title: Exposure of tumor-associated macrophages to apoptotic MCF-7 cells promotes breast cancer growth and metastasis.
abstract: Tumor-associated macrophages (TAMs) have been found to be associated with the progression and metastasis of breast cancer. To clarify the mechanisms underlying the crosstalk between TAMs and cancer stem cells (CSCs) in breast cancer recurrence and metastasis, we used a co-culture model of macrophages and apoptotic human breast cancer cell line MCF-7 cells to investigate the effects of TAMs on MCF-7 in vitro and in vivo. Macrophages co-cultured with apoptotic MCF-7 had increased tumor growth and metastatic ability in a nude mouse transplantation assay. The macrophages exposed to apoptotic cells also induce an increase in the proportion of CD44+/CD24- cancer stem-like cells, as well as their proliferative ability accompanied with an increase in mucin1 (MUC1) expression. During this process, macrophages secreted increased amounts of interleukin 6 (IL-6) leading to increased phosphorylation of signal transducers and activators of transcription 3 (STAT3), which likely explains the increased transcription of STAT3 target genes such as TGF-β1 and HIF-1α. Our results indicate that when cancer cells endure chemotherapy induced apoptosis, macrophages in their microenvironment can then activate cancer stem cells to promote cancer growth and metastasis by secreting IL-6, which activates STAT3 phosphorylation to regulate the transcription of its downstream target genes.
authors.affiliation: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China. zhouna@bjmu.edu.cn.
authors.forename: Na
authors.initials: N
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China. onepiecezyz1989@gmail.com.
authors.forename: Yizhuang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China. xuehuizhang@bjmu.edu.cn.
authors.forename: Xuehui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Beijing N&N Genetech Company, Beijing 100082, China. tanlab232@gmail.com.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lei
authors.affiliation: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China. huruobi@bjmu.edu.cn.
authors.forename: Ruobi
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China. lihui@bjmu.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China. maoyiqing@bjmu.edu.cn.
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China. xixi1125@bjmu.edu.cn.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China. david.irwin@utoronto.ca.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada. david.irwin@utoronto.ca.
authors.forename: David M
authors.initials: DM
authors.lastname: Irwin
authors.affiliation: Beijing N&N Genetech Company, Beijing 100082, China. 59023@bjmu.edu.cn.
authors.forename: Gang
authors.initials: G
authors.lastname: Niu
authors.affiliation: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China. tanlab@bjmu.edu.cn.
authors.forename: Huanran
authors.initials: H
authors.lastname: Tan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D061986:MCF-7 Cells; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D018396:Mucin-1 / Q000378:metabolism; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D015850:Interleukin-6; D018396:Mucin-1; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C577056:muc1 protein, mouse
keywords: IL-6; STAT3; TAMs; apoptosis; cancer stem cells; metastasis