Exosomal Non-Coding RNAs: Diagnostic, Prognostic and Therapeutic Applications in Cancer

Non-coding RNAs, such as microRNAs and long non-coding RNAs, are important regulatory molecules which are corrupted in cancer, often in a tissue and stage specific manner. Accumulated data suggests that these promising biomarkers, may also form the basis of novel targeted therapeutic strategies. The role of exosomes in cancer development and metastasis pathways is also increasingly well described. These endosome derived extracellular vesicles which are trafficked horizontally between tumor cells, and vertically between tumor cells and the surrounding microenvironment, carry bioactive cargos, which can reprogram the phenotype of recipient cells with important oncogenic consequences. Exosomes are enriched with non-coding RNA content. Within exosomes, non-coding RNAs are secreted into the peripheral circulation and other bodily fluids where they are protected from enzymatic degradation by the surrounding phospholipid membrane. Exosomes are therefore a highly promising source of diagnostic and prognostic material in cancer. Furthermore, as exosomes are natural ncRNA carriers, they may be adapted for the purpose of drug delivery by the introduction of exogenous ncRNAs or by manipulating their endogenous ncRNA content. In the current review, we will explore these highly clinically relevant themes by examining the roles of exosomal ncRNAs in cancer diagnostics, prognostics and therapy.

[1]  M. Tewari,et al.  Exosomes in human semen carry a distinctive repertoire of small non-coding RNAs with potential regulatory functions , 2014, Nucleic acids research.

[2]  Sidhartha Hazari,et al.  Increased expression of P-glycoprotein and doxorubicin chemoresistance of metastatic breast cancer is regulated by miR-298. , 2012, The American journal of pathology.

[3]  Gunther Hartmann,et al.  SiRNA delivery with exosome nanoparticles , 2011, Nature Biotechnology.

[4]  G. Illei,et al.  Exosomes from human saliva as a source of microRNA biomarkers. , 2010, Oral diseases.

[5]  Jian Zhang,et al.  Exosomal miR-221/222 enhances tamoxifen resistance in recipient ER-positive breast cancer cells , 2014, Breast Cancer Research and Treatment.

[6]  B. Davidson,et al.  Transvascular delivery of small interfering RNA to the central nervous system , 2007, Nature.

[7]  Ming Liu,et al.  Combined detection of serum exosomal miR-21 and HOTAIR as diagnostic and prognostic biomarkers for laryngeal squamous cell carcinoma , 2014, Medical Oncology.

[8]  Dominique,et al.  Combining Agents that Target the Tumor Microenvironment Improves the Efficacy of Anticancer Therapy , 2008, Clinical Cancer Research.

[9]  Qun Yu,et al.  Increased Exosomal MicroRNA-21 and MicroRNA-146a Levels in the Cervicovaginal Lavage Specimens of Patients with Cervical Cancer , 2014, International journal of molecular sciences.

[10]  J. Mattick,et al.  Long non-coding RNAs: insights into functions , 2009, Nature Reviews Genetics.

[11]  W. Jiang,et al.  Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes , 2014, Oncogene.

[12]  C. Mirkin,et al.  Exosome encased spherical nucleic acid gold nanoparticle conjugates as potent microRNA regulation agents. , 2014, Small.

[13]  J Ma,et al.  MicroRNA and drug resistance , 2010, Cancer Gene Therapy.

[14]  J. Benoit,et al.  A review of the current status of siRNA nanomedicines in the treatment of cancer. , 2013, Biomaterials.

[15]  Shunsuke Noguchi,et al.  Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[16]  Y. Matsumura,et al.  Exosome can prevent RNase from degrading microRNA in feces. , 2011, Journal of gastrointestinal oncology.

[17]  C. Ponting,et al.  Evolution and Functions of Long Noncoding RNAs , 2009, Cell.

[18]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[19]  F. Sánchez‐Madrid,et al.  Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs , 2013, Nature Communications.

[20]  G. Calin,et al.  MicroRNAome genome: A treasure for cancer diagnosis and therapy , 2014, CA: a cancer journal for clinicians.

[21]  Y. Wang,et al.  Mechanism of chemoresistance mediated by miR-140 in human osteosarcoma and colon cancer cells , 2009, Oncogene.

[22]  Amaia Agirre,et al.  A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool. , 2014, Neuro-oncology.

[23]  Howard Y. Chang,et al.  Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis , 2010, Nature.

[24]  G. Raposo,et al.  Exosomes: endosomal-derived vesicles shipping extracellular messages. , 2004, Current opinion in cell biology.

[25]  S. Thibodeau,et al.  Characterization of human plasma-derived exosomal RNAs by deep sequencing , 2013, BMC Genomics.

[26]  G. Packham,et al.  MicroRNAs: critical regulators of epithelial to mesenchymal (EMT) and mesenchymal to epithelial transition (MET) in cancer progression , 2012, Biology of the cell.

[27]  J. Rinn,et al.  Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression , 2009, Proceedings of the National Academy of Sciences.

[28]  H. Nielsen,et al.  High levels of microRNA-21 in the stroma of colorectal cancers predict short disease-free survival in stage II colon cancer patients , 2010, Clinical & Experimental Metastasis.

[29]  K. Mimori,et al.  Identification of a bona fide microRNA biomarker in serum exosomes that predicts hepatocellular carcinoma recurrence after liver transplantation , 2015, British Journal of Cancer.

[30]  Lucy Pigati,et al.  MicroRNAs are exported from malignant cells in customized particles , 2012, Nucleic acids research.

[31]  A. Engert,et al.  Dendritic Cells Release HLA-B-Associated Transcript-3 Positive Exosomes to Regulate Natural Killer Function , 2008, PloS one.

[32]  George A Calin,et al.  Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. , 2014, Cancer cell.

[33]  Hamid Cheshmi Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers , 2011 .

[34]  M. Wei,et al.  Micro‐RNA‐21 regulates TGF‐β‐induced myofibroblast differentiation by targeting PDCD4 in tumor‐stroma interaction , 2011, International journal of cancer.

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

[36]  G. Szabo,et al.  Exosome-mediated delivery of functionally active miRNA-155 inhibitor to macrophages. , 2014, Nanomedicine : nanotechnology, biology, and medicine.

[37]  Y. Toiyama,et al.  Serum miR-21 as a diagnostic and prognostic biomarker in colorectal cancer. , 2013, Journal of the National Cancer Institute.

[38]  Domenico Coppola,et al.  MicroRNA-155 Regulates Cell Survival, Growth, and Chemosensitivity by Targeting FOXO3a in Breast Cancer* , 2010, The Journal of Biological Chemistry.

[39]  M. Wood,et al.  Exosomes for targeted siRNA delivery across biological barriers. , 2013, Advanced drug delivery reviews.

[40]  M. Wood,et al.  Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes , 2011, Nature Biotechnology.

[41]  J. Lötvall,et al.  MicroRNA in exosomes isolated directly from the liver circulation in patients with metastatic uveal melanoma , 2014, BMC Cancer.

[42]  Lesley Cheng,et al.  Characterization and deep sequencing analysis of exosomal and non-exosomal miRNA in human urine. , 2014, Kidney international.

[43]  C. Croce,et al.  MicroRNAs in cancer: small molecules with a huge impact. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  B. Quah,et al.  The immunogenicity of dendritic cell-derived exosomes. , 2005, Blood cells, molecules & diseases.

[45]  Shinobu Ueda,et al.  Systemically Injected Exosomes Targeted to EGFR Deliver Antitumor MicroRNA to Breast Cancer Cells. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[46]  R. Schiffelers,et al.  Exosome mimetics: a novel class of drug delivery systems , 2012, International journal of nanomedicine.

[47]  G. Almeida-Porada,et al.  Mesenchymal stem cells as therapeutics and vehicles for gene and drug delivery. , 2010, Advanced drug delivery reviews.

[48]  Shuai Jiang,et al.  MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. , 2010, Cancer research.

[49]  Lesley Cheng,et al.  Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood , 2014, Journal of extracellular vesicles.

[50]  N. Wang,et al.  Isolation and purification of exosomes in urine. , 2010, Methods in molecular biology.

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

[52]  T. Patel,et al.  Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer , 2014, FEBS open bio.

[53]  Michael C. Ostrowski,et al.  Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1. , 2014, Cancer research.

[54]  Matthias John,et al.  RNAi-mediated gene silencing in non-human primates , 2006, Nature.

[55]  T. Anchordoquy,et al.  Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[56]  H. Allgayer,et al.  MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer , 2008, Oncogene.

[57]  Per Sunnerhagen,et al.  Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes , 2012, Nucleic acids research.

[58]  K. Pantel,et al.  Increased serum levels of circulating exosomal microRNA-373 in receptor-negative breast cancer patients , 2014, Oncotarget.

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

[60]  F. Slack,et al.  Junk DNA and the long non-coding RNA twist in cancer genetics , 2015, Oncogene.

[61]  Raghu Kalluri,et al.  Exosomes in tumor microenvironment influence cancer progression and metastasis , 2013, Journal of Molecular Medicine.

[62]  S. Zhong,et al.  Exosomes from Drug-Resistant Breast Cancer Cells Transmit Chemoresistance by a Horizontal Transfer of MicroRNAs , 2014, PloS one.

[63]  D. Barh,et al.  Microrna let-7: an emerging next-generation cancer therapeutic , 2010, Current oncology.

[64]  S. Kauppinen,et al.  Therapeutic Silencing of MicroRNA-122 in Primates with Chronic Hepatitis C Virus Infection , 2010, Science.

[65]  J. Cooper,et al.  Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice , 2014, Movement disorders : official journal of the Movement Disorder Society.

[66]  Howard Y. Chang,et al.  Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs , 2007, Cell.

[67]  Cicek Gercel-Taylor,et al.  MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. , 2008, Gynecologic oncology.

[68]  G. Calin,et al.  Exosomes as divine messengers: are they the Hermes of modern molecular oncology? , 2014, Cell Death and Differentiation.

[69]  H. Ishwaran,et al.  Exosome Transfer from Stromal to Breast Cancer Cells Regulates Therapy Resistance Pathways , 2014, Cell.

[70]  Keith L Ligon,et al.  Delivery of Functional Anti-miR-9 by Mesenchymal Stem Cell–derived Exosomes to Glioblastoma Multiforme Cells Conferred Chemosensitivity , 2013, Molecular therapy. Nucleic acids.

[71]  Tao Wang,et al.  Exosomal miR-1290 and miR-375 as prognostic markers in castration-resistant prostate cancer. , 2015, European urology.

[72]  Naoto Tsuchiya,et al.  Circulating Exosomal microRNAs as Biomarkers of Colon Cancer , 2014, PloS one.

[73]  Muneesh Tewari,et al.  Quantitative and stoichiometric analysis of the microRNA content of exosomes , 2014, Proceedings of the National Academy of Sciences.

[74]  M. Wood,et al.  Biological gene delivery vehicles: beyond viral vectors. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[75]  Zuhong Lu,et al.  miRNA in Plasma Exosome is Stable under Different Storage Conditions , 2014, Molecules.

[76]  Thomas Boehm,et al.  Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance , 1997, Nature.

[77]  J. Woodburn,et al.  The epidermal growth factor receptor and its inhibition in cancer therapy. , 1999, Pharmacology & therapeutics.

[78]  Jiang He,et al.  In vitro evaluation of endothelial exosomes as carriers for small interfering ribonucleic acid delivery , 2014, International journal of nanomedicine.

[79]  N. Smalheiser Exosomal transfer of proteins and RNAs at synapses in the nervous system , 2007, Biology Direct.