251 : The role of chemokine receptor CCR7 and Its ligands CCL19 and CCL21 in tumor progression of pancreatic ductal adenocarcinoma

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• 作者：Jan Sperveslage ; Sunna Frank ; Carola Heneweer ; Jan Egberts ; Bodo Schniewind ; Malte Buchholz ; Frank Bergmann ; Nathalia Giese ; Johanna Munding ; Stephan Hahn ; Holger Kalthoff ; Guenter Kloeppel ; Bence Sipos
• 刊名：Cytokine
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：63
• 期：3
• 页码：302
• 全文大小：40 K

文摘

Pancreatic ductal adenocarcinoma (PDAC) representing one of the most aggressive human neoplasms has a high potential to metastasize to lymph nodes and to the liver. The goal of this study was to define the significance of chemokines/chemokine receptors for the invasion of PDAC cells into lymph vessels and for the formation of lymph nodes metastases. The role of the chemokine receptor CCR7 in the lymphatic spread of PDAC was evaluated in extensive in vitro and in vivo experiments. CCR7 was expressed in all analyzed PDAC cell lines at the mRNA level. FACS analysis revealed low constitutive CCR7 protein expression of monolayer cultures that could be upregulated up to 70 % depending on the PDAC cell line by culturing the cells as spheroids. In migration assays pancreatic carcinoma PT45P1 and BxPc3 cells from spheroid cultures and PT45P1 cells transfected with CCR7 showed enhanced migration towards the two ligands CCL19 and CCL21. This chemotactic effect could be inhibited by neutralizing antibodies against CCL19, CCL21 and CCR7. In a nude mouse model, orthotopically injected CCR7 transfected PT45P1 cells gave rise to significantly larger tumors and showed a higher frequency of lymph node metastases than mock transfected cells. The analysis of immunofluorescence stains showed a significant upregulation of CCL21 in peritumoral and intratumoral lymph vessels compared with lymph vessels in disease-free human pancreata. Immunhistochemial stains of PDAC specimens revealed a correlation of CCL19 expression with reduced lymph vessel invasion. Interestingly, nuclear CCL19 expression was found to be associated with longer patient survival compared with cytoplasmic CCL19 expression. Moderate-to-strong immunohistochemical CCR7 expression, found in 58/121 well-characterized human PDACs, correlated with high rates of lymph vessel invasion. Conversely, PDACs completely lacking CCR7 expression showed only low rates of lymph vessel invasion and lymph node metastases. In conclusion, CCR7 expression significantly promotes lymphatic spread in PDAC.