The chemokine crosstalk at the 'tumor-vessel interface'
Final Report Abstract
During the funding period of the priority research programme 1190, we concentrated our scientific research on unraveling bi-directional communication pathways between tumors and their microenvironment. Amongst other factors, these pathways are facilitated by chemokines, small-cytokine like molecules with a role in cell motility and organ-specific metastasis. It was known that several chemokines play a role in angiogenesis, either as facilitators or inhibitors. But the analysis of the chemokine receptor repertoire of ECs was hitherto incomplete and not necessarily focused on cells of a microvascular origin. For the first time, we analyzed the chemokine receptor repertoire of primary microvascular ECs, which comprise the first target for angiogenic agents produced by the tumor. Our analysis showed that microvascular ECs express a wide variety of chemokine receptors. We identified that CCL20 the corresponding chemokine to one of these receptors, namely CCR6, is abundantly expressed by tumor cells in an EGFR-dependent manner. Interestingly, CCL20 expression correlated to tumor progression, metastasis and survival rates. In further in vitro experiments, it was established that CCL20 acted as a pro-angiogenic factor on ECs. This observation could be further corroborated in in vivo experiments utilizing matrigel plugs and syngeneic tumor models in CCR6-/--mice. The reduced tumor growth in CCR6-/--mice bearing a CCR6+/+ immune system, accompanied by a lesser tumor vessel density observed in CCR6-/--mice, suggests that the role of CCR6 in the tumor microenvironment of CCL20-expressing tumor entities, including melanoma, breast cancer, colon carcinoma and head and neck squamous cell carcinoma, has a higher impact on tumor progression than its role in immune cell recruitment. Further research will determine, if blockade of CCL20 action in the tumor microenvironment could be a viable point of action for future multipronged anti-tumor therapies, e.g. combining classical chemotherapy/radiotherapy, EGFR inhibition and blockade of chemokine action. Furthermore, we could identify that the homeostatic, skin-specific chemokine CCL27, which is acting as a recruitment factor for CCR10-positive skin homing T cells, is responsible for maintaining a strong immune surveillance against malignant cells. Expression of CCL27 is lost during skin carcinogenesis in an EGFR-dependent manner leading to immune escape of the nascent tumor. Inhibition of CCL27 in in vivo tumor models presented with more progressive and malignant, e.g. metastasizing, tumors. In skin tumor therapy, EGFR inhibition might present a rational approach not only by downregulation of tumor growth factors, but also by upregulation of factors enhancing tumor immune response.
