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Cited by 374Extracellular vesicles in diseaseMicroRNA in disease regulationImmune cells in cancer

Macrophages derived exosomes deliver miR-223 to epithelial ovarian cancer cells to elicit a chemoresistant phenotype

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Zhu, Xiaolan, Shen, Huiling, Yin, Xinming, Yang, Meiling, Wei, Hong, Chen, Qi, Feng, Fan, Liu, Yueqin +2 more·2019·Journal of Experimental & Clinical Cancer Research
DOI 10.1186/s13046-019-1095-1PMC PMC6377760
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Abstract

BACKGROUND: How exosomal microRNAs (miRNAs) derived from macrophages contribute to the development of drug resistance in the context of the hypoxic tumor microenvironment in epithelial ovarian cancer (EOC) remains poorly understood. METHODS: The miRNA levels were detected by qRT-PCR. Protein levels of HIF-1α, CD163 and PTEN-PI3K/AKT pathway were assessed by Western blot (WB) and Immunohistochemistry (IHC). Exosomes were isolated, and then confirmed by Transmission electron microscopy (TEM), Nanoparticle Tracking Analysis (NTA) and WB. Internalization of macrophages-secreted exosomes in EOC cells was detected by Confocal microscope. Subsequently, Dual-luciferase reporter assay verified PTEN was the target of miR-223. Gain- and loss-of-function experiments, rescue experiments, and SKOV3 xenograft models were performed to uncover the underlying mechanisms of miR-223 and PTEN-PI3K/AKT pathway, as well as the exosomal miR-223 in inducing multidrug resistance in vitro and in vivo. RESULTS: Here, we showed hypoxic EOC cells triggered macrophages recruitment and induced macrophages into a tumor-associated macrophage (TAM)-like phenotype; exosomes derived from hypoxic macrophages enhanced the malignant phenotype of EOC cells, miR-223 was enriched in exosomes released from macrophages under hypoxia, which could be transferred to the co-cultivated EOC cells, accompanied by enhanced drug resistant of EOC cells. Besides, results from a functional assay revealed that exosomal miR-223 derived from macrophages promoted the drug resistance of EOC cells via the PTEN-PI3K/AKT pathway both in vivo and in vitro. Furthermore, patients with high HIF-1a expression had statistically higher CD163+ cell infiltration and intertumoral levels of miR-223. Finally, circulating exosomal miR-223 levels were closely related to the recurrence of EOC. CONCLUSIONS: These data indicate a unique role of exosomal miR-223 in the cross-talk between macrophages and EOC cells in chemotherapy resistance, through a novel exosomal miR-223/PTEN-PI3K/AKT signaling pathway.

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  1. [1]Liu D Zhang XX Li MC Cao CH Wan DY Xi BX C/EBPbeta enhances platinum resistance of ovarian cancer cells by reprogramming H3K79 methylation Nat Commun 2018 9 1739 10.1038/s41467-018-03590-5 29712898 PMC5928165 · DOI
  2. [2]Koelwyn GJ Quail DF Zhang X White RM Jones LW Exercise-dependent regulation of the tumour microenvironment Nat Rev Cancer 2017 17 620 632 10.1038/nrc.2017.78 28943640 · DOI
  3. [3]Welford AF Biziato D Coffelt SB Nucera S Fisher M Pucci F TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice J Clin Invest 2011 121 1969 1973 10.1172/JCI44562 21490397 PMC3083764 · DOI
  4. [4]Brown JM Recht L Strober S The promise of targeting macrophages in Cancer therapy Clin Cancer Res 2017 23 3241 3250 10.1158/1078-0432.CCR-16-3122 28341752 PMC5529121 · DOI
  5. [5]Squadrito ML Etzrodt M De Palma M Pittet MJ MicroRNA-mediated control of macrophages and its implications for cancer Trends Immunol 2013 34 350 359 10.1016/j.it.2013.02.003 23498847 PMC3700601 · DOI
  6. [6]Wen Z Liu H Li M Li B Gao W Shao Q Increased metabolites of 5-lipoxygenase from hypoxic ovarian cancer cells promote tumor-associated macrophage infiltration Oncogene 2015 34 1241 1252 10.1038/onc.2014.85 24662827 · DOI
  7. [7]DeNardo DG Brennan DJ Rexhepaj E Ruffell B Shiao SL Madden SF Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy Cancer Discov 2011 1 54 67 10.1158/2159-8274.CD-10-0028 22039576 PMC3203524 · DOI · Paper page
  8. [8]Na YR Je S Seok SH Metabolic features of macrophages in inflammatory diseases and cancer Cancer Lett 2018 413 46 58 10.1016/j.canlet.2017.10.044 29100962 · DOI
  9. [9]Song M Liu T Shi C Zhang X Chen X Bioconjugated manganese dioxide nanoparticles enhance chemotherapy response by priming tumor-associated macrophages toward M1-like phenotype and attenuating tumor hypoxia ACS Nano 2016 10 633 647 10.1021/acsnano.5b06779 26650065 PMC5242343 · DOI
  10. [10]Yogev O Henderson S Hayes MJ Marelli SS Ofir-Birin Y Regev-Rudzki N Herpesviruses shape tumour microenvironment through exosomal transfer of viral microRNAs PLoS Pathog 2017 13 e1006524 10.1371/journal.ppat.1006524 28837697 PMC5570218 · DOI
  11. [11]Pucci F Pittet MJ Molecular pathways: tumor-derived microvesicles and their interactions with immune cells in vivo Clin Cancer Res 2013 19 2598 2604 23426276 PMC3655093
  12. [12]King HW Michael MZ Gleadle JM Hypoxic enhancement of exosome release by breast cancer cells BMC Cancer 2012 12 421 10.1186/1471-2407-12-421 22998595 PMC3488584 · DOI · Paper page
  13. [13]Kucharzewska P Christianson HC Welch JE Svensson KJ Fredlund E Ringner M Morgelin M Bourseau-Guilmain E Bengzon J Belting M Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development Proc Natl Acad Sci U S A 2013 110 7312 7317 10.1073/pnas.1220998110 23589885 PMC3645587 · DOI · Paper page
  14. [14]Dorayappan KDP Wallbillich JJ Cohn DE Selvendiran K The biological significance and clinical applications of exosomes in ovarian cancer Gynecol Oncol 2016 142 199 205 10.1016/j.ygyno.2016.03.036 27058839 PMC4917458 · DOI
  15. [15]Dorayappan KDP Wanner R Wallbillich JJ Saini U Zingarelli R Suarez AA Hypoxia-induced exosomes contribute to a more aggressive and chemoresistant ovarian cancer phenotype: a novel mechanism linking STAT3/Rab proteins Oncogene 2018 37 3806 3821 10.1038/s41388-018-0189-0 29636548 PMC6043362 · DOI
  16. [16]Shurtleff MJ, Temoche-Diaz MM, Karfilis KV, Ri S, Schekman R. Y-box protein 1 is required to sort microRNAs into exosomes in cells and in a cell-free reaction. eLife.2016;5: pii: e19276. PMC5047747 27559612
  17. [17]Aucher A Rudnicka D Davis DM MicroRNAs transfer from human macrophages to hepato-carcinoma cells and inhibit proliferation J Immunol 2013 191 6250 6260 10.4049/jimmunol.1301728 24227773 PMC3858238 · DOI · Paper page
  18. [18]Laios A O'Toole S Flavin R Martin C Kelly L Ring M Potential role of miR-9 and miR-223 in recurrent ovarian cancer Mol Cancer 2008 7 35 10.1186/1476-4598-7-35 18442408 PMC2383925 · DOI
  19. [19]de Melo Maia B Rodrigues IS Akagi EM Soares do Amaral N Ling H Monroig P MiR-223-5p works as an oncomiR in vulvar carcinoma by TP63 suppression Oncotarget 2016 7 49217 49231 27359057 PMC5226502
  20. [20]Singh M Chaudhry P Fabi F Asselin E Cisplatin-induced caspase activation mediates PTEN cleavage in ovarian cancer cells: a potential mechanism of chemoresistance BMC Cancer 2013 13 233 10.1186/1471-2407-13-233 23663432 PMC3661380 · DOI
  21. [21]Frankson R Yu ZH Bai Y Li Q Zhang RY Zhang ZY Therapeutic targeting of oncogenic tyrosine phosphatases Cancer Res 2017 77 5701 5705 10.1158/0008-5472.CAN-17-1510 28855209 PMC5827927 · DOI · Paper page
  22. [22]Xia H Ooi LL Hui KM MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer Hepatology 2013 58 629 641 10.1002/hep.26369 23471579 · DOI
  23. [23]Zhu X Shen H Yin X Long L Xie C Liu Y miR-186 regulation of Twist1 and ovarian cancer sensitivity to cisplatin Oncogene 2016 35 323 332 10.1038/onc.2015.84 25867064 · DOI
  24. [24]O'Connell RM Taganov KD Boldin MP Cheng G Baltimore D MicroRNA-155 is induced during the macrophage inflammatory response Proc Natl Acad Sci U S A 2007 104 1604 1609 10.1073/pnas.0610731104 17242365 PMC1780072 · DOI · Paper page
  25. [25]Murdoch C Giannoudis A Lewis CE Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues Blood 2004 104 2224 2234 10.1182/blood-2004-03-1109 15231578 · DOI
  26. [26]Anderson JD Johansson HJ Graham CS Vesterlund M Pham MT Bramlett CS Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-KappaB signaling Stem Cells 2016 34 601 613 10.1002/stem.2298 26782178 PMC5785927 · DOI
  27. [27]Hsu YL Hung JY Chang WA Lin YS Pan YC Tsai PH Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1 Oncogene 2017 36 4929 4942 10.1038/onc.2017.105 28436951 · DOI
  28. [28]Valadi H Ekstrom K Bossios A Sjostrand M Lee JJ Lotvall JO Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells Nat Cell Biol 2007 9 654 659 10.1038/ncb1596 17486113 · DOI · Paper page
  29. [29]Semenza GL Hypoxia-inducible factors in physiology and medicine Cell 2012 148 399 408 10.1016/j.cell.2012.01.021 22304911 PMC3437543 · DOI · Paper page
  30. [30]Zhu C Mustafa D Zheng PP van der Weiden M Sacchetti A Brandt M Activation of CECR1 in M2-like TAMs promotes paracrine stimulation-mediated glial tumor progression Neuro-Oncology 2017 19 648 659 10.1093/neuonc/nox081 28453746 PMC5464467 · DOI
  31. [31]Priceman SJ Sung JL Shaposhnik Z Burton JB Torres-Collado AX Moughon DL Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy Blood 2010 115 1461 1471 10.1182/blood-2009-08-237412 20008303 PMC2826767 · DOI
  32. [32]Tripathi C Tewari BN Kanchan RK Baghel KS Nautiyal N Shrivastava R Macrophages are recruited to hypoxic tumor areas and acquire a pro-angiogenic M2-polarized phenotype via hypoxic cancer cell derived cytokines Oncostatin M and Eotaxin Oncotarget 2014 5 5350 5368 10.18632/oncotarget.2110 25051364 PMC4170629 · DOI
  33. [33]Gercel-Taylor C Atay S Tullis RH Kesimer M Taylor DD Nanoparticle analysis of circulating cell-derived vesicles in ovarian cancer patients Anal Biochem 2012 428 44 53 10.1016/j.ab.2012.06.004 22691960 · DOI
  34. [34]Zhang W Zhou X Yao Q Liu Y Zhang H Dong Z HIF-1-mediated production of exosomes during hypoxia is protective in renal tubular cells Am J Physiol Renal Physiol 2017 313 F906 FF13 10.1152/ajprenal.00178.2017 28679592 PMC5668579 · DOI
  35. [35]Steinbichler TB Dudas J Riechelmann H Skvortsova II The role of exosomes in cancer metastasis Semin Cancer Biol 2017 44 170 181 10.1016/j.semcancer.2017.02.006 28215970 · DOI
  36. [36]Hackenbeck T Huber R Schietke R Knaup KX Monti J Wu X The GTPase RAB20 is a HIF target with mitochondrial localization mediating apoptosis in hypoxia Biochim Biophys Acta 2011 1813 1 13 10.1016/j.bbamcr.2010.10.019 21056597 · DOI
  37. [37]Wang T Gilkes DM Takano N Xiang L Luo W Bishop CJ Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis Proc Natl Acad Sci U S A 2014 111 E3234 E3242 10.1073/pnas.1410041111 24938788 PMC4128139 · DOI · Paper page
  38. [38]Colombo M Raposo G Thery C Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles Annu Rev Cell Dev Biol 2014 30 255 289 10.1146/annurev-cellbio-101512-122326 25288114 · DOI · Paper page
  39. [39]Kosaka N Iguchi H Hagiwara K Yoshioka Y Takeshita F Ochiya T Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis J Biol Chem 2013 288 10849 10859 10.1074/jbc.M112.446831 23439645 PMC3624465 · DOI
  40. [40]Eto K Iwatsuki M Watanabe M Ishimoto T Ida S Imamura Y The sensitivity of gastric cancer to trastuzumab is regulated by the miR-223/FBXW7 pathway Int J Cancer 2015 136 1537 1545 10.1002/ijc.29168 25159729 · DOI
  41. [41]Zhou X Jin W Jia H Yan J Zhang G MiR-223 promotes the cisplatin resistance of human gastric cancer cells via regulating cell cycle by targeting FBXW7 J Exp Clin Canc Res: CR 2015 34 28 10.1186/s13046-015-0145-6 PMC4387683 25888377 · DOI
  42. [42]Fazi F Rosa A Fatica A Gelmetti V De Marchis ML Nervi C A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis Cell 2005 123 819 831 10.1016/j.cell.2005.09.023 16325577 · DOI
  43. [43]Fukao T Fukuda Y Kiga K Sharif J Hino K Enomoto Y An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling Cell 2007 129 617 631 10.1016/j.cell.2007.02.048 17482553 · DOI · Paper page
  44. [44]Zhang J Chen GQ Hypoxia-HIF-1alpha-C/EBPalpha/Runx1 signaling in leukemic cell differentiation Pathophysiology 2009 16 297 303 10.1016/j.pathophys.2009.02.005 19285840 · DOI
  45. [45]Chen Q Qin R Fang Y Li H Berberine sensitizes human ovarian Cancer cells to cisplatin through miR-93/PTEN/Akt signaling pathway Cell Physiol Biochem 2015 36 956 965 10.1159/000430270 26087719 · DOI
  46. [46]Keniry M Parsons R The role of PTEN signaling perturbations in cancer and in targeted therapy Oncogene 2008 27 5477 5485 10.1038/onc.2008.248 18794882 · DOI
  47. [47]Cowell JK Qin H Hu T Wu Q Bhole A Ren M Mutation in the FGFR1 tyrosine kinase domain or inactivation of PTEN is associated with acquired resistance to FGFR inhibitors in FGFR1-driven leukemia/lymphomas Int J Cancer 2017 141 1822 1829 10.1002/ijc.30848 28646488 PMC5850950 · DOI

Cited by

Sorted by citations

Authors
Zhu, X., Shen, H., Yin, X., Yang, M., Wei, H., Chen, Q., Feng, F., Liu, Y., Xu, W., & Li, Y.
Affiliations
  • Jiangsu University (CN)
  • Affiliated Hospital of Jiangsu University (CN)
Corresponding author
  • Xu, Wenlin
  • Li, Yuefeng
ORCID
Venue
Journal of Experimental & Clinical Cancer Research
Publisher
Springer Science and Business Media LLC
Published
2019-02-15
Volume
38
Issue
1
Pages
81-81
ISSN
  • 0392-9078 (ISSN-L)
  • 1756-9966
DOI
10.1186/s13046-019-1095-1
PMC
PMC6377760
OpenAlex
W2916430222
Cited by
374
References
0
Citations by year
2026: 20 · 2025: 29 · 2024: 67 · 2023: 56 · 2022: 67 · 2021: 62 · 2020: 59 · 2019: 14
FWCI
16.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Natural Science Foundation of China (81402165, 81672913, 81871343)
  • Social Development Project of Jiangsu (BE2018693, BE2017698)
  • Basic Research Program of Jiangsu Province (BK20171311, BK20181226)
  • Six Talent Peaks Project in Jiangsu Province (2016-WSW-125)
  • “333 Project” research projects in Jiangsu Province (BRA2016141)
  • Jiangsu Provincial Medical Youth Talent (QNRC2016460, FRC201788)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
epithelial ovarian cancer, exosomes, macrophages, miR-223, chemoresistance, tumor-associated macrophages, PTEN/PI3K/AKT pathway, HIF-1α, tumor hypoxia, tumor microenvironment, exosomal microRNA transfer, CD163, tumor recurrence, circulating exosomes
MeSH terms
Tumor Hypoxia, Carcinoma, Ovarian Epithelial, Animals, Female, Humans, Macrophages, Ovarian Neoplasms, Phenotype, Signal Transduction, Drug Resistance, Neoplasm, MicroRNAs, Mice, Exosomes, Heterografts

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