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Beta-6-integrin in colorectal carcinoma: patho-functions and perspectives as a therapeutic target

Subject Area Gastroenterology
Term from 2020 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 437201724
 
Final Report Year 2024

Final Report Abstract

In patients with colorectal cancer (CRC), distant metastasis is the most important cause of death. Consequently, the question of the mechanisms of metastasis is of great clinical relevance. Our own previous work has shown that integrin-β6 (ITGB6) could play an important role in this process. The aim of the present project was to elucidate the molecular mechanisms of ITGB6 action in CRC metastasis, with the ultimate goal of providing new approaches for the therapeutic treatment of metastatic CRC. The project identified two important mechanisms of ITGB6 action. 1) We found that ITGB6 on the surface of tumor cells controls their attachment to endothelial cells in the target organs of the metastasis. This occurs via the binding of ITGB6 to fibronectin on the cell surface of endothelial cells. Interestingly, ITGB6 is proteolysis-resistant on the surface of tumor cells, which means that the ITGB6- mediated adhesion function is not affected in malignant tumors, which often have increased proteolytic activity. ITGB6-mediated attachment of tumor cells to endothelial cells can be efficiently blocked by various soluble competitors. 2) We detected that ITGB6 contributes to the immune evasion of tumor cells via the activation of latent TGF-β and that the immune reactivity against corresponding tumors can be significantly enhanced by inhibiting ITGB6. Both findings have very good prospects for translation into clinical application because ITGB6 can be efficiently inhibited by soluble molecules. For analyses of the ITGB6-associated immune micro-environment in CRC tumor models a rapid and efficient semi-quantitative PCR-based detection system for the analysis of various immune cells in mice was established. In addition, a flow model for analyzing the interaction of tumor cells with endothelial cells was successfully established. The aforementioned methodological developments enabled numerous further collaborative projects in the areas of CRC and inflammatory bowel disease. Various data quality measures were implemented: 1) data documentation by means of an electronic laboratory notebook, 2) reproduction of the central results by another member of staff and 3) the indication of Research Resorts Identifiers in publications.

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