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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2017 | Research

Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells

Authors: Peiming Zheng, Lei Chen, Xiangliang Yuan, Qin Luo, Yi Liu, Guohua Xie, Yanhui Ma, Lisong Shen

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

Abstract

Background

Cisplatin-based chemotherapy is frequently used to treat advanced gastric cancer (GC). However, the resistance often occurs with the mechanisms being not well understood. Recently, emerging evidence indicates that tumor-associated macrophages (TAMs) play an important role in chemoresistance of cancer. As the important mediators in intercellular communications, exosomes secreted by host cells mediate the exchange of genetic materials and proteins to be involved in tumor aggressiveness. The aim of the study was to investigate whether exosomes derived from TAMs mediate cisplatin resistance in gastric cancer.

Methods

M2 polarized macrophages were obtained from mouse bone marrow or human PBMCs stimulated with IL-4 and IL-13. Exosomes isolated from M2 macrophages culture medium were characterized, and miRNA expression profiles of M2 derived exosomes (M2-exos) were analyzed using miRNA microarray. In vitro cell coculture was further conducted to investigate M2-exos mediated crosstalk between TAMs and tumor cells. Moreover, the in vivo experiments were performed using a subcutaneous transplantation tumor model in athymic nude mice.

Results

In this study, we showed that M2 polarized macrophages promoted cisplatin (DDP) resistance in gastric cancer cells and exosomes derived from M2 macrophages (M2-exos) are involved in mediating the resistance to DDP. Using miRNA profiles assay, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and cell lysate isolated from M2 polarized macrophage. Functional studies revealed that exosomal miR-21 can be directly transferred from macrophages to the gastric cancer cells, where it suppresses cell apoptosis and enhances activation of PI3K/AKT signaling pathway by down-regulation of PTEN.

Conclusions

Our findings suggest that exosomal transfer of tumor-associated macrophages derived miR-21 confer DDP resistance in gastric cancer, and targeting exosome communication may be a promising new therapeutic strategy for gastric cancer patients.

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Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRefPubMed

Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32.CrossRefPubMed

Orditura M, Galizia G, Sforza V, Gambardella V, Fabozzi A, Laterza MM, Andreozzi F, Ventriglia J, Savastano B, Mabilia A, et al. Treatment of gastric cancer. World J Gastroenterol. 2014;20:1635–49.CrossRefPubMedPubMedCentral

Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:1014–22.CrossRefPubMedPubMedCentral

Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.CrossRefPubMedPubMedCentral

Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.CrossRefPubMed

Noy R, Pollard Jeffrey W. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41:49–61.CrossRefPubMedPubMedCentral

Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51.CrossRefPubMedPubMedCentral

Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–95.CrossRefPubMedPubMedCentral

10.

Mills CD. M1 and M2 macrophages: oracles of health and disease. Crit Rev Immunol. 2012;32:463–88.CrossRefPubMed

11.

Murray Peter J, Allen Judith E, Biswas Subhra K, Fisher Edward A, Gilroy Derek W, Goerdt S, Gordon S, Hamilton John A, Ivashkiv Lionel B, Lawrence T, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20.CrossRefPubMedPubMedCentral

12.

Chen J, Yao Y, Gong C, Yu F, Su S, Chen J, Liu B, Deng H, Wang F, Lin L, et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. 2011;19:541–55.CrossRefPubMedPubMedCentral

13.

Cardoso AP, Pinto ML, Pinto AT, Oliveira MI, Pinto MT, Goncalves R, Relvas JB, Figueiredo C, Seruca R, Mantovani A, et al. Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y(1086), c-Src, Erk1/2 and Akt phosphorylation and smallGTPase activity. Oncogene. 2014;33:2123–33.CrossRefPubMed

14.

Wu MH, Lee WJ, Hua KT, Kuo ML, Lin MT. Macrophage infiltration induces gastric cancer invasiveness by activating the beta-catenin pathway. PLoS One. 2015;10:e0134122.CrossRefPubMedPubMedCentral

15.

Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27:462–72.CrossRefPubMedPubMedCentral

16.

Mantovani A, Allavena P. The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med. 2015;212:435–45.CrossRefPubMedPubMedCentral

17.

Thery C. Exosomes: secreted vesicles and intercellular communications. F1000 Biol Rep. 2011;3:15.CrossRefPubMedPubMedCentral

18.

Tkach M, Thery C. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016;164:1226–32.CrossRefPubMed

19.

Penfornis P, Vallabhaneni KC, Whitt J, Pochampally R. Extracellular vesicles as carriers of microRNA, proteins and lipids in tumor microenvironment. Int J Cancer. 2016;138:14–21.CrossRefPubMed

20.

Boelens Mirjam C, Wu Tony J, Nabet Barzin Y, Xu B, Qiu Y, Yoon T, Azzam Diana J, Twyman-Saint Victor C, Wiemann Brianne Z, Ishwaran H, et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell. 2014;159:499–513.CrossRefPubMedPubMedCentral

21.

Qu Z, Wu J, Wu J, Luo D, Jiang C, Ding Y. Exosomes derived from HCC cells induce sorafenib resistance in hepatocellular carcinoma both in vivo and in vitro. J Exp Clin Cancer Res. 2016;35:159.CrossRefPubMedPubMedCentral

22.

Wang X, Xu C, Hua Y, Sun L, Cheng K, Jia Z, Han Y, Dong J, Cui Y, Yang Z. Exosomes play an important role in the process of psoralen reverse multidrug resistance of breast cancer. J Exp Clin Cancer Res. 2016;35:186.CrossRefPubMedPubMedCentral

23.

Challagundla KB, Wise PM, Neviani P, Chava H, Murtadha M, Xu T, Kennedy R, Ivan C, Zhang X, Vannini I, et al. Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J Natl Cancer Inst. 2015;107:djv135.CrossRefPubMedPubMedCentral

24.

Au Yeung CL, Co N-N, Tsuruga T, Yeung T-L, Kwan S-Y, Leung CS, Li Y, Lu ES, Kwan K, Wong K-K, et al. Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat Commun. 2016;7:11150.CrossRefPubMedPubMedCentral

25.

Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3:23–35.CrossRefPubMed

26.

Szakács G, Annereau J-P, Lababidi S, Shankavaram U, Arciello A, Bussey KJ, Reinhold W, Guo Y, Kruh GD, Reimers M, et al. Predicting drug sensitivity and resistance. Cancer Cell. 2004;6:129–37.CrossRefPubMed

27.

Dong J, Zhao Y-P, Zhou L, Zhang T-P, Chen G. Bcl-2 Upregulation induced by miR-21 via a direct interaction is associated with apoptosis and chemoresistance in MIA PaCa-2 pancreatic cancer cells. Arch Med Res. 2011;42:8–14.CrossRefPubMed

28.

Klemm F, Joyce JA. Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol. 2015;25:198–213.CrossRefPubMed

29.

ELA S, Mager I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov. 2013;12:347–57.CrossRef

30.

Sousa D, Lima RT, Vasconcelos MH. Intercellular transfer of cancer drug resistance traits by extracellular vesicles. Trends Mol Med. 2015;21:595–608.CrossRefPubMed

31.

Qu L, Ding J, Chen C, Wu Z-J, Liu B, Gao Y, Chen W, Liu F, Sun W, Li X-F, et al. Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA. Cancer Cell. 2016;29:653–68.CrossRefPubMed

32.

Richards KE, Zeleniak AE, Fishel ML, Wu J, Littlepage LE, Hill R. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene. 2017;36:1770–78.CrossRefPubMed

33.

Dehghanzadeh R, Jadidi-Niaragh F, Gharibi T, Yousefi M. MicroRNA-induced drug resistance in gastric cancer. Biomed Pharmacother. 2015;74:191–9.CrossRefPubMed

34.

Riquelme I, Letelier P, Riffo-Campos A, Brebi P, Roa J. Emerging role of miRNAs in the drug resistance of gastric cancer. Int J Mol Sci. 2016;17:424.CrossRefPubMedPubMedCentral

35.

Giovannetti E, Erozenci A, Smit J, Danesi R, Peters GJ. Molecular mechanisms underlying the role of microRNAs (miRNAs) in anticancer drug resistance and implications for clinical practice. Crit Rev Oncol Hematol. 2012;81:103–22.CrossRefPubMed

36.

Shi GH, Ye DW, Yao XD, Zhang SL, Dai B, Zhang HL, Shen YJ, Zhu Y, Zhu YP, Xiao WJ, Ma CG. Involvement of microRNA-21 in mediating chemo-resistance to docetaxel in androgen-independent prostate cancer PC3 cells. Acta Pharmacol Sin. 2010;31:867–73.CrossRefPubMedPubMedCentral

37.

Xiong B. MiR-21 regulates biological behavior through the PTEN/PI-3 K/Akt signaling pathway in human colorectal cancer cells. Int J Oncol. 2013;42:219–28.PubMed

38.

Yang S-m, Huang C, Li X-f, Yu M-z, He Y, Li J. miR-21 confers cisplatin resistance in gastric cancer cells by regulating PTEN. Toxicology. 2013;306:162–8.CrossRefPubMed

Title: Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells
Authors: Peiming Zheng
Lei Chen
Xiangliang Yuan
Qin Luo
Yi Liu
Guohua Xie
Yanhui Ma
Lisong Shen
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-017-0528-y

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Abstract

Background

Methods

Results

Conclusions

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