| CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. | |
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MedLine Citation:
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PMID: 22472119 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cancer stem cells (CSC) play critical roles in cancer initiation, progression, and therapeutic refractoriness. Although many studies have focused on the genes and pathways involved in stemness, characterization of the factors in the tumor microenvironment that regulate CSCs is lacking. In this study, we investigated the effects of stromal fibroblasts on breast cancer stem cells. We found that compared with normal fibroblasts, primary cancer-associated fibroblasts (CAF) and fibroblasts activated by cocultured breast cancer cells produce higher levels of chemokine (C-C motif) ligand 2 (CCL2), which stimulates the stem cell-specific, sphere-forming phenotype in breast cancer cells and CSC self-renewal. Increased CCL2 expression in activated fibroblasts required STAT3 activation by diverse breast cancer-secreted cytokines, and in turn, induced NOTCH1 expression and the CSC features in breast cancer cells, constituting a cancer-stroma-cancer signaling circuit. In a xenograft model of paired fibroblasts and breast cancer tumor cells, loss of CCL2 significantly inhibited tumorigenesis and NOTCH1 expression. In addition, upregulation of both NOTCH1 and CCL2 was associated with poor differentiation in primary breast cancers, further supporting the observation that NOTCH1 is regulated by CCL2. Our findings therefore suggest that CCL2 represents a potential therapeutic target that can block the cancer-host communication that prompts CSC-mediated disease progression. |
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Authors:
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Akihiro Tsuyada; Amy Chow; Jun Wu; George Somlo; Peiguo Chu; Sofia Loera; Thehang Luu; Arthur Xuejun Li; Xiwei Wu; Wei Ye; Shiuan Chen; Weiying Zhou; Yang Yu; Yuan-Zhong Wang; Xiubao Ren; Hui Li; Peggy Scherle; Yukio Kuroki; Shizhen Emily Wang |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-04-03 |
Journal Detail:
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Title: Cancer research Volume: 72 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2012 Jun |
Date Detail:
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Created Date: 2012-06-04 Completed Date: 2012-08-10 Revised Date: 2013-06-06 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 2768-79 Citation Subset: IM |
Copyright Information:
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©2012 AACR |
Affiliation:
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Division of Tumor Cell Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California 91010, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Breast Neoplasms / pathology* Cell Communication* Cell Line, Tumor Chemokine CCL2 / physiology* Female Fibroblasts / physiology* Humans Mice Neoplastic Stem Cells / physiology* Organic Chemicals / diagnostic use Phenotype Receptor, Notch1 / physiology STAT3 Transcription Factor / physiology Signal Transduction |
| Grant Support | |
ID/Acronym/Agency:
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P30 CA033572/CA/NCI NIH HHS; R00 CA125892/CA/NCI NIH HHS; R00 CA125892/CA/NCI NIH HHS; R00 CA125892-04/CA/NCI NIH HHS; R00 CA125892-04S1/CA/NCI NIH HHS; R00 CA125892-05/CA/NCI NIH HHS; R00 CA125892-06/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Ccl2 protein, mouse; 0/Chemokine CCL2; 0/Notch1 protein, mouse; 0/Organic Chemicals; 0/PKH67; 0/Receptor, Notch1; 0/STAT3 Transcription Factor |
| Comments/Corrections | |
Comment In:
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Cancer Res. 2013 Jan 15;73(2):1031
[PMID:
23316034
]
Cancer Res. 2013 Jan 15;73(2):1032-3 [PMID: 23316033 ] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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