Exosomes in lung cancer diagnosis and treatment. From the translating research into future clinical practice.

Lung cancer is one of the main causes of cancer-related death worldwide. Despite advances in lung cancer pathophysiology, diagnosis and prognosis, a better understanding of the disease is strongly needed in order to establish novel diagnostic and therapeutic approaches that should improve treatment outcomes. Exosomes are a type of cell-secreted extracellular vesicles, which transfer a wide variety of biomolecules, such as proteins, mRNAs, microRNAs, and lipids, are implicated in intercellular communication and modulate tumor-host interactions. The potential value of exosomes and their contents in lung cancer diagnosis, prognosis and prediction of treatment outcome is supported by ample literature. Growing attention has been drawn specifically to the critical role of exosomal miRNAs in lung cancer pathogenesis and their potential clinical utility, especially due to their ability to modulate gene expression post-transcriptionally. Owing to their universal presence in the blood and other bodily fluids, exosomes are considered candidate biomarkers. Furthermore, their ability to deliver biomolecules and drugs to recipient cells renders them possible drug delivery vehicles in lung cancer. Here we review the pathological functions of exosomes in cancer and discuss their possible clinical utility as biomarkers and therapeutic agents in the management of lung cancer.

[1]  Marta Di Nicola,et al.  microRNAs Derived from Circulating Exosomes as Noninvasive Biomarkers for Screening and Diagnosing Lung Cancer , 2013, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[2]  B. Chan,et al.  Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. , 2015, Translational lung cancer research.

[3]  Jayoung Kim,et al.  Cyclooxygenase-2 expression is induced by celecoxib treatment in lung cancer cells and is transferred to neighbor cells via exosomes. , 2017, International journal of oncology.

[4]  Yanmei Xu,et al.  Differential miRNA expression in pleural effusions derived from extracellular vesicles of patients with lung cancer, pulmonary tuberculosis, or pneumonia , 2016, Tumor Biology.

[5]  A. Dobrovic,et al.  Prevalence and natural history of ALK positive non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors , 2014, Clinical epidemiology.

[6]  A. D’Andrea,et al.  Circulating miR-29a and miR-150 correlate with delivered dose during thoracic radiation therapy for non-small cell lung cancer , 2016, Radiation oncology.

[7]  Yan Sun,et al.  Comparative Proteomic Analysis of Exosomes and Microvesicles in Human Saliva for Lung Cancer. , 2018, Journal of proteome research.

[8]  K. Wang,et al.  The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis , 2016, Oncotarget.

[9]  Michael A. Hollingsworth,et al.  Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver , 2015, Nature Cell Biology.

[10]  Aled Clayton,et al.  Cancer exosomes trigger fibroblast to myofibroblast differentiation. , 2010, Cancer research.

[11]  P. Lichter,et al.  Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts. , 2015, Blood.

[12]  William E. Fondrie,et al.  Triple SILAC quantitative proteomic analysis reveals differential abundance of cell signaling proteins between normal and lung cancer-derived exosomes. , 2016, Journal of proteomics.

[13]  J. Neuzil,et al.  Exosomal miR-126 as a circulating biomarker in non-small-cell lung cancer regulating cancer progression , 2017, Scientific Reports.

[14]  W. Grizzle,et al.  Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. , 2010, The American journal of pathology.

[15]  B. Chauffert,et al.  Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. , 2010, The Journal of clinical investigation.

[16]  B. Garcia,et al.  Corrigendum: Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET , 2016, Nature Network Boston.

[17]  Yanmei Xu,et al.  Identification of differential expressed PE exosomal miRNA in lung adenocarcinoma, tuberculosis, and other benign lesions , 2017, Medicine.

[18]  K. Jöckel,et al.  Evaluation of long noncoding RNA MALAT1 as a candidate blood-based biomarker for the diagnosis of non-small cell lung cancer , 2013, BMC Research Notes.

[19]  V. Govorun,et al.  Isolation of exosomes by differential centrifugation: Theoretical analysis of a commonly used protocol , 2015, Scientific Reports.

[20]  P. Pauwels,et al.  Exosomal miRNA Analysis in Non-small Cell Lung Cancer (NSCLC) Patients' Plasma Through qPCR: A Feasible Liquid Biopsy Tool. , 2016, Journal of visualized experiments : JoVE.

[21]  H. D. del Portillo,et al.  Size-exclusion chromatography as a stand-alone methodology identifies novel markers in mass spectrometry analyses of plasma-derived vesicles from healthy individuals , 2015, Journal of extracellular vesicles.

[22]  Ji-Ho Park,et al.  Exosome Classification by Pattern Analysis of Surface-Enhanced Raman Spectroscopy Data for Lung Cancer Diagnosis. , 2017, Analytical chemistry.

[23]  M. Provencio,et al.  Liquid biopsy based biomarkers in non-small cell lung cancer for diagnosis and treatment monitoring. , 2016, Translational lung cancer research.

[24]  B. Shen,et al.  Comparative analysis of microRNA expression profiles between A549, A549/DDP and their respective exosomes , 2017, Oncotarget.

[25]  G. Camussi,et al.  Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. , 2011, Cancer research.

[26]  A. Möller,et al.  Exosomes derived from mesenchymal non‐small cell lung cancer cells promote chemoresistance , 2017, International journal of cancer.

[27]  S. Hanash,et al.  Plasma-derived extracellular vesicle proteins as a source of biomarkers for lung adenocarcinoma , 2017, Oncotarget.

[28]  K. R. Jakobsen,et al.  Exosomal proteins as potential diagnostic markers in advanced non-small cell lung carcinoma , 2015, Journal of extracellular vesicles.

[29]  Fang Wei,et al.  Detection of Tumor Cell-Specific mRNA and Protein in Exosome-Like Microvesicles from Blood and Saliva , 2014, PloS one.

[30]  F. Wang,et al.  A six-microRNA panel in plasma was identified as a potential biomarker for lung adenocarcinoma diagnosis , 2016, Oncotarget.

[31]  R. Kerbel,et al.  Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR , 2009, Proceedings of the National Academy of Sciences.

[32]  Weiying Zhou,et al.  Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. , 2014, Cancer cell.

[33]  Douglas D. Taylor,et al.  Exosomal microRNA: a diagnostic marker for lung cancer. , 2008, Clinical lung cancer.

[34]  Olivier Lantz,et al.  Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC , 2015, Oncoimmunology.

[35]  T. Whiteside,et al.  Isolation of Biologically Active Exosomes from Plasma of Patients with Cancer. , 2017, Methods in molecular biology.

[36]  W. Wenyu,et al.  MiR-146a-5p level in serum exosomes predicts therapeutic effect of cisplatin in non-small cell lung cancer. , 2017, European review for medical and pharmacological sciences.

[37]  G. Grau,et al.  Membrane microparticles mediate transfer of P-glycoprotein to drug sensitive cancer cells , 2009, Leukemia.

[38]  Xianrang Song,et al.  Circulating exosomes contain protein biomarkers of metastatic non‐small‐cell lung cancer , 2018, Cancer science.

[39]  C. Gatsonis,et al.  Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening , 2012 .

[40]  Alfredo Cesario,et al.  Soluble Epidermal Growth Factor Receptors (sEGFRs) in Cancer: Biological Aspects and Clinical Relevance , 2016, International journal of molecular sciences.

[41]  Maria Daglia,et al.  Exosome biogenesis, bioactivities and functions as new delivery systems of natural compounds. , 2017, Biotechnology advances.

[42]  B. Kramer,et al.  The National Lung Screening Trial: Results stratified by demographics, smoking history, and lung cancer histology , 2013, Cancer.

[43]  N. Girard,et al.  Comparisons of microRNA Patterns in Plasma before and after Tumor Removal Reveal New Biomarkers of Lung Squamous Cell Carcinoma , 2013, PloS one.

[44]  Jingcheng Zhou,et al.  Circulating exosomal microRNA‐96 promotes cell proliferation, migration and drug resistance by targeting LMO7 , 2016, Journal of cellular and molecular medicine.

[45]  Xuetao Cao,et al.  Tumor Exosomal RNAs Promote Lung Pre-metastatic Niche Formation by Activating Alveolar Epithelial TLR3 to Recruit Neutrophils. , 2016, Cancer cell.

[46]  M. Provencio,et al.  Different exosome cargo from plasma/bronchoalveolar lavage in non‐small‐cell lung cancer , 2014, Genes, chromosomes & cancer.

[47]  N. Girard,et al.  New driver mutations in non-small-cell lung cancer. , 2011, The Lancet. Oncology.

[48]  B. Shen,et al.  Cisplatin-resistant lung cancer cell–derived exosomes increase cisplatin resistance of recipient cells in exosomal miR-100–5p-dependent manner , 2017, International journal of nanomedicine.

[49]  Michael E. Egger,et al.  Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment. , 2016, Cancer letters.

[50]  F. Aqil,et al.  Exosomal miRNAs as biomarkers of recurrent lung cancer , 2016, Tumor Biology.

[51]  J. Leonard,et al.  FedExosomes: Engineering Therapeutic Biological Nanoparticles that Truly Deliver , 2013, Pharmaceuticals.

[52]  Mustafa Kotmakçı,et al.  Extracellular Vesicles as Natural Nanosized Delivery Systems for Small-Molecule Drugs and Genetic Material: Steps towards the Future Nanomedicines. , 2015, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[53]  P. Altevogt,et al.  Vesiclepedia: A Compendium for Extracellular Vesicles with Continuous Community Annotation , 2012, PLoS biology.

[54]  Bethan Psaila,et al.  The metastatic niche: adapting the foreign soil , 2009, Nature Reviews Cancer.

[55]  T. Rasmussen,et al.  Exosomal proteins as prognostic biomarkers in non‐small cell lung cancer , 2016, Molecular oncology.

[56]  Steven E. Schild,et al.  Non-small cell lung cancer, version 5.2017: Clinical practice guidelines in oncology , 2017 .

[57]  Meg Duroux,et al.  A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy. , 2014, Biochimica et biophysica acta.

[58]  J. Rosenblatt,et al.  Myeloid‐derived suppressor cells as effectors of immune suppression in cancer , 2016, International journal of cancer.

[59]  Jayoung Kim,et al.  Identification and characterization of proteins isolated from microvesicles derived from human lung cancer pleural effusions , 2013, Proteomics.

[60]  K. Ohyashiki,et al.  Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. , 2014, Blood.

[61]  A. Jemal,et al.  Cancer statistics, 2017 , 2017, CA: a cancer journal for clinicians.

[62]  Yu Wang,et al.  Serum long non coding RNA MALAT-1 protected by exosomes is up-regulated and promotes cell proliferation and migration in non-small cell lung cancer. , 2017, Biochemical and biophysical research communications.

[63]  J. Lötvall,et al.  EVpedia: an integrated database of high-throughput data for systemic analyses of extracellular vesicles , 2013, Journal of extracellular vesicles.

[64]  Jun Qin,et al.  Functions and application of exosomes. , 2014, Acta poloniae pharmaceutica.

[65]  Michael T. McManus,et al.  MicroRNAs and cancer. , 2003, Seminars in cancer biology.

[66]  Y. Yoshioka,et al.  Epidermal growth factor receptor localized to exosome membranes as a possible biomarker for lung cancer diagnosis. , 2013, Die Pharmazie.

[67]  T. Lv,et al.  Expression profiles and clinical value of plasma exosomal Tim-3 and Galectin-9 in non-small cell lung cancer. , 2018, Biochemical and biophysical research communications.

[68]  Yi-Lin Chen,et al.  Liquid biopsy genotyping in lung cancer: ready for clinical utility? , 2017, Oncotarget.

[69]  Imre Mäger,et al.  Extracellular vesicles: biology and emerging therapeutic opportunities , 2013, Nature Reviews Drug Discovery.

[70]  Tina Koestler,et al.  Abstract B136: Plasma EGFR mutation detection using a combined exosomal RNA and circulating tumor DNA approach in patients with acquired resistance to first-generation EGFR-TKIs , 2015 .

[71]  M. Mason,et al.  Cancer exosomes trigger mesenchymal stem cell differentiation into pro-angiogenic and pro-invasive myofibroblasts , 2014, Oncotarget.

[72]  D. Xie,et al.  Evaluation of Tumor-Derived Exosomal miRNA as Potential Diagnostic Biomarkers for Early-Stage Non–Small Cell Lung Cancer Using Next-Generation Sequencing , 2017, Clinical Cancer Research.

[73]  M. Ringnér,et al.  Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development , 2013, Proceedings of the National Academy of Sciences.

[74]  R. Stephens,et al.  Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. , 2006, Cancer cell.

[75]  Yuan Zhang,et al.  Proteomic identification of exosomal LRG1: A potential urinary biomarker for detecting NSCLC , 2011, Electrophoresis.

[76]  Carmen Visus,et al.  Tumor-Derived Microvesicles Promote Regulatory T Cell Expansion and Induce Apoptosis in Tumor-Reactive Activated CD8+ T Lymphocytes1 , 2009, The Journal of Immunology.

[77]  R. Coffey,et al.  Proteomic Analysis of Exosomes from Mutant KRAS Colon Cancer Cells Identifies Intercellular Transfer of Mutant KRAS* , 2012, Molecular & Cellular Proteomics.

[78]  M. Bache,et al.  Dynamics of Heat Shock Protein 70 Serum Levels As a Predictor of Clinical Response in Non-Small-Cell Lung Cancer and Correlation with the Hypoxia-Related Marker Osteopontin , 2017, Front. Immunol..

[79]  R. Shackelford,et al.  The liquid biopsy in lung cancer , 2016, Genes & cancer.

[80]  J. Le Pecq,et al.  A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer , 2005, Journal of Translational Medicine.

[81]  C. Théry,et al.  Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. , 2014, Annual review of cell and developmental biology.

[82]  P. Pauwels,et al.  Liquid biopsies in lung cancer: the new ambrosia of researchers. , 2014, Biochimica et biophysica acta.

[83]  D. Ribatti,et al.  Multiple myeloma exosomes establish a favourable bone marrow microenvironment with enhanced angiogenesis and immunosuppression , 2016, The Journal of pathology.

[84]  P. Pauwels,et al.  Exosomes isolation and characterization in serum is feasible in non-small cell lung cancer patients: critical analysis of evidence and potential role in clinical practice , 2016, Oncotarget.

[85]  G. Raposo,et al.  The complex ultrastructure of the endolysosomal system. , 2014, Cold Spring Harbor perspectives in biology.

[86]  G. Calin,et al.  PDL1 Regulation by p53 via miR-34 , 2015, Journal of the National Cancer Institute.

[87]  Á. Zaballos,et al.  Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival , 2010, European Respiratory Journal.

[88]  Lynne T. Bemis,et al.  Standardization of sample collection, isolation and analysis methods in extracellular vesicle research , 2013, Journal of extracellular vesicles.

[89]  A. Poliakov,et al.  Induction of myeloid‐derived suppressor cells by tumor exosomes , 2009, International journal of cancer.