参与了这两种特性。-连环蛋白是EMT和干细胞的关键分子。到目前为止，已经发现了近100种核β-catenin的结合伙伴，其中一些是受宿主细胞调节的。在本项目中，我们拟研究肿瘤细胞/宿主细胞相互作用对结直肠癌肝转移侵袭前EMT和干性的影响。我们对这些过程的主要指示分子是ß-catenin，它在侵袭前沿的肿瘤细胞中有核定位，我们发现它被转录激活。在第二个资助期的申请中，我们将继续鉴定和进一步表征宿主细胞分泌的分子，作用于肿瘤细胞，最终导致ß-catenin启动子的激活。在第一个资助期内确定的候选分子将在离体试验中进行验证，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，我们将继续研究β-catenin mRNA和蛋白的空间和细胞内分布与临床预后参数的相关性。这些数据将有助于进一步阐明β-catenin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信号级联反应的新候选分子。

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.