Abstract
BackgroundCC-chemokine receptor 7 (CCR7), a known lymph node homing receptor for immune cells, has been reported as a key molecule in lymph node metastasis. We hypothesized a clinicopathological correlation and functional causality between CCR7 expression and lymph node metastasis in patients with esophageal squamous cell carcinoma (ESCC).MethodsWe performed immunohistochemical analysis of 105 consecutive and 61 exclusive pathological T1 ESCC patients, followed by adhesion assay and in vivo experiment using a newly developed lymph node metastasis mouse model. The adhesive ability in response to CC-chemokine ligand 21/secondary lymphoid-tissue chemokine (CCL21/SLC) was assessed in the presence or absence of lymphatic endothelial cells and anti-CCR7 antibody. We established a heterotopic transplantation mouse model and analyzed lymph node metastasis by quantitative real-time RT-PCR.ResultsPositive CCR7 expression in immunohistochemistory was detected in 28 (27%) of 105 consecutive patients and 17 (28%) of 61 T1 patients, which significantly correlated with lymph node metastasis (p = 0.037 and p = 0.040, respectively) and poor five-year survival (p = 0.013 and p = 0.012, respectively). Adhesion assay revealed an enhanced adhesive ability of CCR7-expressing cells in response to CCL21/SLC, in particular, in the presence of lymphatic endothelial cells (p = 0.005). In the mouse model, lymph nodes from mice transplanted with CCR7-expressing cells showed significantly higher DNA levels at 5 weeks (p = 0.019), indicating a high metastatic potential of CCR7-expressing cells.ConclusionThese results demonstrated the significant clinicopathological relationship and functional causality between CCR7 expression and lymph node metastasis in ESCC patients.
Highlights
CC-chemokine receptor 7 (CCR7), a known lymph node homing receptor for immune cells, has been reported as a key molecule in lymph node metastasis
A report by Müller et al yielded important and noteworthy findings [7]. They found that the interaction between a chemokine and its corresponding chemokine receptor had a critical role in organ-specific cancer metastasis and they suggested that the CC-chemokine receptor 7 (CCR7) and CC-chemokine ligand 21/secondary lymphoid-tissue chemokine (CCL21/ SLC) axis might be responsible for lymph node metastasis
We tested whether the correlation was applicable to early stage esophageal squamous cell carcinoma (ESCC), because ESCC often leads to early lymph node metastasis when compared with other solid gastrointestinal cancers
Summary
CC-chemokine receptor 7 (CCR7), a known lymph node homing receptor for immune cells, has been reported as a key molecule in lymph node metastasis. A report by Müller et al yielded important and noteworthy findings [7]. They found that the interaction between a chemokine and its corresponding chemokine receptor had a critical role in organ-specific cancer metastasis and they suggested that the CC-chemokine receptor 7 (CCR7) and CC-chemokine ligand 21/secondary lymphoid-tissue chemokine (CCL21/ SLC) axis might be responsible for lymph node metastasis. CCR7 has been shown to be a homing receptor that controls the migration of immune cells to secondary lymphoid tissue organs in response to CCL21/SLC. Müller et al demonstrated that this cell homing mechanism applied to CCR7-expressing cancer cells, allowing lymph node metastasis to be established as a consequence
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