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Exosomes as a Tool for Disease Progression Monitoring in Humans...
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Exosomes as a Tool for Disease Progression Monitoring in Humans and Animals

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 50709

Special Issue Editors

Dr. Enrico Iaccino

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Guest Editor
Department of Experimental and Clinical Medicine, Università Magna Græcia di Catanzaro, Catanzaro, Italy
Interests: liquid biopsy; exosomes; phage display; peptides
Dr. Selena Mimmi

E-Mail Website
Guest Editor
Department of Experimental and Clinical Medicine, Università Magna Græcia di Catanzaro, Catanzaro, Italy
Interests: B cell neoplasia; biomarkers; peptides
Dr. Shibu Krishnan

E-Mail Website
Guest Editor
Department of Pharmacy, Drug Delivery, Uppsala University, Uppsala, Sweden
Interests: proteomics; biomarkers; mass spectrometry

Special Issue Information

Dear Colleagues,

For years thought to be “unfunctional garbage bags”, exosomes are now considered as one of the most potentially applicable tools for monitoring several disease conditions, both in humans and in animals. Due to their endosomal origin, exosomes are released in the extracellular space by almost all cell types during different physiological conditions. Reflecting the genomic, proteomic, and lipidomic profile of their parental cells, circulating exosomes are potential biomarkers for the prediction of disease burden both at an early stage and in response to therapy, which could have a relevant impact on precision medicine.

In particular, in combination with liquid biopsy tests, exosomes together with their rich content of biomolecular components could allow the screening of individual patients for the presence of disease indicators using a simple blood test, thus providing an alternative approach to the costly, invasive, and sometimes “risky” traditional procedures.

This Special Issue will discuss recent advances in the field of exosomes as indicators of disease progression both in humans and in animals.

Dr. Enrico Iaccino
Dr. Selena Mimmi
Dr. Shibu Krishnan
Guest Editors

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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

  • liquid biopsy
  • exosomes
  • extracellular vesicles
  • cancer biomarkers
  • metastatic niche
  • cardiovascular diseases
  • neurological diseases
  • veterinary diseases

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Related Special Issue

Published Papers (10 papers)

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Research

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12 pages, 1307 KiB  
Article
Serum Extracellular Vesicle-Derived circHIPK3 and circSMARCA5 Are Two Novel Diagnostic Biomarkers for Glioblastoma Multiforme
by Michele Stella, Luca Falzone, Angela Caponnetto, Giuseppe Gattuso, Cristina Barbagallo, Rosalia Battaglia, Federica Mirabella, Giuseppe Broggi, Roberto Altieri, Francesco Certo, Rosario Caltabiano, Giuseppe Maria Vincenzo Barbagallo, Paolo Musumeci, Marco Ragusa, Cinzia Di Pietro, Massimo Libra, Michele Purrello and Davide Barbagallo
Pharmaceuticals 2021, 14(7), 618; https://doi.org/10.3390/ph14070618 - 27 Jun 2021
Cited by 84 | Viewed by 5391
Abstract
Glioblastoma multiforme (GBM) is the most frequent and deadly human brain cancer. Early diagnosis through non-invasive biomarkers may render GBM more easily treatable, improving the prognosis of this currently incurable disease. We suggest the use of serum extracellular vesicle (sEV)-derived circular RNAs (circRNAs) [...] Read more.
Glioblastoma multiforme (GBM) is the most frequent and deadly human brain cancer. Early diagnosis through non-invasive biomarkers may render GBM more easily treatable, improving the prognosis of this currently incurable disease. We suggest the use of serum extracellular vesicle (sEV)-derived circular RNAs (circRNAs) as highly stable minimally invasive diagnostic biomarkers for GBM diagnosis. EVs were isolated by size exclusion chromatography from sera of 23 GBM and 5 grade 3 glioma (GIII) patients, and 10 unaffected controls (UC). The expression of two candidate circRNAs (circSMARCA5 and circHIPK3) was assayed by droplet digital PCR. CircSMARCA5 and circHIPK3 were significantly less abundant in sEVs from GBM patients with respect to UC (fold-change (FC) of −2.15 and −1.92, respectively) and GIII (FC of −1.75 and −1.4, respectively). Receiver operating characteristic curve (ROC) analysis, based on the expression of sEV-derived circSMARCA5 and circHIPK3, allowed us to distinguish GBM from UC (area under the curve (AUC) 0.823 (0.667–0.979) and 0.855 (0.704 to 1.000), with a 95% confidence interval (CI), respectively). Multivariable ROC analysis, performed by combining the expression of sEV-derived circSMARCA5 and circHIPK3 with preoperative neutrophil to lymphocyte (NLR), platelet to lymphocyte (PLR) and lymphocyte to monocyte (LMR) ratios, three known diagnostic and prognostic GBM markers, allowed an improvement in the GBM diagnostic accuracy (AUC 0.901 (0.7912 to 1.000), 95% CI). Our data suggest sEV-derived circSMARCA5 and circHIPK3 as good diagnostic biomarkers for GBM, especially when associated with preoperative NLR, PLR and LMR. Full article
(This article belongs to the Special Issue Exosomes as a Tool for Disease Progression Monitoring in Humans and Animals)
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13 pages, 1204 KiB  
Article
Small EVs-Associated DNA as Complementary Biomarker to Circulating Tumor DNA in Plasma of Metastatic Colorectal Cancer Patients
by Silvia Galbiati, Francesco Damin, Dario Brambilla, Lucia Ferraro, Nadia Soriani, Anna M. Ferretti, Valentina Burgio, Monica Ronzoni, Riccardo Vago, Laura Sola and Marcella Chiari
Pharmaceuticals 2021, 14(2), 128; https://doi.org/10.3390/ph14020128 - 6 Feb 2021
Cited by 11 | Viewed by 2860
Abstract
It is widely accepted that assessing circular tumor DNA (ctDNA) in the plasma of cancer patients is a promising practice to evaluate somatic mutations from solid tumors noninvasively. Recently, it was reported that isolation of extracellular vesicles improves the detection of mutant DNA [...] Read more.
It is widely accepted that assessing circular tumor DNA (ctDNA) in the plasma of cancer patients is a promising practice to evaluate somatic mutations from solid tumors noninvasively. Recently, it was reported that isolation of extracellular vesicles improves the detection of mutant DNA from plasma in metastatic patients; however, no consensus on the presence of dsDNA in exosomes has been reached yet. We analyzed small extracellular vesicle (sEV)-associated DNA of eleven metastatic colorectal cancer (mCRC) patients and compared the results obtained by microarray and droplet digital PCR (ddPCR) to those reported on the ctDNA fraction. We detected the same mutations found in tissue biopsies and ctDNA in all samples but, unexpectedly, in one sample, we found a KRAS mutation that was not identified either in ctDNA or tissue biopsy. Furthermore, to assess the exact location of sEV-associated DNA (outside or inside the vesicle), we treated with DNase I sEVs isolated with three different methodologies. We found that the DNA inside the vesicles is only a small fraction of that surrounding the vesicles. Its amount seems to correlate with the total amount of circulating tumor DNA. The results obtained in our experimental setting suggest that integrating ctDNA and sEV-associated DNA in mCRC patient management could provide a complete real-time assessment of the cancer mutation status. Full article
(This article belongs to the Special Issue Exosomes as a Tool for Disease Progression Monitoring in Humans and Animals)
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Review

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12 pages, 14655 KiB  
Review
Exosome microRNAs in Metabolic Syndrome as Tools for the Early Monitoring of Diabetes and Possible Therapeutic Options
by Erika Cione, Roberto Cannataro, Luca Gallelli, Giovambattista De Sarro and Maria Cristina Caroleo
Pharmaceuticals 2021, 14(12), 1257; https://doi.org/10.3390/ph14121257 - 2 Dec 2021
Cited by 25 | Viewed by 4893
Abstract
Exosomes are nano-sized extracellular vesicles produced and released by almost all cell types. They play an essential role in cell–cell communications by delivering cellular bioactive compounds such as functional proteins, metabolites, and nucleic acids, including microRNA, to recipient cells. Thus, they are involved [...] Read more.
Exosomes are nano-sized extracellular vesicles produced and released by almost all cell types. They play an essential role in cell–cell communications by delivering cellular bioactive compounds such as functional proteins, metabolites, and nucleic acids, including microRNA, to recipient cells. Thus, they are involved in various physio-pathological conditions. Exosome-miRNAs are associated with numerous diseases, including type 2 diabetes, a complex multifactorial metabolic disorder linked to obesity. In addition, exosome-miRNAs are emerging as essential regulators in the progression of diabetes, principally for pancreatic β-cell injury and insulin resistance. Here, we have clustered the recent findings concerning exosome-miRNAs associated with β-cell dysfunction to provide a novel approach for the early diagnosis and therapy of diabetes. Full article
(This article belongs to the Special Issue Exosomes as a Tool for Disease Progression Monitoring in Humans and Animals)
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13 pages, 943 KiB  
Review
Exosomes in Dogs and Cats: An Innovative Approach to Neoplastic and Non-Neoplastic Diseases
by Emanuela Diomaiuto, Valeria Principe, Adriana De Luca, Flaviana Laperuta, Chiara Alterisio and Antonio Di Loria
Pharmaceuticals 2021, 14(8), 766; https://doi.org/10.3390/ph14080766 - 4 Aug 2021
Cited by 18 | Viewed by 4800
Abstract
Exosomes are extracellular vesicles with a diameter between 40 and 120 nm, which are derived from all types of cells and released into all biological fluids, such as blood plasma, serum, urine, breast milk, colostrum, and more. They contain proteins, nucleic acids (mRNA, [...] Read more.
Exosomes are extracellular vesicles with a diameter between 40 and 120 nm, which are derived from all types of cells and released into all biological fluids, such as blood plasma, serum, urine, breast milk, colostrum, and more. They contain proteins, nucleic acids (mRNA, miRNA, other non-coding RNA, and DNA), and lipids. Exosomes represent a potentially accurate footprint of the miRNA profile of the parental cell and can therefore be proposed as potential and sensitive biomarkers, both in diagnosing and monitoring a variety of diseases in humans and animals. Liquid biopsy offers itself as a non-invasive or minimally invasive, pain-free, time-saving alternative to conventional tissue biopsy. Exosomes in both human and veterinary medicine find their major application in neoplastic diseases, but applications in the field of veterinary cardiology, nephrology, reproduction, parasitology, and regenerative medicine are currently being explored. Exosomes can therefore be used as diagnostic, prognostic, and, in some cases, therapeutic tools for several conditions. The aim of this review was to assess the current applications of exosomes in veterinary medicine, particularly in dog and cat patients. Full article
(This article belongs to the Special Issue Exosomes as a Tool for Disease Progression Monitoring in Humans and Animals)
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18 pages, 661 KiB  
Review
Circulating Melanoma-Derived Extracellular Vesicles: Impact on Melanoma Diagnosis, Progression Monitoring, and Treatment Response
by Stephanie M. Bollard, Cristina Casalou, Chia Yin Goh, Desmond J. Tobin, Pamela Kelly, Amanda McCann and Shirley M. Potter
Pharmaceuticals 2020, 13(12), 475; https://doi.org/10.3390/ph13120475 - 18 Dec 2020
Cited by 18 | Viewed by 4763
Abstract
Malignant melanoma, one of the most aggressive human malignancies, is responsible for 80% of skin cancer deaths. Whilst early detection of disease progression or metastasis can improve patient survival, this remains a challenge due to the lack of reliable biomarkers. Importantly, these clinical [...] Read more.
Malignant melanoma, one of the most aggressive human malignancies, is responsible for 80% of skin cancer deaths. Whilst early detection of disease progression or metastasis can improve patient survival, this remains a challenge due to the lack of reliable biomarkers. Importantly, these clinical challenges are not unique to humans, as melanoma affects many other species, including companion animals, such as the dog and horse. Extracellular vesicles (EVs) are tiny nanoparticles involved in cell-to-cell communication. Several protein and genomic EV markers have been described in the literature, as well as a wide variety of methods for isolating EVs from body fluids. As such, they may be valuable biomarkers in cancer and may address some clinical challenges in the management melanoma. This review aimed to explore the translational applications of EVs as biomarkers in melanoma, as well as their role in the clinical setting in humans and animals. A summary of melanoma-specific protein and genomic EV markers is presented, followed by a discussion of the role EVs in monitoring disease progression and treatment response. Finally, herein, we reviewed the advantages and disadvantages of methods utilised to isolate EVs from bodily fluids in melanoma patients (human and animals) and describe some of the challenges that will need to be addressed before EVs can be introduced in the clinical setting. Full article
(This article belongs to the Special Issue Exosomes as a Tool for Disease Progression Monitoring in Humans and Animals)
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24 pages, 2899 KiB  
Review
The Case of Medication-Related Osteonecrosis of the Jaw Addressed from a Pathogenic Point of View. Innovative Therapeutic Strategies: Focus on the Most Recent Discoveries on Oral Mesenchymal Stem Cell-Derived Exosomes
by Amerigo Giudice, Alessandro Antonelli, Emanuela Chiarella, Francesco Baudi, Tullio Barni and Anna Di Vito
Pharmaceuticals 2020, 13(12), 423; https://doi.org/10.3390/ph13120423 - 25 Nov 2020
Cited by 25 | Viewed by 4653
Abstract
Bisphosphonates-related osteonecrosis of the jaw (BRONJ) was firstly reported by Marx in 2003. Since 2014, the term medication-related osteonecrosis of the jaw (MRONJ) is recommended by the American Association of Oral and Maxillofacial Surgeons (AAOMS). Development of MRONJ has been associated to the [...] Read more.
Bisphosphonates-related osteonecrosis of the jaw (BRONJ) was firstly reported by Marx in 2003. Since 2014, the term medication-related osteonecrosis of the jaw (MRONJ) is recommended by the American Association of Oral and Maxillofacial Surgeons (AAOMS). Development of MRONJ has been associated to the assumption of bisphosphonates but many MRONJ-promoting factors have been identified. A strong involvement of immunity components has been suggested. Therapeutic intervention includes surgical and non-surgical treatments, as well as regenerative medicine procedures for the replacement of the lost tissues. The literature confirms that the combination of mesenchymal stem cells (MSCs), biomaterials and local biomolecules can support the regeneration/repair of different structures. In this review, we report the major open topics in the pathogenesis of MRONJ. Then, we introduce the oral tissues recognized as sources of MSCs, summing up in functional terms what is known about the exosomes release in physiological and pathological conditions. Full article
(This article belongs to the Special Issue Exosomes as a Tool for Disease Progression Monitoring in Humans and Animals)
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25 pages, 1141 KiB  
Review
Exosomes in Gliomas: Biogenesis, Isolation, and Preliminary Applications in Nanomedicine
by Eugenia Romano, Paolo Antonio Netti and Enza Torino
Pharmaceuticals 2020, 13(10), 319; https://doi.org/10.3390/ph13100319 - 19 Oct 2020
Cited by 28 | Viewed by 4437
Abstract
Exosomes are phospholipid-based particles endogenously produced by both normal and tumor cells. Initially identified as a pathway for shuttling cellular waste, for a long time they were thought to act as “garbage bags”, and only in the past few years have they emerged [...] Read more.
Exosomes are phospholipid-based particles endogenously produced by both normal and tumor cells. Initially identified as a pathway for shuttling cellular waste, for a long time they were thought to act as “garbage bags”, and only in the past few years have they emerged as a promising drug delivery system. In this review, we provide an overview of the knowledge about exosome architecture and biogenesis and the recent progress in isolation methods. Furthermore, we describe the mechanisms involved in both extra- and intracellular communication with a focus on glioma brain tumors. Glioma is considered a rare disease and is the most prominent aggressive brain malignancy. How exosomes target glial tumoral cells in vivo remains largely unknown. However, they are able to influence numerous physio-pathological aspects. Here, we discuss the role they play in this heterogeneous and complex microenvironment and their potential applications. Full article
(This article belongs to the Special Issue Exosomes as a Tool for Disease Progression Monitoring in Humans and Animals)
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14 pages, 626 KiB  
Review
Role of Chronic Lymphocytic Leukemia (CLL)-Derived Exosomes in Tumor Progression and Survival
by Nancy Nisticò, Domenico Maisano, Enrico Iaccino, Eleonora Vecchio, Giuseppe Fiume, Salvatore Rotundo, Ileana Quinto and Selena Mimmi
Pharmaceuticals 2020, 13(9), 244; https://doi.org/10.3390/ph13090244 - 14 Sep 2020
Cited by 24 | Viewed by 4736
Abstract
Chronic lymphocytic leukemia (CLL) is a B-lymphoproliferative disease, which consists of the abnormal proliferation of CD19/CD5/CD20/CD23 positive lymphocytes in blood and lymphoid organs, such as bone marrow, lymph nodes and spleen. The neoplastic transformation and expansion of tumor B cells are commonly recognized [...] Read more.
Chronic lymphocytic leukemia (CLL) is a B-lymphoproliferative disease, which consists of the abnormal proliferation of CD19/CD5/CD20/CD23 positive lymphocytes in blood and lymphoid organs, such as bone marrow, lymph nodes and spleen. The neoplastic transformation and expansion of tumor B cells are commonly recognized as antigen-driven processes, mediated by the interaction of antigens with the B cell receptor (BCR) expressed on the surface of B-lymphocytes. The survival and progression of CLL cells largely depend on the direct interaction of CLL cells with receptors of accessory cells of tumor microenvironment. Recently, much interest has been focused on the role of tumor release of small extracellular vesicles (EVs), named exosomes, which incorporate a wide range of biologically active molecules, particularly microRNAs and proteins, which sustain the tumor growth. Here, we will review the role of CLL-derived exosomes as diagnostic and prognostic biomarkers of the disease. Full article
(This article belongs to the Special Issue Exosomes as a Tool for Disease Progression Monitoring in Humans and Animals)
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16 pages, 646 KiB  
Review
Exosomal miRNAs as Potential Diagnostic Biomarkers in Alzheimer’s Disease
by Ida Manna, Selene De Benedittis, Andrea Quattrone, Domenico Maisano, Enrico Iaccino and Aldo Quattrone
Pharmaceuticals 2020, 13(9), 243; https://doi.org/10.3390/ph13090243 - 12 Sep 2020
Cited by 56 | Viewed by 6288
Abstract
Alzheimer’s disease (AD), a neurodegenerative disease, is linked to a variety of internal and external factors present from the early stages of the disease. There are several risk factors related to the pathogenesis of AD, among these exosomes and microRNAs (miRNAs) are of [...] Read more.
Alzheimer’s disease (AD), a neurodegenerative disease, is linked to a variety of internal and external factors present from the early stages of the disease. There are several risk factors related to the pathogenesis of AD, among these exosomes and microRNAs (miRNAs) are of particular importance. Exosomes are nanocarriers released from many different cell types, including neuronal cells. Through the transfer of bioactive molecules, they play an important role both in the maintenance of physiological and in pathological conditions. Exosomes could be carriers of potential biomarkers useful for the assessment of disease progression and for therapeutic applications. miRNAs are small noncoding endogenous RNA sequences active in the regulation of protein expression, and alteration of miRNA expression can result in a dysregulation of key genes and pathways that contribute to disease development. Indeed, the involvement of exosomal miRNAs has been highlighted in various neurodegenerative diseases, and this opens the possibility that dysregulated exosomal miRNA profiles may influence AD disease. The advances in exosome-related biomarker detection in AD are summarized. Finally, in this review, we highlight the use of exosomal miRNAs as essential biomarkers in preclinical and clinical studies in Alzheimer’s disease, also taking a look at their potential clinical value. Full article
(This article belongs to the Special Issue Exosomes as a Tool for Disease Progression Monitoring in Humans and Animals)
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18 pages, 1518 KiB  
Review
Uncovering the Exosomes Diversity: A Window of Opportunity for Tumor Progression Monitoring
by Domenico Maisano, Selena Mimmi, Rossella Russo, Antonella Fioravanti, Giuseppe Fiume, Eleonora Vecchio, Nancy Nisticò, Ileana Quinto and Enrico Iaccino
Pharmaceuticals 2020, 13(8), 180; https://doi.org/10.3390/ph13080180 - 4 Aug 2020
Cited by 40 | Viewed by 6109
Abstract
Cells can communicate through special “messages in the bottle”, which are recorded in the bloodstream inside vesicles, namely exosomes. The exosomes are nanovesicles of 30–100 nm in diameter that carry functionally active biological material, such as proteins, messanger RNA (mRNAs), and micro RNA [...] Read more.
Cells can communicate through special “messages in the bottle”, which are recorded in the bloodstream inside vesicles, namely exosomes. The exosomes are nanovesicles of 30–100 nm in diameter that carry functionally active biological material, such as proteins, messanger RNA (mRNAs), and micro RNA (miRNAs). Therefore, they are able to transfer specific signals from a parental cell of origin to the surrounding cells in the microenvironment and to distant organs through the circulatory and lymphatic stream. More and more interest is rising for the pathological role of exosomes produced by cancer cells and for their potential use in tumor monitoring and patient follow up. In particular, the exosomes could be an appropriate index of proliferation and cancer cell communication for monitoring the minimal residual disease, which cannot be easily detectable by common diagnostic and monitoring techniques. The lack of unequivocal markers for tumor-derived exosomes calls for new strategies for exosomes profile characterization aimed at the adoption of exosomes as an official tumor biomarker for tumor progression monitoring. Full article
(This article belongs to the Special Issue Exosomes as a Tool for Disease Progression Monitoring in Humans and Animals)
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