Abstract
BackgroundTumor 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.MethodsPanc-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.ResultsCCR7 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.ConclusionsThese 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.
Highlights
Tumor metastasis is responsible for >90% of pancreatic cancer mortality
CCL21/chemokine receptor 7 (CCR7) promoted metastasis and survival of cluster of differentiation 133 (CD133)+ pancreatic cancer stem-like cells and regulated CD133+ pancreatic cancer stem-like cells metastasis by modulating Epithelial-mesenchymal transition (EMT) and Extracellular-signal regulated kinase (Erk)/NFκB pathway. These results indicate a specific role for CCL21/CCR7 in promoting EMT and metastasis in CD133+ pancreatic cancer stem-like cells
After 3 days, the purity of CD133+ was 91.84% and 14.73%, respectively (Fig 1A).To confirm that CD133+ cell fractions were enriched in Cancer stem cells (CSCs), we quantified octamer-binding transcription factor-4 (Oct-4) and sry-related HMG box-containing (Sox2) mRNA levels in cells by real time-quantitative polymerase chain reaction (RT-qPCR)
Summary
Extensive research has determined that metastasis involves several steps, including invasion of adjacent tissues, generation of circulating tumor cells (CTCs), intravasation in blood or lymphatic vessels, survival in the vasculature, and extravasation and growth at secondary sites [1, 2]. In the context of cancer, EMT facilitates the dissemination of cancer cells and endows them with properties essential for metastasis, including stemness, invasiveness, and the ability to survive in the circulation and seed at secondary site. Seminal work demonstrated that EMT generates mesenchymal-like cells with properties associated with CSCs [11], and the abilities of epithelial cancer cells to undergo EMT and acquire CSC properties are believed to play critical roles in metastasis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
