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Cancers
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Exosomes in Cancers Therapy
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Exosomes in Cancers Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 54394

Special Issue Editors

Dr. Farrukh Aqil

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Guest Editor
Department of Medicine, University of Louisville, Louisville, KY 40202, USA
Interests: drug delivery; nanotechnology; cancer chemoprevention and treatment; breast; lung and ovarian cancers; exosomes
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Ramesh Chandra Gupta

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Guest Editor
Department of Pharmacology & Toxicology, James Graham Brown Cancer Center, 580 S. Preston St., Rm 304E, University of Louisville, Louisville, KY 40202
Interests: 32P-postlabelg techniques; natural compounds and extracts; cancers; exosomes; siRNAs; drugs

Special Issue Information

Exosomes are biological nanovesicles that are involved in cell-cell communication and have a natural ability to carry functional biomolecules, such as small RNAs, DNAs, and proteins. Because of their size, exosomes are explored as nanodevices for the development of new therapeutic applications. Exosomes are widely distributed in various biological fluids such as blood, urine, and milk. The physical and biological stability, as well as tolerability and the possibility of facile scale-up of manufacturing process makes exosomes an ideal nanoparticle for drug delivery with wide therapeutic applications for various diseases including cancer. 

The field of exosome-based therapeutics gained much momentum after successful demonstration of dendritic cell (DC)-derived exosomes for cancer immunotherapy and targeted RNAi delivery. Other cell types that have been used as exosome factories include mesenchymal stem cells (MSCs), human and murine cancer cells, etc. Exosomes from these donor cells were shown to deliver interfering RNAs (siRNA and miRNAs) and therapeutic small molecules (e.g., doxorubicin and curcumin). Immature DCs have favorable properties with respect to immunogenicity and could be modified to express a targeting peptide on their surface. Exosome-like particles and lipids derived from fruits (e.g., grapes and grapefruit) have been examined as an alternative drug carrier. Further, milk-derived exosomes have been demonstrated to serve as a vehicle to deliver both hydrophilic and lipophilic small molecules, including chemotherapeutic drugs and siRNA. However, further knowledge is vital to understand the roles of various types of exosomes and exosome mimitics as delivery vehicle to delivery small and large molecules for cancer therapy. 

This Special Issue of Cancers therefore welcomes new research articles and timely reviews on all aspects of exosomes, exosome-mediated delivery, and their role in cancer therapy.

Dr. Farrukh Aqil
Prof. Dr. Ramesh Chandra Gupta
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Exosomes
  • Cancer
  • Chemoprevention
  • Drug Delivery
  • Extracellular vesicles

Published Papers (11 papers)

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Editorial

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4 pages, 367 KiB  
Editorial
Exosomes in Cancer Therapy
by Farrukh Aqil and Ramesh C. Gupta
Cancers 2022, 14(3), 500; https://doi.org/10.3390/cancers14030500 - 20 Jan 2022
Cited by 15 | Viewed by 2219
Abstract
Exosomes or small extracellular vesicles (EVs) are natural nanoparticles and known to play essential roles in intercellular communications, carrying a cargo of a broad variety of lipids, proteins, metabolites, RNAs (mRNA, miRNA, tRNA, long non-coding RNA), and DNAs (mtDNA, ssDNA, dsDNA) [...] Full article
(This article belongs to the Special Issue Exosomes in Cancers Therapy)
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Research

Jump to: Editorial, Review

20 pages, 3887 KiB  
Article
Targeted Oral Delivery of Paclitaxel Using Colostrum-Derived Exosomes
by Raghuram Kandimalla, Farrukh Aqil, Sara S. Alhakeem, Jeyaprakash Jeyabalan, Neha Tyagi, Ashish Agrawal, Jun Yan, Wendy Spencer, Subbarao Bondada and Ramesh C. Gupta
Cancers 2021, 13(15), 3700; https://doi.org/10.3390/cancers13153700 - 23 Jul 2021
Cited by 50 | Viewed by 4238
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) is the most common type accounting for 84% of all lung cancers. Paclitaxel (PAC) is a widely used drug in the treatment of a broad spectrum of human cancers, [...] Read more.
Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) is the most common type accounting for 84% of all lung cancers. Paclitaxel (PAC) is a widely used drug in the treatment of a broad spectrum of human cancers, including lung. While efficacious, PAC generally is not well tolerated and its limitations include low aqueous solubility, and significant toxicity. To overcome the dose-related toxicity of solvent-based PAC, we utilized bovine colostrum-derived exosomes as a delivery vehicle for PAC for the treatment of lung cancer. Colostrum provided higher yield of exosomes and could be loaded with higher amount of PAC compared to mature milk. Exosomal formulation of PAC (ExoPAC) showed higher antiproliferative activity and inhibition of colony formation against A549 cells compared with PAC alone, and also showed antiproliferative activity against a drug-resistant variant of A549. To further enhance its efficacy, exosomes were attached with a tumor-targeting ligand, folic acid (FA). FA-ExoPAC given orally showed significant inhibition (>50%) of subcutaneous tumor xenograft while similar doses of PAC showed insignificant inhibition. In the orthotopic lung cancer model, oral dosing of FA-ExoPAC achieved greater efficacy (55% growth inhibition) than traditional i.v. PAC (24–32% growth inhibition) and similar efficacy as i.v. Abraxane (59% growth inhibition). The FA-ExoPAC given i.v. exceeded the therapeutic efficacy of Abraxane (76% growth inhibition). Finally, wild-type animals treated with p.o. ExoPAC did not show gross, systemic or immunotoxicity. Solvent-based PAC caused immunotoxicity which was either reduced or completely mitigated by its exosomal formulations. These studies show that a tumor-targeted oral formulation of PAC (FA-ExoPAC) significantly improved the overall efficacy and safety profile while providing a user-friendly, cost-effective alternative to bolus i.v. PAC and i.v. Abraxane. Full article
(This article belongs to the Special Issue Exosomes in Cancers Therapy)
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17 pages, 3329 KiB  
Article
Platelet Microparticles Protect Acute Myelogenous Leukemia Cells against Daunorubicin-Induced Apoptosis
by Daniel Cacic, Håkon Reikvam, Oddmund Nordgård, Peter Meyer and Tor Hervig
Cancers 2021, 13(8), 1870; https://doi.org/10.3390/cancers13081870 - 14 Apr 2021
Cited by 11 | Viewed by 2571
Abstract
The role of platelets in cancer development and progression is increasingly evident, and several platelet–cancer interactions have been discovered, including the uptake of platelet microparticles (PMPs) by cancer cells. PMPs inherit a myriad of proteins and small RNAs from the parental platelets, which [...] Read more.
The role of platelets in cancer development and progression is increasingly evident, and several platelet–cancer interactions have been discovered, including the uptake of platelet microparticles (PMPs) by cancer cells. PMPs inherit a myriad of proteins and small RNAs from the parental platelets, which in turn can be transferred to cancer cells following internalization. However, the exact effect this may have in acute myelogenous leukemia (AML) is unknown. In this study, we sought to investigate whether PMPs could transfer their contents to the THP-1 cell line and if this could change the biological behavior of the recipient cells. Using acridine orange stained PMPs, we demonstrated that PMPs were internalized by THP-1 cells, which resulted in increased levels of miR-125a, miR-125b, and miR-199. In addition, co-incubation with PMPs protected THP-1 and primary AML cells against daunorubicin-induced cell death. We also showed that PMPs impaired cell growth, partially inhibited cell cycle progression, decreased mitochondrial membrane potential, and induced differentiation toward macrophages in THP-1 cells. Our results suggest that this altering of cell phenotype, in combination with decrease in cell activity may offer resistance to daunorubicin-induced apoptosis, as serum starvation also yielded a lower frequency of dead and apoptotic cells when treated with daunorubicin. Full article
(This article belongs to the Special Issue Exosomes in Cancers Therapy)
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Review

Jump to: Editorial, Research

19 pages, 1689 KiB  
Review
The Role of Extracellular HSP70 in the Function of Tumor-Associated Immune Cells
by Manuel Linder and Elke Pogge von Strandmann
Cancers 2021, 13(18), 4721; https://doi.org/10.3390/cancers13184721 - 21 Sep 2021
Cited by 28 | Viewed by 5111
Abstract
Extracellular vesicles released by tumor cells (T-EVs) are known to contain danger-associated molecular patterns (DAMPs), which are released in response to cellular stress to alert the immune system to the dangerous cell. Part of this defense mechanism is the heat shock protein 70 [...] Read more.
Extracellular vesicles released by tumor cells (T-EVs) are known to contain danger-associated molecular patterns (DAMPs), which are released in response to cellular stress to alert the immune system to the dangerous cell. Part of this defense mechanism is the heat shock protein 70 (HSP70), and HSP70-positive T-EVs are known to trigger anti-tumor immune responses. Moreover, extracellular HSP70 acts as an immunogen that contributes to the cross-presentation of major histocompatibility complex (MHC) class I molecules. However, the release of DAMPs, including HSP70, may also induce chronic inflammation or suppress immune cell activity, promoting tumor growth. Here, we summarize the current knowledge on soluble, membrane-bound, and EV-associated HSP70 regarding their functions in regulating tumor-associated immune cells in the tumor microenvironment. The molecular mechanisms involved in the translocation of HSP70 to the plasma membrane of tumor cells and its release via exosomes or soluble proteins are summarized. Furthermore, perspectives for immunotherapies aimed to target HSP70 and its receptors for cancer treatment are discussed and presented. Full article
(This article belongs to the Special Issue Exosomes in Cancers Therapy)
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18 pages, 1262 KiB  
Review
Exosomes: A Forthcoming Era of Breast Cancer Therapeutics
by Banashree Bondhopadhyay, Sandeep Sisodiya, Faisal Abdulrahman Alzahrani, Muhammed A. Bakhrebah, Atul Chikara, Vishakha Kasherwal, Asiya Khan, Jyoti Rani, Sajad Ahmad Dar, Naseem Akhter, Pranay Tanwar, Usha Agrawal and Showket Hussain
Cancers 2021, 13(18), 4672; https://doi.org/10.3390/cancers13184672 - 17 Sep 2021
Cited by 17 | Viewed by 4650
Abstract
Despite the recent advancements in therapeutics and personalized medicine, breast cancer remains one of the most lethal cancers among women. The prognostic and diagnostic aids mainly include assessment of tumor tissues with conventional methods towards better therapeutic strategies. However, current era of gene-based [...] Read more.
Despite the recent advancements in therapeutics and personalized medicine, breast cancer remains one of the most lethal cancers among women. The prognostic and diagnostic aids mainly include assessment of tumor tissues with conventional methods towards better therapeutic strategies. However, current era of gene-based research may influence the treatment outcome particularly as an adjunct to diagnostics by exploring the role of non-invasive liquid biopsies or circulating markers. The characterization of tumor milieu for physiological fluids has been central to identifying the role of exosomes or small extracellular vesicles (sEVs). These exosomes provide necessary communication between tumor cells in the tumor microenvironment (TME). The manipulation of exosomes in TME may provide promising diagnostic/therapeutic strategies, particularly in triple-negative breast cancer patients. This review has described and highlighted the role of exosomes in breast carcinogenesis and how they could be used or targeted by recent immunotherapeutics to achieve promising intervention strategies. Full article
(This article belongs to the Special Issue Exosomes in Cancers Therapy)
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19 pages, 1977 KiB  
Review
DC-Derived Exosomes for Cancer Immunotherapy
by Yi Yao, Chunmei Fu, Li Zhou, Qing-Sheng Mi and Aimin Jiang
Cancers 2021, 13(15), 3667; https://doi.org/10.3390/cancers13153667 - 21 Jul 2021
Cited by 44 | Viewed by 4092
Abstract
As the initiators of adaptive immune responses, DCs play a central role in regulating the balance between CD8 T cell immunity versus tolerance to tumor antigens. Exploiting their function to potentiate host anti-tumor immunity, DC-based vaccines have been one of most promising and [...] Read more.
As the initiators of adaptive immune responses, DCs play a central role in regulating the balance between CD8 T cell immunity versus tolerance to tumor antigens. Exploiting their function to potentiate host anti-tumor immunity, DC-based vaccines have been one of most promising and widely used cancer immunotherapies. However, DC-based cancer vaccines have not achieved the promised success in clinical trials, with one of the major obstacles being tumor-mediated immunosuppression. A recent discovery on the critical role of type 1 conventional DCs (cDC1s) play in cross-priming tumor-specific CD8 T cells and determining the anti-tumor efficacy of cancer immunotherapies, however, has highlighted the need to further develop and refine DC-based vaccines either as monotherapies or in combination with other therapies. DC-derived exosomes (DCexos) have been heralded as a promising alternative to DC-based vaccines, as DCexos are more resistance to tumor-mediated suppression and DCexo vaccines have exhibited better anti-tumor efficacy in pre-clinical animal models. However, DCexo vaccines have only achieved limited clinical efficacy and failed to induce tumor-specific T cell responses in clinical trials. The lack of clinical efficacy might be partly due to the fact that all current clinical trials used peptide-loaded DCexos from monocyte-derived DCs. In this review, we will focus on the perspective of expanding current DCexo research to move DCexo cancer vaccines forward clinically to realize their potential in cancer immunotherapy. Full article
(This article belongs to the Special Issue Exosomes in Cancers Therapy)
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36 pages, 3154 KiB  
Review
Extracellular Vesicles as Mediators of Cancer Disease and as Nanosystems in Theranostic Applications
by Renato Burgos-Ravanal, América Campos, Magda C. Díaz-Vesga, María Fernanda González, Daniela León, Lorena Lobos-González, Lisette Leyton, Marcelo J. Kogan and Andrew F. G. Quest
Cancers 2021, 13(13), 3324; https://doi.org/10.3390/cancers13133324 - 02 Jul 2021
Cited by 14 | Viewed by 4682
Abstract
Cancer remains a leading cause of death worldwide despite decades of intense efforts to understand the molecular underpinnings of the disease. To date, much of the focus in research has been on the cancer cells themselves and how they acquire specific traits during [...] Read more.
Cancer remains a leading cause of death worldwide despite decades of intense efforts to understand the molecular underpinnings of the disease. To date, much of the focus in research has been on the cancer cells themselves and how they acquire specific traits during disease development and progression. However, these cells are known to secrete large numbers of extracellular vesicles (EVs), which are now becoming recognized as key players in cancer. EVs contain a large number of different molecules, including but not limited to proteins, mRNAs, and miRNAs, and they are actively secreted by many different cell types. In the last two decades, a considerable body of evidence has become available indicating that EVs play a very active role in cell communication. Cancer cells are heterogeneous, and recent evidence reveals that cancer cell-derived EV cargos can change the behavior of target cells. For instance, more aggressive cancer cells can transfer their “traits” to less aggressive cancer cells and convert them into more malignant tumor cells or, alternatively, eliminate those cells in a process referred to as “cell competition”. This review discusses how EVs participate in the multistep acquisition of specific traits developed by tumor cells, which are referred to as “the hallmarks of cancer” defined by Hanahan and Weinberg. Moreover, as will be discussed, EVs play an important role in drug resistance, and these more recent advances may explain, at least in part, why pharmacological therapies are often ineffective. Finally, we discuss literature proposing the use of EVs for therapeutic and prognostic purposes in cancer. Full article
(This article belongs to the Special Issue Exosomes in Cancers Therapy)
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24 pages, 1269 KiB  
Review
Extracellular Vesicles and Their Current Role in Cancer Immunotherapy
by Carla Giacobino, Marta Canta, Cristina Fornaguera, Salvador Borrós and Valentina Cauda
Cancers 2021, 13(9), 2280; https://doi.org/10.3390/cancers13092280 - 10 May 2021
Cited by 20 | Viewed by 3408
Abstract
Extracellular vesicles (EVs) are natural particles formed by the lipid bilayer and released from almost all cell types to the extracellular environment both under physiological conditions and in presence of a disease. EVs are involved in many biological processes including intercellular communication, acting [...] Read more.
Extracellular vesicles (EVs) are natural particles formed by the lipid bilayer and released from almost all cell types to the extracellular environment both under physiological conditions and in presence of a disease. EVs are involved in many biological processes including intercellular communication, acting as natural carriers in the transfer of various biomolecules such as DNA, various RNA types, proteins and different phospholipids. Thanks to their transfer and targeting abilities, they can be employed in drug and gene delivery and have been proposed for the treatment of different diseases, including cancer. Recently, the use of EVs as biological carriers has also been extended to cancer immunotherapy. This new technique of cancer treatment involves the use of EVs to transport molecules capable of triggering an immune response to damage cancer cells. Several studies have analyzed the possibility of using EVs in new cancer vaccines, which represent a particular form of immunotherapy. In the literature there are only few publications that systematically group and collectively discuss these studies. Therefore, the purpose of this review is to illustrate and give a partial reorganization to what has been produced in the literature so far. We provide basic notions on cancer immunotherapy and describe some clinical trials in which therapeutic cancer vaccines are tested. We thus focus attention on the potential of EV-based therapeutic vaccines in the treatment of cancer patients, overviewing the clinically relevant trials, completed or still in progress, which open up new perspectives in the fight against cancer. Full article
(This article belongs to the Special Issue Exosomes in Cancers Therapy)
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28 pages, 67916 KiB  
Review
Surface-Enhanced Raman Scattering (SERS) Spectroscopy for Sensing and Characterization of Exosomes in Cancer Diagnosis
by Luca Guerrini, Eduardo Garcia-Rico, Ana O’Loghlen, Vincenzo Giannini and Ramon A. Alvarez-Puebla
Cancers 2021, 13(9), 2179; https://doi.org/10.3390/cancers13092179 - 30 Apr 2021
Cited by 47 | Viewed by 6405
Abstract
Exosomes are emerging as one of the most intriguing cancer biomarkers in modern oncology for early cancer diagnosis, prognosis and treatment monitoring. Concurrently, several nanoplasmonic methods have been applied and developed to tackle the challenging task of enabling the rapid, sensitive, affordable analysis [...] Read more.
Exosomes are emerging as one of the most intriguing cancer biomarkers in modern oncology for early cancer diagnosis, prognosis and treatment monitoring. Concurrently, several nanoplasmonic methods have been applied and developed to tackle the challenging task of enabling the rapid, sensitive, affordable analysis of exosomes. In this review, we specifically focus our attention on the application of plasmonic devices exploiting surface-enhanced Raman spectroscopy (SERS) as the optosensing technique for the structural interrogation and characterization of the heterogeneous nature of exosomes. We summarized the current state-of-art of this field while illustrating the main strategic approaches and discuss their advantages and limitations. Full article
(This article belongs to the Special Issue Exosomes in Cancers Therapy)
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25 pages, 2338 KiB  
Review
Expedition into Exosome Biology: A Perspective of Progress from Discovery to Therapeutic Development
by Arif Tasleem Jan, Safikur Rahman, Raied Badierah, Eun Ju Lee, Ehab H. Mattar, Elrashdy M. Redwan and Inho Choi
Cancers 2021, 13(5), 1157; https://doi.org/10.3390/cancers13051157 - 08 Mar 2021
Cited by 26 | Viewed by 6042
Abstract
Exosomes are membrane-enclosed distinct cellular entities of endocytic origin that shuttle proteins and RNA molecules intercellularly for communication purposes. Their surface is embossed by a huge variety of proteins, some of which are used as diagnostic markers. Exosomes are being explored for potential [...] Read more.
Exosomes are membrane-enclosed distinct cellular entities of endocytic origin that shuttle proteins and RNA molecules intercellularly for communication purposes. Their surface is embossed by a huge variety of proteins, some of which are used as diagnostic markers. Exosomes are being explored for potential drug delivery, although their therapeutic utilities are impeded by gaps in knowledge regarding their formation and function under physiological condition and by lack of methods capable of shedding light on intraluminal vesicle release at the target site. Nonetheless, exosomes offer a promising means of developing systems that enable the specific delivery of therapeutics in diseases like cancer. This review summarizes information on donor cell types, cargoes, cargo loading, routes of administration, and the engineering of exosomal surfaces for specific peptides that increase target specificity and as such, therapeutic delivery. Full article
(This article belongs to the Special Issue Exosomes in Cancers Therapy)
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31 pages, 2771 KiB  
Review
Trends in Research on Exosomes in Cancer Progression and Anticancer Therapy
by Dona Sinha, Sraddhya Roy, Priyanka Saha, Nabanita Chatterjee and Anupam Bishayee
Cancers 2021, 13(2), 326; https://doi.org/10.3390/cancers13020326 - 17 Jan 2021
Cited by 66 | Viewed by 8536
Abstract
Exosomes, the endosome-derived bilayered extracellular nanovesicles with their contribution in many aspects of cancer biology, have become one of the prime foci of research. Exosomes derived from various cells carry cargoes similar to their originator cells and their mode of generation is different [...] Read more.
Exosomes, the endosome-derived bilayered extracellular nanovesicles with their contribution in many aspects of cancer biology, have become one of the prime foci of research. Exosomes derived from various cells carry cargoes similar to their originator cells and their mode of generation is different compared to other extracellular vesicles. This review has tried to cover all aspects of exosome biogenesis, including cargo, Rab-dependent and Rab-independent secretion of endosomes and exosomal internalization. The bioactive molecules of the tumor-derived exosomes, by virtue of their ubiquitous presence and small size, can migrate to distal parts and propagate oncogenic signaling and epigenetic regulation, modulate tumor microenvironment and facilitate immune escape, tumor progression and drug resistance responsible for cancer progression. Strategies improvised against tumor-derived exosomes include suppression of exosome uptake, modulation of exosomal cargo and removal of exosomes. Apart from the protumorigenic role, exosomal cargoes have been selectively manipulated for diagnosis, immune therapy, vaccine development, RNA therapy, stem cell therapy, drug delivery and reversal of chemoresistance against cancer. However, several challenges, including in-depth knowledge of exosome biogenesis and protein sorting, perfect and pure isolation of exosomes, large-scale production, better loading efficiency, and targeted delivery of exosomes, have to be confronted before the successful implementation of exosomes becomes possible for the diagnosis and therapy of cancer. Full article
(This article belongs to the Special Issue Exosomes in Cancers Therapy)
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