Immunosuppression of breast cancer cells mediated by transforming growth factor-β in exosomes from cancer cells

Rong,Lei; Li,Rong; Li,Shaoying; Luo,Rongcheng

doi:10.3892/ol.2015.3841

Immunosuppression of breast cancer cells mediated by transforming growth factor-β in exosomes from cancer cells

Authors:
- Lei Rong
- Rong Li
- Shaoying Li
- Rongcheng Luo
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Affiliations: Department of Oncology, Nanfang Hospital, Nanfang Medical University, Guangzhou, Guangdong 510515, P.R. China
Published online on: October 29, 2015 https://doi.org/10.3892/ol.2015.3841
Pages: 500-504

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Abstract

Exosomes derived from tumor cells are essential for processes involved in tumor progression, including angiogenesis, tumor cell proliferation and immunoregulation. In addition, exosome secretion may contribute to the mechanisms of hypoxia‑induced angiogenesis and metastasis of tumors. In the present study, as it is one of the most common cancers in females, breast cancer, cell lines were cultured under hypoxic (1% O2) and normoxic conditions to evaluate the effects of hypoxia on exosome production. Under hypoxic conditions an increase in the number of exosomes in the medium, determined by CD63 immunoblotting, was observed. Application of these exosomes to T cells revealed that they were able to suppress T cell proliferation. As transforming growth factor‑β (TGF‑β), interleukin‑10, and prostaglandin E2 are important factors in the mediation of T cell suppression, the exosomes were subsequently treated with antibodies against these three factors. The results revealed that anti‑TGF‑β was capable of ameliorating the immunosuppressive effects of exosomes. These data demonstrate that hypoxia enhances the secretion of exosomes by breast cancer cells, which acts to suppress T cell proliferation via TGF‑β. The findings have significant implications for understanding the underlying mechanisms of immunosuppression in tumor microenvironments, and for the potential development of cancer therapies.

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1	Hanahan D and Weinberg RA: Hallmarks of cancer: the next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
2	Corrado C, Raimondo S, Chiesi A, Ciccia F, De Leo G and Alessandro R: Exosomes as intercellular signaling organelles involved in health and disease: basic science and clinical applications. Int J Mol Sci. 14:5338–5366. 2013. View Article : Google Scholar : PubMed/NCBI
3	Ahmed KA and Xiang J: Mechanisms of cellular communication through intercellular protein transfer. J Cell Mol Med. 15:1458–1473. 2011. View Article : Google Scholar : PubMed/NCBI
4	Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W and Geuze HJ: Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci. 113:3365–3374. 2000.PubMed/NCBI
5	Schorey JS and Bhatnagar S: Exosome function: from tumor immunology to pathogen biology. Traffic. 9:871–881. 2008. View Article : Google Scholar : PubMed/NCBI
6	van Niel G, Porto-Carreiro I, Simoes S and Raposo G: Exosomes: a common pathway for a specialized function. J Biochem. 140:13–21. 2006. View Article : Google Scholar : PubMed/NCBI
7	Bard MP, Hegmans JP, Hemmes A, et al: Proteomic analysis of exosomes isolated from human malignant pleural effusions. Am J Respir Cell Mol Biol. 31:114–121. 2004. View Article : Google Scholar : PubMed/NCBI
8	Street JM, Barran PE, Mackay CL, et al: Identification and proteomic profiling of exosomes in human cerebrospinal fluid. J Transl Med. 10:52012. View Article : Google Scholar : PubMed/NCBI
9	Hessvik NP, Sandvig K and Llorente A: Exosomal miRNAs as Biomarkers for Prostate Cancer. Front Genet. 4:362013. View Article : Google Scholar : PubMed/NCBI
10	Xiao D, Ohlendorf J, Chen Y, et al: Identifying mRNA, microRNA and protein profiles of melanoma exosomes. PloS One. 7:e468742012. View Article : Google Scholar : PubMed/NCBI
11	Díaz-Valdés N, Basagoiti M, Dotor J, et al: Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression. Cancer Res. 71:812–821. 2011. View Article : Google Scholar : PubMed/NCBI
12	Mizoguchi M, Guan Y, Yoshimoto K, et al: Clinical implications of microRNAs in human glioblastoma. Front Oncol. 3:192013. View Article : Google Scholar : PubMed/NCBI
13	Gailhouste L, Gomez-Santos L and Ochiya T: Potential applications of miRNAs as diagnostic and prognostic markers in liver cancer. Front Biosci (Landmark Ed). 18:199–223. 2013. View Article : Google Scholar : PubMed/NCBI
14	Kahlert C and Kalluri R: Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl). 91:431–437. 2013. View Article : Google Scholar : PubMed/NCBI
15	Katakowski M, Buller B, Zheng X, et al: Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett. 335:201–204. 2013. View Article : Google Scholar : PubMed/NCBI
16	Chiba M, Kimura M and Asari S: Exosomes secreted from human colorectal cancer cell lines contain mRNAs, microRNAs and natural antisense RNAs, that can transfer into the human hepatoma HepG2 and lung cancer A549 cell lines. Oncol Rep. 28:1551–1558. 2012.PubMed/NCBI
17	Borghesi L and Milcarek C: Innate versus adaptive immunity: a paradigm past its prime? Cancer Res. 67:3989–3993. 2007. View Article : Google Scholar : PubMed/NCBI
18	Lizée G, Overwijk WW, Radvanyi L, Gao J, Sharma P and Hwu P: Harnessing the power of the immune system to target cancer. Annu Rev Med. 64:71–90. 2013. View Article : Google Scholar : PubMed/NCBI
19	Tao Z, Shi A, Lu C, Song T, Zhang Z and Zhao J: Breast cancer: Epidemiology and etiology. Cell Biochem Biophys. Dec 28–2014.(Epub ahead of print). PubMed/NCBI
20	Murawa P, Murawa D, Adamczyk B and Połom K: Breast cancer: Actual methods of treatment and future trends. Rep Pract Oncol Radiother. 19:165–172. 2014. View Article : Google Scholar : PubMed/NCBI
21	Edge SB: Quality measurement in breast cancer. J Surg Oncol. 110:509–517. 2014. View Article : Google Scholar : PubMed/NCBI
22	Al-Nedawi K: The yin-yang of microvesicles (exosomes) in cancer biology. Front Oncol. 4:1722014. View Article : Google Scholar : PubMed/NCBI
23	Tickner JA, Urquhart AJ, Stephenson SA, Richard DJ and O'Byrne KJ: Functions and therapeutic roles of exosomes in cancer. Front Oncol. 4:1272014. View Article : Google Scholar : PubMed/NCBI
24	Jui HY, Lin CH, Hsu WT, et al: Autologous mesenchymal stem cells prevent transplant arteriosclerosis by enhancing local expression of interleukin-10, interferon-γ, and indoleamine 2,3-dioxygenase. Cell Transplant. 21:971–984. 2012. View Article : Google Scholar : PubMed/NCBI
25	Sun L, Akiyama K, Zhang H, et al: Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem Cells. 27:1421–1432. 2009. View Article : Google Scholar : PubMed/NCBI
26	Epple LM, Griffiths SG, Dechkovskaia AM, et al: Medulloblastoma exosome proteomics yield functional roles for extracellular vesicles. PloS One. 7:e420642012. View Article : Google Scholar : PubMed/NCBI
27	Vignali DA, Collison LW and Workman CJ: How regulatory T cells work. Nat Rev Immunol. 8:523–532. 2008. View Article : Google Scholar : PubMed/NCBI
28	Belkaid Y and Tarbell K: Regulatory T cells in the control of host-microorganism interactions(*). Annu Rev Immunol. 27:551–589. 2009. View Article : Google Scholar : PubMed/NCBI
29	Zou W: Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 6:295–307. 2006. View Article : Google Scholar : PubMed/NCBI