title: Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells.
abstract: BACKGROUND
  Tumor-associated macrophages (TAMs) are alternatively activated cells induced by interleukin-4 (IL-4)-releasing CD4+ T cells. TAMs promote breast cancer invasion and metastasis; however, the mechanisms underlying these interactions between macrophages and tumor cells that lead to cancer metastasis remain elusive. Previous studies have found microRNAs (miRNAs) circulating in the peripheral blood and have identified microvesicles, or exosomes, as mediators of cell-cell communication. Therefore, one alternative mechanism for the promotion of breast cancer cell invasion by TAMs may be through macrophage-secreted exosomes, which would deliver invasion-potentiating miRNAs to breast cancer cells.
  
  
  RESULTS
  We utilized a co-culture system with IL-4-activated macrophages and breast cancer cells to verify that miRNAs are transported from macrophages to breast cancer cells. The shuttling of fluorescently-labeled exogenous miRNAs from IL-4-activated macrophages to co-cultivated breast cancer cells without direct cell-cell contact was observed. miR-223, a miRNA specific for IL-4-activated macrophages, was detected within the exosomes released by macrophages and was significantly elevated in the co-cultivated SKBR3 and MDA-MB-231 cells. The invasiveness of the co-cultivated breast cancer cells decreased when the IL-4-activated macrophages were treated with a miR-223 antisense oligonucleotide (ASO) that would inhibit miR-223 expression. Furthermore, results from a functional assay revealed that miR-223 promoted the invasion of breast cancer cells via the Mef2c-β-catenin pathway.
  
  
  CONCLUSIONS
  We conclude that macrophages regulate the invasiveness of breast cancer cells through exosome-mediated delivery of oncogenic miRNAs. Our data provide insight into the mechanisms underlying the metastasis-promoting interactions between macrophages and breast cancer cells.
authors.affiliation: Breast Tumor Center, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou, PR China.
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.forename: Jingqi
authors.initials: J
authors.lastname: Chen
authors.forename: Fang
authors.initials: F
authors.lastname: Su
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.forename: Fengxi
authors.initials: F
authors.lastname: Su
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.forename: Yujie
authors.initials: Y
authors.lastname: Liu
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Huang
authors.forename: Erwei
authors.initials: E
authors.lastname: Song
mesh_terms: D020413:3' Untranslated Regions; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology / Q000502:physiology; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D026161:MADS Domain Proteins / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D015847:Interleukin-4; D049410:Luciferases, Renilla; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D035683:MicroRNAs; D018006:Myogenic Regulatory Factors; D051176:beta Catenin; C578040:MEF2C protein, human; C525067:MIR223, human