The role of chemokine/chemokine receptor systems in tumor progression of pancreatic ductal carcinoma
Final Report Abstract
In our studies we started off with a comparative screening of chemokines and chemokine receptors in PDAC cells, normal pancreata, LECs and BECs to reveal possible interactions between tumor cells and vessels mediated by the chemokine / chemokine receptor axis. Interesting candidate genes that were differentially expressed were further validated on protein level by immunohistochemistry, immunofluorescence and ELISA and were partly analyzed in functional assays. The subprojects based on this initial screening resulted in the following findings: The chemokine receptor CCR7 known to be a key molecule in the homing of T cells from peripheral tissues to lymph nodes has been validated by extensive in vitro and in vivo experiments to significantly promote the lymphatic spread of pancreatic cancer. - The expression of the CCR7 ligand CCL19 correlated with reduced lymph vessel invasion and nuclear CCL19 expression was found to be associated with longer patient survival compared with cytoplasmic CCL19 expression. This possible dual role of CCL19 expression in progression of PDACs may also be useful as a prognostic marker for pancreatic cancer. - In addition, our experiments showed that the two chemokines CCL24 and CCL26 were upregulated on mRNA and protein level in PDAC specimens compared with normal pancreatic tissues. These two chemokines may play a role in tumor immune evasion in PDACs by changing the Th1/Th2 tumor environment. - The comparative analysis of chemokine expression between blood and lymphatic endothelial cells revealed upregulation of CCL23 mRNA expression in blood endothelial cells which was verified on protein level by ELISA. An immunohistochemical screening for the CCL23 receptor CCR1 in various different tumors showed CCR1 expression in tumors that are prone to form blood-borne metastases like sarcomas indicating a possible mechanism for haematogenous spread. In migration assays CCR1 transduced HT-1080 sarcoma cells showed enhanced migration compared with mock control transduced cells when stimulated with CCL23. - When analyzing the CXCR2 expression in PDAC specimen and normal pancreatic tissues, CXCR2 expression was more abundant in normal pancreata than in tumor specimens. The CXCR2 ligands CXCL6, CXCL2 and CXCL1 were significantly downregulated in tumor cells. The interaction of RelA, senescence-associated cytokine response and CXCR2 are involved in tumor surveillance in PDAC.
