Migrating cancer stem cells: An integrated concept of malignant tumor progression.

ED01-02

Most colorectal adenocarcinomas (CRC) have mutations in the APC gene leading to overexpression of the Wnt-pathway effector b-catenin. By acting as a transcriptional activator, nuclear b-catenin is decisively involved in two fundamental processes in embryonic development: epithelial to mesenchymal transition (EMT) and generation of stem cells (e.g. in intestine development). We have previously shown, that in particular tumor cells at the invasive front of CRCs accumulate nuclear b-catenin, undergo an EMT and aberrantly express EMT-associated transcriptional repressors, like ZEB1. The amount of these cells strongly correlates with clinical outcome and metastasis formation. We further showed that ZEB1 represses target genes involved in basement membrane formation and epithelial cell polarity. In contrast tumor cells in central tumor areas are differentiated and often show membranous, E-cadherin-bound b-catenin. Strikingly, also metastases show again a differentiated phenotype and lack nuclear b-catenin, indicating a regulatory role of the tumor environment for malignant progression. Based on the developmental functions of b-catenin and our data we propose, that the EMT-associated tumor cells at the invasive front act as "migrating cancer stem cells" which can re-differentiate and, depending on the range of dissemination, give raise to the primary carcinoma or metastases. In support of this hypothesis, we defined b-catenin target genes overexpressed in invading tumor cells: 1. A stem cell phenotype is supported by the b-catenin target genes hTERT and survivin. 2. Furthermore we identified target genes like uPA, MT1-MMP, and laminin5-g2 chain, which synergize to exert EMT and promigratory activity. We suggest that both primary tumors and metastases are derived from a pool of EMT-associated "migrating cancer stem cells" at the tumor host interface, which are defined by strong nuclear b-catenin accumulation and expression of its target genes. This gives these cells a feature, which drives malignant tumor progression including metastasis: the unusual combination of abilities allowing simultanously to migrate and behave as a cancer stem cell. Since ZEB1 might be the crucial mediator of EMT in tumor cells, it could be a promising therapeutic target to interfere with malignant tumor progression.