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Open Access Research article

CC-Chemokine receptor CCR7: a key molecule for lymph node metastasis in esophageal squamous cell carcinoma

Tomoyuki Irino, Hiroya Takeuchi*, Sachiko Matsuda, Yoshiro Saikawa, Hirofumi Kawakubo, Norihito Wada, Tsunehiro Takahashi, Rieko Nakamura, Kazumasa Fukuda, Tai Omori and Yuko Kitagawa

Author Affiliations

Department of Surgery, Keio University School of Medicine, 35, Shinanomachi, Shinjuku-ku Tokyo 160-8582, Japan

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BMC Cancer 2014, 14:291  doi:10.1186/1471-2407-14-291

Published: 26 April 2014

Abstract

Background

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. We hypothesized a clinicopathological correlation and functional causality between CCR7 expression and lymph node metastasis in patients with esophageal squamous cell carcinoma (ESCC).

Methods

We 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.

Results

Positive 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.

Conclusion

These results demonstrated the significant clinicopathological relationship and functional causality between CCR7 expression and lymph node metastasis in ESCC patients.

Keywords:
Chemokine; CCL21; Chemokine receptor; CCR7; Esophageal squamous cell carcinoma