The Role of Extracellular Vesicles in Diseases of the Ear, Nose, and Throat
Abstract
:1. Introduction
2. Biology of Extracellular Vesicles
2.1. EV Biogenesis
2.2. EV Cargo
2.3. EV Isolation
2.4. EV Characterization
3. Role of EVs in Diseases of the Ear, Nose, and Throat
3.1. Head and Neck Cancer
3.2. Otitis Media
3.3. Chronic Rhinosinusitis
3.4. Acquired Cholesteatoma
3.5. Ototoxicity
4. Summary and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Carnino, J.M.; Lee, H. Extracellular vesicles in respiratory disease. Adv. Clin. Chem. 2022, 108, 105–127. [Google Scholar] [CrossRef]
- Carnino, J.M.; Lee, H.; Jin, Y. Isolation and characterization of extracellular vesicles from Broncho- alveolar lavage fluid: A review and comparison of different methods. Respir. Res. 2019, 20, 240. [Google Scholar] [CrossRef] [Green Version]
- Carnino, J.M.; Ni, K.; Jin, Y. Post-translational Modification Regulates Formation and Cargo-Loading of Extracellular Vesicles. Front. Immunol. 2020, 11, 948. [Google Scholar] [CrossRef] [PubMed]
- Carnino, J.M.; Hao Kwok, Z.; Jin, Y. Extracellular Vesicles: A Novel Opportunity for Precision Medicine in Respiratory Diseases. Front. Med. 2021, 8, 661679. [Google Scholar] [CrossRef]
- Babaei, M.; Rezaie, J. Application of stem cell-derived exosomes in ischemic diseases: Opportunity and limitations. J. Transl. Med. 2021, 19, 196. [Google Scholar] [CrossRef] [PubMed]
- Mansouri, N.; Willis, G.R.; Fernandez-Gonzalez, A.; Reis, M.; Nassiri, S.; Mitsialis, S.A.; Kourembanas, S. Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypes. JCI Insight. 2019, 4, 128060. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- van Niel, G.; D’Angelo, G.; Raposo, G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 2018, 19, 213–228. [Google Scholar] [CrossRef]
- Doyle, L.M.; Wang, M.Z. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells 2019, 8, 727. [Google Scholar] [CrossRef] [Green Version]
- Witwer, K.W.; Goberdhan, D.C.; O’Driscoll, L.; Thery, C.; Welsh, J.A.; Blenkiron, C.; Buzas, E.I.; Di Vizio, D.; Erdbrugger, U.; Falcon-Perez, J.M.; et al. Updating MISEV: Evolving the minimal requirements for studies of extracellular vesicles. J. Extracell. Vesicles 2021, 10, e12182. [Google Scholar] [CrossRef]
- Thery, C.; Witwer, K.W.; Aikawa, E.; Alcaraz, M.J.; Anderson, J.D.; Andriantsitohaina, R.; Antoniou, A.; Arab, T.; Archer, F.; Atkin-Smith, G.K.; 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 2018, 7, 1535750. [Google Scholar] [CrossRef]
- Villarroya-Beltri, C.; Baixauli, F.; Gutierrez-Vazquez, C.; Sanchez-Madrid, F.; Mittelbrunn, M. Sorting it out: Regulation of exosome loading. Semin. Cancer Biol. 2014, 28, 3–13. [Google Scholar] [CrossRef] [Green Version]
- Chen, Y.; Zhao, Y.; Yin, Y.; Jia, X.; Mao, L. Mechanism of cargo sorting into small extracellular vesicles. Bioengineered 2021, 12, 8186–8201. [Google Scholar] [CrossRef]
- de Gassart, A.; Geminard, C.; Fevrier, B.; Raposo, G.; Vidal, M. Lipid raft-associated protein sorting in exosomes. Blood 2003, 102, 4336–4344. [Google Scholar] [CrossRef] [Green Version]
- Dogrammatzis, C.; Deschamps, T.; Kalamvoki, M. Biogenesis of Extracellular Vesicles during Herpes Simplex Virus 1 Infection: Role of the CD63 Tetraspanin. J. Virol. 2019, 93, e01850-18. [Google Scholar] [CrossRef] [Green Version]
- Villarroya-Beltri, C.; Gutierrez-Vazquez, C.; Sanchez-Cabo, F.; Perez-Hernandez, D.; Vazquez, J.; Martin-Cofreces, N.; Martinez-Herrera, D.J.; Pascual-Montano, A.; Mittelbrunn, M.; Sanchez-Madrid, F. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 2013, 4, 2980. [Google Scholar] [CrossRef] [Green Version]
- Bolukbasi, M.F.; Mizrak, A.; Ozdener, G.B.; Madlener, S.; Strobel, T.; Erkan, E.P.; Fan, J.B.; Breakefield, X.O.; Saydam, O. miR-1289 and “Zipcode”-like Sequence Enrich mRNAs in Microvesicles. Mol. Ther. Nucleic Acids 2012, 1, e10. [Google Scholar] [CrossRef] [PubMed]
- Yokoi, A.; Villar-Prados, A.; Oliphint, P.A.; Zhang, J.; Song, X.; De Hoff, P.; Morey, R.; Liu, J.; Roszik, J.; Clise-Dwyer, K.; et al. Mechanisms of nuclear content loading to exosomes. Sci. Adv. 2019, 5, eaax8849. [Google Scholar] [CrossRef] [Green Version]
- Haraszti, R.A.; Didiot, M.C.; Sapp, E.; Leszyk, J.; Shaffer, S.A.; Rockwell, H.E.; Gao, F.; Narain, N.R.; DiFiglia, M.; Kiebish, M.A.; et al. High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources. J. Extracell. Vesicles 2016, 5, 32570. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gardiner, C.; Di Vizio, D.; Sahoo, S.; Thery, C.; Witwer, K.W.; Wauben, M.; Hill, A.F. Techniques used for the isolation and characterization of extracellular vesicles: Results of a worldwide survey. J. Extracell. Vesicles 2016, 5, 32945. [Google Scholar] [CrossRef] [PubMed]
- Lucchetti, D.; Fattorossi, A.; Sgambato, A. Extracellular Vesicles in Oncology: Progress and Pitfalls in the Methods of Isolation and Analysis. Biotechnol. J. 2019, 14, e1700716. [Google Scholar] [CrossRef]
- Konoshenko, M.Y.; Lekchnov, E.A.; Vlassov, A.V.; Laktionov, P.P. Isolation of Extracellular Vesicles: General Methodologies and Latest Trends. Biomed Res. Int. 2018, 2018, 8545347. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gamez-Valero, A.; Monguio-Tortajada, M.; Carreras-Planella, L.; Franquesa, M.; Beyer, K.; Borras, F.E. Size-Exclusion Chromatography-based isolation minimally alters Extracellular Vesicles’ characteristics compared to precipitating agents. Sci. Rep. 2016, 6, 33641. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kowal, J.; Arras, G.; Colombo, M.; Jouve, M.; Morath, J.P.; 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. USA 2016, 113, E968–E977. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Heath, N.; Grant, L.; De Oliveira, T.M.; Rowlinson, R.; Osteikoetxea, X.; Dekker, N.; Overman, R. Rapid isolation and enrichment of extracellular vesicle preparations using anion exchange chromatography. Sci. Rep. 2018, 8, 5730. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gallart-Palau, X.; Serra, A.; Wong, A.S.; Sandin, S.; Lai, M.K.; Chen, C.P.; Kon, O.L.; Sze, S.K. Extracellular vesicles are rapidly purified from human plasma by PRotein Organic Solvent PRecipitation (PROSPR). Sci. Rep. 2015, 5, 14664. [Google Scholar] [CrossRef] [Green Version]
- Crowell, A.M.; Wall, M.J.; Doucette, A.A. Maximizing recovery of water-soluble proteins through acetone precipitation. Anal. Chim. Acta 2013, 796, 48–54. [Google Scholar] [CrossRef] [PubMed]
- Deregibus, M.C.; Figliolini, F.; D’Antico, S.; Manzini, P.M.; Pasquino, C.; De Lena, M.; Tetta, C.; Brizzi, M.F.; Camussi, G. Charge-based precipitation of extracellular vesicles. Int. J. Mol. Med. 2016, 38, 1359–1366. [Google Scholar] [CrossRef] [Green Version]
- Rider, M.A.; Hurwitz, S.N.; Meckes, D.G., Jr. ExtraPEG: A Polyethylene Glycol-Based Method for Enrichment of Extracellular Vesicles. Sci. Rep. 2016, 6, 23978. [Google Scholar] [CrossRef]
- Brownlee, Z.; Lynn, K.D.; Thorpe, P.E.; Schroit, A.J. A novel “salting-out” procedure for the isolation of tumor-derived exosomes. J. Immunol. Methods 2014, 407, 120–126. [Google Scholar] [CrossRef] [Green Version]
- Kanwar, S.S.; Dunlay, C.J.; Simeone, D.M.; Nagrath, S. Microfluidic device (ExoChip) for on-chip isolation, quantification and characterization of circulating exosomes. Lab Chip 2014, 14, 1891–1900. [Google Scholar] [CrossRef]
- Chen, C.; Skog, J.; Hsu, C.H.; Lessard, R.T.; Balaj, L.; Wurdinger, T.; Carter, B.S.; Breakefield, X.O.; Toner, M.; Irimia, D. Microfluidic isolation and transcriptome analysis of serum microvesicles. Lab Chip 2010, 10, 505–511. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liangsupree, T.; Multia, E.; Riekkola, M.L. Modern isolation and separation techniques for extracellular vesicles. J. Chromatogr. A 2021, 1636, 461773. [Google Scholar] [CrossRef]
- Sunkara, V.; Woo, H.K.; Cho, Y.K. Emerging techniques in the isolation and characterization of extracellular vesicles and their roles in cancer diagnostics and prognostics. Analyst 2016, 141, 371–381. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Filipe, V.; Hawe, A.; Jiskoot, W. Critical evaluation of Nanoparticle Tracking Analysis (NTA) by NanoSight for the measurement of nanoparticles and protein aggregates. Pharm. Res. 2010, 27, 796–810. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Morales-Kastresana, A.; Telford, B.; Musich, T.A.; McKinnon, K.; Clayborne, C.; Braig, Z.; Rosner, A.; Demberg, T.; Watson, D.C.; Karpova, T.S.; et al. Labeling Extracellular Vesicles for Nanoscale Flow Cytometry. Sci. Rep. 2017, 7, 1878. [Google Scholar] [CrossRef] [Green Version]
- Linares, R.; Tan, S.; Gounou, C.; Brisson, A.R. Imaging and Quantification of Extracellular Vesicles by Transmission Electron Microscopy. Methods Mol. Biol. 2017, 1545, 43–54. [Google Scholar] [CrossRef] [PubMed]
- Qu, X.; Li, J.W.; Chan, J.; Meehan, K. Extracellular Vesicles in Head and Neck Cancer: A Potential New Trend in Diagnosis, Prognosis, and Treatment. Int. J. Mol. Sci. 2020, 21, 8260. [Google Scholar] [CrossRef]
- Hofmann, L.; Ludwig, S.; Vahl, J.M.; Brunner, C.; Hoffmann, T.K.; Theodoraki, M.N. The Emerging Role of Exosomes in Diagnosis, Prognosis, and Therapy in Head and Neck Cancer. Int. J. Mol. Sci. 2020, 21, 4072. [Google Scholar] [CrossRef]
- Wang, X.; Wu, S.; Liu, F.; Ke, D.; Wang, X.; Pan, D.; Xu, W.; Zhou, L.; He, W. An Immunogenic Cell Death-Related Classification Predicts Prognosis and Response to Immunotherapy in Head and Neck Squamous Cell Carcinoma. Front. Immunol. 2021, 12, 781466. [Google Scholar] [CrossRef]
- You, Y.; Shan, Y.; Chen, J.; Yue, H.; You, B.; Shi, S.; Li, X.; Cao, X. Matrix metalloproteinase 13-containing exosomes promote nasopharyngeal carcinoma metastasis. Cancer Sci. 2015, 106, 1669–1677. [Google Scholar] [CrossRef]
- Ponte, F.; Kim, H.N.; Warren, A.; Iyer, S.; Han, L.; Mannen, E.; Gomez-Acevedo, H.; Nookaew, I.; Almeida, M.; Manolagas, S.C. Mmp13 deletion in mesenchymal cells increases bone mass and may attenuate the cortical bone loss caused by estrogen deficiency. Sci. Rep. 2022, 12, 10257. [Google Scholar] [CrossRef] [PubMed]
- Shan, Y.; You, B.; Shi, S.; Shi, W.; Zhang, Z.; Zhang, Q.; Gu, M.; Chen, J.; Bao, L.; Liu, D.; et al. Hypoxia-Induced Matrix Metalloproteinase-13 Expression in Exosomes from Nasopharyngeal Carcinoma Enhances Metastases. Cell Death Dis. 2018, 9, 382. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zuo, L.; Xie, Y.; Tang, J.; Xin, S.; Liu, L.; Zhang, S.; Yan, Q.; Zhu, F.; Lu, J. Targeting Exosomal EBV-LMP1 Transfer and miR-203 Expression via the NF- kappaB Pathway: The Therapeutic Role of Aspirin in NPC. Mol. Ther. Nucleic Acids 2019, 17, 175–184. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liao, C.; Zhou, Q.; Zhang, Z.; Wu, X.; Zhou, Z.; Li, B.; Peng, J.; Shen, L.; Li, D.; Luo, X.; et al. Epstein-Barr virus-encoded latent membrane protein 1 promotes extracellular vesicle secretion through syndecan-2 and synaptotagmin- like-4 in nasopharyngeal carcinoma cells. Cancer Sci. 2020, 111, 857–868. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, Z.; Yu, X.; Zhou, Z.; Li, B.; Peng, J.; Wu, X.; Luo, X.; Yang, L. LMP1-positive extracellular vesicles promote radioresistance in nasopharyngeal carcinoma cells through P38 MAPK signaling. Cancer Med. 2019, 8, 6082–6094. [Google Scholar] [CrossRef] [Green Version]
- He, L.; Ping, F.; Fan, Z.; Zhang, C.; Deng, M.; Cheng, B.; Xia, J. Salivary exosomal miR-24-3p serves as a potential detective biomarker for oral squamous cell carcinoma screening. Biomed. Pharmacother. 2020, 121, 109553. [Google Scholar] [CrossRef]
- Ono, K.; Eguchi, T.; Sogawa, C.; Calderwood, S.K.; Futagawa, J.; Kasai, T.; Seno, M.; Okamoto, K.; Sasaki, A.; Kozaki, K.I. HSP-enriched properties of extracellular vesicles involve survival of metastatic oral cancer cells. J. Cell Biochem. 2018, 119, 7350–7362. [Google Scholar] [CrossRef] [Green Version]
- Fujiwara, T.; Eguchi, T.; Sogawa, C.; Ono, K.; Murakami, J.; Ibaragi, S.; Asaumi, J.I.; Calderwood, S.K.; Okamoto, K.; Kozaki, K.I. Carcinogenic epithelial-mesenchymal transition initiated by oral cancer exosomes is inhibited by anti-EGFR antibody cetuximab. Oral Oncol. 2018, 86, 251–257. [Google Scholar] [CrossRef]
- Economopoulou, P.; Kotsantis, I.; Psyrri, A. Tumor Microenvironment and Immunotherapy Response in Head and Neck Cancer. Cancers 2020, 12, 3377. [Google Scholar] [CrossRef]
- Ludwig, S.; Floros, T.; Theodoraki, M.N.; Hong, C.S.; Jackson, E.K.; Lang, S.; Whiteside, T.L. Suppression of Lymphocyte Functions by Plasma Exosomes Correlates with Disease Activity in Patients with Head and Neck Cancer. Clin. Cancer Res. 2017, 23, 4843–4854. [Google Scholar] [CrossRef]
- Maybruck, B.T.; Pfannenstiel, L.W.; Diaz-Montero, M.; Gastman, B.R. Tumor-derived exosomes induce CD8(+) T cell suppressors. J. Immunother. Cancer 2017, 5, 65. [Google Scholar] [CrossRef]
- Li, L.; Li, C.; Wang, S.; Wang, Z.; Jiang, J.; Wang, W.; Li, X.; Chen, J.; Liu, K.; Li, C.; et al. Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype. Cancer Res. 2016, 76, 1770–1780. [Google Scholar] [CrossRef] [Green Version]
- Li, L.; Cao, B.; Liang, X.; Lu, S.; Luo, H.; Wang, Z.; Wang, S.; Jiang, J.; Lang, J.; Zhu, G. Microenvironmental oxygen pressure orchestrates an anti- and pro-tumoral gammadelta T cell equilibrium via tumor-derived exosomes. Oncogene 2019, 38, 2830–2843. [Google Scholar] [CrossRef] [PubMed]
- Ludwig, S.; Sharma, P.; Theodoraki, M.N.; Pietrowska, M.; Yerneni, S.S.; Lang, S.; Ferrone, S.; Whiteside, T.L. Molecular and Functional Profiles of Exosomes From HPV(+) and HPV(-) Head and Neck Cancer Cell Lines. Front. Oncol. 2018, 8, 445. [Google Scholar] [CrossRef] [PubMed]
- Theodoraki, M.N.; Yerneni, S.S.; Hoffmann, T.K.; Gooding, W.E.; Whiteside, T.L. Clinical Significance of PD-L1(+) Exosomes in Plasma of Head and Neck Cancer Patients. Clin. Cancer Res. 2018, 24, 896–905. [Google Scholar] [CrossRef] [Green Version]
- Skog, J.; Wurdinger, T.; van Rijn, S.; Meijer, D.H.; Gainche, L.; Sena-Esteves, M.; Curry, W.T., Jr.; Carter, B.S.; Krichevsky, A.M.; Breakefield, X.O. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 2008, 10, 1470–1476. [Google Scholar] [CrossRef] [PubMed]
- Al-Nedawi, K.; Meehan, B.; Micallef, J.; Lhotak, V.; May, L.; Guha, A.; Rak, J. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat. Cell Biol. 2008, 10, 619–624. [Google Scholar] [CrossRef] [PubMed]
- You, B.; Cao, X.; Shao, X.; Ni, H.; Shi, S.; Shan, Y.; Gu, Z.; You, Y. Clinical and biological significance of HAX-1 overexpression in nasopharyngeal carcinoma. Oncotarget 2016, 7, 12505–12524. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dickman, C.T.; Lawson, J.; Jabalee, J.; MacLellan, S.A.; LePard, N.E.; Bennewith, K.L.; Garnis, C. Selective extracellular vesicle exclusion of miR-142-3p by oral cancer cells promotes both internal and extracellular malignant phenotypes. Oncotarget 2017, 8, 15252–15266. [Google Scholar] [CrossRef] [Green Version]
- Bao, L.; You, B.; Shi, S.; Shan, Y.; Zhang, Q.; Yue, H.; Zhang, J.; Zhang, W.; Shi, Y.; Liu, Y.; et al. Metastasis-associated miR-23a from nasopharyngeal carcinoma-derived exosomes mediates angiogenesis by repressing a novel target gene TSGA10. Oncogene 2018, 37, 2873–2889. [Google Scholar] [CrossRef]
- Duan, B.; Shi, S.; Yue, H.; You, B.; Shan, Y.; Zhu, Z.; Bao, L.; You, Y. Exosomal miR-17-5p promotes angiogenesis in nasopharyngeal carcinoma via targeting BAMBI. J. Cancer 2019, 10, 6681–6692. [Google Scholar] [CrossRef] [PubMed]
- Lu, J.; Liu, Q.H.; Wang, F.; Tan, J.J.; Deng, Y.Q.; Peng, X.H.; Liu, X.; Zhang, B.; Xu, X.; Li, X.P. Exosomal miR-9 inhibits angiogenesis by targeting MDK and regulating PDK/AKT pathway in nasopharyngeal carcinoma. J. Exp. Clin. Cancer Res. 2018, 37, 147. [Google Scholar] [CrossRef] [Green Version]
- Sato, S.; Vasaikar, S.; Eskaros, A.; Kim, Y.; Lewis, J.S.; Zhang, B.; Zijlstra, A.; Weaver, A.M. EPHB2 carried on small extracellular vesicles induces tumor angiogenesis via activation of ephrin reverse signaling. JCI Insight 2019, 4, e132447. [Google Scholar] [CrossRef] [PubMed]
- Gu, M.; Li, L.; Zhang, Z.; Chen, J.; Zhang, W.; Zhang, J.; Han, L.; Tang, M.; You, B.; Zhang, Q.; et al. PFKFB3 promotes proliferation, migration and angiogenesis in nasopharyngeal carcinoma. J. Cancer 2017, 8, 3887–3896. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ludwig, N.; Yerneni, S.S.; Azambuja, J.H.; Gillespie, D.G.; Menshikova, E.V.; Jackson, E.K.; Whiteside, T.L. Tumor-derived exosomes promote angiogenesis via adenosine A2B receptor signaling. Angiogenesis 2020, 23, 599–610. [Google Scholar] [CrossRef]
- Kolenda, T.; Przybyla, W.; Kapalczynska, M.; Teresiak, A.; Zajaczkowska, M.; Blizniak, R.; Lamperska, K.M. Tumor microenvironment—Unknown niche with powerful therapeutic potential. Rep. Pract. Oncol. Radiother. 2018, 23, 143–153. [Google Scholar] [CrossRef] [PubMed]
- Marsh, D.; Suchak, K.; Moutasim, K.A.; Vallath, S.; Hopper, C.; Jerjes, W.; Upile, T.; Kalavrezos, N.; Violette, S.M.; Weinreb, P.H.; et al. Stromal features are predictive of disease mortality in oral cancer patients. J. Pathol. 2011, 223, 470–481. [Google Scholar] [CrossRef]
- Wu, X.; Zhou, Z.; Xu, S.; Liao, C.; Chen, X.; Li, B.; Peng, J.; Li, D.; Yang, L. Extracellular vesicle packaged LMP1-activated fibroblasts promote tumor progression via autophagy and stroma-tumor metabolism coupling. Cancer Lett. 2020, 478, 93–106. [Google Scholar] [CrossRef] [PubMed]
- Hou, J.; Wang, F.; Liu, X.; Song, M.; Yin, X. Tumor-derived exosomes enhance invasion and metastasis of salivary adenoid cystic carcinoma cells. J. Oral Pathol. Med. 2018, 47, 144–151. [Google Scholar] [CrossRef]
- Xu, Z.; Zheng, X.; Zheng, J. Tumor-derived exosomes educate fibroblasts to promote salivary adenoid cystic carcinoma metastasis via NGF-NTRK1 pathway. Oncol. Lett. 2019, 18, 4082–4091. [Google Scholar] [CrossRef]
- Evrard, D.; Szturz, P.; Tijeras-Raballand, A.; Astorgues-Xerri, L.; Abitbol, C.; Paradis, V.; Raymond, E.; Albert, S.; Barry, B.; Faivre, S. Macrophages in the microenvironment of head and neck cancer: Potential targets for cancer therapy. Oral Oncol. 2019, 88, 29–38. [Google Scholar] [CrossRef] [PubMed]
- Cai, J.; Qiao, B.; Gao, N.; Lin, N.; He, W. Oral squamous cell carcinoma-derived exosomes promote M2 subtype macrophage polarization mediated by exosome-enclosed miR-29a-3p. Am. J. Physiol. Cell Physiol. 2019, 316, C731–C740. [Google Scholar] [CrossRef]
- Hsieh, C.H.; Tai, S.K.; Yang, M.H. Snail-overexpressing Cancer Cells Promote M2-Like Polarization of Tumor- Associated Macrophages by Delivering MiR-21-Abundant Exosomes. Neoplasia 2018, 20, 775–788. [Google Scholar] [CrossRef] [PubMed]
- Tong, F.; Mao, X.; Zhang, S.; Xie, H.; Yan, B.; Wang, B.; Sun, J.; Wei, L. HPV + HNSCC-derived exosomal miR-9 induces macrophage M1 polarization and increases tumor radiosensitivity. Cancer Lett. 2020, 478, 34–44. [Google Scholar] [CrossRef] [PubMed]
- Pucci, M.; Raimondo, S.; Urzi, O.; Moschetti, M.; Di Bella, M.A.; Conigliaro, A.; Caccamo, N.; La Manna, M.P.; Fontana, S.; Alessandro, R. Tumor-Derived Small Extracellular Vesicles Induce Pro-Inflammatory Cytokine Expression and PD-L1 Regulation in M0 Macrophages via IL-6/STAT3 and TLR4 Signaling Pathways. Int. J. Mol. Sci. 2021, 22, 12118. [Google Scholar] [CrossRef] [PubMed]
- Kanno, Y.; Chen, C.Y.; Lee, H.L.; Chiou, J.F.; Chen, Y.J. Molecular Mechanisms of Chemotherapy Resistance in Head and Neck Cancers. Front. Oncol. 2021, 11, 640392. [Google Scholar] [CrossRef] [PubMed]
- Khoo, X.H.; Paterson, I.C.; Goh, B.H.; Lee, W.L. Cisplatin-Resistance in Oral Squamous Cell Carcinoma: Regulation by Tumor Cell-Derived Extracellular Vesicles. Cancers 2019, 11, 1166. [Google Scholar] [CrossRef] [Green Version]
- Liu, T.; Chen, G.; Sun, D.; Lei, M.; Li, Y.; Zhou, C.; Li, X.; Xue, W.; Wang, H.; Liu, C.; et al. Exosomes containing miR-21 transfer the characteristic of cisplatin resistance by targeting PTEN and PDCD4 in oral squamous cell carcinoma. Acta Biochim. Biophys. Sin. 2017, 49, 808–816. [Google Scholar] [CrossRef] [Green Version]
- Kulkarni, B.; Gondaliya, P.; Kirave, P.; Rawal, R.; Jain, A.; Garg, R.; Kalia, K. Exosome-mediated delivery of miR-30a sensitize cisplatin-resistant variant of oral squamous carcinoma cells via modulating Beclin1 and Bcl2. Oncotarget 2020, 11, 1832–1845. [Google Scholar] [CrossRef]
- Kirave, P.; Gondaliya, P.; Kulkarni, B.; Rawal, R.; Garg, R.; Jain, A.; Kalia, K. Exosome mediated miR-155 delivery confers cisplatin chemoresistance in oral cancer cells via epithelial-mesenchymal transition. Oncotarget 2020, 11, 1157–1171. [Google Scholar] [CrossRef]
- Harmes, K.M.; Blackwood, R.A.; Burrows, H.L.; Cooke, J.M.; Harrison, R.V.; Passamani, P.P. Otitis media: Diagnosis and treatment. Am. Fam. Physician 2013, 88, 435–440. [Google Scholar] [PubMed]
- Lim, D.J.; Birck, H. Ultrastructural pathology of the middle ear mucosa in serous otitis media. Ann. Otol. Rhinol. Laryngol. 1971, 80, 838–853. [Google Scholar] [CrossRef] [PubMed]
- Ryan, A.F.; Jung, T.T.; Juhn, S.K.; Li, J.D.; Andalibi, A.; Lin, J.; Bakaletz, L.O.; Post, C.J.; Ehrlich, G.D. Recent advances in otitis media. 4A. Molecular biology. Ann. Otol. Rhinol. Laryngol. Suppl. 2005, 194, 42–49. [Google Scholar] [CrossRef] [PubMed]
- Thornton, R.B.; Wiertsema, S.P.; Kirkham, L.A.; Rigby, P.J.; Vijayasekaran, S.; Coates, H.L.; Richmond, P.C. Neutrophil extracellular traps and bacterial biofilms in middle ear effusion of children with recurrent acute otitis media--a potential treatment target. PLoS ONE 2013, 8, e53837. [Google Scholar] [CrossRef] [PubMed]
- Preciado, D.; Goyal, S.; Rahimi, M.; Watson, A.M.; Brown, K.J.; Hathout, Y.; Rose, M.C. MUC5B Is the predominant mucin glycoprotein in chronic otitis media fluid. Pediatr. Res. 2010, 68, 231–236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Moon, H.G.; Cao, Y.; Yang, J.; Lee, J.H.; Choi, H.S.; Jin, Y. Lung epithelial cell-derived extracellular vesicles activate macrophage- mediated inflammatory responses via ROCK1 pathway. Cell Death Dis. 2015, 6, e2016. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Val, S.; Jeong, S.; Poley, M.; Krueger, A.; Nino, G.; Brown, K.; Preciado, D. Purification and characterization of microRNAs within middle ear fluid exosomes: Implication in otitis media pathophysiology. Pediatr. Res. 2017, 81, 911–918. [Google Scholar] [CrossRef] [Green Version]
- Marcus, S.; DelGaudio, J.M.; Roland, L.T.; Wise, S.K. Chronic Rhinosinusitis: Does Allergy Play a Role? Med. Sci. 2019, 7, 30. [Google Scholar] [CrossRef] [Green Version]
- Piszczatowska, K.; Czerwaty, K.; Cyran, A.M.; Fiedler, M.; Ludwig, N.; Brzost, J.; Szczepanski, M.J. The Emerging Role of Small Extracellular Vesicles in Inflammatory Airway Diseases. Diagnostics 2021, 11, 222. [Google Scholar] [CrossRef]
- Fokkens, W.J.; Lund, V.J.; Hopkins, C.; Hellings, P.W.; Kern, R.; Reitsma, S.; Toppila-Salmi, S.; Bernal-Sprekelsen, M.; Mullol, J.; Alobid, I.; et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology 2020, 58, 1–464. [Google Scholar] [CrossRef]
- Mueller, S.K.; Nocera, A.L.; Dillon, S.T.; Gu, X.; Wendler, O.; Otu, H.H.; Libermann, T.A.; Bleier, B.S. Noninvasive exosomal proteomic biosignatures, including cystatin SN, peroxiredoxin-5, and glycoprotein VI, accurately predict chronic rhinosinusitis with nasal polyps. Int. Forum Allergy Rhinol. 2019, 9, 177–186. [Google Scholar] [CrossRef] [PubMed]
- Miyake, M.M.; Workman, A.D.; Nocera, A.L.; Wu, D.; Mueller, S.K.; Finn, K.; Amiji, M.M.; Bleier, B.S. Discriminant analysis followed by unsupervised cluster analysis including exosomal cystatins predict presence of chronic rhinosinusitis, phenotype, and disease severity. Int. Forum Allergy Rhinol. 2019, 9, 1069–1076. [Google Scholar] [CrossRef] [PubMed]
- Mueller, S.K.; Nocera, A.L.; Dillon, S.T.; Libermann, T.A.; Wendler, O.; Bleier, B.S. Tissue and Exosomal Serine Protease Inhibitors Are Significantly Overexpressed in Chronic Rhinosinusitis With Nasal Polyps. Am. J. Rhinol. Allergy 2019, 33, 359–368. [Google Scholar] [CrossRef] [PubMed]
- Si, Y.; Chen, Y.B.; Chen, S.J.; Zheng, Y.Q.; Liu, X.; Liu, Y.; Jiang, H.L.; Xu, G.; Li, Z.H.; Huang, Q.H.; et al. TLR4 drives the pathogenesis of acquired cholesteatoma by promoting local inflammation and bone destruction. Sci. Rep. 2015, 5, 16683. [Google Scholar] [CrossRef] [Green Version]
- Brook, I.; Burke, P. The management of acute, serous and chronic otitis media: The role of anaerobic bacteria. J. Hosp. Infect. 1992, 22, 75–87. [Google Scholar] [CrossRef]
- Kuo, C.L.; Lien, C.F.; Shiao, A.S. Mastoid obliteration for pediatric suppurative cholesteatoma: Long-term safety and sustained effectiveness after 30 years’ experience with cartilage obliteration. Audiol. Neurootol. 2014, 19, 358–369. [Google Scholar] [CrossRef]
- Tomlin, J.; Chang, D.; McCutcheon, B.; Harris, J. Surgical technique and recurrence in cholesteatoma: A meta-analysis. Audiol. Neurootol. 2013, 18, 135–142. [Google Scholar] [CrossRef]
- Gong, N.; Zhu, W.; Xu, R.; Teng, Z.; Deng, C.; Zhou, H.; Xia, M.; Zhao, M. Keratinocytes-derived exosomal miRNA regulates osteoclast differentiation in middle ear cholesteatoma. Biochem. Biophys. Res. Commun. 2020, 525, 341–347. [Google Scholar] [CrossRef]
- Wong, E.H.C.; Dong, Y.Y.; Coray, M.; Cortada, M.; Levano, S.; Schmidt, A.; Brand, Y.; Bodmer, D.; Muller, L. Inner ear exosomes and their potential use as biomarkers. PLoS ONE 2018, 13, e0198029. [Google Scholar] [CrossRef] [Green Version]
- Francis, S.P.; Kramarenko, I.I.; Brandon, C.S.; Lee, F.S.; Baker, T.G.; Cunningham, L.L. Celastrol inhibits aminoglycoside-induced ototoxicity via heat shock protein 32. Cell Death Dis. 2011, 2, e195. [Google Scholar] [CrossRef] [Green Version]
- Taleb, M.; Brandon, C.S.; Lee, F.S.; Lomax, M.I.; Dillmann, W.H.; Cunningham, L.L. Hsp70 inhibits aminoglycoside-induced hair cell death and is necessary for the protective effect of heat shock. J. Assoc. Res. Otolaryngol. 2008, 9, 277–289. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Breglio, A.M.; May, L.A.; Barzik, M.; Welsh, N.C.; Francis, S.P.; Costain, T.Q.; Wang, L.; Anderson, D.E.; Petralia, R.S.; Wang, Y.X.; et al. Exosomes mediate sensory hair cell protection in the inner ear. J. Clin. Investig. 2020, 130, 2657–2672. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hao, F.; Shan, C.; Zhang, Y.; Zhang, Y.; Jia, Z. Exosomes Derived from microRNA-21 Overexpressing Neural Progenitor Cells Prevent Hearing Loss from Ischemia-Reperfusion Injury in Mice via Inhibiting the Inflammatory Process in the Cochlea. ACS Chem. Neurosci. 2022, 13, 2464–2472. [Google Scholar] [CrossRef] [PubMed]
- Yang, T.; Li, W.; Peng, A.; Liu, J.; Wang, Q. Exosomes Derived from Bone Marrow-Mesenchymal Stem Cells Attenuates Cisplatin-Induced Ototoxicity in a Mouse Model. J. Clin. Med. 2022, 11, 4743. [Google Scholar] [CrossRef]
- Yang, T.; Li, W.; Peng, A.; Wang, Q. Exosomes derived from heat shock preconditioned bone marrow mesenchymal stem cells alleviate cisplatin-induced ototoxicity in mice. J. Biol. Eng. 2022, 16, 24. [Google Scholar] [CrossRef] [PubMed]
- Lai, R.; Cai, C.; Wu, W.; Hu, P.; Wang, Q. Exosomes derived from mouse inner ear stem cells attenuate gentamicin-induced ototoxicity in vitro through the miR-182-5p/FOXO3 axis. J. Tissue Eng. Regen. Med. 2020, 14, 1149–1156. [Google Scholar] [CrossRef] [PubMed]
Reported Role of EVs | References |
---|---|
Metastasis and Proliferation:
| [37,40,42,43,44,45,46,47,48] |
Lymphocyte regulation:
| [50,51,53,54,55] |
Angiogenesis:
| [59,60,61,62,63,64,65] |
Microenvironment remodeling:
| [68,69,70,72,73,74,75] |
Drug resistance:
| [77,78,79] |
Disease | Reported Role of EVs | References |
---|---|---|
Otitis Media | Disease-related bacterial products drive differential expression of miRNAs within human middle ear epithelial cells (HMEECs). Exosomes collected from COM patients have a high abundance of miRNAs, most significantly miR-223-3p, miR-451a, miR-16a-2p, miR-320e, and miR-25-3p; and these miRNAs target genes that upregulate many IL-8-mediated cellular functions and CXCR1/2-mediated signaling. | [86,87] |
Chronic Rhinosinusitis | Significant differences in EV-cargo protein profiles were found between CRSwNP and control individuals, specifically molecular markers of CRSwNP including cystatin, glycoprotein VI, and peroxiredoxin-5. Elevated levels of epithelial protease inhibitors cystatin-1 and -2 are found in EVs isolated from nasal fluids of CRS patients. EVs from CRS patients potentially lead to the formation of polyps via their role in upregulating pappalysin and serpins. | [91,92,93] |
Acquired Cholesteatoma | Exosomal miR-17 of keratinocyte origin leads to the upregulation of fibroblast protein expression. | [98] |
Ototoxicity | In response to heat stress, cells of the inner ear release exosomes carrying Hsp70 which interacts with TLR4 on the hair cells, thereby providing a protective effect from aminoglycoside antibiotics. In mice treated with cisplatin, inner ear EVs are reduced in number and have significantly lower cargo protein concentration; proteomic analysis shows a significant increase in protein expression of Tmem 33, Pgm1, Eif3f, Rps24, Cct8, Hsd17b4, Aldh3a1, Ddost, Aldh3a1, Eif3c, Luc7l2, and Acadvl. Delivery of NPC-EVs transfected with miR-21 in vivo reduces caspase-3/parvalbumin expression, increases IL-10 expression, and prevents an increase in TNF-α and IL-1β expression of cochlear hair cells. Hypoxic BMSCs reduce cisplatin-induced ototoxicity by upregulating HIF-1α, superoxide dismutase 1 (SOD1), and SOD2 expression. Trans-tympanic delivery of HS-BMSC-Exos reverses cisplatin-induced upregulation of IL-1β, IL-6, TNF-α, NLRP3, ASC, cleaved caspase-1, and pro-caspase-1. Delivery of IEC-Exo-miR-182-5p to gentamicin-treated HEI-OC1 cells increases Bcl-2 expression and decreases FOXO3 and Bax expression. | [99,102,103,104,105,106] |
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Carnino, J.M.; Miyawaki, S.; Rampam, S. The Role of Extracellular Vesicles in Diseases of the Ear, Nose, and Throat. Med. Sci. 2023, 11, 6. https://doi.org/10.3390/medsci11010006
Carnino JM, Miyawaki S, Rampam S. The Role of Extracellular Vesicles in Diseases of the Ear, Nose, and Throat. Medical Sciences. 2023; 11(1):6. https://doi.org/10.3390/medsci11010006
Chicago/Turabian StyleCarnino, Jonathan M, Steven Miyawaki, and Sanjeev Rampam. 2023. "The Role of Extracellular Vesicles in Diseases of the Ear, Nose, and Throat" Medical Sciences 11, no. 1: 6. https://doi.org/10.3390/medsci11010006
APA StyleCarnino, J. M., Miyawaki, S., & Rampam, S. (2023). The Role of Extracellular Vesicles in Diseases of the Ear, Nose, and Throat. Medical Sciences, 11(1), 6. https://doi.org/10.3390/medsci11010006