CCL21/CCR7 Axis Contributed to CD133(+) Pancreatic Cancer Stem-Like Cell Metastasis via EMT and Erk/NF-κB Pathway

BACKGROUND: Tumor metastasis is driven by malignant cells and stromal cell components of the tumor microenvironment. Cancer stem cells (CSCs) are thought to be responsible for metastasis by altering the tumor microenvironment. Epithelial-mesenchymal transition (EMT) processes contribute to specific stages of the metastatic cascade, promoted by cytokines and chemokines secreted by stromal cell components in the tumor microenvironment. C-C chemokine receptor 7 (CCR7) interacts with its ligand, chemokine ligand 21(CCL21), to mediate metastasis in some cancer cells lines. This study investigated the role of CCL21/CCR7 in promoting EMT and metastasis of cluster of differentiation 133(+) (CD133(+)) pancreatic cancer stem-like cells. METHODS: Panc-1, AsPC-1, and MIA PaCa-2 pancreatic cancer cells were selected because of their aggressive invasive potentials. CCR7 expression levels were examined in total, CD133(+) and CD133(−) cell fractions by Immunofluorescence analysis and real time-quantitative polymerase chain reaction (RT-qPCR). The role of CCL21/CCR7 in mediating metastasis and survival of CD133(+) pancreatic cancer stem-like cells was detected by Transwell assays and flow cytometry, respectively. EMT and lymph node metastasis related markers (E-cadherin, N- cadherin, LYVE-1) were analyzed by western blot. CCR7 expression levels were analyzed by immunohistochemical staining and RT-qPCR in resected tumor tissues, metastatic lymph nodes, normal lymph nodes and adjacent normal tissues from patients with pancreatic carcinoma. RESULTS: CCR7 expression was significantly increased in CD133(+) pancreatic cancer stem-like cells, resected pancreatic cancer tissues, and metastatic lymph nodes, compared with CD133(−) cancer cells, adjacent normal tissues and normal lymph nodes, respectively. CCL21/CCR7 promoted metastasis and survival of CD133(+) pancreatic cancer stem-like cells and regulated CD133(+) pancreatic cancer stem-like cells metastasis by modulating EMT and Erk/NF-κB pathway. CONCLUSIONS: These results indicate a specific role for CCL21/CCR7 in promoting EMT and metastasis in CD133(+) pancreatic cancer stem-like cells. Furthermore the data also indicated the potential importance of developing therapeutic strategies targeting cancer stem-like cells and CCL21/CCR7 for reducing metastasis.