Skip to main content
Top
Published in: Tumor Biology 9/2016

01-09-2016 | Original Article

Exosomes derived from gastric cancer cells activate NF-κB pathway in macrophages to promote cancer progression

Authors: Lijun Wu, Xu Zhang, Bin Zhang, Hui Shi, Xiao Yuan, Yaoxiang Sun, Zhaoji Pan, Hui Qian, Wenrong Xu

Published in: Tumor Biology | Issue 9/2016

Login to get access

Abstract

Exosomes are nano-sized membrane vesicles secreted by both normal and cancer cells. Emerging evidence indicates that cancer cells derived exosomes contribute to cancer progression through the modulation of tumor microenvironment. However, the effects of exosomes derived from gastric cancer cells on macrophages are not well understood. In this study, we investigated the biological role of gastric cancer cells derived exosomes in the activation of macrophages. We demonstrated that gastric cancer cells derived exosomes activated macrophages to express increased levels of proinflammatory factors, which in turn promoted tumor cell proliferation and migration. In addition, gastric cancer cells derived exosomes remarkably upregulated the phosphorylation of NF-κB in macrophages. Inhibiting the activation of NF-κB reversed the upregulation of proinflammatory factors in macrophages and blocked their promoting effects on gastric cancer cells. Moreover, we found that gastric cancer cells derived exosomes could also activate macrophages from human peripheral blood monocytes through the activation of NF-κB. In conclusion, our results suggest that gastric cancer cells derived exosomes stimulate the activation of NF-κB pathway in macrophages to promote cancer progression, which provides a potential therapeutic approach for gastric cancer by interfering with the interaction between exosomes and macrophages in tumor microenvironment.
Appendix
Available only for authorised users
Literature
1.
go back to reference Shen L, Shan YS, Hu HM, Price TJ, Sirohi B, Yeh KH, et al. Management of gastric cancer in Asia: resource-stratified guidelines. Lancet Oncol. 2013;14:e535–47.CrossRefPubMed Shen L, Shan YS, Hu HM, Price TJ, Sirohi B, Yeh KH, et al. Management of gastric cancer in Asia: resource-stratified guidelines. Lancet Oncol. 2013;14:e535–47.CrossRefPubMed
2.
4.
go back to reference Zhang W, Peng P, Kuang Y, Yang J, Cau D, You Y, et al. Characterization of exosomes derived from ovarian cancer cells and normal ovarian epithelial cells by nanoparticle tracking analysis. Tumour Biol. 2015:1–9. Zhang W, Peng P, Kuang Y, Yang J, Cau D, You Y, et al. Characterization of exosomes derived from ovarian cancer cells and normal ovarian epithelial cells by nanoparticle tracking analysis. Tumour Biol. 2015:1–9.
5.
go back to reference Christoph K, Raghu K. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl). 2013;91(4):431–7.CrossRef Christoph K, Raghu K. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl). 2013;91(4):431–7.CrossRef
6.
go back to reference Li C, Liu DR, Li GG, Wang HH, Li XW, Zhang W, et al. CD97 promotes gastric cancer cell proliferation and invasion through exosome-mediated MAPK signaling pathway. World J Gastroenterol. 2015;21(20):6215–28.CrossRefPubMedPubMedCentral Li C, Liu DR, Li GG, Wang HH, Li XW, Zhang W, et al. CD97 promotes gastric cancer cell proliferation and invasion through exosome-mediated MAPK signaling pathway. World J Gastroenterol. 2015;21(20):6215–28.CrossRefPubMedPubMedCentral
7.
go back to reference Yang TT, Zhang X, Wang M, Zhang J, Huang F, Cai J, et al. Activation of mesenchymal stem cells by macrophages prompts human gastric cancer growth through NF-κB pathway. PLoS ONE. 2014;9(5):e97569.CrossRefPubMedPubMedCentral Yang TT, Zhang X, Wang M, Zhang J, Huang F, Cai J, et al. Activation of mesenchymal stem cells by macrophages prompts human gastric cancer growth through NF-κB pathway. PLoS ONE. 2014;9(5):e97569.CrossRefPubMedPubMedCentral
8.
go back to reference Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9:239–52.CrossRefPubMed Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9:239–52.CrossRefPubMed
9.
go back to reference Li YS, Zhao LM, Shi BH, Ma SS, Xu Z, Ge Y, et al. Functions of miR-146a and miR-222 in tumor-associated macrophages in breast cancer. Sci Rep. 2015;5:18648–63.CrossRefPubMedPubMedCentral Li YS, Zhao LM, Shi BH, Ma SS, Xu Z, Ge Y, et al. Functions of miR-146a and miR-222 in tumor-associated macrophages in breast cancer. Sci Rep. 2015;5:18648–63.CrossRefPubMedPubMedCentral
10.
go back to reference Cho HJ, Jung JI, Lim DY, Kwon GT, Her S, Park JH, et al. Bone marrow-derived, alternatively activated macrophages enhance solid tumor growth and lung metastasis of mammary carcinoma cells in a Balb/C mouse orthotopic model. Breast Cancer Res. 2012;14(3):R81.CrossRefPubMedPubMedCentral Cho HJ, Jung JI, Lim DY, Kwon GT, Her S, Park JH, et al. Bone marrow-derived, alternatively activated macrophages enhance solid tumor growth and lung metastasis of mammary carcinoma cells in a Balb/C mouse orthotopic model. Breast Cancer Res. 2012;14(3):R81.CrossRefPubMedPubMedCentral
11.
go back to reference Aga M, Bentz GL, Raffa S, Torrisi MR, Kondo S, Wakisaka N, et al. Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene. 2014;33(37):4613–22.CrossRefPubMedPubMedCentral Aga M, Bentz GL, Raffa S, Torrisi MR, Kondo S, Wakisaka N, et al. Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene. 2014;33(37):4613–22.CrossRefPubMedPubMedCentral
14.
go back to reference Ji R, Zhang B, Zhang X, Xue J, Yuan X, Yan Y, et al. Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer. Cell Cycle. 2015;14(15):2473–83.CrossRefPubMedPubMedCentral Ji R, Zhang B, Zhang X, Xue J, Yuan X, Yan Y, et al. Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer. Cell Cycle. 2015;14(15):2473–83.CrossRefPubMedPubMedCentral
15.
go back to reference Milane L, Singh A, Mattheolabakis G, Suresh M, Amiji MM. Exosome mediated communication within the tumor microenvironment. J Control Release. 2015;219:278–94.CrossRefPubMed Milane L, Singh A, Mattheolabakis G, Suresh M, Amiji MM. Exosome mediated communication within the tumor microenvironment. J Control Release. 2015;219:278–94.CrossRefPubMed
16.
go back to reference Yu D, Wu Y, Zhang X, Lv M, Chen X, Yang SJ, et al. Exosomes from adriamycin-resistant breast cancer cells transmit drug resistance partly by delivering miR-222. Tumour Biol. 2015:1–9. Yu D, Wu Y, Zhang X, Lv M, Chen X, Yang SJ, et al. Exosomes from adriamycin-resistant breast cancer cells transmit drug resistance partly by delivering miR-222. Tumour Biol. 2015:1–9.
17.
go back to reference Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang WC, et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature. 2015;527(7576):100–4.CrossRefPubMedPubMedCentral Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang WC, et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature. 2015;527(7576):100–4.CrossRefPubMedPubMedCentral
18.
go back to reference Gu JM, Qian H, Shen L, Zhang X, Zhu W, Huang L, et al. Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through TGF-β/Smad pathway. PLoS ONE. 2012;7(12):e52465.CrossRefPubMedPubMedCentral Gu JM, Qian H, Shen L, Zhang X, Zhu W, Huang L, et al. Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through TGF-β/Smad pathway. PLoS ONE. 2012;7(12):e52465.CrossRefPubMedPubMedCentral
19.
go back to reference Challagundla KB, Wise PM, Neviani P, Ghava H, Murtadha M, Kennedy R, et al. Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J Natl Cancer Inst. 2015;107(7):djv135.CrossRefPubMedPubMedCentral Challagundla KB, Wise PM, Neviani P, Ghava H, Murtadha M, Kennedy R, et al. Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J Natl Cancer Inst. 2015;107(7):djv135.CrossRefPubMedPubMedCentral
20.
go back to reference Paggetti J, Haderk F, Seiffert M, Janji B, Distler U, Ammerlaan W, et al. Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts. Blood. 2015;126(9):1106–17.CrossRefPubMedPubMedCentral Paggetti J, Haderk F, Seiffert M, Janji B, Distler U, Ammerlaan W, et al. Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts. Blood. 2015;126(9):1106–17.CrossRefPubMedPubMedCentral
21.
go back to reference Ding G, Zhou L, Qian Y, Fu M, Chen J, Chen J, et al. Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p. Oncotarget. 2015;6(30):29877–88.PubMedPubMedCentral Ding G, Zhou L, Qian Y, Fu M, Chen J, Chen J, et al. Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p. Oncotarget. 2015;6(30):29877–88.PubMedPubMedCentral
22.
go back to reference Zhou D, Huang C, Lin Z, Zhan S, Kong L, Fang C, et al. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cell Signal. 2014;26:192–7.CrossRefPubMed Zhou D, Huang C, Lin Z, Zhan S, Kong L, Fang C, et al. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cell Signal. 2014;26:192–7.CrossRefPubMed
24.
go back to reference Cai X, Yin Y, Li N, Zhu D, Zhang J, Zhang CY, et al. Re-polarization of tumor-associated macrophages to pro-inflammatory M1 macrophages by microRNA-155. J Mol Cell Biol. 2012;4(5):341–3.CrossRefPubMed Cai X, Yin Y, Li N, Zhu D, Zhang J, Zhang CY, et al. Re-polarization of tumor-associated macrophages to pro-inflammatory M1 macrophages by microRNA-155. J Mol Cell Biol. 2012;4(5):341–3.CrossRefPubMed
25.
go back to reference Ma SS, Liu M, Xu ZB, Li YS, Guo H, Ge Y, et al. A double feedback loop mediated by microRNA-23a/27a/24-2 regulates M1 versus M2 macrophage polarization and thus regulates cancer progression. Oncotarget. 2016;7(12):13502–19. Ma SS, Liu M, Xu ZB, Li YS, Guo H, Ge Y, et al. A double feedback loop mediated by microRNA-23a/27a/24-2 regulates M1 versus M2 macrophage polarization and thus regulates cancer progression. Oncotarget. 2016;7(12):13502–19.
26.
go back to reference Chow A, Zhou W, Liu L, Fong MY, Champer J, Van Haute D, et al. Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB. Sci Rep. 2014;4:5750–66.CrossRefPubMedPubMedCentral Chow A, Zhou W, Liu L, Fong MY, Champer J, Van Haute D, et al. Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB. Sci Rep. 2014;4:5750–66.CrossRefPubMedPubMedCentral
27.
go back to reference Baig MS, Zaichick SV, Mao M, de Abreu AL, Bakhshi FR, Hart PC, et al. NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1. J Exp Med. 2015;212(10):1725–38.CrossRefPubMedPubMedCentral Baig MS, Zaichick SV, Mao M, de Abreu AL, Bakhshi FR, Hart PC, et al. NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1. J Exp Med. 2015;212(10):1725–38.CrossRefPubMedPubMedCentral
28.
go back to reference Yang Z, Xian H, Hu J, Tian S, Qin Y, Wang RF, et al. USP18 negatively regulates NF-κB signaling by targeting TAK1 and NEMO for deubiquitination through distinct mechanisms. Sci Rep. 2015;5:12738.CrossRefPubMedPubMedCentral Yang Z, Xian H, Hu J, Tian S, Qin Y, Wang RF, et al. USP18 negatively regulates NF-κB signaling by targeting TAK1 and NEMO for deubiquitination through distinct mechanisms. Sci Rep. 2015;5:12738.CrossRefPubMedPubMedCentral
29.
go back to reference Scirpo R, Fiorotto R, Villani A, Amenduni M, Spirlic C. Strazzabosco. Stimulation of nuclear receptor peroxisome proliferator-activated receptor-γ limits NF-κB-dependent inflammation in mouse cystic fibrosis biliary epithelium. Hepatology. 2015;62(5):1551–62.CrossRefPubMedPubMedCentral Scirpo R, Fiorotto R, Villani A, Amenduni M, Spirlic C. Strazzabosco. Stimulation of nuclear receptor peroxisome proliferator-activated receptor-γ limits NF-κB-dependent inflammation in mouse cystic fibrosis biliary epithelium. Hepatology. 2015;62(5):1551–62.CrossRefPubMedPubMedCentral
30.
go back to reference Bovy N, Blomme B, Frères P, Dederen S, Nivelles O, Lion M, et al. Endothelial exosomes contribute to the antitumor response during breast cancer neoadjuvant chemotherapy via microRNA transfer. Oncotarget. 2015;6(12):10253–66.CrossRefPubMedPubMedCentral Bovy N, Blomme B, Frères P, Dederen S, Nivelles O, Lion M, et al. Endothelial exosomes contribute to the antitumor response during breast cancer neoadjuvant chemotherapy via microRNA transfer. Oncotarget. 2015;6(12):10253–66.CrossRefPubMedPubMedCentral
31.
go back to reference Abd Elmageed ZY, Yang Y, Thomas R, Ranjan M, Mondal D, Moroz K, et al. Neoplastic reprogramming of patient-derived adipose stem cells by prostate cancer cell-associated exosomes. Stem Cells. 2014;32(4):983–97.CrossRefPubMedPubMedCentral Abd Elmageed ZY, Yang Y, Thomas R, Ranjan M, Mondal D, Moroz K, et al. Neoplastic reprogramming of patient-derived adipose stem cells by prostate cancer cell-associated exosomes. Stem Cells. 2014;32(4):983–97.CrossRefPubMedPubMedCentral
32.
go back to reference Mathivanan S, Fahner CJ, Reid GE, Simpson RJ. ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res. 2012;40(Database issue):D1241–4.CrossRefPubMed Mathivanan S, Fahner CJ, Reid GE, Simpson RJ. ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res. 2012;40(Database issue):D1241–4.CrossRefPubMed
33.
go back to reference Burke M, Choksawangkarn W, Edwards N, Ostrand-Rosenberg S, Fenselau C. Exosomes from myeloid-derived suppressor cells carry biologically active proteins. J Proteome Res. 2014;13(2):836–43.CrossRefPubMed Burke M, Choksawangkarn W, Edwards N, Ostrand-Rosenberg S, Fenselau C. Exosomes from myeloid-derived suppressor cells carry biologically active proteins. J Proteome Res. 2014;13(2):836–43.CrossRefPubMed
34.
go back to reference Luga V, Zhang L, Viloria-Petit AM, Oqunjimi AA, Inanlou MR, Chiu E, et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell. 2012;151(7):1542–56.CrossRefPubMed Luga V, Zhang L, Viloria-Petit AM, Oqunjimi AA, Inanlou MR, Chiu E, et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell. 2012;151(7):1542–56.CrossRefPubMed
35.
go back to reference Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell. 2014;159(3):499–513.CrossRefPubMedPubMedCentral Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell. 2014;159(3):499–513.CrossRefPubMedPubMedCentral
36.
go back to reference Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012;18(6):883–91.CrossRefPubMedPubMedCentral Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012;18(6):883–91.CrossRefPubMedPubMedCentral
37.
go back to reference Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A. 2012;109(31):E2110–6.CrossRefPubMedPubMedCentral Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A. 2012;109(31):E2110–6.CrossRefPubMedPubMedCentral
38.
go back to reference Kogure T, Yan IK, Lin WL, Patel T. Extracellular vesicle–mediated transfer of a novel long noncoding RNA TUC339: a mechanism of intercellular signaling in human hepatocellular cancer. Genes Cancer. 2013;4:261–72.CrossRefPubMedPubMedCentral Kogure T, Yan IK, Lin WL, Patel T. Extracellular vesicle–mediated transfer of a novel long noncoding RNA TUC339: a mechanism of intercellular signaling in human hepatocellular cancer. Genes Cancer. 2013;4:261–72.CrossRefPubMedPubMedCentral
Metadata
Title
Exosomes derived from gastric cancer cells activate NF-κB pathway in macrophages to promote cancer progression
Authors
Lijun Wu
Xu Zhang
Bin Zhang
Hui Shi
Xiao Yuan
Yaoxiang Sun
Zhaoji Pan
Hui Qian
Wenrong Xu
Publication date
01-09-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 9/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-016-5071-5

Other articles of this Issue 9/2016

Tumor Biology 9/2016 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine