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


CONCLUSIONS
These results demonstrated the significant clinicopathological relationship and functional causality between CCR7 expression and lymph node metastasis in ESCC patients.
Tomoyuki
T
Irino
Department of Surgery, Keio University School of Medicine, 35, Shinanomachi, Shinjuku-ku Tokyo 160-8582, Japan. htakeuchi@a6.keio.jp.
Hiroya
H
Takeuchi
Sachiko
S
Matsuda
Yoshiro
Y
Saikawa
Hirofumi
H
Kawakubo
Norihito
N
Wada
Tsunehiro
T
Takahashi
Rieko
R
Nakamura
Kazumasa
K
Fukuda
Tai
T
Omori
Yuko
Y
Kitagawa
D000328:Adult; D000368:Aged; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D054421:Chemokine CCL21 / Q000096:biosynthesis / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology*; D008207:Lymphatic Metastasis / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D054400:Receptors, CCR7 / Q000096:biosynthesis* / Q000235:genetics; D016042:Transplantation, Heterotopic
C515478:CCL21 protein, human; D054421:Chemokine CCL21; D054400:Receptors, CCR7