Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells

By Mei Yang, Jingqi Chen, F. Su, Bin Yu, F. Su, Ling Lin, Yujie Liu, Jian-Dong Huang, E. Song. Molecular Cancer, 2011

680 citations recorded by the source corpus.

BackgroundTumor-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.ResultsWe 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.ConclusionsWe 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.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1db227dd3eac8d2ef3cb320de2e9856a85793bef

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Citations in the corpus

Macrophages in Tumor Microenvironments and the Progression of Tumors (2012, background): “miR-233-regulating tumor invasion is considered to work through the mef2c-βcatinen pathway [74].”
Stroma Cells in Tumor Microenvironment and Breast Cancer (2012, positive): “Another study found that macrophages activated by IL-4 also regulate the invasiveness of breast cancer cells through exosome-mediated delivery of oncogenic miR-223 via the Mef2c/β-catenin pathway [111].”
Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018, background): “Secretion of miRNAs via exosomes have also been reported to be regulated by signaling molecules, such as interleukin-4 (IL4) (132) and Docosahexaenoic acid (DHA) (133).”
Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. (2012, background): “miR-223 can bind to target sites in the 3′-UTR of Mef2c (66), causing an increased accumulation of b-catenin in the nuclei of breast cancer cells to encourage local invasion (67).”
The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses (2020, background): “However, exosomes released by stromal cells such as TAMs and CAFs can elicit tumor invasion and metastasis via miR-223, miR21, miR-143, and miR-378e (154, 206).”
New horizons in tumor microenvironment biology: challenges and opportunities (2015, background): “The miRNAs can also be transmitted from stroma cells to cancer cells as exemplified by microvesicledelivered miR-223, which is highly expressed in IL-4activated TAMs but not in breast cancer cells and which, upon transmission from TAMs to cocultured cancer cells, promotes tumor invasion and metastas”
Exosomes in cancer: small particle, big player (2015, background): “miR-223 IL-4-activated macrophages Breast cancer cells Promotes cell invasion [44]”
Exosome-Mediated Transfer of miR-133b from Multipotent Mesenchymal Stromal Cells to Neural Cells Contributes to Neurite Outgrowth (2012, neutral): “Exosomes act as mediators of cell-cell communication [55–58] and are carriers for functional miRNA delivery [5, 6, 59].”
Exosomes in Cancer Development, Metastasis and Drug Resistance: A Comprehensive Review (2013, positive): “In relation to tumors, in a breast model, Yang and colleagues showed that exosome-secreted miRNAs enhance the invasive potential of breast cancer cell lines [130].”