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CCL2 is critical for immunosuppression to promote cancer metastasis.
MedLine Citation:
PMID:  23143679     Owner:  NLM     Status:  Publisher    
We previously found that cancer metastasis is accelerated by immunosuppression during Snail-induced epithelial-to-mesenchymal transition (EMT). However, the molecular mechanism still remained unclear. Here, we demonstrate that CCL2 is a critical determinant for both tumor metastasis and immunosuppression induced by Snail(+) tumor cells. CCL2 is significantly upregulated in various human tumor cells accompanied by Snail expression induced by snail transduction or TGFβ treatment. The Snail(+) tumor-derived CCL2 amplifies EMT events in other cells including Snail(-) tumor cells and epithelial cells within tumor microenvironment. CCL2 secondarily induces Lipocalin 2 (LCN2) in the Snail(+) tumor cells in an autocrine manner. CCL2 and LCN2 cooperatively generate immunoregulatory dendritic cells (DCreg) having suppressive activity accompanied by lowered expression of costimulatory molecules such as HLA-DR but increased expression of immunosuppressive molecules such as PD-L1 in human PBMCs. The CCL2/LCN2-induced DCreg cells subsequently induce immunosuppressive CD4(+)FOXP3(+) Treg cells, and finally impair tumor-specific CTL induction. In murine established tumor model, however, CCL2 blockade utilizing the specific siRNA or neutralizing mAb significantly inhibits Snail(+) tumor growth and metastasis following systemic induction of anti-tumor immune responses in host. These results suggest that CCL2 is more than a chemoattractant factor that is the significant effector molecule responsible for immune evasion of Snail(+) tumor cells. CCL2 would be an attractive target for treatment to eliminate cancer cells via amelioration of tumor metastasis and immunosuppression.
Chie Kudo-Saito; Hiromi Shirako; Misa Ohike; Nobuo Tsukamoto; Yutaka Kawakami
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-11
Journal Detail:
Title:  Clinical & experimental metastasis     Volume:  -     ISSN:  1573-7276     ISO Abbreviation:  Clin. Exp. Metastasis     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8409970     Medline TA:  Clin Exp Metastasis     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Division of Cellular Signalling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan,
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