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Molecular Cancer
Published in: Molecular Cancer 1/2019

Open Access 01-12-2019 | Biomarkers | Review

Exosomes in the tumor microenvironment as mediators of cancer therapy resistance

Authors: Irene Li, Barzin Y. Nabet

Published in: Molecular Cancer | Issue 1/2019

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Abstract

Exosomes are small extracellular vesicles that contain genetic material, proteins, and lipids. They function as potent signaling molecules between cancer cells and the surrounding cells that comprise the tumor microenvironment (TME). Exosomes derived from both tumor and stromal cells have been implicated in all stages of cancer progression and play an important role in therapy resistance. Moreover, due to their nature as mediators of cell-cell communication, they are integral to TME-dependent therapy resistance. In this review, we discuss current exosome isolation and profiling techniques and their role in TME interactions and therapy resistance. We also explore emerging clinical applications of both exosomes as biomarkers, direct therapeutic targets, and engineered nanocarriers. In order to fully understand the TME, careful interrogation of exosomes and their cargo is critical. This understanding is a promising avenue for the development of effective clinical applications.
Literature
1.
Friedl P, Alexander S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell. 2011;147(5):992–1009.PubMedCrossRef
2.
3.
4.
Bissell MJ, Hines WC. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med. 2011;17(3):320–9.PubMedPubMedCentralCrossRef
5.
McMillin DW, Negri JM, Mitsiades CS. The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nat Rev Drug Discov. 2013;12(3):217–28.PubMedCrossRef
6.
Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013;501:346.PubMedCrossRef
7.
Li H, Courtois ET, Sengupta D, Tan Y, Chen KH, Goh JJL, et al. Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat Genet. 2017;49(5):708–18.PubMedCrossRef
8.
9.
Lambrechts D, Wauters E, Boeckx B, Aibar S, Nittner D, Burton O, et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat Med. 2018;24(8):1277–89.PubMedCrossRef
10.
Tirosh I, Izar B, Prakadan SM, Wadsworth MH, Treacy D, Trombetta JJ, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 2016;352(6282):189–96.PubMedPubMedCentralCrossRef
11.
Rodda LB, Lu E, Bennett ML, Sokol CL, Wang X, Luther SA, et al. Single-Cell RNA Sequencing of Lymph Node Stromal Cells Reveals Niche-Associated Heterogeneity. Immunity. 2018;48(5):1014–1028.e6.PubMedCrossRefPubMedCentral
12.
13.
Kowal J, Tkach M, Théry C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol. 2014;29:116–25.PubMedCrossRef
14.
15.
Théry C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006;3(22):1934–2616.
16.
17.
18.
19.
Wu M, Ouyang Y, Wang Z, Zhang R, Huang P-H, Chen C, et al. Isolation of exosomes from whole blood by integrating acoustics and microfluidics. Proc Natl Acad Sci. 2017;114(40):10584–9.PubMedCrossRefPubMedCentral
20.
Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2019;8(1):1535750.CrossRef
21.
Dragovic RA, Collett GP, Hole P, Ferguson DJP, Redman CW, Sargent IL, et al. Isolation of syncytiotrophoblast microvesicles and exosomes and their characterisation by multicolour flow cytometry and fluorescence nanoparticle tracking analysis. Methods. 2015;87:64–74.PubMedPubMedCentralCrossRef
22.
Llorente A, Skotland T, Sylvänne T, Kauhanen D, Róg T, Orłowski A, et al. Molecular lipidomics of exosomes released by PC-3 prostate cancer cells. Biochim Biophys Acta - Mol Cell Biol Lipids. 2013;1831(7):1302–9.CrossRef
23.
Zhang H, Freitas D, Kim HS, Fabijanic K, Li Z, Chen H, et al. Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation. Nat Cell Biol. 2018;20(3):332–43.PubMedPubMedCentralCrossRef
24.
Thakur BK, Zhang H, Becker A, Matei I, Huang Y, Costa-Silva B, et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 2014;24(6):766–9.PubMedPubMedCentralCrossRef
25.
Kim KM, Abdelmohsen K, Mustapic M, Kapogiannis D, Gorospe M. RNA in extracellular vesicles. Wiley Interdiscip Rev RNA. 2017;8(4):e1413.CrossRef
26.
Pocsfalvi G, Stanly C, Vilasi A, Fiume I, Capasso G, Turiák L, et al. Mass spectrometry of extracellular vesicles. Mass Spectrom Rev. 2016;35(1):3–21.PubMedCrossRef
27.
Soekmadji C, Hill AF, Wauben MH, Buzás EI, Di Vizio D, Gardiner C, et al. Towards mechanisms and standardization in extracellular vesicle and extracellular RNA studies: results of a worldwide survey. J Extracell Vesicles. 2018;7(1):1535745.PubMedPubMedCentralCrossRef
28.
Keerthikumar S, Gangoda L, Gho YS, Mathivanan S. Bioinformatics tools for extracellular vesicles research. In: Hill AF, editor. Exosomes and microvesicles: methods and protocols. New York, NY: Springer New York; 2017. p. 189–196.
29.
Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol. 2008;10(5):619–24.PubMedCrossRef
30.
Melo SA, Sugimoto H, O’Connell JT, Kato N, Villanueva A, Vidal A, et al. Cancer exosomes perform cell-independent MicroRNA biogenesis and promote tumorigenesis. Cancer Cell. 2014;26(5):707–21.PubMedPubMedCentralCrossRef
31.
Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9.PubMedCrossRef
32.
Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10(12):1470–6.PubMedPubMedCentralCrossRef
33.
Qu JL, Qu XJ, Zhao MF, Teng YE, Zhang Y, Hou KZ, et al. Gastric cancer exosomes promote tumour cell proliferation through PI3K/Akt and MAPK/ERK activation. Dig Liver Dis. 2009;41(12):875–80.PubMedCrossRef
34.
Ristorcelli E, Beraud E, Mathieu S, Lombardo D, Verine A. Essential role of notch signaling in apoptosis of human pancreatic tumoral cells mediated by exosomal nanoparticles. Int J Cancer. 2009;125(5):1016–26.PubMedCrossRef
35.
Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1(1):27–30.PubMedCrossRef
36.
37.
Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992;359(6398):843–5.PubMedCrossRef
38.
Ding B-S, Cao Z, Lis R, Nolan DJ, Guo P, Simons M, et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature. 2014;505(7481):97–102.PubMedCrossRef
39.
Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell. 2014;25(4):501–15.PubMedPubMedCentralCrossRef
40.
Umezu T, Ohyashiki K, Kuroda M, Ohyashiki JH. Leukemia cell to endothelial cell communication via exosomal miRNAs. Oncogene. 2012;32:2747.PubMedCrossRef
41.
42.
43.
Erez N, Truitt M, Olson P, Arron ST, Hanahan D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell. 2010;17(2):135–47.PubMedCrossRef
44.
Kumar V, Donthireddy L, Marvel D, Condamine T, Wang F, Lavilla-Alonso S, et al. Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors. Cancer Cell. 2017;32(5):654–668.e5.PubMedPubMedCentralCrossRef
45.
LeBleu VS, Teng Y, O’Connell JT, Charytan D, Müller GA, Müller CA, et al. Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis. Nat Med. 2013;19(2):227–31.PubMedPubMedCentralCrossRef
46.
Scherz-Shouval R, Santagata S, Mendillo ML, Sholl LM, Ben-Aharon I, Beck AH, et al. The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell. 2014;158(3):564–78.PubMedPubMedCentralCrossRef
47.
48.
Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121(3):335–48.PubMedCrossRef
49.
Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, et al. Stromal elements act to restrain, rather than support, Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2014;25(6):735–47.PubMedPubMedCentralCrossRef
50.
Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu C-C, Simpson TR, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas Cancer with reduced survival. Cancer Cell. 2014;25(6):719–34.PubMedPubMedCentralCrossRef
51.
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.PubMedPubMedCentralCrossRef
52.
Luga V, Zhang L, Viloria-Petit AM, Ogunjimi 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.PubMedCrossRef
53.
Zhao H, Yang L, Baddour J, Achreja A, Bernard V, Moss T, et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. Elife. 2016;27:5.
54.
Sansone P, Savini C, Kurelac I, Chang Q, Amato LB, Strillacci A, et al. Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proc Natl Acad Sci. 2017;1704862114:201704862.
55.
Hu Y, Yan C, Mu L, Huang K, Li X, Tao D, et al. Fibroblast-derived exosomes contribute to Chemoresistance through priming Cancer stem cells in colorectal Cancer. PLoS One. 2015;10(5):e0125625.PubMedPubMedCentralCrossRef
56.
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.PubMedPubMedCentralCrossRef
57.
Nabet BY, Qiu Y, Shabason JE, Wu TJ, Yoon T, Kim BC, et al. Exosome RNA Unshielding Couples Stromal Activation to Pattern Recognition Receptor Signaling in Cancer. Cell. 2017;170(2):352–366.e13.PubMedCrossRefPubMedCentral
58.
59.
Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.PubMedCrossRef
60.
Bobrie A, Colombo M, Raposo G, Théry C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic. 2011;12(12):1659–68.PubMedCrossRef
61.
Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9(8):581–93.PubMedCrossRef
62.
Moroishi T, Hayashi T, Pan W, Fujita Y, Holt MV, Qin J, et al. The hippo pathway kinases LATS1 / 2 suppress Cancer immunity. Cell. 2016;167(6):1525–39.PubMedPubMedCentralCrossRef
63.
Yu S, Liu C, Su K, Wang J, Liu Y, Zhang L, et al. Tumor exosomes inhibit differentiation of bone marrow dendritic cells. J Immunol. 2007;178(11):6867–75.PubMedCrossRef
64.
Liu Y, Xiang X, Zhuang X, Zhang S, Liu C, Cheng Z, et al. Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. Am J Pathol. 2010;176(5):2490–9.PubMedPubMedCentralCrossRef
65.
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.PubMedPubMedCentralCrossRef
66.
Liu Y, Gu Y, Han Y, Zhang Q, Jiang Z, Zhang X, et al. Tumor Exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell. 2016;30(2):243–56.PubMedCrossRef
67.
Dreux M, Garaigorta U, Boyd B, Décembre E, Chung J, Whitten-Bauer C, et al. Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity. Cell Host Microbe. 2012;12(4):558–70.PubMedPubMedCentralCrossRef
68.
Li J, Liu K, Liu Y, Xu Y, Zhang F, Yang H, et al. Exosomes mediate the cell-to-cell transmission of IFN-α-induced antiviral activity. Nat Immunol. 2013;14:793–803.PubMedCrossRef
69.
Baglio SR, van Eijndhoven MAJ, Koppers-Lalic D, Berenguer J, Lougheed SM, Gibbs S, et al. Sensing of latent EBV infection through exosomal transfer of 5′pppRNA. Proc Natl Acad Sci. 2016;113(5):587–96.CrossRef
70.
Becker A, Thakur BK, Weiss JM, Kim HS, Peinado H, Lyden D. Extracellular vesicles in Cancer: cell-to-cell mediators of metastasis. Cancer Cell. 2016;30(6):836–48.PubMedPubMedCentralCrossRef
71.
Peinado H, Zhang H, Matei IR, Costa-Silva B, Hoshino A, Rodrigues G, et al. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer. 2017;17:302.PubMedCrossRef
72.
Peinado H, Alec 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. 2012;18(6):883-91.
73.
Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17(6):816-26.
74.
Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang W-C, et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature. 2015;527(7576):100–4.PubMedPubMedCentralCrossRef
75.
Hoshino A, Costa-Silva B, Shen T-L, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527(7578):329–35.PubMedPubMedCentralCrossRef
76.
Keklikoglou I, Cianciaruso C, Güç E, Squadrito ML, Spring LM, Tazzyman S, et al. Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models. Nat Cell Biol. 2018;21(2):190-202.
77.
Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350–5.
78.
79.
Minn AJ, Wherry EJ. Combination Cancer therapies with immune checkpoint blockade: convergence on interferon signaling. Cell. 2016;165(2):272–5.PubMedCrossRef
80.
Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;7718(560):382-6.
81.
Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015;523(7559):177–82.PubMedPubMedCentralCrossRef
82.
de Jong OG, Verhaar MC, Chen Y, Vader P, Gremmels H, Posthuma G, et al. Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes AU - de Jong. Olivier G J Extracell Vesicles. 2012;1(1):18396.CrossRef
83.
Newman AM, Bratman SV, To J, Wynne JF, Eclov NCW, Modlin LA, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20(5):548–54.PubMedPubMedCentralCrossRef
84.
Newman AM, Lovejoy AF, Klass DM, Kurtz DM, Chabon JJ, Scherer F, et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol. 2016;34(5):547-55.
85.
Vader P, Mol EA, Pasterkamp G, Schiffelers RM. Extracellular vesicles for drug delivery. Adv Drug Deliv Rev. 2016;106:148–56.PubMedCrossRef
86.
87.
Luan X, Sansanaphongpricha K, Myers I, Chen H, Yuan H, Sun D. Engineering exosomes as refined biological nanoplatforms for drug delivery. Acta Pharmacol Sin. 2017;38:754.PubMedPubMedCentralCrossRef
88.
Tian Y, Li S, Song J, Ji T, Zhu M, Anderson GJ, et al. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials. 2014;35(7):2383–90.PubMedCrossRef
89.
Kamerkar S, Lebleu VS, Sugimoto H, Yang S, Ruivo CF, Melo SA, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature. 2017;546(7659):498–503.PubMedPubMedCentralCrossRef
90.
Kranz LM, Diken M, Haas H, Kreiter S, Loquai C, Reuter KC, et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. 2016;534(7607):396–401.PubMedCrossRef
91.
Yeo RWY, Lai RC, Zhang B, Tan SS, Yin Y, Teh BJ, et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev. 2013;65(3):336–41.PubMedCrossRef
Metadata
Title
Exosomes in the tumor microenvironment as mediators of cancer therapy resistance
Authors
Irene Li
Barzin Y. Nabet
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Biomarkers
Published in
Molecular Cancer / Issue 1/2019
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-019-0975-5

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