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      CCL2 mediates crosstalk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells

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          Abstract

          Cancer stem cells (CSCs) 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 (BC) stem cells. We found that compared to normal fibroblasts, primary cancer-associated fibroblasts (CAFs) and fibroblasts activated by co-cultured BC cells produce higher levels of chemokine (C-C motif) ligand 2 (CCL2), which stimulates the stem cell-specific, sphere-forming phenotype in BC cells and CSC self-renewal. Increased CCL2 expression in activated fibroblasts required STAT3 activation by diverse BC-secreted cytokines, and in turn, induced NOTCH1 expression and the CSC features in BC cells, constituting a “cancer-stroma-cancer” signaling circuit. In a xenograft model of paired fibroblasts and BC 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 BCs, 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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          Author and article information

          Journal
          2984705R
          2786
          Cancer Res
          Cancer Res.
          Cancer Research
          0008-5472
          1538-7445
          23 April 2012
          03 April 2012
          1 June 2012
          01 June 2013
          : 72
          : 11
          : 2768-2779
          Affiliations
          [1 ]Division of Tumor Cell Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California
          [2 ]Division of Comparative Medicine, City of Hope Beckman Research Institute and Medical Center, Duarte, California
          [3 ]Department of Medical Oncology, City of Hope Beckman Research Institute and Medical Center, Duarte, California
          [4 ]Department of Pathology, City of Hope Beckman Research Institute and Medical Center, Duarte, California
          [5 ]Department of Information Science, City of Hope Beckman Research Institute and Medical Center, Duarte, California
          [6 ]Department of Bioinformatics Core Facility, City of Hope Beckman Research Institute and Medical Center, Duarte, California
          [7 ]Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan
          [8 ]Graduate School of Medicine, Sapporo Medical University, Sapporo, Japan
          [9 ]Department of Immunology & Biotherapy, Tianjin Cancer Hospital, Tianjin, China
          [10 ]Incyte Corporation, Wilmington, Delaware
          Author notes
          Corresponding author: S. Emily Wang ( ewang@ 123456coh.org ), Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, 1500 E Duarte Road, KCRB Room 2007; Duarte, CA 91010, U.S.A., TEL: 1-626-2564673 x63118; FAX: 1-626-3018972
          Article
          PMC3367125 PMC3367125 3367125 nihpa368945
          10.1158/0008-5472.CAN-11-3567
          3367125
          22472119
          16f864da-8768-4dbe-80d1-8888a98282e7
          History
          Funding
          Funded by: National Cancer Institute : NCI
          Award ID: R00 CA125892-06 || CA
          Funded by: National Cancer Institute : NCI
          Award ID: R00 CA125892-05 || CA
          Funded by: National Cancer Institute : NCI
          Award ID: R00 CA125892-04S1 || CA
          Funded by: National Cancer Institute : NCI
          Award ID: R00 CA125892-04 || CA
          Categories
          Article

          tumor microenvironment,breast cancer,cancer stem cells,chemokine (C-C motif) ligand 2,stromal fibroblasts

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