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1
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Zheng M, Yang Z, Shi L, Zhao L, Liu K, Tang N. The role of lncRNAs in AKI and CKD: Molecular mechanisms, biomarkers, and potential therapeutic targets. Genes Dis 2025; 12:101509. [PMID: 40083322 PMCID: PMC11904545 DOI: 10.1016/j.gendis.2024.101509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 02/04/2024] [Accepted: 11/02/2024] [Indexed: 03/16/2025] Open
Abstract
Exosomes, a type of extracellular vesicle, are commonly found in different body fluids and are rich in nucleic acids (circRNA, lncRNAs, miRNAs, mRNAs, tRNAs, etc.), proteins, and lipids. They are involved in intercellular communication. lncRNAs are responsible for the modulation of gene expression, thus affecting the pathological process of kidney injury. This review summarizes the latest knowledge on the roles of exosome lncRNAs and circulating lncRNAs in the pathogenesis, biomarker discovery, and treatment of chronic kidney disease, renal fibrosis, and acute kidney injury, providing an overview of novel regulatory approaches and lncRNA delivery systems.
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Affiliation(s)
- Minhui Zheng
- Shanghai Innostar Bio-Technology Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Zixuan Yang
- Shanghai Innostar Bio-Technology Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Lei Shi
- Shanghai Innostar Bio-Technology Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Liyuan Zhao
- Anhui University of Traditional Chinese Medicine, Hefei, Anhui 230000, China
- Yangtze Delta Drug Advanced Research Institute, Yangtze Delta Pharmaceutical College, Nantong, Jiangsu 226133, China
| | - Kelan Liu
- Intensive Care Unit, Liyang People's Hospital, Liyang, Jiangsu 213300, China
| | - Naping Tang
- Shanghai Innostar Bio-Technology Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China
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2
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Yi YF, Fan ZQ, Liu C, Ding YT, Chen Y, Wen J, Jian XH, Li YF. Immunomodulatory effects and clinical application of exosomes derived from mesenchymal stem cells. World J Stem Cells 2025; 17:103560. [DOI: 10.4252/wjsc.v17.i3.103560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/16/2025] [Accepted: 02/17/2025] [Indexed: 03/21/2025] Open
Abstract
Exosomes (Exos) are extracellular vesicles secreted by cells and serve as crucial mediators of intercellular communication. They play a pivotal role in the pathogenesis and progression of various diseases and offer promising avenues for therapeutic interventions. Exos derived from mesenchymal stem cells (MSCs) have significant immunomodulatory properties. They effectively regulate immune responses by modulating both innate and adaptive immunity. These Exos can inhibit excessive inflammatory responses and promote tissue repair. Moreover, they participate in antigen presentation, which is essential for activating immune responses. The cargo of these Exos, including ligands, proteins, and microRNAs, can suppress T cell activity or enhance the population of immunosuppressive cells to dampen the immune response. By inhibiting lymphocyte proliferation, acting on macrophages, and increasing the population of regulatory T cells, these Exos contribute to maintaining immune and metabolic homeostasis. Furthermore, they can activate immune-related signaling pathways or serve as vehicles to deliver microRNAs and other bioactive substances to target tumor cells, which holds potential for immunotherapy applications. Given the immense therapeutic potential of MSC-derived Exos, this review comprehensively explores their mechanisms of immune regulation and therapeutic applications in areas such as infection control, tumor suppression, and autoimmune disease management. This article aims to provide valuable insights into the mechanisms behind the actions of MSC-derived Exos, offering theoretical references for their future clinical utilization as cell-free drug preparations.
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Affiliation(s)
- Yang-Fei Yi
- Department of Anatomy, Hunan Normal University School of Medicine, Changsha 410005, Hunan Province, China
| | - Zi-Qi Fan
- Department of Anatomy, Hunan Normal University School of Medicine, Changsha 410005, Hunan Province, China
| | - Can Liu
- Department of Anatomy, Hunan Normal University School of Medicine, Changsha 410005, Hunan Province, China
| | - Yi-Tong Ding
- Department of Anatomy, Hunan Normal University School of Medicine, Changsha 410005, Hunan Province, China
| | - Yao Chen
- Department of Anatomy, Hunan Normal University School of Medicine, Changsha 410005, Hunan Province, China
| | - Jie Wen
- Department of Anatomy, Hunan Normal University School of Medicine, Changsha 410005, Hunan Province, China
- Department of Pediatric Orthopedics, Hunan Provincial People’s Hospital, Changsha 410013, Hunan Province, China
| | - Xiao-Hong Jian
- Department of Anatomy, Hunan Normal University School of Medicine, Changsha 410005, Hunan Province, China
| | - Yu-Fei Li
- Department of Anatomy, Hunan Normal University School of Medicine, Changsha 410005, Hunan Province, China
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3
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Vetsika EK, Katsianou MA, Sarantis P, Palamaris K, Papavassiliou AG, Piperi C. Pediatric gliomas immunity challenges and immunotherapy advances. Cancer Lett 2025; 618:217640. [PMID: 40090572 DOI: 10.1016/j.canlet.2025.217640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/18/2025]
Abstract
Pediatric gliomas, the most frequent brain tumors in children, are characterized by heterogeneity and a unique tumor immune microenvironment. They are categorized into different subtypes, including low-grade gliomas like pilocytic astrocytomas and high-grade gliomas such as diffuse midline gliomas and diffuse intrinsic pontine gliomas, each exhibiting distinct immunological profiles. The tumor immune microenvironment in pediatric gliomas is shaped by cellular and non-cellular components, including immune cells, cytokines, and the extracellular matrix, involved in tumor progression, immune evasion, and response to therapy. While pediatric low-grade gliomas often display an immunosuppressed microenvironment, high-grade gliomas are characterized by complex immune infiltrates and intricate immunosuppressive mechanisms. The blood-brain barrier further obscures immune cell recruitment and therapeutic delivery. Despite advances in understanding adult gliomas, the immunobiology of pediatric tumors is poorly investigated, with limited data on the interactions between glioma cells and immune populations such as T and natural killer cells, as well as tumor-associated macrophages. Herein, we provide an update of the current knowledge on tumor immune microenvironment interactions in pediatric gliomas, highlighting the immunosuppressive mechanisms and emerging immunotherapeutic strategies aiming at overcoming these barriers to improve clinical outcomes for affected children.
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Affiliation(s)
- Eleni-Kyriaki Vetsika
- Centre of New Biotechnologies and Precision Medicine (CNBPM), School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria A Katsianou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Kostas Palamaris
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 10679, Athens, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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4
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Zhao B, Li Z, Li R. Exosomes in oral squamous cell carcinoma: functions, challenges, and potential applications. Front Oncol 2025; 14:1502283. [PMID: 39886659 PMCID: PMC11779712 DOI: 10.3389/fonc.2024.1502283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 12/05/2024] [Indexed: 02/01/2025] Open
Abstract
Oral squamous cell carcinoma (OSCC) accounts for approximately 90% of all oral cancers, significantly impacting the survival and quality of life of patients. Exosomes, small extracellular vesicles released by cells, play a crucial role in intercellular communication in cancer. Nevertheless, their function and mechanism in OSCC remain elusive. Search Pubmed, Web of Science, and Cochrane Library using keywords OSCC, exome, diagnosis, and treatment to review the research progress of exome in OSCC. Based on these results, this review starting from the biosynthesis, structure, and contents of exosomes, elaborates on the research progress of exosomes in the diagnosis and treatment of OSCC. It explores the potential of exosomes in the diagnosis and treatment of OSCC, and briefly describes the challenges researchers currently face.
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Affiliation(s)
- Bo Zhao
- Key Laboratory of Advanced Intelligent Protective Equipment Technology (Hebei University of Technology), Ministry of Education, Tianjin, China
- Department of Stomatology, Tianjin First Central Hospital, Tianjin, China
| | - Zuntai Li
- Department of Stomatology, Tianjin First Central Hospital, Tianjin, China
| | - Ronghua Li
- Department of Stomatology, Tianjin First Central Hospital, Tianjin, China
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5
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Afshar Y, Sharifi N, Kamroo A, Yazdanpanah N, Saleki K, Rezaei N. Implications of glioblastoma-derived exosomes in modifying the immune system: state-of-the-art and challenges. Rev Neurosci 2024:revneuro-2024-0095. [PMID: 39528347 DOI: 10.1515/revneuro-2024-0095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024]
Abstract
Glioblastoma is a brain cancer with a poor prognosis. Failure of classical chemotherapy and surgical treatments indicates that new therapeutic approaches are needed. Among cell-free options, exosomes are versatile extracellular vesicles (EVs) that carry important cargo across barriers such as the blood-brain barrier (BBB) to their target cells. This makes exosomes an interesting option for the treatment of glioblastoma. Moreover, exosomes can comprise many therapeutic cargos, including lipids, proteins, and nucleic acids, sampled from special intercellular compartments of their origin cell. Cells exposed to various immunomodulatory stimuli can generate exosomes enriched in specific therapeutic molecules. Notably, the secretion of exosomes could modify the immune response in innate and adaptive immune systems. For instance, glioblastoma-associated exosomes (GBex) uptake by macrophages could influence macrophage dynamics (e.g., shifting CD markers expression). Expression of critical immunoregulatory proteins such as cytotoxic T-lymphocyte antigen-1 (CTLA1) and programmed death-1 (PD-1) on GBex indicates the direct crosstalk of these nano-size vesicles with the immune system. The present study reviews the role of exosomes in immune system cells, including B cells, T cells, natural killer (NK) cells, and dendritic cells (DCs), as well as novel technologies in the field.
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Affiliation(s)
- Yashmin Afshar
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, 1416634793, Iran
| | - Negin Sharifi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, 1416634793, Iran
- Faculty of Medicine, Tehran Medical Science Branch, Islamic Azad University, Tehran, 1584743311, Iran
| | - Amirhossein Kamroo
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, 1416634793, Iran
- School of Medicine, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
- Students' Scientific Research Center, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
| | - Niloufar Yazdanpanah
- Research Center for Immunodeficiencies, Children's Medical Center, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, 1416634793, Iran
| | - Kiarash Saleki
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, 1416634793, Iran
- Student Research Committee, Babol University of Medical Sciences, Babol, 4717647745, Iran
- USERN Office, Babol University of Medical Sciences, Babol, 4717647745, Iran
- Department of E-Learning in Medical Sciences, Faculty of Medical Education and Learning Technologies, Shahid Beheshti University of Medical Sciences, Tehran, 1985717443, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, 1416634793, Iran
- Department of Immunology, School of Medicine, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Stockholms, 10316, Sweden
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6
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Ye Z, Li G, Lei J. Influencing immunity: role of extracellular vesicles in tumor immune checkpoint dynamics. Exp Mol Med 2024; 56:2365-2381. [PMID: 39528800 PMCID: PMC11612210 DOI: 10.1038/s12276-024-01340-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 08/06/2024] [Accepted: 08/09/2024] [Indexed: 11/16/2024] Open
Abstract
Immune checkpoint proteins (ICPs) serve as critical regulators of the immune system, ensuring protection against damage due to overly activated immune responses. However, within the tumor environment, excessive ICP activation weakens antitumor immunity. Despite the development of numerous immune checkpoint blockade (ICB) drugs in recent years, their broad application has been inhibited by uncertainties about their clinical efficacy. A thorough understanding of ICP regulation in the tumor microenvironment is essential for advancing the development of more effective and safer ICB therapies. Extracellular vesicles (EVs), which are pivotal mediators of cell-cell communication, have been extensively studied and found to play key roles in the functionality of ICPs. Nonetheless, a comprehensive review summarizing the current knowledge about the crosstalk between EVs and ICPs in the tumor environment is lacking. In this review, we summarize the interactions between EVs and several widely studied ICPs as well as their potential clinical implications, providing a theoretical basis for further investigation of EV-related ICB therapeutic approaches.
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Affiliation(s)
- Ziyang Ye
- Division of Thyroid Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Genpeng Li
- Division of Thyroid Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jianyong Lei
- Division of Thyroid Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China.
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7
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Rasouli A, Roshangar L, Hosseini M, Pourmohammadfazel A, Nikzad S. Beyond boundaries: The therapeutic potential of exosomes in neural microenvironments in neurological disorders. Neuroscience 2024; 553:98-109. [PMID: 38964450 DOI: 10.1016/j.neuroscience.2024.06.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 06/18/2024] [Accepted: 06/25/2024] [Indexed: 07/06/2024]
Abstract
Neurological disorders are a diverse group of conditions that can significantly impact individuals' quality of life. The maintenance of neural microenvironment homeostasis is essential for optimal physiological cellular processes. Perturbations in this delicate balance underlie various pathological manifestations observed across various neurological disorders. Current treatments for neurological disorders face substantial challenges, primarily due to the formidable blood-brain barrier and the intricate nature of neural tissue structures. These obstacles have resulted in a paucity of effective therapies and inefficiencies in patient care. Exosomes, nanoscale vesicles that contain a complex repertoire of biomolecules, are identifiable in various bodily fluids. They hold substantial promise in numerous therapeutic interventions due to their unique attributes, including targeted drug delivery mechanisms and the ability to cross the BBB, thereby enhancing their therapeutic potential. In this review, we investigate the therapeutic potential of exosomes across a range of neurological disorders, including neurodegenerative disorders, traumatic brain injury, peripheral nerve injury, brain tumors, and stroke. Through both in vitro and in vivo studies, our findings underscore the beneficial influence of exosomes in enhancing the neural microenvironment following neurological diseases, offering promise for improved neural recovery and management in these conditions.
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Affiliation(s)
- Arefe Rasouli
- Department of Anatomical Sciences, School of Medicine Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Roshangar
- Department of Anatomical Sciences, School of Medicine Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammadbagher Hosseini
- Department of Pediatrics, School of Medicine Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Pourmohammadfazel
- Department of Anatomical Sciences, School of Medicine Tabriz University of Medical Sciences, Tabriz, Iran
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8
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Yang Z, Wu H, Wang Z, Bian E, Zhao B. The role and application of small extracellular vesicles in glioma. Cancer Cell Int 2024; 24:229. [PMID: 38951882 PMCID: PMC11218314 DOI: 10.1186/s12935-024-03389-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 05/28/2024] [Indexed: 07/03/2024] Open
Abstract
Small extracellular vesicles (sEVs) are cell-derived, nanometer-sized particles enclosed by a lipid bilayer. All kinds of biological molecules, including proteins, DNA fragments, RNA, lipids, and metabolites, can be selectively loaded into sEVs and transmitted to recipient cells that are near and distant. Growing shreds of evidence show the significant biological function and the clinical significance of sEVs in cancers. Numerous recent studies have validated that sEVs play an important role in tumor progression and can be utilized to diagnose, stage, grading, and monitor early tumors. In addition, sEVs have also served as drug delivery nanocarriers and cancer vaccines. Although it is still infancy, the field of basic and translational research based on sEVs has grown rapidly. In this review, we summarize the latest research on sEVs in gliomas, including their role in the malignant biological function of gliomas, and the potential of sEVs in non-invasive diagnostic and therapeutic approaches, i.e., as nanocarriers for drug or gene delivery and cancer vaccines.
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Affiliation(s)
- Zhihao Yang
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui Province, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, 230601, Anhui Province, China
| | - HaoYuan Wu
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui Province, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, 230601, Anhui Province, China
| | - ZhiWei Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui Province, China
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, 230601, Anhui Province, China
| | - ErBao Bian
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui Province, China.
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, 230601, Anhui Province, China.
| | - Bing Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui Province, China.
- Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, 230601, Anhui Province, China.
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Liguori GL. Challenges and Promise for Glioblastoma Treatment through Extracellular Vesicle Inquiry. Cells 2024; 13:336. [PMID: 38391949 PMCID: PMC10886570 DOI: 10.3390/cells13040336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/31/2024] [Accepted: 02/08/2024] [Indexed: 02/24/2024] Open
Abstract
Glioblastoma (GB) is a rare but extremely aggressive brain tumor that significantly impacts patient outcomes, affecting both duration and quality of life. The protocol established by Stupp and colleagues in 2005, based on radiotherapy and chemotherapy with Temozolomide, following maximum safe surgical resection remains the gold standard for GB treatment; however, it is evident nowadays that the extreme intratumoral and intertumoral heterogeneity, as well as the invasiveness and tendency to recur, of GB are not compatible with a routine and unfortunately ineffective treatment. This review article summarizes the main challenges in the search for new valuable therapies for GB and focuses on the impact that extracellular vesicle (EV) research and exploitation may have in the field. EVs are natural particles delimited by a lipidic bilayer and filled with functional cellular content that are released and uptaken by cells as key means of cell communication. Furthermore, EVs are stable in body fluids and well tolerated by the immune system, and are able to cross physiological, interspecies, and interkingdom barriers and to target specific cells, releasing inherent or externally loaded functionally active molecules. Therefore, EVs have the potential to be ideal allies in the fight against GB and to improve the prognosis for GB patients. The present work describes the main preclinical results obtained so far on the use of EVs for GB treatment, focusing on both the EV sources and molecular cargo used in the various functional studies, primarily in vivo. Finally, a SWOT analysis is performed, highlighting the main advantages and pitfalls of developing EV-based GB therapeutic strategies. The analysis also suggests the main directions to explore to realize the possibility of exploiting EVs for the treatment of GB.
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Affiliation(s)
- Giovanna L Liguori
- Institute of Genetics and Biophysics (IGB) "Adriano Buzzati-Traverso", National Research Council (CNR) of Italy, 80131 Naples, Italy
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10
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Dai J, Jiang Y, Hu H, Zhang S, Chen Y. Extracellular vesicles as modulators of glioblastoma progression and tumor microenvironment. Pathol Oncol Res 2024; 30:1611549. [PMID: 38379858 PMCID: PMC10876843 DOI: 10.3389/pore.2024.1611549] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 01/16/2024] [Indexed: 02/22/2024]
Abstract
Glioblastoma is the most aggressive brain tumor with extremely poor prognosis in adults. Routine treatments include surgery, chemotherapy, and radiotherapy; however, these may lead to rapid relapse and development of therapy-resistant tumor. Glioblastoma cells are known to communicate with macrophages, microglia, endothelial cells, astrocytes, and immune cells in the tumor microenvironment (TME) to promote tumor preservation. It was recently demonstrated that Glioblastoma-derived extracellular vesicles (EVs) participate in bidirectional intercellular communication in the TME. Apart from promoting glioblastoma cell proliferation, migration, and angiogenesis, EVs and their cargos (primarily proteins and miRNAs) can act as biomarkers for tumor diagnosis and prognosis. Furthermore, they can be used as therapeutic tools. In this review, the mechanisms of Glioblastoma-EVs biogenesis and intercellular communication with TME have been summarized. Moreover, there is discussion surrounding EVs as novel diagnostic structures and therapeutic tools for glioblastoma. Finally, unclear questions that require future investigation have been reviewed.
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Affiliation(s)
- Jie Dai
- Department of Pathology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Yong Jiang
- Department of Neurosurgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Haoyue Hu
- Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Shuang Zhang
- Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Yue Chen
- Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
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11
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Baselga M, Iruzubieta P, Castiella T, Monzón M, Monleón E, Berga C, Schuhmacher AJ, Junquera C. Spheresomes are the main extracellular vesicles in low-grade gliomas. Sci Rep 2023; 13:11180. [PMID: 37430101 DOI: 10.1038/s41598-023-38084-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 07/03/2023] [Indexed: 07/12/2023] Open
Abstract
Cancer progression and its impact on treatment response and prognosis is deeply regulated by tumour microenvironment (TME). Cancer cells are in constant communication and modulate TME through several mechanisms, including transfer of tumour-promoting cargos through extracellular vesicles (EVs) or oncogenic signal detection by primary cilia. Spheresomes are a specific EV that arise from rough endoplasmic reticulum-Golgi vesicles. They accumulate beneath cell membrane and are released to the extracellular medium through multivesicular spheres. This study describes spheresomes in low-grade gliomas using electron microscopy. We found that spheresomes are more frequent than exosomes in these tumours and can cross the blood-brain barrier. Moreover, the distinct biogenesis processes of these EVs result in unique cargo profiles, suggesting different functional roles. We also identified primary cilia in these tumours. These findings collectively contribute to our understanding of glioma progression and metastasis.
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Affiliation(s)
- Marta Baselga
- Institute for Health Research Aragon (IIS Aragón), 50009, Zaragoza, Spain
| | - Pablo Iruzubieta
- Department of Human Anatomy and Histology, University of Zaragoza, 50009, Zaragoza, Spain
| | - Tomás Castiella
- Department of Pathological Anatomy, Legal Medicine, and Toxicology, University of Zaragoza, 50009, Zaragoza, Spain
| | - Marta Monzón
- Institute for Health Research Aragon (IIS Aragón), 50009, Zaragoza, Spain
- Department of Human Anatomy and Histology, University of Zaragoza, 50009, Zaragoza, Spain
| | - Eva Monleón
- Institute for Health Research Aragon (IIS Aragón), 50009, Zaragoza, Spain.
- Department of Human Anatomy and Histology, University of Zaragoza, 50009, Zaragoza, Spain.
| | - Carmen Berga
- Department of Human Anatomy and Histology, University of Zaragoza, 50009, Zaragoza, Spain
| | - Alberto J Schuhmacher
- Institute for Health Research Aragon (IIS Aragón), 50009, Zaragoza, Spain
- Fundación Agencia Aragonesa para la Investigación y el Desarrollo (ARAID), 50018, Zaragoza, Spain
| | - Concepción Junquera
- Institute for Health Research Aragon (IIS Aragón), 50009, Zaragoza, Spain
- Department of Human Anatomy and Histology, University of Zaragoza, 50009, Zaragoza, Spain
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12
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Skouras P, Gargalionis AN, Piperi C. Exosomes as Novel Diagnostic Biomarkers and Therapeutic Tools in Gliomas. Int J Mol Sci 2023; 24:10162. [PMID: 37373314 DOI: 10.3390/ijms241210162] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Exosomes constitute small extracellular vesicles that contain lipids, proteins, nucleic acids, and glycoconjugates from the secreted cells and are capable of transmitting signals between cells and coordinating cellular communication. By this means, they are ultimately involved in physiology and disease, including development, homeostasis, and immune system regulation, as well as contributing to tumor progression and neurodegenerative diseases pathology. Recent studies have shown that gliomas secrete a panel of exosomes which have been associated with cell invasion and migration, tumor immune tolerance, potential for malignant transformation, neovascularization, and resistance to treatment. Exosomes have therefore emerged as intercellular communicators, which mediate the tumor-microenvironment interactions and exosome-regulated glioma cell stemness and angiogenesis. They may induce tumor proliferation and malignancy in normal cells by carrying pro-migratory modulators from cancer cells as well as many different molecular cancer modifiers, such as oncogenic transcripts, miRNAs, mutant oncoproteins, etc., which promote the communication of cancer cells with the surrounding stromal cells and provide valuable information on the molecular profile of the existing tumor. Moreover, engineered exosomes can provide an alternative system for drug delivery and enable efficient treatment. In the present review, we discuss the latest findings regarding the role of exosomes in glioma pathogenesis, their utility in non-invasive diagnosis, and potential applications to treatment.
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Affiliation(s)
- Panagiotis Skouras
- Department of Neurosurgery, 'Evangelismos' Hospital, Medical School, National and Kapodistrian University of Athens, 10676 Athens, Greece
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Antonios N Gargalionis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Department of Biopathology, 'Eginition' Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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13
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Avgoulas DI, Tasioulis KS, Papi RM, Pantazaki AA. Therapeutic and Diagnostic Potential of Exosomes as Drug Delivery Systems in Brain Cancer. Pharmaceutics 2023; 15:pharmaceutics15051439. [PMID: 37242681 DOI: 10.3390/pharmaceutics15051439] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/26/2023] [Accepted: 05/03/2023] [Indexed: 05/28/2023] Open
Abstract
Cancer is designated as one of the principal causes of mortality universally. Among different types of cancer, brain cancer remains the most challenging one due to its aggressiveness, the ineffective permeation ability of drugs through the blood-brain barrier (BBB), and drug resistance. To overcome the aforementioned issues in fighting brain cancer, there is an imperative need for designing novel therapeutic approaches. Exosomes have been proposed as prospective "Trojan horse" nanocarriers of anticancer theranostics owing to their biocompatibility, increased stability, permeability, negligible immunogenicity, prolonged circulation time, and high loading capacity. This review provides a comprehensive discussion on the biological properties, physicochemical characteristics, isolation methods, biogenesis and internalization of exosomes, while it emphasizes their therapeutic and diagnostic potential as drug vehicle systems in brain cancer, highlighting recent advances in the research field. A comparison of the biological activity and therapeutic effectiveness of several exosome-encapsulated cargo including drugs and biomacromolecules underlines their great supremacy over the non-exosomal encapsulated cargo in the delivery, accumulation, and biological potency. Various studies on cell lines and animals give prominence to exosome-based nanoparticles (NPs) as a promising and alternative approach in the management of brain cancer.
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Affiliation(s)
- Dimitrios I Avgoulas
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Konstantinos S Tasioulis
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Rigini M Papi
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Anastasia A Pantazaki
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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14
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Macedo-Pereira A, Martins C, Lima J, Sarmento B. Digging the intercellular crosstalk via extracellular vesicles: May exosomes be the drug delivery solution for target glioblastoma? J Control Release 2023; 358:98-115. [PMID: 37120033 DOI: 10.1016/j.jconrel.2023.04.038] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/04/2023] [Accepted: 04/24/2023] [Indexed: 05/01/2023]
Abstract
Glioblastoma (GBM) is an adult's most aggressive brain tumor. The advances in molecular pathology and cell signaling pathways have deepened researchers' understanding of intercellular communication mechanisms that can induce tumor progression, namely the release of extracellular vesicles. Exosomes are small extracellular vesicles in various biological fluids released by almost all cells, thus carrying various biomolecules specific to their parental cell. Several pieces of evidence indicate that exosomes mediate intercellular communication in the tumor microenvironment and cross the blood-brain barrier (BBB), valuable tools for diagnostic and therapeutic applications under the scope of brain diseases such as brain tumors. This review aims to resume the several biological characteristics and the interplay between glioblastoma and exosomes, describing highlight studies that demonstrate the role of exosomes in the tumor microenvironment of GBM and their potential for non-invasive diagnoses and therapeutic approaches, namely, as nanocarriers for drug or gene delivery and cancer vaccines.
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Affiliation(s)
- Ana Macedo-Pereira
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo, Allen 208, 4200-393 Porto, Portugal; FMUP - Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Cláudia Martins
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo, Allen 208, 4200-393 Porto, Portugal; INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Jorge Lima
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo, Allen 208, 4200-393 Porto, Portugal; FMUP - Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
| | - Bruno Sarmento
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo, Allen 208, 4200-393 Porto, Portugal; INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal; IUCS - CESPU, Rua Central de Gandra 1317, 4585-116 Gandra, Portugal.
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15
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Aibaidula A(Z, Fain CE, Garcia LC, Wier A, Bouchal SM, Bauman MM, Jung MY, Sarkaria JN, Johnson AJ, Parney IF. Spectral flow cytometry identifies distinct nonneoplastic plasma extracellular vesicle phenotype in glioblastoma patients. Neurooncol Adv 2023; 5:vdad082. [PMID: 37638345 PMCID: PMC10457026 DOI: 10.1093/noajnl/vdad082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023] Open
Abstract
Background Glioblastoma (GBM) is the most common malignant brain tumor and has a poor prognosis. Imaging findings at diagnosis and in response to treatment are nonspecific. Developing noninvasive assays to augment imaging would be helpful. Plasma extracellular vesicles (EVs) are a promising biomarker source for this. Here, we develop spectral flow cytometry techniques that demonstrate differences in bulk plasma EV phenotype between GBM patients and normal donors that could serve as the basis of a liquid biopsy. Methods Plasma EVs were stained for EV-associated tetraspanins (CD9/CD63/CD81), markers indicating cell of origin (CD11b/CD31/CD41a/CD45), and actin/phalloidin (to exclude cell debris). EVs were analyzed using spectral flow cytometry. Multiparametric analysis using t-distributed stochastic neighbor embedding (t-SNE) and self-organizing maps on flow cytometry data (FlowSOM) was performed comparing GBM and normal donor (ND) plasma EVs. Results Size exclusion chromatography plus spectral-based flow cytometer threshold settings enriched plasma EVs while minimizing background noise. GBM patients had increased CD9+, CD63+, CD81+, and myeloid-derived (CD11b+) EVs. Multiparametric analysis demonstrated distinct surface marker expression profiles in GBM plasma EVs compared to ND EVs. Fifteen plasma EV sub-populations differing in size and surface marker expression were identified, six enriched in GBM patients and two in normal donors. Conclusions Multiparametric analysis demonstrates that GBM patients have a distinct nonneoplastic plasma EV phenotype compared to ND. This simple rapid analysis can be performed without purifying tumor EVs and may serve as the basis of a liquid biopsy.
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Affiliation(s)
- Abudumijiti (Zack) Aibaidula
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota, USA
- Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Cori E Fain
- Department of Immunology, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Luz Cumba Garcia
- Department of Immunology, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Annelise Wier
- Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Samantha M Bouchal
- Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota, USA
- Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Megan M Bauman
- Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota, USA
- Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Mi-Yeon Jung
- Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Jann N Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Aaron J Johnson
- Department of Immunology, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Ian F Parney
- Department of Neurological Surgery, Mayo Clinic, Rochester, Minnesota, USA
- Department of Immunology, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota, USA
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16
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Musatova OE, Rubtsov YP. Effects of glioblastoma-derived extracellular vesicles on the functions of immune cells. Front Cell Dev Biol 2023; 11:1060000. [PMID: 36960410 PMCID: PMC10028257 DOI: 10.3389/fcell.2023.1060000] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 02/22/2023] [Indexed: 03/09/2023] Open
Abstract
Glioblastoma is the most aggressive variant of glioma, the tumor of glial origin which accounts for 80% of brain tumors. Glioblastoma is characterized by astoundingly poor prognosis for patients; a combination of surgery, chemo- and radiotherapy used for clinical treatment of glioblastoma almost inevitably results in rapid relapse and development of more aggressive and therapy resistant tumor. Recently, it was demonstrated that extracellular vesicles produced by glioblastoma (GBM-EVs) during apoptotic cell death can bind to surrounding cells and change their phenotype to more aggressive. GBM-EVs participate also in establishment of immune suppressive microenvironment that protects glioblastoma from antigen-specific recognition and killing by T cells. In this review, we collected present data concerning characterization of GBM-EVs and study of their effects on different populations of the immune cells (T cells, macrophages, dendritic cells, myeloid-derived suppressor cells). We aimed at critical analysis of experimental evidence in order to conclude whether glioblastoma-derived extracellular vesicles are a major factor in immune evasion of this deadly tumor. We summarized data concerning potential use of GBM-EVs for non-invasive diagnostics of glioblastoma. Finally, the applicability of approaches aimed at blocking of GBM-EVs production or their fusion with target cells for treatment of glioblastoma was analyzed.
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Affiliation(s)
- Oxana E. Musatova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, RAS, Moscow, Russia
| | - Yury P. Rubtsov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, RAS, Moscow, Russia
- N.N.Blokhin Russian Cancer Research Center, Ministry of Health of the Russian Federation, Moscow, Russia
- *Correspondence: Yury P. Rubtsov,
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17
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Tan M, Ge Y, Wang X, Wang Y, Liu Y, He F, Teng H. Extracellular Vesicles (EVs) in Tumor Diagnosis and Therapy. Technol Cancer Res Treat 2023; 22:15330338231171463. [PMID: 37122245 PMCID: PMC10134167 DOI: 10.1177/15330338231171463] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2023] Open
Abstract
In recent years, extracellular vesicles (EVs) have gained significant attention due to their tremendous potential for clinical applications. EVs play a crucial role in various aspects, including tumorigenesis, drug resistance, immune escape, and reconstruction of the tumor microenvironment. Despite the growing interest in EVs, many questions still need to be addressed before they can be practically applied in clinical settings. This paper aims to review EVs' isolation methods, structure research, the roles of EVs in tumorigenesis and their mechanisms in multiple types of tumors, their potential application in drug delivery, and the expectations for their future in clinical research.
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Affiliation(s)
- Mingdian Tan
- School of Medicine, Asian Liver Center, Stanford, CA, USA
| | - Yizhi Ge
- The Affiliated Cancer Hospital of Nanjing Medical University (Jiangsu Cancer Hospital) and Jiangsu Institute of Cancer Research, Nanjing, China
| | - Xiaogang Wang
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yan Wang
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
- Stanford University School of Medicine, Stanford, CA, USA
| | - Yi Liu
- School of Medicine, Asian Liver Center, Stanford, CA, USA
| | - Feng He
- Stanford University School of Medicine, Stanford, CA, USA
| | - Hongqi Teng
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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18
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Matsuzaka Y, Yashiro R. Advances in Purification, Modification, and Application of Extracellular Vesicles for Novel Clinical Treatments. MEMBRANES 2022; 12:membranes12121244. [PMID: 36557150 PMCID: PMC9787595 DOI: 10.3390/membranes12121244] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 11/30/2022] [Accepted: 12/06/2022] [Indexed: 06/01/2023]
Abstract
Extracellular vesicles (EV) are membrane vesicles surrounded by a lipid bilayer membrane and include microvesicles, apoptotic bodies, exosomes, and exomeres. Exosome-encapsulated microRNAs (miRNAs) released from cancer cells are involved in the proliferation and metastasis of tumor cells via angiogenesis. On the other hand, mesenchymal stem cell (MSC) therapy, which is being employed in regenerative medicine owing to the ability of MSCs to differentiate into various cells, is due to humoral factors, including messenger RNA (mRNA), miRNAs, proteins, and lipids, which are encapsulated in exosomes derived from transplanted cells. New treatments that advocate cell-free therapy using MSC-derived exosomes will significantly improve clinical practice. Therefore, using highly purified exosomes that perform their original functions is desirable. In this review, we summarized advances in the purification, modification, and application of EVs as novel strategies to treat some diseases.
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Affiliation(s)
- Yasunari Matsuzaka
- Division of Molecular and Medical Genetics, Center for Gene and Cell Therapy, The Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
- Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-0031, Japan
| | - Ryu Yashiro
- Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-0031, Japan
- Department of Infectious Diseases, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-0004, Japan
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19
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Krapež G, Kouter K, Jovčevska I, Videtič Paska A. Dynamic Intercell Communication between Glioblastoma and Microenvironment through Extracellular Vesicles. Biomedicines 2022; 10:biomedicines10010151. [PMID: 35052830 PMCID: PMC8773537 DOI: 10.3390/biomedicines10010151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/05/2022] [Accepted: 01/09/2022] [Indexed: 12/30/2022] Open
Abstract
Glioblastoma is simultaneously the most common and most aggressive primary brain tumor in the central nervous system, with poor patient survival and scarce treatment options. Most primary glioblastomas reoccur and evolve radio- and chemoresistant properties which make them resistant to further treatments. Based on gene mutations and expression profiles, glioblastoma is relatively well classified; however, research shows that there is more to glioblastoma biology than that defined solely by its genetic component. Specifically, the overall malignancy of the tumor is also influenced by the dynamic communication to its immediate and distant environment, as important messengers to neighboring cells in the tumor microenvironment extracellular vesicles (EVs) have been identified. EVs and their cargo can modulate the immune microenvironment and other physiological processes, and can interact with the host immune system. They are involved in tumor cell survival and metabolism, tumor initiation, progression, and therapy resistance. However, on the other hand EVs are thought to become an effective treatment alternative, since they can cross the blood–brain barrier, are able of specific cell-targeting and can be loaded with various therapeutic molecules.
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20
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Wang Y, Li P, Mao S, Mo Z, Cao Z, Luo J, Zhou M, Liu X, Zhang S, Yu L. Exosome CTLA-4 Regulates PTEN/CD44 Signal Pathway in Spleen Deficiency Internal Environment to Promote Invasion and Metastasis of Hepatocellular Carcinoma. Front Pharmacol 2021; 12:757194. [PMID: 34744733 PMCID: PMC8564353 DOI: 10.3389/fphar.2021.757194] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 09/09/2021] [Indexed: 01/26/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common primary cancers, and its pathogenesis is complicated and difficult to screen. Currently, there is no effective treatment. In traditional Chinese medicine, a large proportion of patients with HCC have been diagnosed with spleen deficiency (SD) syndrome and treated with tonifying traditional Chinese medicine, which has significant clinical efficacy. However, the role and molecular mechanism of SD in HCC remain unclear. In this study, 40 mice were randomly divided into four groups: control, SD, HCC, and SD-HCC groups. The liver cancer model of SD was established by reserpine induction and orthotopic transplantation. The effects of SD on the proliferation, apoptosis, invasion, and metastasis of HCC cells were studied by cell proliferation, cell apoptosis, cell scratch, and transwell assay. We found that compared with the HCC group, the protein expressions of cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), phosphatase and tensin homolog (PTEN), and AKT (also known as protein kinase B or PKB) in the exosomes of the SD-HCC group were upregulated. In addition, the metastases and self-renewal of exosomes in the SD-HCC group were more aggressive than those in the HCC group, which could be partially reversed with the addition of CTLA-4 inhibitors. Further studies showed that in the internal environment of SD, CTLA-4 promoted tumor invasion and metastasis by regulating the PTEN/CD44 pathway. In conclusion, our findings suggest that during SD in the internal environment, exosome CTLA-4 regulates the PTEN/CD44 signal pathway to promote the proliferation, self-renewal, and metastasis of liver cancer.
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Affiliation(s)
- Yongdan Wang
- Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Pan Li
- Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shuai Mao
- Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China.,AMI Key Laboratory of Chinese Medicine in Guangzhou, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Zhuomao Mo
- Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhirui Cao
- Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jin Luo
- Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Meiling Zhou
- Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xifeng Liu
- School of Life Sciences, Xiangya Medical College, Central South University, Changsha, China
| | - Shijun Zhang
- Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ling Yu
- Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China.,AMI Key Laboratory of Chinese Medicine in Guangzhou, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
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21
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Honoré N, Galot R, van Marcke C, Limaye N, Machiels JP. Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact. Cancers (Basel) 2021; 13:5364. [PMID: 34771526 PMCID: PMC8582541 DOI: 10.3390/cancers13215364] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/20/2021] [Accepted: 10/22/2021] [Indexed: 12/15/2022] Open
Abstract
One reason why some patients experience recurrent disease after a curative-intent treatment might be the persistence of residual tumor cells, called minimal residual disease (MRD). MRD cannot be identified by standard radiological exams or clinical evaluation. Tumor-specific alterations found in the blood indirectly diagnose the presence of MRD. Liquid biopsies thus have the potential to detect MRD, allowing, among other things, the detection of circulating tumor DNA (ctDNA), circulating tumor cells (CTC), or tumor-specific microRNA. Although liquid biopsy is increasingly studied, several technical issues still limit its clinical applicability: low sensitivity, poor standardization or reproducibility, and lack of randomized trials demonstrating its clinical benefit. Being able to detect MRD could give clinicians a more comprehensive view of the risk of relapse of their patients and could select patients requiring treatment escalation with the goal of improving cancer survival. In this review, we are discussing the different methodologies used and investigated to detect MRD in solid cancers, their respective potentials and issues, and the clinical impacts that MRD detection will have on the management of cancer patients.
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Affiliation(s)
- Natasha Honoré
- Institute for Experimental and Clinical Research (IREC, Pôle MIRO), Université Catholique de Louvain (UCLouvain) ,1200 Brussels, Belgium; (R.G.); (C.v.M.)
| | - Rachel Galot
- Institute for Experimental and Clinical Research (IREC, Pôle MIRO), Université Catholique de Louvain (UCLouvain) ,1200 Brussels, Belgium; (R.G.); (C.v.M.)
- Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| | - Cédric van Marcke
- Institute for Experimental and Clinical Research (IREC, Pôle MIRO), Université Catholique de Louvain (UCLouvain) ,1200 Brussels, Belgium; (R.G.); (C.v.M.)
- Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| | - Nisha Limaye
- Genetics of Autoimmune Diseases and Cancer, de Duve Institute, Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium;
| | - Jean-Pascal Machiels
- Institute for Experimental and Clinical Research (IREC, Pôle MIRO), Université Catholique de Louvain (UCLouvain) ,1200 Brussels, Belgium; (R.G.); (C.v.M.)
- Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
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22
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Giacobino C, Canta M, Fornaguera C, Borrós S, Cauda V. Extracellular Vesicles and Their Current Role in Cancer Immunotherapy. Cancers (Basel) 2021; 13:cancers13092280. [PMID: 34068657 PMCID: PMC8126043 DOI: 10.3390/cancers13092280] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/03/2021] [Accepted: 05/07/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary In recent years, immunotherapy has shown great advancement, becoming a powerful tool to combat cancer. In this context, the use of biologically derived vesicles has also acquired importance for cancer immunotherapy. Extracellular vesicles are thus proposed to transport molecules able to trigger an immune response and thus fight cancer cells. As a particular immunotherapeutic approach, a new technique also consists in the exploitation of extracellular vesicles as new cancer vaccines. The present review provides basic notions on cancer immunotherapy and describes several clinical trials in which therapeutic anticancer vaccines are tested. In particular, the potential of extracellular vesicles-based therapeutic vaccines in the treatment of cancer patients is highlighted, even with advanced stage-cancer. A focus on the clinical studies, already completed or still in progress, is offered and a systematic collection and reorganization of the present literature on this topic is proposed to the reader. 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 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.
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Affiliation(s)
- Carla Giacobino
- Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Turin, Italy; (C.G.); (M.C.)
| | - Marta Canta
- Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Turin, Italy; (C.G.); (M.C.)
| | - Cristina Fornaguera
- Grup d’Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Universitat Ramon Llull (URL), Via Augusta 390, 08017 Barcelona, Spain; (C.F.); (S.B.)
| | - Salvador Borrós
- Grup d’Enginyeria de Materials (Gemat), Institut Químic de Sarrià (IQS), Universitat Ramon Llull (URL), Via Augusta 390, 08017 Barcelona, Spain; (C.F.); (S.B.)
| | - Valentina Cauda
- Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Turin, Italy; (C.G.); (M.C.)
- Correspondence:
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