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1
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Saadh MJ, Alhuthali HM, Gonzales Aníbal O, Asenjo-Alarcón JA, Younus DG, Alhili A, Adhab ZH, Alsalmi O, Gharib AF, Pecho RDC, Akhavan-Sigari R. Mesenchymal stem cells and their extracellular vesicles in urological cancers: Prostate, bladder, and kidney. Cell Biol Int 2024; 48:3-19. [PMID: 37947445 DOI: 10.1002/cbin.12098] [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: 07/19/2023] [Revised: 08/31/2023] [Accepted: 10/12/2023] [Indexed: 11/12/2023]
Abstract
Mesenchymal stem cells (MSCs) are recognized for their remarkable ability to differentiate into multiple cell types. They are also known to possess properties that can fight cancer, leading to attempts to modify MSCs for use in anticancer treatments. However, MSCs have also been found to participate in pathways that promote tumor growth. Many studies have been conducted to explore the potential of MSCs for clinical applications, but the results have been inconclusive, possibly due to the diverse nature of MSC populations. Furthermore, the conflicting roles of MSCs in inhibiting tumors and promoting tumor growth hinder their adaptation to anticancer therapies. Antitumorigenic and protumorigenic properties of MSCs in urological cancers such as bladder, prostate, and renal are not as well established, and data comparing them are still limited. MSCs hold significant promise as a vehicle for delivering anticancer agents and suicide genes to tumors. Presently, numerous studies have concentrated on the products derived from MSCs, such as extracellular vesicles (EVs), as a form of cell-free therapy. This work aimed to review and discuss the current knowledge of MSCs and their EVs in urological cancer therapy.
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Affiliation(s)
| | - Hayaa M Alhuthali
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | | | | | | | - Ahmed Alhili
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | | | - Ohud Alsalmi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Amal F Gharib
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | | | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Tuebingen, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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2
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Johnson V, Vasu S, Kumar US, Kumar M. Surface-Engineered Extracellular Vesicles in Cancer Immunotherapy. Cancers (Basel) 2023; 15:2838. [PMID: 37345176 PMCID: PMC10216164 DOI: 10.3390/cancers15102838] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/14/2023] [Accepted: 05/15/2023] [Indexed: 06/23/2023] Open
Abstract
Extracellular vesicles (EVs) are lipid bilayer-enclosed bodies secreted by all cell types. EVs carry bioactive materials, such as proteins, lipids, metabolites, and nucleic acids, to communicate and elicit functional alterations and phenotypic changes in the counterpart stromal cells. In cancer, cells secrete EVs to shape a tumor-promoting niche. Tumor-secreted EVs mediate communications with immune cells that determine the fate of anti-tumor therapeutic effectiveness. Surface engineering of EVs has emerged as a promising tool for the modulation of tumor microenvironments for cancer immunotherapy. Modification of EVs' surface with various molecules, such as antibodies, peptides, and proteins, can enhance their targeting specificity, immunogenicity, biodistribution, and pharmacokinetics. The diverse approaches sought for engineering EV surfaces can be categorized as physical, chemical, and genetic engineering strategies. The choice of method depends on the specific application and desired outcome. Each has its advantages and disadvantages. This review lends a bird's-eye view of the recent progress in these approaches with respect to their rational implications in the immunomodulation of tumor microenvironments (TME) from pro-tumorigenic to anti-tumorigenic ones. The strategies for modulating TME using targeted EVs, their advantages, current limitations, and future directions are discussed.
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Affiliation(s)
- Vinith Johnson
- Department of Chemical Engineering, Indian Institute of Technology, Tirupati 517619, India
| | - Sunil Vasu
- Department of Radiology, Stanford University, Stanford, CA 94305, USA
| | - Uday S. Kumar
- Department of Chemical Engineering, Indian Institute of Technology, Tirupati 517619, India
| | - Manoj Kumar
- Department of Radiology, Stanford University, Stanford, CA 94305, USA
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3
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Wang S, Sun J, Dastgheyb RM, Li Z. Tumor-derived extracellular vesicles modulate innate immune responses to affect tumor progression. Front Immunol 2022; 13:1045624. [PMID: 36405712 PMCID: PMC9667034 DOI: 10.3389/fimmu.2022.1045624] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 10/18/2022] [Indexed: 04/23/2024] Open
Abstract
Immune cells are capable of influencing tumor progression in the tumor microenvironment (TME). Meanwhile, one mechanism by which tumor modulate immune cells function is through extracellular vesicles (EVs), which are cell-derived extracellular membrane vesicles. EVs can act as mediators of intercellular communication and can deliver nucleic acids, proteins, lipids, and other signaling molecules between cells. In recent years, studies have found that EVs play a crucial role in the communication between tumor cells and immune cells. Innate immunity is the first-line response of the immune system against tumor progression. Therefore, tumor cell-derived EVs (TDEVs) which modulate the functional change of innate immune cells serve important functions in the context of tumor progression. Emerging evidence has shown that TDEVs dually enhance or suppress innate immunity through various pathways. This review aims to summarize the influence of TDEVs on macrophages, dendritic cells, neutrophils, and natural killer cells. We also summarize their further effects on the progression of tumors, which may provide new ideas for developing novel tumor therapies targeting EVs.
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Affiliation(s)
- Siqi Wang
- Scientific Research Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- School of Medicine, Sun Yat-sen University, Shenzhen, China
| | - Jiaxin Sun
- Scientific Research Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- School of Medicine, Sun Yat-sen University, Shenzhen, China
| | - Raha M. Dastgheyb
- School of Medicine, Johns Hopkins University, Baltimore, MD, United States
| | - Zhigang Li
- Scientific Research Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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4
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Bioactivity of Exosomes Derived from Trained Natural Killer Cells versus Non-Trained One: More Functional and Antitumor Activity. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5396628. [PMID: 36060136 PMCID: PMC9433262 DOI: 10.1155/2022/5396628] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/07/2022] [Accepted: 07/27/2022] [Indexed: 11/18/2022]
Abstract
Background Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system, capable of killing viral-infected and cancerous cells. NK cell-mediated immunotherapy has remarkably changed the current paradigm of cancer treatment in recent years. It emerged as a safe and effective therapeutic approach for patients with advanced-stage leukemia. Several immune-escape mechanisms can be enacted by cancer cells to avoid NK-mediated killing. Exosomes released by NK cells that carry proteins and miRNAs can exert an antitumor effect. In the present study, we hypothesized that maybe exosomes derived from trained natural killer cells show more antitumor effect in comparison to non-trained one. Methods PBMC was separated by the Ficoll method and cultured with IL-2 for 21 days to expand NK cells. The NK cells were co-cultured with K562 for 72 hours and exosome-derived co-cultured (as trained) and natural killer cell-derived exosomes (as non-trained) were extracted by Exo kit. The exosomes were confirmed by dynamic light scattering (DLS), transmission electron microscopy (TEM), flow cytometry, and western blotting. The K562 cells were separately treated by trained and non-trained exosomes and MTT assay, apoptosis, and real-time PCR were performed. Results Based on flow cytometry, CD56 marker was 89.7% and 40.1% for NK cells and NK-derived exosomes, respectively. CD63 and CD9 were positive for exosomes by western blotting. The morphology of exosome was confirmed by TEM. Treated K562 cells by trained exosomes indicated the diminished cell viability and higher apoptosis. Furthermore, the trained exosomes showed up-regulation in both P53 and caspase3 genes as compared with non-trained sample. Discussion. Trained Exos showed a potent inhibitory effect on proliferation and induced apoptosis on K562 cell lines compared to the same dose of non-trained Exos. According to the results of qRT-PCR, trained Exos exerted an antitumor activity through up-regulation of caspase 3 and P53 in the apoptotic signaling pathway in tumor cells. Our findings indicate an effective action of trained Exos against cancer cells.
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5
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Yuan P, Li Z, Shao B, Zeng T, Wu X, Wang Y, Zhao Y, Wu W. Extracellular vesicles derived from starving BMSCs enhance survival of chondrocyte aggregates in grafts by attenuating chondrocyte apoptosis and enabling stable cartilage regeneration for craniofacial reconstruction. Acta Biomater 2022; 140:659-673. [PMID: 34902618 DOI: 10.1016/j.actbio.2021.12.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 11/25/2021] [Accepted: 12/08/2021] [Indexed: 12/12/2022]
Abstract
The improvement of cell survival in cartilage tissue engineering remains a challenge, especially for large-sized, specifically shaped cartilage grafts used in reconstructing craniofacial defects. In this study, we found that bone marrow mesenchymal stem cells (BMSCs) pre-conditioned in a starving environment enhanced the anti-apoptosis potential of co-transplanted chondrocytes, which significantly enhanced their survival rates before host nutrition was resumed. Further examination revealed that extracellular vesicles (EVs) derived from starving BMSCs played essential roles in ameliorating apoptosis and regulating autophagy of chondrocytes, thereby enhancing the survival of cultured chondrocytes. In vivo studies demonstrated that EVs derived from starving BMSCs significantly improved the survival of chondrocyte bricks, which confirmed the effects of nasal augmentation. These pre-treated chondrocyte bricks showed continuous cartilage growth in vivo and acquired chondrogenesis comparable to that following the chondrocyte-BMSC co-transplantation approach. This study provided new insights on how BMSC-derived EVs improved cartilage reconstruction in the craniofacial regions and offered a new approach for regenerating cartilaginous organs based on cell macroaggregates. STATEMENT OF SIGNIFICANCE: The use of extracellular vesicles (EVs) of mesenchymal stem cells has been considered as a promising approach in cartilage tissue engineering. In the present study, for the first time, we investigated the protective effect of EVs secreted by starving bone marrow mesenchymal stem cells (BMSCs) on chondrocytes in vitro and in vivo. The results demonstrated that EVs secreted by starving BMSCs inhibited chondrocyte apoptosis and chondrocyte autophagy through many microRNAs, thereby improving the survival of grafts. Transcriptomic analysis revealed the potential mechanisms of this protective effect.
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Affiliation(s)
- Pingping Yuan
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology Department of Oral & Maxillofacial Surgery, School of Stomatology the Fourth Military Medical University, Xi'an, Shaanxi, PR China; Center of Oral Implantology, Inner Mongolia Autonomous Region People's Hospital & Inner Mongolia Medical University, Hohhot, Inner Mongolia 010010, China
| | - Zhiye Li
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology Department of Oral & Maxillofacial Surgery, School of Stomatology the Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Bo Shao
- Center of Oral Implantology, Inner Mongolia Autonomous Region People's Hospital & Inner Mongolia Medical University, Hohhot, Inner Mongolia 010010, China
| | - Tian Zeng
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology Department of Oral & Maxillofacial Surgery, School of Stomatology the Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Xiaopeng Wu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology Department of Oral & Maxillofacial Surgery, School of Stomatology the Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Yinggang Wang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology Department of Oral & Maxillofacial Surgery, School of Stomatology the Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Yimin Zhao
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology Department of Oral & Maxillofacial Surgery, School of Stomatology the Fourth Military Medical University, Xi'an, Shaanxi, PR China
| | - Wei Wu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology Department of Oral & Maxillofacial Surgery, School of Stomatology the Fourth Military Medical University, Xi'an, Shaanxi, PR China.
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Jahan S, Mukherjee S, Ali S, Bhardwaj U, Choudhary RK, Balakrishnan S, Naseem A, Mir SA, Banawas S, Alaidarous M, Alyenbaawi H, Iqbal D, Siddiqui AJ. Pioneer Role of Extracellular Vesicles as Modulators of Cancer Initiation in Progression, Drug Therapy, and Vaccine Prospects. Cells 2022; 11:490. [PMID: 35159299 PMCID: PMC8833976 DOI: 10.3390/cells11030490] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/25/2022] [Accepted: 01/28/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer is one of the leading diseases, causing deaths worldwide. Nearly 10 million deaths were reported in 2020 due to cancer alone. Several factors are involved in cancer progressions, such as lifestyle and genetic characteristics. According to a recent report, extracellular vesicles (EVs) are involved in cancer initiation, progression, and therapy failure. EVs can play a major role in intracellular communication, the maintenance of tissue homeostasis, and pathogenesis in several types of diseases. In a healthy person, EVs carry different cargoes, such as miRNA, lncRNA etc., to help other body functions. On the other hand, the same EV in a tumor microenvironment carries cargoes such as miRNA, lncRNA, etc., to initiate or help cancer progression at various stages. These stages may include the proliferation of cells and escape from apoptosis, angiogenesis, cell invasion, and metastasis, reprogramming energy metabolism, evasion of the immune response, and transfer of mutations. Tumor-derived EVs manipulate by altering normal functions of the body and affect the epigenetics of normal cells by limiting the genetic makeup through transferring mutations, histone modifications, etc. Tumor-derived EVs also pose therapy resistance through transferring drug efflux pumps and posing multiple drug resistances. Such EVs can also help as biomarkers for different cancer types and stages, which ultimately help with cancer diagnosis at early stages. In this review, we will shed light on EVs' role in performing normal functions of the body and their position in different hallmarks of cancer, in altering the genetics of a normal cell in a tumor microenvironment, and their role in therapy resistance, as well as the importance of EVs as diagnostic tools.
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Affiliation(s)
- Sadaf Jahan
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Shouvik Mukherjee
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Shaheen Ali
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Urvashi Bhardwaj
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Ranjay Kumar Choudhary
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Santhanaraj Balakrishnan
- Medical Equipment Technology, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Asma Naseem
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Shabir Ahmad Mir
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Saeed Banawas
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
- Department of Biomedical Sciences, Oregon State University, Corvallis, OR 97331, USA
| | - Mohammed Alaidarous
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Hadeel Alyenbaawi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Danish Iqbal
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Arif Jamal Siddiqui
- Department of Biology, College of Science, University of Hail, Hail 81451, Saudi Arabia
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7
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Aharon A, Horn G, Bar-Lev TH, Zagagi Yohay E, Waks T, Levin M, Deshet Unger N, Avivi I, Globerson Levin A. Extracellular Vesicles Derived from Chimeric Antigen Receptor-T Cells: A Potential Therapy for Cancer. Hum Gene Ther 2021; 32:1224-1241. [PMID: 34494460 DOI: 10.1089/hum.2021.192] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Chimeric antigen receptor (CAR)-T cells are genetically engineered T cells, directed against a tumor-associated antigen. Extracellular vesicles (EVs) derived from CAR-T cells (CAR-T EVs) may preserve CAR-T activity and overcome one of the major obstacles responsible for CAR-T cell failure in patients with solid tumors. This study aimed to compare CAR-T EVs with their parental cells and explore their cell penetration and cytotoxic activity. Anti-HER-2 CARs were stimulated with specific target cells. EVs were isolated from the cell media and characterized for their content and functions. We found that CAR-T EVs contained a mixture of small and large EVs. Stimulated anti-HER-2+ CAR-T EVs expressed lower cytokine levels compared with their parental CAR-T cells (such as interferon gamma). Higher levels of granzyme B were found in CAR-T EVs (≥20 × ) compared with EVs from unstimulated cells (p < 0.001). Anti-HER-2+ CAR-T EVs bound and penetrated specifically into HER-2 expressing target cells. Similar cytotoxic effects measured by caspase-3/7 activity were found in CAR-T cells and their derived EVs. However, while the CAR-T cells induced massive apoptosis during the first 24 h, CAR-T EVs required 60 - 90 h. In summary, CAR-T EVs provide a novel potent immunotherapy approach that may be effective against solid tumors.
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Affiliation(s)
- Anat Aharon
- Hematology Research Laboratory for Extracellular Vesicles, Hematology Division, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Galit Horn
- Immunology Laboratory, Research & Development Department, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Tali Hana Bar-Lev
- Hematology Research Laboratory for Extracellular Vesicles, Hematology Division, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Einav Zagagi Yohay
- Hematology Research Laboratory for Extracellular Vesicles, Hematology Division, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Tova Waks
- Immunology Laboratory, Research & Development Department, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.,Immunology Department, The Weizmann Institute, Rehovot, Israel
| | - Maya Levin
- Hematology Research Laboratory for Extracellular Vesicles, Hematology Division, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Naamit Deshet Unger
- Immunology Laboratory, Research & Development Department, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Irit Avivi
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Hematology Division, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Anat Globerson Levin
- Immunology Laboratory, Research & Development Department, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.,Dotan Center for Advanced Therapies, Tel-Aviv Sourasky Medical Center and Tel Aviv University, Tel Aviv, Israel
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8
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Thakur A, Ke X, Chen YW, Motallebnejad P, Zhang K, Lian Q, Chen HJ. The mini player with diverse functions: extracellular vesicles in cell biology, disease, and therapeutics. Protein Cell 2021; 13:631-654. [PMID: 34374936 PMCID: PMC9233731 DOI: 10.1007/s13238-021-00863-6] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/08/2021] [Indexed: 12/31/2022] Open
Abstract
Extracellular vesicles (EVs) are tiny biological nanovesicles ranging from approximately 30-1000 nm in diameter that are released into the extracellular matrix of most cell types and in biofluids. The classification of EVs includes exosomes, microvesicles, and apoptotic bodies, dependent on various factors such as size, markers, and biogenesis pathways. The transition of EV relevance from that of being assumed as a trash bag to be a key player in critical physiological and pathological conditions has been revolutionary in many ways. EVs have been recently revealed to play a crucial role in stem cell biology and cancer progression via intercellular communication, contributing to organ development and the progression of cancer. This review focuses on the significant research progress made so far in the role of the crosstalk between EVs and stem cells and their niche, and cellular communication among different germ layers in developmental biology. In addition, it discusses the role of EVs in cancer progression and their application as therapeutic agents or drug delivery vehicles. All such discoveries have been facilitated by tremendous technological advancements in EV-associated research, especially the microfluidics systems. Their pros and cons in the context of characterization of EVs are also extensively discussed in this review. This review also deliberates the role of EVs in normal cell processes and disease conditions, and their application as a diagnostic and therapeutic tool. Finally, we propose future perspectives for EV-related research in stem cell and cancer biology.
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Affiliation(s)
- Abhimanyu Thakur
- The Pritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USA.,The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA
| | - Xiaoshan Ke
- The Pritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USA.,The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA
| | - Ya-Wen Chen
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, Hastings Center for Pulmonary Research, University of Southern California, Los Angeles, CA, 90089, USA.,Department of Stem Cell Biology and Regenerative Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA
| | - Pedram Motallebnejad
- The Pritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USA.,The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA
| | - Kui Zhang
- The Pritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USA.,The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA
| | - Qizhou Lian
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong. .,Prenatal Diagnostic Center and Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. .,HKUMed Laboratory of Cellular Therapeutics, the University of Hong Kong, Pok Fu Lam, Hong Kong.
| | - Huanhuan Joyce Chen
- The Pritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USA. .,The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA.
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Decruyenaere P, Offner F, Vandesompele J. Circulating RNA biomarkers in diffuse large B-cell lymphoma: a systematic review. Exp Hematol Oncol 2021; 10:13. [PMID: 33593440 PMCID: PMC7885416 DOI: 10.1186/s40164-021-00208-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 02/06/2021] [Indexed: 12/31/2022] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype of non-Hodgkin's lymphomas (NHL). DLBCL is an aggressive malignancy that displays a great heterogeneity in terms of morphology, genetics and biological behavior. While a sustained complete remission is obtained in the majority of patients with standard immunochemotherapy, patients with refractory of relapsed disease after first-line treatment have a poor prognosis. This patient group represents an important unmet need in lymphoma treatment. In recent years, improved understanding of the underlying molecular pathogenesis had led to new classification and prognostication tools, including the development of cell-free biomarkers in liquid biopsies. Although the majority of studies have focused on the use of cell-free fragments of DNA (cfDNA), there has been an increased interest in circulating-free coding and non-coding RNA, including messenger RNA (mRNA), microRNA (miRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA), as well as RNA encapsulated in extracellular vesicles or tumor-educated platelets (TEPs). We performed a systematic search in PubMed to identify articles that evaluated circulating RNA as diagnostic, subtype, treatment response or prognostic biomarkers in a human DLBCL population. A total of 35 articles met the inclusion criteria. The aim of this systematic review is to present the current understanding of circulating RNA molecules as biomarker in DLBCL and to discuss their future potential.
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Affiliation(s)
- Philippe Decruyenaere
- Department of Hematology, Ghent University Hospital, 9K12, Campus UZ Ghent, Corneel Heymanslaan 10, 9000 Ghent, Belgium
- OncoRNALab, Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Fritz Offner
- Department of Hematology, Ghent University Hospital, 9K12, Campus UZ Ghent, Corneel Heymanslaan 10, 9000 Ghent, Belgium
| | - Jo Vandesompele
- OncoRNALab, Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
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10
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Shende P, Trivedi R. Biofluidic material-based carriers: Potential systems for crossing cellular barriers. J Control Release 2021; 329:858-870. [PMID: 33053397 DOI: 10.1016/j.jconrel.2020.10.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/07/2020] [Accepted: 10/09/2020] [Indexed: 11/24/2022]
Abstract
Biofluids act as a repository for disease biomarkers and are excellent diagnostic tools applied in establishing a disease profile based on clinical testing, evaluation and monitoring the progression of patients suffering from various conditions. Furthermore, biofluids and their derived components such proteins, pigments, enzymes, hormones and cells carry a potential in the development of therapeutic drug delivery systems or as cargo materials for targeting the drug to the site of action. The presence of biofluids with respect to their specific location reveals the information of disease progression and mechanism, delivery aspects such as routes of administration as well as pharmacological factors such as binding affinity, rate of kinetics, efficacy, bioavailability and patient compliance. This review focuses on the properties and functional benefits of some biofluids, namely blood, saliva, bile, urine, amniotic fluid, synovial fluid and cerebrospinal fluid. It also covers the therapeutic and targeting action of fluid-derived substances in various micro- or nano-systems like nanohybrids, nanoparticles, self-assembled micelles, microparticles, cell-based systems, etc. The formulation of such biologically-oriented systems demonstrate the advantages of natural origin, biocompatibility and biodegradability and offer new techniques for overcoming the challenges experienced in conventional therapies.
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Affiliation(s)
- Pravin Shende
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS, V. L. Mehta Road, Vile Parle (W), Mumbai, India..
| | - Riddhi Trivedi
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS, V. L. Mehta Road, Vile Parle (W), Mumbai, India
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11
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Cavallari C, Camussi G, Brizzi MF. Extracellular Vesicles in the Tumour Microenvironment: Eclectic Supervisors. Int J Mol Sci 2020; 21:E6768. [PMID: 32942702 PMCID: PMC7555174 DOI: 10.3390/ijms21186768] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/11/2020] [Accepted: 09/14/2020] [Indexed: 12/12/2022] Open
Abstract
The tumour microenvironment (TME) plays a crucial role in the regulation of cell survival and growth by providing inhibitory or stimulatory signals. Extracellular vesicles (EV) represent one of the most relevant cell-to-cell communication mechanism among cells within the TME. Moreover, EV contribute to the crosstalk among cancerous, immune, endothelial, and stromal cells to establish TME diversity. EV contain proteins, mRNAs and miRNAs, which can be locally delivered in the TME and/or transferred to remote sites to dictate tumour behaviour. EV in the TME impact on cancer cell proliferation, invasion, metastasis, immune-escape, pre-metastatic niche formation and the stimulation of angiogenesis. Moreover, EV can boost or inhibit tumours depending on the TME conditions and their cell of origin. Therefore, to move towards the identification of new targets and the development of a novel generation of EV-based targeting approaches to gain insight into EV mechanism of action in the TME would be of particular relevance. The aim here is to provide an overview of the current knowledge of EV released from different TME cellular components and their role in driving TME diversity. Moreover, recent proposed engineering approaches to targeting cells in the TME via EV are discussed.
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Affiliation(s)
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy;
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Nazimek K, Bryniarski K. Perspectives in Manipulating EVs for Therapeutic Applications: Focus on Cancer Treatment. Int J Mol Sci 2020; 21:ijms21134623. [PMID: 32610582 PMCID: PMC7369858 DOI: 10.3390/ijms21134623] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 06/26/2020] [Accepted: 06/26/2020] [Indexed: 02/07/2023] Open
Abstract
Extracellular vesicles (EVs) receive special attention from oncologists due to their assumed usefulness as prognostic markers, vaccines to induce anti-cancer immune response, and physiological delivery tools. The latter application, which supports the reduction of side effects of treatment, is still fraught with many challenges, including established methods for loading EVs with selected cargo and directing them towards target cells. EVs could be loaded with selected cargo either in vitro using several physicochemical techniques, or in vivo by modification of parental cell, which may have an advantage over in vitro procedures, since some of them significantly influence EVs’ properties. Otherwise, our research findings suggest that EVs could be passively supplemented with micro RNAs (miRNAs) or miRNA antagonists to induce expected biological effect. Furthermore, our observations imply that antigen-specific antibody light chains could coat the surface of EVs to increase the specificity of cell targeting. Finally, the route of EVs’ administration also determines their bioavailability and eventually induced therapeutic effect. Besides, EV membrane lipids may possibly possess immune adjuvant activity. The review summarizes the current knowledge on the possibilities to manipulate EVs to use them as a delivery tool, with the special emphasis on anti-cancer therapy.
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Breast Cancer Derived Extracellular Vesicles in Bone Metastasis Induction and Their Clinical Implications as Biomarkers. Int J Mol Sci 2020; 21:ijms21103573. [PMID: 32443642 PMCID: PMC7278927 DOI: 10.3390/ijms21103573] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer incidence and mortality are rapidly growing worldwide. The main risk factors for cancer can be associated with aging as well as the growth of the population and socioeconomic condition. Breast cancer, a crucial public health problem, is the second cause of death among women. About 70% of patients with advanced breast cancer have bone metastases. In bone metastasis, cancer cells and osteoclasts form a vicious cycle: cancer cells promote osteoclast differentiation and activation that, in turn, induce cancer cell seeding and proliferation in the bone. Growing evidence shows that extracellular vesicles (EVs) play a key role in carcinogenesis, proliferation, pre-metastatic niche formation, angiogenesis, metastasis, and chemoresistance in several tumors, such as breast, lung, prostate, and liver cancer. Here, we discuss the role of EVs released by breast cancer cells, focusing on bone metastasis induction and their clinical implications as biomarkers.
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Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor In Exosome-Mediated Cytotoxicity Against Tumor. Cancers (Basel) 2020; 12:cancers12030661. [PMID: 32178479 PMCID: PMC7140072 DOI: 10.3390/cancers12030661] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 03/05/2020] [Accepted: 03/10/2020] [Indexed: 01/18/2023] Open
Abstract
Despite the pivotal role of natural killer (NK) cells in defenses against tumors, their exploitation in cancer treatment is still limited due to their reduced ability to reaching tumor sites and the inhibitory effects of tumor microenvironment (TME) on their function. In this study, we have characterized the exosomes from IL2- or IL15-cultured human NK cells. Both cytokines induced comparable amounts of exosomes with similar cargo composition. Analysis of molecules contained within or exposed at the exosome surface, allowed the identification of molecules playing important roles in the NK cell function including IFN-γ, Lymphocyte Function-Associated Antigen (LFA-1), DNAX Accessory Molecule-1 (DNAM1) and Programmed Cell Death Protein (PD-1). Importantly, we show that DNAM1 is involved in exosome-mediated cytotoxicity as revealed by experiments using blocking antibodies to DNAM1 or DNAM1 ligands. In addition, antibody-mediated inhibition of exosome cytotoxicity results in a delay in target cell apoptosis. We also provide evidence that NK-exosomes may exert their cytolytic activity after short time interval and even at low concentrations. Regarding their possible use in immunotherapy, NK exosomes, detectable in peripheral blood, can diffuse into tissues and exert their cytolytic effect at tumor sites. This property offers a clue to integrate cancer treatments with NK exosomes.
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Alessio N, Brigida AL, Peluso G, Antonucci N, Galderisi U, Siniscalco D. Stem Cell-Derived Exosomes in Autism Spectrum Disorder. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:944. [PMID: 32033002 PMCID: PMC7037429 DOI: 10.3390/ijerph17030944] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 01/31/2020] [Accepted: 02/02/2020] [Indexed: 02/06/2023]
Abstract
Neurodevelopmental lifelong pathologies defined by problems with social interaction, communication capacity and presence of repetitive/stereotyped clusters of behavior and interests are grouped under the definition of autism spectrum disorder (ASD). ASD prevalence is still increasing, indicating the need to identify specific biomarkers and novel pharmacotherapies. Neuroinflammation and neuro-immune cross-talk dysregulation are specific hallmarks of ASD, offering the possibility of treating these disorders by stem cell therapy. Indeed, cellular strategies have been postulated, proposed and applied to ASD. However, less is known about the molecular action mechanisms of stem cells. As a possibility, the positive and restorative effects mediated by stem cells could be due to their paracrine activity, by which stem cells produce and release several ameliorative and anti-inflammatory molecules. Among the secreted complex tools, exosomes are sub-organelles, enriched by RNA and proteins, that provide cell-to-cell communication. Exosomes could be the mediators of many stem cell-associated therapeutic activities. This review article describes the potential role of exosomes in alleviating ASD symptoms.
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Affiliation(s)
- Nicola Alessio
- Department of Experimental Medicine, Division of Molecular Biology, Biotechnology and Histology. University of Campania “Luigi Vanvitelli”, via S. Maria di Costantinopoli 16, 80138 Naples, Italy; (N.A.); (U.G.)
| | | | - Gianfranco Peluso
- Research Institute on Terrestrial Ecosystems (IRET), National Research Council of Italy, (CNR), via P. Castellino 111, 80131 Naples, Italy;
| | - Nicola Antonucci
- Biomedical Centre for Autism Research and Therapy, 70126 Bari, Italy;
| | - Umberto Galderisi
- Department of Experimental Medicine, Division of Molecular Biology, Biotechnology and Histology. University of Campania “Luigi Vanvitelli”, via S. Maria di Costantinopoli 16, 80138 Naples, Italy; (N.A.); (U.G.)
| | - Dario Siniscalco
- Department of Experimental Medicine, Division of Molecular Biology, Biotechnology and Histology. University of Campania “Luigi Vanvitelli”, via S. Maria di Costantinopoli 16, 80138 Naples, Italy; (N.A.); (U.G.)
- Centre for Autism—La Forza del Silenzio, 81036 Caserta, Italy
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Susa F, Limongi T, Dumontel B, Vighetto V, Cauda V. Engineered Extracellular Vesicles as a Reliable Tool in Cancer Nanomedicine. Cancers (Basel) 2019; 11:E1979. [PMID: 31835327 PMCID: PMC6966613 DOI: 10.3390/cancers11121979] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 12/03/2019] [Accepted: 12/04/2019] [Indexed: 12/15/2022] Open
Abstract
Fast diagnosis and more efficient therapies for cancer surely represent one of the huge tasks for the worldwide researchers' and clinicians' community. In the last two decades, our understanding of the biology and molecular pathology of cancer mechanisms, coupled with the continuous development of the material science and technological compounds, have successfully improved nanomedicine applications in oncology. This review argues on nanomedicine application of engineered extracellular vesicles (EVs) in oncology. All the most innovative processes of EVs engineering are discussed together with the related degree of applicability for each one of them in cancer nanomedicines.
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Affiliation(s)
| | | | | | | | - Valentina Cauda
- Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Turin, Italy; (F.S.); (T.L.); (B.D.); (V.V.)
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Brossa A, Buono L, Fallo S, Fiorio Pla A, Munaron L, Bussolati B. Alternative Strategies to Inhibit Tumor Vascularization. Int J Mol Sci 2019; 20:E6180. [PMID: 31817884 PMCID: PMC6940973 DOI: 10.3390/ijms20246180] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 11/26/2019] [Accepted: 12/04/2019] [Indexed: 02/06/2023] Open
Abstract
Endothelial cells present in tumors show different origin, phenotype, and genotype with respect to the normal counterpart. Various mechanisms of intra-tumor vasculogenesis sustain the complexity of tumor vasculature, which can be further modified by signals deriving from the tumor microenvironment. As a result, resistance to anti-VEGF therapy and activation of compensatory pathways remain a challenge in the treatment of cancer patients, revealing the need to explore alternative strategies to the classical anti-angiogenic drugs. In this review, we will describe some alternative strategies to inhibit tumor vascularization, including targeting of antigens and signaling pathways overexpressed by tumor endothelial cells, the development of endothelial vaccinations, and the use of extracellular vesicles. In addition, anti-angiogenic drugs with normalizing effects on tumor vessels will be discussed. Finally, we will present the concept of endothelial demesenchymalization as an alternative approach to restore normal endothelial cell phenotype.
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Affiliation(s)
- Alessia Brossa
- Department of Molecular Biotechnology and Health Sciences, Universitty of Torino, 10126 Torino, Italy; (A.B.); (L.B.); (S.F.)
| | - Lola Buono
- Department of Molecular Biotechnology and Health Sciences, Universitty of Torino, 10126 Torino, Italy; (A.B.); (L.B.); (S.F.)
| | - Sofia Fallo
- Department of Molecular Biotechnology and Health Sciences, Universitty of Torino, 10126 Torino, Italy; (A.B.); (L.B.); (S.F.)
| | - Alessandra Fiorio Pla
- Department of Life Science and Systems Biology, University of Torino, 10126 Torino, Italy; (A.F.P.); (L.M.)
| | - Luca Munaron
- Department of Life Science and Systems Biology, University of Torino, 10126 Torino, Italy; (A.F.P.); (L.M.)
| | - Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, Universitty of Torino, 10126 Torino, Italy; (A.B.); (L.B.); (S.F.)
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