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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

Open Access 01-12-2021 | Lung Cancer | Research

Circulating extracellular vesicles from individuals at high-risk of lung cancer induce pro-tumorigenic conversion of stromal cells through transfer of miR-126 and miR-320

Authors: Francesca Pontis, Luca Roz, Mavis Mensah, Miriam Segale, Massimo Moro, Giulia Bertolini, Ilaria Petraroia, Giovanni Centonze, Anna Maria Ferretti, Paola Suatoni, Ugo Pastorino, Orazio Fortunato, Gabriella Sozzi

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

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Abstract

Background

Extracellular vesicles (EVs) containing specific subsets of functional biomolecules are released by all cell types and analysis of circulating EVs can provide diagnostic and prognostic information. To date, little is known regarding the role of EVs both as biomarkers and potential key players in human lung cancer.

Methods

Plasma EVs were isolated from 40 cancer-free heavy-smokers classified according to a validated 24-microRNA signature classifier (MSC) at high (MSCpos-EVs) or low (MSCneg-EVs) risk to develop lung cancer. EVs origin and functional properties were investigated using in vitro 3D cultures and in vivo models. The prognostic value of miRNAs inside EVs was assessed in training and in validation cohorts of 54 and 48 lung cancer patients, respectively.

Results

Different membrane composition, biological cargo and pro-tumorigenic activity were observed in MSCpos vs MSCneg-EVs. Mechanistically, in vitro and in vivo results showed that miR-126 and miR-320 from MSCpos-EVs increased pro-angiogenic phenotype of endothelial cells and M2 polarization of macrophage, respectively. MSCpos-EVs prompted 3D proliferation of non-tumorigenic epithelial cells through c-Myc transfer. Moreover, hypoxia was shown to stimulate the secretion of EVs containing c-Myc from fibroblasts, miR-126-EVs from endothelial cells and miR-320-EVs from granulocytes. Lung cancer patients with higher levels of mir-320 into EVs displayed a significantly shorter overall survival in training [HR2.96] and validation sets [HR2.68].

Conclusion

Overall our data provide a new perspective on the pro-tumorigenic role of circulating EVs in high risk smokers and highlight the significance of miR-320-EVs as a new prognostic biomarker in lung cancer patients.
Appendix
Available only for authorised users
Literature
1.
2.
Seijo LM, Peled N, Ajona D, Boeri M, Field JK, et al. Biomarkers in Lung Cancer Screening: Achievements, Promises, and Challenges. J Thorac Oncol. 2019;14:343–57.PubMedCrossRef
3.
de Koning HJ, van der Aalst CM, de Jong PA, Scholten ET, Nackaerts K, et al. Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial. N Engl J Med. 2020;382:503–13.CrossRefPubMed
4.
Pastorino U, Silva M, Sestini S, Sabia F, Boeri M, et al. Prolonged Lung Cancer Screening Reduced 10-year Mortality in the MILD Trial. Ann Oncol. 2019;30(10):1672.
5.
Kramer BS, Berg CD, Aberle DR, Prorok PC. Lung cancer screening with low-dose helical CT: results from the National Lung Screening Trial (NLST). J Med Screen. 2011;18:109–11.PubMedPubMedCentralCrossRef
6.
7.
Willms E, Cabanas C, Mager I, Wood MJA, Vader P. Extracellular Vesicle Heterogeneity: Subpopulations, Isolation Techniques, and Diverse Functions in Cancer Progression. Front Immunol. 2018;9:738.PubMedPubMedCentralCrossRef
8.
9.
Mathieu M, Martin-Jaular L, Lavieu G, Thery C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21:9–17.PubMedCrossRef
10.
Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.PubMedCrossRef
11.
Jella KK, Nasti TH, Li Z, Malla SR, Buchwald ZS, et al. Exosomes, their biogenesis and role in inter-cellular communication, tumor microenvironment and cancer immunotherapy. Vaccines (Basel). 2018;6:(4):69.
12.
Colombo M, Raposo G, Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30:255–89.CrossRefPubMed
13.
Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2:569–79.PubMedCrossRef
14.
Fatima F, Nawaz M. Vesiculated long non-coding RNAs: offshore packages deciphering trans-regulation between Cells, cancer progression and resistance to therapies. Noncoding RNA. 2017;3:(1):10.
15.
Ruivo CF, Adem B, Silva M, Melo SA. The Biology of Cancer Exosomes: Insights and New Perspectives. Cancer Res. 2017;77:6480–8.PubMedCrossRef
16.
Garzon R, Fabbri M, Cimmino A, Calin GA, Croce CM. MicroRNA expression and function in cancer. Trends Mol Med. 2006;12:580–7.PubMedCrossRef
17.
Boeri M, Verri C, Conte D, Roz L, Modena P, et al. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci U S A. 2011;108:3713–8.PubMedPubMedCentralCrossRef
18.
Sozzi G, Boeri M, Rossi M, Verri C, Suatoni P, et al. Clinical Utility of a Plasma-Based miRNA Signature Classifier Within Computed Tomography Lung Cancer Screening: A Correlative MILD Trial Study. J Clin Oncol. 2014;32:768–73.PubMedPubMedCentralCrossRef
19.
Fortunato O, Borzi C, Milione M, Centonze G, Conte D, et al. Circulating mir-320a promotes immunosuppressive macrophages M2 phenotype associated with lung cancer risk. Int J Cancer. 2019;144(11):2746–61.
20.
Fortunato O, Boeri M, Moro M, Verri C, Mensah M, et al. Mir-660 is downregulated in lung cancer patients and its replacement inhibits lung tumorigenesis by targeting MDM2-p53 interaction. Cell Death Dis. 2017;5(12):e1564.
21.
Borzi C, Calzolari L, Centonze G, Milione M, Sozzi G, et al. mir-660-p53-mir-486 network: a new key regulatory pathway in lung tumorigenesis. Int J Mol Sci. 2017;18:(1):222.
22.
Boeri M, Sestini S, Fortunato O, Verri C, Suatoni P, et al. Recent advances of microRNA-based molecular diagnostics to reduce false-positive lung cancer imaging. Expert Rev Mol Diagn. 2015;15:801–13.PubMedCrossRef
23.
Workman P, Aboagye EO, Balkwill F, Balmain A, Bruder G, et al. Guidelines for the welfare and use of animals in cancer research. Br J Cancer. 2010;102:1555–77.PubMedPubMedCentralCrossRef
24.
Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, , 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.CrossRef
25.
Ombrato L, Malanchi I. The EMT universe: space between cancer cell dissemination and metastasis initiation. Crit Rev Oncog. 2014;19:349–61.PubMedCrossRef
26.
Molino M, Woolkalis MJ, Prevost N, PraticÃ3 D, Barnathan ES, , et al. CXCR4 on human endothelial cells can serve as both a mediator of biological responses and as a receptor for HIV-2. Biochim Biophys Acta. 2000;1500:227–40.PubMedCrossRef
27.
Xu J, Liang J, Meng YM, Yan J, Yu XJ, et al. Vascular CXCR4 Expression Promotes Vessel Sprouting and Sensitivity to Sorafenib Treatment in Hepatocellular Carcinoma. Clin Cancer Res. 2017;23:4482–92.PubMedCrossRef
28.
Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, et al. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell. 2008;15:261–71.PubMedPubMedCentralCrossRef
29.
30.
Taverna S, Amodeo V, Saieva L, Russo A, Giallombardo M, et al. Exosomal shuttling of miR-126 in endothelial cells modulates adhesive and migratory abilities of chronic myelogenous leukemia cells. Mol Cancer. 2014;13:169.PubMedPubMedCentralCrossRef
31.
Lee H, Zhang D, Zhu Z, Dela Cruz CS, Jin Y. Epithelial cell-derived microvesicles activate macrophages and promote inflammation via microvesicle-containing microRNAs. Sci Rep. 2016;6:35250.PubMedPubMedCentralCrossRef
32.
Borzi C, Calzolari L, Ferretti AM, Caleca L, Pastorino U, et al. c-Myc shuttled by tumour-derived extracellular vesicles promotes lung bronchial cell proliferation through miR-19b and miR-92a. Cell Death Dis. 2019;10:759.PubMedPubMedCentralCrossRef
33.
Karoor V, Le M, Merrick D, Fagan KA, Dempsey EC, et al. Alveolar hypoxia promotes murine lung tumor growth through a VEGFR-2/EGFR-dependent mechanism. Cancer Prev Res (Phila). 2012;5:1061–71.CrossRef
34.
Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. 2007;11:335–47.PubMedPubMedCentralCrossRef
35.
Kumar A, Deep G. Hypoxia in tumor microenvironment regulates exosome biogenesis: Molecular mechanisms and translational opportunities. Cancer Lett. 2020;479:23–30.PubMedCrossRef
36.
Rupaimoole R, Wu SY, Pradeep S, Ivan C, Pecot CV, et al. Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression. Nat Commun. 2014;5:5202.PubMedCrossRef
37.
Boeri M, Milione M, Proto C, Signorelli D, Lo RG, et al. Circulating miRNAs and PD-L1 Tumor Expression Are Associated with Survival in Advanced NSCLC Patients Treated with Immunotherapy: a Prospective Study. Clin Cancer Res. 2019;25(7):2166–73.
38.
Fortunato O, Gasparini P, Boeri M, Sozzi G. Exo-miRNAs as a new tool for liquid biopsy in lung cancer. Cancers (Basel). 2019;11:(6):888.
39.
Rabinowits G, Gercel-Taylor C, Day JM, Taylor DD, Kloecker GH. Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer. 2009;10:42–6.PubMedCrossRef
40.
Cazzoli R, Buttitta F, Di NM, Malatesta S, Marchetti A, et al. microRNAs derived from circulating exosomes as noninvasive biomarkers for screening and diagnosing lung cancer. J Thorac Oncol. 2013;8:1156–62.PubMedPubMedCentralCrossRef
41.
42.
Fabbri M, Paone A, Calore F, Galli R, Gaudio E, et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A. 2012;109:E2110–6.PubMedPubMedCentralCrossRef
43.
Utermöhlen O, Jakobshagen K, Blissenbach B, Wiegmann K, Merz T, et al. Emergence of AnnexinVpos CD31neg CD42blow/neg extracellular vesicles in plasma of humans at extreme altitude. PLoS ONE. 2019;14(8):e0220133.
44.
Oba R, Isomura M, Igarashi A, Nagata K. Circulating CD3(+)HLA-DR(+) Extracellular Vesicles as a Marker for Th1/Tc1-Type Immune Responses. J Immunol Res. 2019;2019:6720819.PubMedPubMedCentralCrossRef
45.
46.
Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell. 2009;16:183–94.PubMedPubMedCentralCrossRef
47.
Daijo H, Hoshino Y, Kai S, Suzuki K, Nishi K, et al. Cigarette smoke reversibly activates hypoxia-inducible factor 1 in a reactive oxygen species-dependent manner. Sci Rep. 2016;6:34424.PubMedPubMedCentralCrossRef
48.
Carcereny CE, Viñolas SN, GascÃ3n VP, . Angiogenesis inhibitors in the treatment of non-small-cell lung cancer (NSCLC). Clin Transl Oncol. 2008;10:198–203.CrossRef
49.
Santos S, Peinado VI, Ramirez J, Morales-Blanhir J, Bastos R, et al. Enhanced expression of vascular endothelial growth factor in pulmonary arteries of smokers and patients with moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003;167:1250–6.PubMedCrossRef
50.
Chevillet JR, Kang Q, Ruf IK, Briggs HA, Vojtech LN, et al. Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc Natl Acad Sci U S A. 2014;111:14888–93.PubMedPubMedCentralCrossRef
51.
Jin X, Chen Y, Chen H, Fei S, Chen D, et al. Evaluation of Tumor-Derived Exosomal miRNA as Potential Diagnostic Biomarkers for Early-Stage Non-Small Cell Lung Cancer Using Next-Generation Sequencing. Clin Cancer Res. 2017;23:5311–9.PubMedCrossRef
Metadata
Title
Circulating extracellular vesicles from individuals at high-risk of lung cancer induce pro-tumorigenic conversion of stromal cells through transfer of miR-126 and miR-320
Authors
Francesca Pontis
Luca Roz
Mavis Mensah
Miriam Segale
Massimo Moro
Giulia Bertolini
Ilaria Petraroia
Giovanni Centonze
Anna Maria Ferretti
Paola Suatoni
Ugo Pastorino
Orazio Fortunato
Gabriella Sozzi
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-02040-3

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