Metastasis is the main reason for poor patients prognosis and high cancer mortality. To invasively migrate into the surrounding tissue and to disseminate to a remote organ, tumor cells have to change their epithelial phenotype into a mesenchymal phenotype via a process called epithelial-to-mesenchymal transition (EMT). To generate a solid metastasis, disseminated tumor cells must proliferate and resume the epithelial phenotype via the opposite process of mesenchymal-to-epithelial transition (MET). Little is known about the EMT/MET regulation, and means to inhibit them are under intense investigation. The tumor microenvironment (TME), containing different cell types (e.g., immune cells), plays a decisive role during descripted processes. Two transmembranal proteins, EMMPRIN and Connexin 43 (Cx43), have been implicated in metastasis, and are associated with significant prognostic impact in various tumor entities. Existing data and our own results indicate, that both proteins may be involved in EMT/MET regulation by mediating interactions between tumor cells and tumor-associated macrophages (TAMs). We hypothesize that cytokines that induce EMT oppositely regulate the expression of these two proteins in early and late stages of metastasis. We propose to investigate the effects of TAMs and cytokines secreted by TAMs on the EMMPRIN/Cx43 expression, and to correlate it to the expression of known EMT/MET markers, to ascertain whether combined EMMPRIN/Cx43 expression profiles can be used as clinical marker of the EMT/MET axis and patients prognosis. To explore whether EMMPRIN and/or Cx43 regulate the expression of each other or of other EMT/MET markers, we will overexpress Cx43 and knock down EMMPRIN expression in vitro. These transfected cell lines will be implanted in vivo in the chick embryo chorioallantoic membrane (CAM) model and in athymic BALB/c mice and will be compared to their parental cells. The results of our functional studies will then be verified on human tissue samples of a representative cohort of patients suffering from oral squamous cell carcinoma (OSCC). Lastly, we will target EMMPRIN expression using the human anti-EMMPRIN monoclonal antibody we developed (h161-mAb) to examine its potential as a new therapeutic option to improve patient prognosis and reduce cancer induced mortality.
The presented project is being carried out in cooperation with the Immunotherapy Laboratory of the Carmel Medical Center in Haifa, Israel, and with the Institute of Pathology of the University Medical Center Göttingen.