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      Is Open Access

      Exosomes: Small vesicles with big roles in cancer, vaccine development, and therapeutics

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          Abstract

          Cancer is a deadly disease that is globally and consistently one of the leading causes of mortality every year. Despite the availability of chemotherapy, radiotherapy, immunotherapy, and surgery, a cure for cancer has not been attained. Recently, exosomes have gained significant attention due to the therapeutic potential of their various components including proteins, lipids, nucleic acids, miRNAs, and lncRNAs. Exosomes constitute a set of tiny extracellular vesicles with an approximate diameter of 30–100 nm. They are released from different cells and are present in biofluids including blood, cerebrospinal fluid (CSF), and urine. They perform crucial multifaceted functions in the malignant progression of cancer via autocrine, paracrine, and endocrine communications. The ability of exosomes to carry different cargoes including drug and molecular information to recipient cells make them a novel tool for cancer therapeutics. In this review, we discuss the major components of exosomes and their role in cancer progression. We also review important literature about the potential role of exosomes as vaccines and delivery carriers in the context of cancer therapeutics.

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          Highlights

          • •

            Role of various constituents of exosomes in the context of cancer development, and progression.

          • •

            Targeting the mediators of exosomal release and uptake for cancer therapeutics.

          • •

            Application of cell type-specific exosomes in immunotherapy and cancer vaccines.

          • •

            Exosome based delivery systems for cancer therapeutics.

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          Most cited references191

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          Tumour exosome integrins determine organotropic metastasis

          Ayuko Hoshino, Bruno Costa-Silva, Tang-Long Shen … (2015)
          Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.
          Article 0 comments Cited 1327 times – based on 0 reviews     Review now
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            Doxil®--the first FDA-approved nano-drug: lessons learned.

            Yechezkel Barenholz (2012)
            Doxil®, the first FDA-approved nano-drug (1995), is based on three unrelated principles: (i) prolonged drug circulation time and avoidance of the RES due to the use of PEGylated nano-liposomes; (ii) high and stable remote loading of doxorubicin driven by a transmembrane ammonium sulfate gradient, which also allows for drug release at the tumor; and (iii) having the liposome lipid bilayer in a "liquid ordered" phase composed of the high-T(m) (53 °C) phosphatidylcholine, and cholesterol. Due to the EPR effect, Doxil is "passively targeted" to tumors and its doxorubicin is released and becomes available to tumor cells by as yet unknown means. This review summarizes historical and scientific perspectives of Doxil development and lessons learned from its development and 20 years of its use. It demonstrates the obligatory need for applying an understanding of the cross talk between physicochemical, nano-technological, and biological principles. However, in spite of the large reward, ~2 years after Doxil-related patents expired, there is still no FDA-approved generic "Doxil" available. Copyright © 2012 Elsevier B.V. All rights reserved.
            Article 0 comments Cited 748 times – based on 0 reviews     Review now
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              Is Open Access

              Routes and mechanisms of extracellular vesicle uptake

              Laura Mulcahy, Ryan Pink, David Carter (2014)
              Extracellular vesicles (EVs) are small vesicles released by donor cells that can be taken up by recipient cells. Despite their discovery decades ago, it has only recently become apparent that EVs play an important role in cell-to-cell communication. EVs can carry a range of nucleic acids and proteins which can have a significant impact on the phenotype of the recipient. For this phenotypic effect to occur, EVs need to fuse with target cell membranes, either directly with the plasma membrane or with the endosomal membrane after endocytic uptake. EVs are of therapeutic interest because they are deregulated in diseases such as cancer and they could be harnessed to deliver drugs to target cells. It is therefore important to understand the molecular mechanisms by which EVs are taken up into cells. This comprehensive review summarizes current knowledge of EV uptake mechanisms. Cells appear to take up EVs by a variety of endocytic pathways, including clathrin-dependent endocytosis, and clathrin-independent pathways such as caveolin-mediated uptake, macropinocytosis, phagocytosis, and lipid raft–mediated internalization. Indeed, it seems likely that a heterogeneous population of EVs may gain entry into a cell via more than one route. The uptake mechanism used by a given EV may depend on proteins and glycoproteins found on the surface of both the vesicle and the target cell. Further research is needed to understand the precise rules that underpin EV entry into cells.
              Article 0 comments Cited 699 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Abhimanyu Thakur
                Marcelo Brocchi
                Huanhuan Joyce Chen
                Journal
                Journal ID (nlm-ta): Bioact Mater
                Journal ID (iso-abbrev): Bioact Mater
                Title: Bioactive Materials
                Publisher: KeAi Publishing
                ISSN (Electronic): 2452-199X
                Publication date PMC-release: 28 August 2021
                Publication date Collection: April 2022
                Publication date (Electronic): 28 August 2021
                Volume: 10
                Pages: 281-294
                Affiliations
                [a ]Pritzker School of Molecular Engineering, The University of Chicago, United States
                [b ]Ben May Department for Cancer Research, The University of Chicago, United States
                [c ]Tropical Disease Laboratory, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil
                Author notes
                [∗ ]Corresponding author. Pritzker School of Molecular Engineering, The University of Chicago, United States. abhimanyu@ 123456uchicago.edu
                [∗∗ ]Corresponding author. mbrocchi@ 123456unicamp.br
                [∗∗∗ ]Corresponding author. Pritzker School of Molecular Engineering, The University of Chicago, United States. joycechen@ 123456uchicago.edu
                [1]

                Authors contributed equally.

                Article
                Publisher Item ID: S2452-199X(21)00405-9
                DOI: 10.1016/j.bioactmat.2021.08.029
                PMC ID: 8636666
                PubMed ID: 34901546
                SO-VID: df1a27c2-f579-4002-856c-f9fd5ea3d541
                Copyright © © 2021 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 14 July 2021
                Date revision received : 23 August 2021
                Date accepted : 25 August 2021
                Categories
                Subject: Article

                Keywords: cancer,exosome,therapeutics,extracellular vesicles,exosomal vaccine,exosomal delivery system
                Data availability:
                Keywords: cancer, exosome, therapeutics, extracellular vesicles, exosomal vaccine, exosomal delivery system

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