title: CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells.
abstract: 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.
authors.affiliation: Division of Tumor Cell Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, California 91010, USA.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tsuyada
authors.forename: Amy
authors.initials: A
authors.lastname: Chow
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.forename: Peiguo
authors.initials: P
authors.lastname: Chu
authors.forename: Sofia
authors.initials: S
authors.lastname: Loera
authors.forename: Thehang
authors.initials: T
authors.lastname: Luu
authors.forename: Arthur Xuejun
authors.initials: AX
authors.lastname: Li
authors.forename: Xiwei
authors.initials: X
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Ye
authors.forename: Shiuan
authors.initials: S
authors.lastname: Chen
authors.forename: Weiying
authors.initials: W
authors.lastname: Zhou
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Yuan-Zhong
authors.initials: YZ
authors.lastname: Wang
authors.forename: Xiubao
authors.initials: X
authors.lastname: Ren
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Peggy
authors.initials: P
authors.lastname: Scherle
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kuroki
authors.forename: Shizhen Emily
authors.initials: SE
authors.lastname: Wang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002450:Cell Communication; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000502:physiology*; D009930:Organic Chemicals; D010641:Phenotype; D051881:Receptor, Notch1 / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C497762:Notch1 protein, mouse; D009930:Organic Chemicals; C451241:PKH67; D051881:Receptor, Notch1; D050796:STAT3 Transcription Factor