Exosome-Based Cancer Therapy: Implication for Targeting Cancer Stem Cells

Drug resistance, difficulty in specific targeting and self-renewal properties of cancer stem cells (CSCs) all contribute to cancer treatment failure and relapse. CSCs have been suggested as both the seeds of the primary cancer, and the roots of chemo- and radio-therapy resistance. The ability to precisely deliver drugs to target CSCs is an urgent need for cancer therapy, with nanotechnology-based drug delivery system being one of the most promising tools to achieve this in the clinic. Exosomes are cell-derived natural nanometric vesicles that are widely distributed in body fluids and involved in multiple disease processes, including tumorigenesis. Exosome-based nanometric vehicles have a number of advantages: they are non-toxic, non-immunogenic, and can be engineered to have robust delivery capacity and targeting specificity. This enables exosomes as a powerful nanocarrier to deliver anti-cancer drugs and genes for CSC targeting therapy. Here, we will introduce the current explorations of exosome-based delivery system in cancer therapy, with particular focus on several exosomal engineering approaches that have improved their efficiency and specificity for CSC targeting.

[1]  Heikki Saari,et al.  Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[2]  Qiao Li,et al.  Tumor cell-derived exosomes: a message in a bottle. , 2012, Biochimica et biophysica acta.

[3]  S. Futaki,et al.  Combined treatment with a pH-sensitive fusogenic peptide and cationic lipids achieves enhanced cytosolic delivery of exosomes , 2015, Scientific Reports.

[4]  Richard J Simpson,et al.  Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes. , 2012, Methods.

[5]  Jung-Ah Cho,et al.  Exosomes: A new delivery system for tumor antigens in cancer immunotherapy , 2005, International journal of cancer.

[6]  Myung Soo Kim,et al.  Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. , 2016, Nanomedicine : nanotechnology, biology, and medicine.

[7]  D. Cholujová,et al.  Bacterial Ghosts as Novel Efficient Targeting Vehicles for DNA Delivery to the Human Monocyte-Derived Dendritic Cells , 2005, Journal of immunotherapy.

[8]  Ciro Tetta,et al.  Exosome/microvesicle-mediated epigenetic reprogramming of cells. , 2011, American journal of cancer research.

[9]  O. De Wever,et al.  Bone marrow stromal cell-derived exosomes as communicators in drug resistance in multiple myeloma cells. , 2014, Blood.

[10]  N. Wall,et al.  Survivin-T34A: molecular mechanism and therapeutic potential , 2010, OncoTargets and therapy.

[11]  Lei Mu,et al.  Fibroblast-Derived Exosomes Contribute to Chemoresistance through Priming Cancer Stem Cells in Colorectal Cancer , 2015, PloS one.

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

[13]  A. Atrasheuskaya,et al.  Bacterial Ghosts as an Oral Vaccine: a Single Dose of Escherichia coli O157:H7 Bacterial Ghosts Protects Mice against Lethal Challenge , 2005, Infection and Immunity.

[14]  I. Nazarenko,et al.  CD44 and EpCAM: cancer-initiating cell markers. , 2008, Current molecular medicine.

[15]  P. Askenase,et al.  Diagnostic and therapeutic potentials of exosomes in CNS diseases , 2015, Brain Research.

[16]  V. Canzonieri,et al.  Exosomal doxorubicin reduces the cardiac toxicity of doxorubicin. , 2015, Nanomedicine.

[17]  M. Magnani,et al.  Erythrocyte-mediated delivery of drugs, peptides and modified oligonucleotides , 2002, Gene Therapy.

[18]  S. Zhong,et al.  Exosomes decrease sensitivity of breast cancer cells to adriamycin by delivering microRNAs , 2015, Tumor Biology.

[19]  J. Aerts,et al.  Tumour-derived exosomes as antigen delivery carriers in dendritic cell-based immunotherapy for malignant mesothelioma , 2013, Journal of extracellular vesicles.

[20]  Dongmei Sun,et al.  A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[21]  B. Chauffert,et al.  Membrane-associated Hsp 72 from tumor-derived exosomes mediates STAT 3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells , 2010 .

[22]  Michael Chopp,et al.  Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. , 2013, Cancer letters.

[23]  Silvia Maria Doglia,et al.  Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[24]  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.

[25]  M. V. Filatov,et al.  Exosomes are natural carriers of exogenous siRNA to human cells in vitro , 2013, Cell Communication and Signaling.

[26]  Sanchita Bhatnagar,et al.  Exosome Function: From Tumor Immunology to Pathogen Biology , 2008, Traffic.

[27]  P. Bhattacharyya,et al.  Death by design: where curcumin sensitizes drug-resistant tumours. , 2012, Anticancer research.

[28]  Bhavesh C. Variya,et al.  Novel targets for paclitaxel nano formulations: Hopes and hypes in triple negative breast cancer. , 2016, Pharmacological research.

[29]  X. Leleu,et al.  Induction of miR-146a by multiple myeloma cells in mesenchymal stromal cells stimulates their pro-tumoral activity. , 2016, Cancer letters.

[30]  S. Zhong,et al.  Exosomes from docetaxel-resistant breast cancer cells alter chemosensitivity by delivering microRNAs , 2014, Tumor Biology.

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

[32]  Guangjun Nie,et al.  How can nanotechnology help membrane vesicle-based cancer immunotherapy development? , 2013, Human vaccines & immunotherapeutics.

[33]  Pieter Vader,et al.  Extracellular vesicles as drug delivery systems: lessons from the liposome field. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[34]  Venkatareddy Nadithe,et al.  Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges , 2016, Acta pharmaceutica Sinica. B.

[35]  Michelle E. Hung,et al.  Stabilization of Exosome-targeting Peptides via Engineered Glycosylation* , 2015, The Journal of Biological Chemistry.

[36]  Joanna M. Roberts,et al.  CD8+ T Cell-Dependent Elimination of Dendritic Cells In Vivo Limits the Induction of Antitumor Immunity1 , 2000, The Journal of Immunology.

[37]  Jun Yao,et al.  Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth , 2015, Nature.

[38]  Saurabh Bandhavkar Cancer stem cells: a metastasizing menace! , 2016, Cancer medicine.

[39]  I. Hwang,et al.  Cell-cell communication via extracellular membrane vesicles and its role in the immune response , 2013, Molecules and cells.

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

[41]  K. Vanderkerken,et al.  The bone marrow microenvironment enhances multiple myeloma progression by exosome-mediated activation of myeloid-derived suppressor cells , 2015, Oncotarget.

[42]  M. Christodoulou,et al.  Chemical approaches to targeting drug resistance in cancer stem cells. , 2013, Drug discovery today.

[43]  L. O’Driscoll,et al.  miR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity , 2015, Oncotarget.

[44]  P. Quesenberry,et al.  Perspectives on the Potential Therapeutic Uses of Vesicles , 2013, Exosomes and microvesicles.

[45]  Biao Lu,et al.  Development of exosome surface display technology in living human cells. , 2016, Biochemical and biophysical research communications.

[46]  Alexander M. Seifalian,et al.  Stem Cells and Cancer: An Overview , 2007, Stem Cell Reviews.

[47]  M. Zöller,et al.  Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. , 2012, The international journal of biochemistry & cell biology.

[48]  F. Aqil,et al.  Bovine milk-derived exosomes for drug delivery. , 2016, Cancer letters.

[49]  Laurence Zitvogel,et al.  Exosomes: composition, biogenesis and function , 2002, Nature Reviews Immunology.

[50]  C. Harrington,et al.  AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB , 2016, Science Signaling.

[51]  Dong Wei,et al.  Phase I Clinical Trial of Autologous Ascites-derived Exosomes Combined With GM-CSF for Colorectal Cancer , 2008, Molecular Therapy.

[52]  Vladimir R Muzykantov,et al.  Drug delivery by red blood cells: vascular carriers designed by mother nature , 2010, Expert opinion on drug delivery.

[53]  Ashutosh Chilkoti,et al.  Co‐opting biology to deliver drugs , 2014, Biotechnology and bioengineering.

[54]  A. Baldwin,et al.  The NF-κB Pathway and Cancer Stem Cells , 2016, Cells.

[55]  D. Meijer,et al.  The Pharmacokinetic and Biological Activity Profile of Dexamethasone Targeted to Sinusoidal Endothelial and Kupffer Cells , 2003, Journal of drug targeting.

[56]  Pieter Vader,et al.  Extracellular vesicles for drug delivery. , 2016, Advanced drug delivery reviews.

[57]  J. Redzic,et al.  Examination of the specificity of tumor cell derived exosomes with tumor cells in vitro. , 2014, Biochimica et biophysica acta.

[58]  R. Bucki,et al.  Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy , 2016, Journal of Nanobiotechnology.

[59]  A. Wong,et al.  Exosomes: Emerging biomarkers and targets for ovarian cancer. , 2015, Cancer letters.

[60]  H. Ishitobi,et al.  Exosome-formed synthetic microRNA-143 is transferred to osteosarcoma cells and inhibits their migration. , 2014, Biochemical and biophysical research communications.

[61]  I. Sargent,et al.  Exosome-mediated delivery of siRNA in vitro and in vivo , 2012, Nature Protocols.

[62]  Yoshihiro Sasaki,et al.  Engineering hybrid exosomes by membrane fusion with liposomes , 2016, Scientific Reports.

[63]  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.

[64]  Jian Song,et al.  A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. , 2014, Biomaterials.

[65]  Samuel A Wickline,et al.  Maximizing exosome colloidal stability following electroporation. , 2014, Analytical biochemistry.

[66]  Andrew McCaskie,et al.  Nanomedicine , 2005, BMJ.

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

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

[69]  B. Shen,et al.  Tumor-derived exosomes in cancer progression and treatment failure , 2015, Oncotarget.

[70]  K. Braeckmans,et al.  Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[71]  D. Scadden,et al.  BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. , 2013, The Journal of clinical investigation.

[72]  P. Kuo,et al.  PLK-1 Silencing in Bladder Cancer by siRNA Delivered With Exosomes. , 2016, Urology.

[73]  J. Gauldie,et al.  Antigen Presentation by Exosomes Released from Peptide-Pulsed Dendritic Cells Is not Suppressed by the Presence of Active CTL1 , 2007, The Journal of Immunology.

[74]  Gary K. Schwartz,et al.  Tumour exosome integrins determine organotropic metastasis , 2015, Nature.

[75]  Mauro Magnani,et al.  Drug delivery by red blood cells , 2011, IUBMB life.

[76]  N. Greig,et al.  Engineered Nanoparticles Against MDR in Cancer: The State of the Art and its Prospective. , 2016, Current pharmaceutical design.

[77]  Joshua L Hood Post isolation modification of exosomes for nanomedicine applications. , 2016, Nanomedicine.

[78]  Jennifer C Jones,et al.  Efficient production and enhanced tumor delivery of engineered extracellular vesicles. , 2016, Biomaterials.

[79]  J. Medema,et al.  Cancer stem cells – important players in tumor therapy resistance , 2014, The FEBS journal.

[80]  M. Jaafari,et al.  Targeting CD44 expressing cancer cells with anti-CD44 monoclonal antibody improves cellular uptake and antitumor efficacy of liposomal doxorubicin. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[81]  R. Schots,et al.  Extracellular vesicle cross-talk in the bone marrow microenvironment: implications in multiple myeloma , 2016, Oncotarget.

[82]  W. Lubitz,et al.  DNA-loaded bacterial ghosts efficiently mediate reporter gene transfer and expression in macrophages. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[83]  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.

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

[85]  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.

[86]  E. Rofstad,et al.  Cancer stem cells (CSCs), cervical CSCs and targeted therapies , 2016, Oncotarget.

[87]  Flavio Rizzolio,et al.  Exosomes increase the therapeutic index of doxorubicin in breast and ovarian cancer mouse models. , 2016, Nanomedicine.

[88]  Ashish Kumar Agrawal,et al.  Exosomal formulation enhances therapeutic response of celastrol against lung cancer. , 2016, Experimental and molecular pathology.

[89]  H. T. Park,et al.  RNAi delivery by exosome-mimetic nanovesicles - Implications for targeting c-Myc in cancer. , 2016, Biomaterials.

[90]  S. Fan,et al.  Significance of CD90+ cancer stem cells in human liver cancer. , 2008, Cancer cell.

[91]  G. Warnock,et al.  Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy , 2015, Oncotarget.

[92]  R. Andriantsitohaina,et al.  Plasma cells release membrane microparticles in a mouse model of multiple myeloma. , 2013, Micron.

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

[94]  Roy A Jensen,et al.  Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy. , 2016, Seminars in cancer biology.

[95]  Graça Raposo,et al.  Extracellular vesicles: Exosomes, microvesicles, and friends , 2013, The Journal of cell biology.

[96]  F. Magni,et al.  Advances in membranous vesicle and exosome proteomics improving biological understanding and biomarker discovery , 2011, Proteomics.

[97]  Zhigang Wang,et al.  Ultrasound-mediated destruction of paclitaxel and oxygen loaded lipid microbubbles for combination therapy in ovarian cancer xenografts. , 2015, Cancer letters.

[98]  Wei Zhao,et al.  Drug Delivery Using Nanoparticles for Cancer Stem-Like Cell Targeting , 2016, Front. Pharmacol..

[99]  H. Nozaki,et al.  Antitumor agents. 228. five new agarofurans, Reissantins A-E, and cytotoxic principles from Reissantia buchananii. , 2003, Journal of natural products.

[100]  Yanning Liu,et al.  Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma , 2015, Journal of Hematology & Oncology.

[101]  D. Mukhopadhyay,et al.  Circulating microvesicles in B-cell chronic lymphocytic leukemia can stimulate marrow stromal cells: implications for disease progression. , 2010, Blood.

[102]  Olivier Lantz,et al.  Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial , 2005, Journal of Translational Medicine.

[103]  N. Wall,et al.  Enhancement of Gemcitabine sensitivity in pancreatic adenocarcinoma by novel exosome-mediated delivery of the Survivin-T34A mutant , 2014, Journal of extracellular vesicles.

[104]  J. Tsibouklis,et al.  Nano carriers for drug transport across the blood–brain barrier , 2017, Journal of drug targeting.

[105]  S. Lim,et al.  Proteolytic Potential of the MSC Exosome Proteome: Implications for an Exosome-Mediated Delivery of Therapeutic Proteasome , 2012, International journal of proteomics.

[106]  D. Cholujová,et al.  Effective gene transfer to melanoma cells using bacterial ghosts. , 2008, Cancer letters.

[107]  Pieter Vader,et al.  Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting , 2016, Journal of extracellular vesicles.

[108]  Manoj Kumar,et al.  Exosomes: Tunable Nano Vehicles for Macromolecular Delivery of Transferrin and Lactoferrin to Specific Intracellular Compartment. , 2016, Journal of biomedical nanotechnology.

[109]  L. Zitvogel,et al.  Updated Technology to Produce Highly Immunogenic Dendritic Cell-derived Exosomes of Clinical Grade: A Critical Role of Interferon-&ggr; , 2011, Journal of immunotherapy.

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

[111]  Jaesung Park,et al.  Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors. , 2013, ACS nano.

[112]  W. Lubitz,et al.  Bacterial Ghosts as antigen and drug delivery system for ocular surface diseases: Effective internalization of Bacterial Ghosts by human conjunctival epithelial cells. , 2011, Journal of biotechnology.

[113]  X. Breakefield,et al.  Delivery of Therapeutic Proteins via Extracellular Vesicles: Review and Potential Treatments for Parkinson’s Disease, Glioma, and Schwannoma , 2016, Cellular and Molecular Neurobiology.

[114]  L. Zitvogel,et al.  Dendritic cell-derived exosomes for cancer therapy. , 2016, The Journal of clinical investigation.

[115]  Xin Hou,et al.  Blood Exosomes Endowed with Magnetic and Targeting Properties for Cancer Therapy. , 2016, ACS nano.

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

[117]  R. Ramesh,et al.  Exploitation of Exosomes as Nanocarriers for Gene-, Chemo-, and Immune-Therapy of Cancer. , 2016, Journal of biomedical nanotechnology.

[118]  David A. Bader,et al.  Facial Expression Recognition System using Statistical Feature and Neural Network , 2012 .

[119]  Yongmin Yan,et al.  Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer , 2015, Cell cycle.

[120]  M. Ramezani,et al.  Synthetic and Biological Vesicular Nano-Carriers Designed for Gene Delivery. , 2015, Current pharmaceutical design.

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