| CCL2 is critical for immunosuppression to promote cancer metastasis. | |
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MedLine Citation:
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PMID: 23143679 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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Chie Kudo-Saito; Hiromi Shirako; Misa Ohike; Nobuo Tsukamoto; Yutaka Kawakami |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-11-11 |
Journal Detail:
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Title: Clinical & experimental metastasis Volume: - ISSN: 1573-7276 ISO Abbreviation: Clin. Exp. Metastasis Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-12 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8409970 Medline TA: Clin Exp Metastasis Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Division of Cellular Signalling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan, kudoc@a3.keio.jp. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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