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Molecular Cancer
Published in: Molecular Cancer 1/2018

Open Access 01-12-2018 | Review

Role of hypoxia-induced exosomes in tumor biology

Authors: Chuchu Shao, Fengming Yang, Suyu Miao, Weitao Liu, Chaoshan Wang, Yongqian Shu, Hua Shen

Published in: Molecular Cancer | Issue 1/2018

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Abstract

Purpose

Hypoxia is a major regulator of angiogenesis and always influences the release of exosomes in various types of tumors. The present review aimed to assess the role of hypoxia-induced exosomes in the tumor biology.

Methods

The relevant publications were retrieved from PubMed using keywords such as hypoxia, exosome, extracellular vesicles, tumor, cancer, and other similar terms.

Results

Recent studies have shown that cancer cells produce more exosomes under hypoxic conditions than do parental cells under normoxic conditions. The secretion and function of exosomes could be influenced by hypoxia in various types of cancer. Hypoxia-induced exosomes play critical roles in tumor angiogenesis, invasion, metastasis, and the immune system.

Conclusions

These findings provide new insights into the complex networks underlying cellular and genomic regulation in response to hypoxia and might provide novel and specific targets for future therapies.
Literature
1.
2.
3.
4.
5.
Brahimi-Horn MC, Chiche J, Pouyssegur J. Hypoxia and cancer. J Mol Med (Berl). 2007;85:1301–7.CrossRef
6.
7.
8.
Harada H, Inoue M, Itasaka S, Hirota K, Morinibu A, Shinomiya K, Zeng L, Ou G, Zhu Y, Yoshimura M, et al. Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels. Nat Commun. 2012;3:783.CrossRefPubMed
9.
Semenza GL. The hypoxic tumor microenvironment: a driving force for breast cancer progression. Biochim Biophys Acta. 2016;1863:382–91.CrossRefPubMed
10.
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WJ. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–8.CrossRefPubMed
11.
Chen T, Ren Z, Ye LC, Zhou PH, Xu JM, Shi Q, Yao LQ, Zhong YS. Factor inhibiting HIF1alpha (FIH-1) functions as a tumor suppressor in human colorectal cancer by repressing HIF1alpha pathway. Cancer Biol Ther. 2015;16:244–52.CrossRefPubMedPubMedCentral
12.
13.
14.
15.
Minciacchi VR, Freeman MR, Di Vizio D. Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. Semin Cell Dev Biol. 2015;40:41–51.CrossRefPubMedPubMedCentral
16.
Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, Dingli F, Loew D, Tkach M, Thery C. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A. 2016;113:E968–77.CrossRefPubMedPubMedCentral
17.
18.
Schorey JS, Cheng Y, Singh PP, Smith VL. Exosomes and other extracellular vesicles in host-pathogen interactions. EMBO Rep. 2015;16:24–43.CrossRefPubMed
19.
Lopez-Verrilli MA, Court FA. Exosomes: mediators of communication in eukaryotes. Biol Res. 2013;46:5–11.CrossRefPubMed
20.
Tkach M, Thery C. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016;164:1226–32.CrossRefPubMed
21.
Syn N, Wang L, Sethi G, Thiery JP, Goh BC. Exosome-mediated metastasis: from epithelial-mesenchymal transition to escape from Immunosurveillance. Trends Pharmacol Sci. 2016;37:606–17.CrossRefPubMed
22.
van Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19(4):213–28.CrossRefPubMed
23.
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;9:654–9.CrossRefPubMed
24.
25.
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
26.
Sun T, Kalionis B, Lv G, Xia S, Gao W. Role of Exosomal noncoding RNAs in lung carcinogenesis. Biomed Res Int. 2015;2015:125807.PubMedPubMedCentral
27.
Li Q, Shao Y, Zhang X, Zheng T, Miao M, Qin L, Wang B, Ye G, Xiao B, Guo J. Plasma long noncoding RNA protected by exosomes as a potential stable biomarker for gastric cancer. Tumour Biol. 2015;36:2007–12.CrossRefPubMed
28.
Gezer U, Ozgur E, Cetinkaya M, Isin M, Dalay N. Long non-coding RNAs with low expression levels in cells are enriched in secreted exosomes. Cell Biol Int. 2014;38:1076–9.PubMed
29.
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:F906–13.CrossRefPubMedPubMedCentral
30.
Park JE, Tan HS, Datta A, Lai RC, Zhang H, Meng W, Lim SK, Sze SK. Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol Cell Proteomics. 2010;9:1085–99.CrossRefPubMedPubMedCentral
31.
Wang T, Gilkes DM, Takano N, Xiang L, Luo W, Bishop CJ, Chaturvedi P, Green JJ, Semenza GL. 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:E3234–42.CrossRefPubMedPubMedCentral
32.
Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17:548–58.CrossRefPubMed
33.
Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12:19–30. 1-13CrossRefPubMed
34.
Bobrie A, Krumeich S, Reyal F, Recchi C, Moita LF, Seabra MC, Ostrowski M, Thery C. Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Res. 2012;72:4920–30.CrossRefPubMed
35.
Kore RA, Edmondson JL, Jenkins SV, Jamshidi-Parsian A, Dings R, Reyna NS, Griffin RJ. Hypoxia-derived exosomes induce putative altered pathways in biosynthesis and ion regulatory channels in glioblastoma cells. Biochem Biophys Rep. 2018;14:104–13.PubMedPubMedCentral
36.
37.
Umezu T, Tadokoro H, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH. Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. Blood. 2014;124:3748–57.CrossRefPubMedPubMedCentral
38.
39.
Borges FT, Melo SA, Ozdemir BC, Kato N, Revuelta I, Miller CA, Gattone VN, LeBleu VS, Kalluri R. TGF-beta1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis. J Am Soc Nephrol. 2013;24:385–92.CrossRefPubMed
40.
Walsh TG, Metharom P, Berndt MC. The functional role of platelets in the regulation of angiogenesis. Platelets. 2015;26:199–211.CrossRefPubMed
41.
42.
Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol. 2006;7:359–71.CrossRefPubMed
43.
44.
Hsu YL, Hung JY, Chang WA, Lin YS, Pan YC, Tsai PH, Wu CY, Kuo PL. Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene. 2017;36:4929–42.CrossRefPubMed
45.
Tadokoro H, Umezu T, Ohyashiki K, Hirano T, Ohyashiki JH. Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells. J Biol Chem. 2013;288:34343–51.CrossRefPubMedPubMedCentral
46.
Mao G, Liu Y, Fang X, Liu Y, Fang L, Lin L, Liu X, Wang N. Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer. Angiogenesis. 2015;18:373–82.CrossRefPubMed
47.
Tan EJ, Olsson AK, Moustakas A. Reprogramming during epithelial to mesenchymal transition under the control of TGFbeta. Cell Adhes Migr. 2015;9:233–46.CrossRef
48.
Peng Z, Wang CX, Fang EH, Wang GB, Tong Q. Role of epithelial-mesenchymal transition in gastric cancer initiation and progression. World J Gastroenterol. 2014;20:5403–10.CrossRefPubMedPubMedCentral
49.
Panebianco C, Saracino C, Pazienza V. Epithelial-mesenchymal transition: molecular pathways of hepatitis viruses-induced hepatocellular carcinoma progression. Tumour Biol. 2014;35:7307–15.CrossRefPubMed
50.
51.
Inge LJ, Rajasekaran SA, Wolle D, Barwe SP, Ryazantsev S, Ewing CM, Isaacs WB, Rajasekaran AK. alpha-catenin overrides Src-dependent activation of beta-catenin oncogenic signaling. Mol Cancer Ther. 2008;7:1386–97.CrossRefPubMedPubMedCentral
52.
53.
Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 2008;68:3645–54.CrossRefPubMed
54.
Ramteke A, Ting H, Agarwal C, Mateen S, Somasagara R, Hussain A, Graner M, Frederick B, Agarwal R, Deep G. Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol Carcinog. 2015;54:554–65.CrossRefPubMed
55.
Xue M, Chen W, Xiang A, Wang R, Chen H, Pan J, Pang H, An H, Wang X, Hou H, Li X. Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1. Mol Cancer. 2017;16:143.CrossRefPubMedPubMedCentral
56.
Li L, Li C, Wang S, Wang Z, Jiang J, Wang W, Li X, Chen J, Liu K, Li C, Zhu G. Exosomes derived from hypoxic oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a Prometastatic phenotype. Cancer Res. 2016;76:1770–80.CrossRefPubMed
57.
Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, Becker A, Hoshino A, Mark MT, Molina H, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17:816–26.CrossRefPubMedPubMedCentral
58.
59.
Sceneay J, Smyth MJ, Moller A. The pre-metastatic niche: finding common ground. Cancer Metastasis Rev. 2013;32:449–64.CrossRefPubMed
60.
Filipazzi P, Burdek M, Villa A, Rivoltini L, Huber V. Recent advances on the role of tumor exosomes in immunosuppression and disease progression. Semin Cancer Biol. 2012;22:342–9.CrossRefPubMed
61.
Poutsiaka DD, Schroder EW, Taylor DD, Levy EM, Black PH. Membrane vesicles shed by murine melanoma cells selectively inhibit the expression of Ia antigen by macrophages. J Immunol. 1985;134:138–44.PubMed
62.
Andreola G, Rivoltini L, Castelli C, Huber V, Perego P, Deho P, Squarcina P, Accornero P, Lozupone F, Lugini L, et al. Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med. 2002;195:1303–16.CrossRefPubMedPubMedCentral
63.
Liu C, Yu S, Zinn K, Wang J, Zhang L, Jia Y, Kappes JC, Barnes S, Kimberly RP, Grizzle WE, Zhang HG. Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J Immunol. 2006;176:1375–85.CrossRefPubMed
64.
Valenti R, Huber V, Filipazzi P, Pilla L, Sovena G, Villa A, Corbelli A, Fais S, Parmiani G, Rivoltini L. Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res. 2006;66:9290–8.CrossRefPubMed
65.
Wen SW, Sceneay J, Lima LG, Wong CS, Becker M, Krumeich S, Lobb RJ, Castillo V, Wong KN, Ellis S, et al. The biodistribution and immune suppressive effects of breast Cancer-derived exosomes. Cancer Res. 2016;76:6816–27.CrossRefPubMed
66.
Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, Lovat F, Fadda P, Mao C, Nuovo GJ, et al. MicroRNAs bind to toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A. 2012;109:E2110–6.CrossRefPubMedPubMedCentral
67.
Szczepanski MJ, Szajnik M, Welsh A, Whiteside TL, Boyiadzis M. Blast-derived microvesicles in sera from patients with acute myeloid leukemia suppress natural killer cell function via membrane-associated transforming growth factor-beta1. Haematologica. 2011;96:1302–9.CrossRefPubMedPubMedCentral
68.
Figueiro F, Muller L, Funk S, Jackson EK, Battastini AM, Whiteside TL. Phenotypic and functional characteristics of CD39(high) human regulatory B cells (Breg). Oncoimmunology. 2016;5:e1082703.CrossRefPubMedPubMedCentral
69.
Liu Y, Xiang X, Zhuang X, Zhang S, Liu C, Cheng Z, Michalek S, Grizzle W, Zhang HG. Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. Am J Pathol. 2010;176:2490–9.CrossRefPubMedPubMedCentral
70.
Chen X, Ying X, Wang X, Wu X, Zhu Q, Wang X. Exosomes derived from hypoxic epithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization. Oncol Rep. 2017;38:522–8.CrossRefPubMed
71.
Ye SB, Zhang H, Cai TT, Liu YN, Ni JJ, He J, Peng JY, Chen QY, Mo HY, Jun-cui, et al. Exosomal miR-24-3p impedes T-cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma. J Pathol. 2016;240:329–40.CrossRefPubMed
72.
Jung KO, Youn H, Lee CH, Kang KW, Chung JK. Visualization of exosome-mediated miR-210 transfer from hypoxic tumor cells. Oncotarget. 2017;8:9899–910.PubMed
73.
74.
Horie K, Kawakami K, Fujita Y, Sugaya M, Kameyama K, Mizutani K, Deguchi T, Ito M. Exosomes expressing carbonic anhydrase 9 promote angiogenesis. Biochem Biophys Res Commun. 2017;492:356–61.CrossRefPubMed
75.
Svensson KJ, Kucharzewska P, Christianson HC, Skold S, Lofstedt T, Johansson MC, Morgelin M, Bengzon J, Ruf W, Belting M. Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells. Proc Natl Acad Sci U S A. 2011;108:13147–52.CrossRefPubMedPubMedCentral
76.
Huang Z, Feng Y. Exosomes derived from hypoxic colorectal Cancer cells promote angiogenesis through Wnt4-induced beta-catenin signaling in endothelial cells. Oncol Res. 2017;25:651–61.CrossRefPubMedPubMedCentral
77.
Shan Y, You B, Shi S, Shi W, Zhang Z, Zhang Q, Gu M, Chen J, Bao L, Liu D, You Y. Hypoxia-induced matrix Metalloproteinase-13 expression in exosomes from nasopharyngeal carcinoma enhances metastases. Cell Death Dis. 2018;9:382.CrossRefPubMedPubMedCentral
78.
Aga M, Bentz GL, Raffa S, Torrisi MR, Kondo S, Wakisaka N, Yoshizaki T, Pagano JS, Shackelford J. Exosomal HIF1alpha supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene. 2014;33:4613–22.CrossRefPubMedPubMedCentral
79.
Berchem G, Noman MZ, Bosseler M, Paggetti J, Baconnais S, Le Cam E, Nanbakhsh A, Moussay E, Mami-Chouaib F, Janji B, Chouaib S. Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-beta and miR23a transfer. Oncoimmunology. 2016;5:e1062968.CrossRefPubMed
Metadata
Title
Role of hypoxia-induced exosomes in tumor biology
Authors
Chuchu Shao
Fengming Yang
Suyu Miao
Weitao Liu
Chaoshan Wang
Yongqian Shu
Hua Shen
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2018
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-018-0869-y

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