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Saadh MJ, Ahmed HH, Sanghvi G, Bin Awang Isa MZ, Singh P, Kaur K, Kumar MR, Husseen B. Recent advances in the delivery of microRNAs via exosomes derived from MSCs, and their role in regulation of ferroptosis. Pathol Res Pract 2025; 270:155984. [PMID: 40315562 DOI: 10.1016/j.prp.2025.155984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 04/09/2025] [Accepted: 04/18/2025] [Indexed: 05/04/2025]
Abstract
Mesenchymal stem cell (MSC) therapy, with its unique properties, has garnered interest in cancer treatment. Exosomes (EXOs)-derived from MSC retain the paracrine components of MSCs and demonstrate increased stability, minimal immunogenicity, and low risk of unintended tumorigenesis. Enhanced endocytosis methods make them versatile delivery vehicles for therapeutic cargo. MSC-EXOs can either promote or inhibit carcinogenesis, mediated by paracrine factors and various RNA molecules, particularly microRNAs (miRNAs). The prospect of using MSC-EXOs as a delivery tool for antitumor miRNAs in solid tumor therapy is promising. Exosomes' intrinsic tumor-targeting abilities and low immunogenicity make them ideal for delivering miRNAs, which have shown potential as cancer therapeutics. miRNAs within MSC-EXOs molecules can stimulate tumor growth or induce non-apoptotic cell death pathways, such as ferroptosis, depending on context. Ferroptosis is a kind of controlled cell death that is associated with the pathophysiology of several illnesses and includes iron metabolism. There is growing evidence that miRNAs carried by exosomes derived from MSCs may control ferroptosis in tumor cells by altering key genes related to antioxidant defense, lipid peroxidation, and iron metabolism. Understanding their complex mechanisms in the tumor microenvironment and optimizing their cargo are critical steps toward harnessing their full therapeutic potential. This review provides a comprehensive overview of MSC-EXOs and their role in cancer treatment. We also discuss the potential of MSC-EXOs as delivery vehicles for miRNAs to enhance therapeutic efficacy, as well as the role of exosomal miRNAs in the induction of ferroptosis.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan.
| | | | - Gaurav Sanghvi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot, Gujarat 360003, India
| | | | - Priyanka Singh
- NIMS School of Allied Sciences and Technology, NIMS University, Jaipur, Rajasthan 303121, India
| | - Kiranjeet Kaur
- Chandigarh Pharmacy College, Chandigarh Group of colleges-Jhanjeri, Mohali, Punjab 140307, India
| | - M Ravi Kumar
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh 531162, India
| | - Beneen Husseen
- Medical laboratory technique college, the Islamic University, Najaf, Iraq; Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
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Kaçaroğlu D, Yaylacı S, Ulaşlı AM. Dual facets of MSC-derived small EVs: regulatory insights into antitumor mechanisms in pancreatic ductal adenocarcinoma. Med Oncol 2025; 42:158. [PMID: 40208413 PMCID: PMC11985665 DOI: 10.1007/s12032-025-02713-5] [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: 01/14/2025] [Accepted: 03/30/2025] [Indexed: 04/11/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense, fibrotic, immunosuppressive, and desmoplastic extracellular matrix. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have emerged as a novel therapeutic strategy. Nonetheless, the potential dual effects of MSC-EVs on tumor cells warrant careful consideration. This study aimed to evaluate the mechanistic effects of MSC-EVs on PDAC. Wharton's Jelly (WJ) MSC-derived small EVs were isolated using ultracentrifugation method and analyzed through nanoparticle tracking analysis (NTA) and flow cytometry. EVs were added to Panc-1 cells at concentrations of 4000-10,000 EVs per cell, and a preliminary MTT assay was performed. In subsequent experiments, EVs were added to Panc-1 cells at concentrations of only 4000, 8000 and 12,000 EVs per cell. After 24 h, apoptosis and cell cycle analyses were performed. The expression of epithelial-mesenchymal transition (EMT)-related and immune-related genes was analyzed. Cell cycle analysis showed higher G1 phase percentage in the control group (31%) compared to MSC EV-treated groups (35-36%). Apoptosis analysis revealed similar viable and necrotic cell percentages among the control (80% viable) and treated groups (approximately 78-79% viable). The CD44, VIM, MMP9, TIMP1, and ZEB1 genes were downregulated in treated groups compared to the control. Although CLDN1 and CDH1 genes were upregulated at the lowest EV concentration, they were downregulated at higher EV concentrations. Immune gene analysis showed downregulation of pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ, IL-1α, IL-1β) and upregulation of the anti-inflammatory cytokine IL-10 in treated groups. This study revealed the dual role of WJ-MSC small EVs in PDAC. While they suppressed cell proliferation and modulated EMT markers, indicating their antitumor potential, they also exhibited an immunosuppressive profile. These findings highlight both the promise and challenges of using WJ-MSC small EVs as therapeutic agents, necessitating further studies to optimize their application and balance their effects.
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Affiliation(s)
- Demet Kaçaroğlu
- Faculty of Medicine, Department of Medical Biology, Lokman Hekim University, Söğütözü, 2179. Sk. No:6, 06530, Çankaya, Ankara, Turkey.
| | - Seher Yaylacı
- Faculty of Medicine, Department of Medical Biology, Lokman Hekim University, Söğütözü, 2179. Sk. No:6, 06530, Çankaya, Ankara, Turkey
| | - Alper Murat Ulaşlı
- Stem Cell Institute, Interdisciplinary Stem Cell and Regenerative Medicine Department, Ankara University, Cevizlidere, Ceyhun Atuf Kansu Cd. No:169, 06520, Çankaya, Ankara, Turkey
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Bakr MM, Al Ankily M, Shamel M. The Protective Effects of MSC-Derived Exosomes Against Chemotherapy-Induced Parotid Gland Cytotoxicity. Int J Dent 2025; 2025:5517092. [PMID: 40223864 PMCID: PMC11986938 DOI: 10.1155/ijod/5517092] [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: 01/08/2025] [Accepted: 03/13/2025] [Indexed: 04/15/2025] Open
Abstract
Background: Fluorouracil (5-FU) is one of the most popular chemotherapeutic agents used in various cancer therapy protocols. Cell-free therapy utilizing exosomes is gaining increased popularity as a safer option due to concerns over potential tumor progression following stem cell therapy. Methods: Parotid glands of albino were treated with a single bone marrow mesenchymal stem cell (BMMSC)-derived exosomes injection (100 μg/kg/dose suspended in 0.2 mL phosphate-buffered saline [PBS]), a single 5-Fu injection (20 mg/kg), and BMMSC-derived exosomes plus 5-FU and compared to control group (daily saline injections). After 30 days, the parotid glands were examined using qualitative histological evaluation, immunohistochemical evaluation using rabbit polyclonal mouse antibody to Ki-67, caspase 3, and iNOS, as well as quantitative real-time polymerase chain reaction (RT-PCR) to evaluate gene expression of TGFβ1, TNF-α, and BCL-2. Results: Histological examination of the parotid gland revealed that BMMSC-derived exosomes restored the glands' architecture and repaired most of the distortion created by 5-FU. Immunohistochemical expression of tumor proliferation and cell death markers were restored to normal levels in the exosome-treated groups that were similar to the control group. Furthermore, BMMSC-derived exosomes reversed the effects of 5-FU on quantitative gene expression levels and showed a significant decrease in TNF-α (p < 0.001) and a significant increase in TGFβ (p < 0.0001) and BCL-2 (p < 0.05) when compared to 5-FU treatment. Conclusion: Within the limitations of the current study, BMMSC-derived exosomes have the potential to counteract the cytotoxic effects of 5-FU on the parotid glands of rats in vivo. Further studies are deemed necessary to simulate clinical scenarios.
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Affiliation(s)
- Mahmoud M. Bakr
- General Dental Practice, School of Medicine and Dentistry, Griffith University, Gold Coast, Queensland 4215, Australia
| | - Mahmoud Al Ankily
- Faculty of Dentistry, Oral Biology Department, The British University in Egypt, Cairo, Egypt
| | - Mohamed Shamel
- Faculty of Dentistry, Oral Biology Department, The British University in Egypt, Cairo, Egypt
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Kareem RA, Sameer HN, Yaseen A, Athab ZH, Adil M, Ahmed HH. A review of the immunomodulatory properties of mesenchymal stem cells and their derived extracellular vesicles in small-cell and non-small-cell lung cancer cells. Int Immunopharmacol 2025; 146:113848. [PMID: 39689606 DOI: 10.1016/j.intimp.2024.113848] [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: 11/11/2024] [Revised: 12/09/2024] [Accepted: 12/10/2024] [Indexed: 12/19/2024]
Abstract
Among the most challenging diseases to treat is lung cancer (LC). While immunotherapy has a checkered history, it has lately shown great promise in the treatment of LC, and interest in this promising new approach is on the rise around the globe. Immunotherapy using mesenchymal stem cells (MSCs) is gaining popularity. Regenerative medicine, cell therapy, and immune modulation are three areas that have shown significant interest in MSCs. More than that, MSCs have recently attracted attention as potential anti-cancer drug delivery vehicles due to their inherent ability to go home to tumor locations. Making MSCs a double-edged sword in the fight against neoplastic illnesses, they are also known to impart pro-oncogenic properties. Additionally, multiple studies have proposed extracellular vesicles (EVs) secreted by MSCs as a potential therapeutic agent or method for delivering anti-cancer drugs. However, there has been conflicting evidence regarding the impact of MSCs or MSC-EV on the behavior of cancer cells, and the exact mechanism for this effect is still unknown. Our research has focused on MSCs and their key characteristics, such as their immunomodulatory capabilities for cancer therapy. Our research has also explored the potential of MSCs and their derivatives to treat small-cell and non-small-cell lung cancers (NSCLC and SCLC, respectively) by leveraging MSCs' immunomodulatory characteristics. At the end of this article, we covered the pros and cons of this therapy procedure, as well as what researchers want to do in the future to make it more suitable for clinical application in LC treatment.
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Affiliation(s)
| | - Hayder Naji Sameer
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar 64001, Iraq
| | | | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
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Luan X, Wang X, Bian G, Li X, Gao Z, Liu Z, Zhang Z, Han T, Zhao J, Zhao H, Luan X, Zhu W, Dong L, Guo F. Exosome applications for the diagnosis and treatment of pancreatic ductal adenocarcinoma: An update (Review). Oncol Rep 2025; 53:13. [PMID: 39575479 PMCID: PMC11605277 DOI: 10.3892/or.2024.8846] [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: 08/08/2024] [Accepted: 10/30/2024] [Indexed: 11/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a malignant neoplasm that typically manifests with subtle clinical manifestations in its early stages and frequently eludes diagnosis until the advanced phases of the disease. The limited therapeutic options available for PDAC significantly contribute to its high mortality rate, highlighting the urgent need for novel biomarkers capable of effectively identifying early clinical manifestations and facilitating precise diagnosis. The pivotal role of cellular exosomes in both the pathogenesis and therapeutic interventions for PDAC has been underscored. Furthermore, researchers have acknowledged the potential of exosomes as targeted drug carriers against regulatory cells in treating PDAC. The present article aims to provide a comprehensive review encompassing recent advancements in utilizing exosomes for elucidating mechanisms underlying disease development, patterns of metastasis, diagnostic techniques and treatment strategies associated with PDAC.
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Affiliation(s)
- Xinchi Luan
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Xuezhe Wang
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Gang Bian
- Department of Gastroenterology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Xiaoxuan Li
- Department of Oncology, Key Laboratory of Cancer Molecular and Translational Research, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266031, P.R. China
| | - Ziru Gao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Zijiao Liu
- School of Clinical and Basic Medicine and Institute of Basic Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Zhishang Zhang
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Tianyue Han
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Jinpeng Zhao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Hongjiao Zhao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Xinyue Luan
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Wuhui Zhu
- Department of Hepatobiliary surgery, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Lili Dong
- Department of Gastroenterology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Feifei Guo
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
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Hass R, von der Ohe J, Luo T. Human mesenchymal stroma/stem-like cell-derived taxol-loaded EVs/exosomes transfer anti-tumor microRNA signatures and express enhanced SDF-1-mediated tumor tropism. Cell Commun Signal 2024; 22:506. [PMID: 39420354 PMCID: PMC11488203 DOI: 10.1186/s12964-024-01886-2] [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: 02/21/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND The release of extracellular vesicles (EVs) including exosomes from human mesenchymal stroma/stem-like cells (MSC) represents valuable cell-free carriers for the delivery of regenerative and medicinal compounds. METHODS EVs/exosomes were isolated by differential centrifugation from four individual MSC as controls and after treatment with a sub-lethal concentration of 10 mM taxol for 24 h, respectively. The isolated EVs/exosomes were characterized and quantified by nano-tracking-analysis and by Western blots. MicroRNAs (miRs) were isolated from the different EVs/exosome populations and expression levels were quantified by qPCR using 1246 miR templates. Cytotoxic effects of the different MSC-derived taxol-loaded EVs/exosomes were determined in five different GFP-transduced cancer cell lines and quantified by a fluoroscan assay with a GFP-detecting fluorimeter. The presence of stroma cell-derived factor 1 (SDF-1) in MSC-derived EVs/exosomes and its enhanced expression in the vesicles after taxol treatment of MSC was quantified by a specific ELISA. RESULTS EVs/exosomes isolated from four individual taxol-treated MSC displayed a larger size and higher yields as the control EVs/exosomes and were used as anti-tumor therapeutic vehicles. Application of each of the four MSC-derived taxol-loaded EVs/exosome populations revealed significant cytotoxic effects in cell lines of five different tumor entities (carcinomas of lung, breast, ovar, colon, astrocytoma) in a concentration-dependent manner. Expression analysis of 1246 miRs in these taxol-loaded EVs/exosomes as compared to the corresponding MSC-derived control EVs/exosomes unraveled a taxol-mediated up-regulation of 11 miRs with predominantly anti-tumorigenic properties. Moreover, various constitutively expressed protein levels were unanimously altered in the MSC cultures. Taxol treatment of the different MSC revealed an up-regulation of tetraspanins and a 2.2-fold to 5.4-fold increased expression of SDF-1 among others. Treatment of cancer cells with MSC-derived taxol-loaded EVs/exosomes in the presence of a neutralizing SDF-1 antibody significantly abolished the cytotoxic effects between 20.3% and 27%. CONCLUSIONS These findings suggested a taxol-mediated increase of anti-cancer properties in MSC that enhance the tropism of derived EVs/exosomes to tumors, thereby specifically focusing the therapeutic effects of the delivered products.
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Affiliation(s)
- Ralf Hass
- Department of Obstetrics and Gynecology, Biochemistry and Tumor Biology Laboratory, Hannover Medical School, 30625, Hannover, Germany.
| | - Juliane von der Ohe
- Department of Obstetrics and Gynecology, Biochemistry and Tumor Biology Laboratory, Hannover Medical School, 30625, Hannover, Germany
| | - Tianjiao Luo
- Department of Obstetrics and Gynecology, Biochemistry and Tumor Biology Laboratory, Hannover Medical School, 30625, Hannover, Germany
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Fakouri A, Razavi ZS, Mohammed AT, Hussein AHA, Afkhami H, Hooshiar MH. Applications of mesenchymal stem cell-exosome components in wound infection healing: new insights. BURNS & TRAUMA 2024; 12:tkae021. [PMID: 39139205 PMCID: PMC11319788 DOI: 10.1093/burnst/tkae021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 03/12/2024] [Accepted: 04/22/2024] [Indexed: 08/15/2024]
Abstract
The healing process at a wound is made up of many types of cells, growth factors, the extracellular matrix, nerves and blood vessels all interacting with each other in complex and changing ways. Microbial colonization and proliferation are possible at the place of injury, which makes infection more likely. Because of this, any cut has a chance of getting an infection. Researchers have found that wound infections make patients more upset and cost the healthcare system a lot of money. Surgical site infections happen a lot to people who have recently had surgery. This study shows that such surgical infection is linked to a high rate of illness and death. This is shown by the fact that 25% of patients get serious sepsis and need to be transferred to an intensive care unit. In both animal models and people, mesenchymal stem cells (MSCs) play an active role in all stages of wound healing and have positive effects. Exosomes are one of the main things MSCs release. They have effects that are similar to those of the parent MSCs. Various effector proteins, messenger RNA and microRNAs can be transported by extracellular vesicles to control the activity of target cells. This has a big impact on the healing process. These results suggest that using MSC-exosomes as a new type of cell-free therapy could be a better and safer option than whole cell therapy. This review is mostly about how to use parts of MSC-exosomes to help wound infections heal.
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Affiliation(s)
- Arshia Fakouri
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad 6813833946, Iran
| | - Zahra-Sadat Razavi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | | | - Hamed Afkhami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
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Deng R, Wu J, Zhu B, Song G, Zhou T, Yang M, Pan L, Wang J, Zou X, Lv Z, Jin X, Xu Y, Lu X, Gui S. Engineered exosomes loaded with M1–8 peptide for targeted therapy of hepatocellular carcinoma. APPLIED MATERIALS TODAY 2024; 37:102071. [DOI: 10.1016/j.apmt.2024.102071] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Zhang N, Shu L, Liu Z, Shi A, Zhao L, Huang S, Sheng G, Yan Z, Song Y, Huang F, Tang Y, Zhang Z. The role of extracellular vesicles in cholangiocarcinoma tumor microenvironment. Front Pharmacol 2024; 14:1336685. [PMID: 38269274 PMCID: PMC10805838 DOI: 10.3389/fphar.2023.1336685] [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: 11/11/2023] [Accepted: 12/26/2023] [Indexed: 01/26/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive malignant tumor that originates from the biliary system. With restricted treatment options at hand, the challenging aspect of early CCA diagnosis leads to a bleak prognosis. Besides the intrinsic characteristics of tumor cells, the generation and progression of CCA are profoundly influenced by the tumor microenvironment, which engages in intricate interactions with cholangiocarcinoma cells. Of notable significance is the role of extracellular vesicles as key carriers in enabling communication between cancer cells and the tumor microenvironment. This review aims to provide a comprehensive overview of current research examining the interplay between extracellular vesicles and the tumor microenvironment in the context of CCA. Specifically, we will emphasize the significant contributions of extracellular vesicles in molding the CCA microenvironment and explore their potential applications in the diagnosis, prognosis assessment, and therapeutic strategies for this aggressive malignancy.
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Affiliation(s)
- Nuoqi Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Lizhuang Shu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zengli Liu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
- Department of General Surgery, Qilu Hospital, Shandong University, Qingdao, Shandong, China
| | - Anda Shi
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Liming Zhao
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Shaohui Huang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Guoli Sheng
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zhangdi Yan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Yan Song
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Fan Huang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Yongchang Tang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zongli Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China
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da Silva AV, Serrenho I, Araújo B, Carvalho AM, Baltazar G. Secretome as a Tool to Treat Neurological Conditions: Are We Ready? Int J Mol Sci 2023; 24:16544. [PMID: 38003733 PMCID: PMC10671352 DOI: 10.3390/ijms242216544] [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: 10/03/2023] [Revised: 11/04/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
Due to their characteristics, mesenchymal stem cells (MSCs) are considered a potential therapy for brain tissue injury or degeneration. Nevertheless, despite the promising results observed, there has been a growing interest in the use of cell-free therapies in regenerative medicine, such as the use of stem cell secretome. This review provides an in-depth compilation of data regarding the secretome composition, protocols used for its preparation, as well as existing information on the impact of secretome administration on various brain conditions, pointing out gaps and highlighting relevant findings. Moreover, due to the ability of MSCs to respond differently depending on their microenvironment, preconditioning of MSCs has been used to modulate their composition and, consequently, their therapeutic potential. The different strategies used to modulate the MSC secretome were also reviewed. Although secretome administration was effective in improving functional impairments, regeneration, neuroprotection, and reducing inflammation in brain tissue, a high variability in secretome preparation and administration was identified, compromising the transposition of preclinical data to clinical studies. Indeed, there are no reports of the use of secretome in clinical trials. Despite the existing limitations and lack of clinical data, secretome administration is a potential tool for the treatment of various diseases that impact the CNS.
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Affiliation(s)
- Andreia Valente da Silva
- Health Sciences Research Center (CICS-UBI), University of Beira Interior, 6201-506 Covilhã, Portugal
| | - Inês Serrenho
- Health Sciences Research Center (CICS-UBI), University of Beira Interior, 6201-506 Covilhã, Portugal
- Center for Neuroscience and Cell Biology (CNC-UC), University of Coimbra, 3004-504 Coimbra, Portugal
| | - Beatriz Araújo
- Health Sciences Research Center (CICS-UBI), University of Beira Interior, 6201-506 Covilhã, Portugal
| | | | - Graça Baltazar
- Health Sciences Research Center (CICS-UBI), University of Beira Interior, 6201-506 Covilhã, Portugal
- Faculty of Health Sciences, University of Beira Interior, 6201-506 Covilhã, Portugal
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Jahangiri B, Khalaj-Kondori M, Asadollahi E, Kian Saei A, Sadeghizadeh M. Dual impacts of mesenchymal stem cell-derived exosomes on cancer cells: unravelling complex interactions. J Cell Commun Signal 2023:10.1007/s12079-023-00794-3. [PMID: 37973719 DOI: 10.1007/s12079-023-00794-3] [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: 06/10/2023] [Accepted: 11/06/2023] [Indexed: 11/19/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent, self-renewing stromal cells found in a variety of adult tissues. MSCs possess a remarkable ability to migrate towards tumor sites, known as homing. This homing process is mediated by various factors, including chemokines, growth factors, and extracellular matrix components present in the tumor microenvironment. MSCs release extracellular vesicles known as exosomes (MSC-Exos), which have been suggested to serve a key role in mediating a wide variety of MSC activities. Through cell-cell communication, MSC-Exos have been shown to alter recipient cell phenotype or function and play as a novel cell-free alternative for MSC-based cell therapy. However, MSC recruitment to tumors allows for their interaction with cancer cells and subsequent regulation of tumor behavior. MSC-Exos act as tumor niche modulators via transferring exosomal contents, such as specific proteins or genetic materials, to the nearby cancer cells, leading to either promotion or suppression of tumorigenesis, angiogenesis, and metastasis, depending on the specific microenvironmental cues and recipient cell characteristics. Consequently, there is still a debate about the precise relationship between tumor cells and MSC-Exos, and it is unclear how MSC-Exos impacts tumor cells. Although the dysregulation of miRNAs is caused by the progression of cancer, they also play a direct role in either promoting or inhibiting tumor growth as they act as either oncogenes or tumor suppressors. The utilization of MSC-Exos may prove to be an effective method for restoring miRNA as a means of treating cancer. This review aimed to present the existing understanding of the impact that MSC-Exos could have on cancer. To begin with, we presented a brief explanation of exosomes, MSCs, and MSC-Exos. Following this, we delved into the impact of MSC-Exos on cancer growth, EMT, metastasis, angiogenesis, resistance to chemotherapy and radiotherapy, and modulation of the immune system. Opposing effects of mesenchymal stem cells-derived exosomes on cancer cells.
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Affiliation(s)
- Babak Jahangiri
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Khalaj-Kondori
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
| | - Elahe Asadollahi
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Kian Saei
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Majid Sadeghizadeh
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
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Hazrati A, Malekpour K, Mirsanei Z, Khosrojerdi A, Rahmani-Kukia N, Heidari N, Abbasi A, Soudi S. Cancer-associated mesenchymal stem/stromal cells: role in progression and potential targets for therapeutic approaches. Front Immunol 2023; 14:1280601. [PMID: 38022534 PMCID: PMC10655012 DOI: 10.3389/fimmu.2023.1280601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Malignancies contain a relatively small number of Mesenchymal stem/stromal cells (MSCs), constituting a crucial tumor microenvironment (TME) component. These cells comprise approximately 0.01-5% of the total TME cell population. MSC differentiation potential and their interaction with the tumor environment enable these cells to affect tumor cells' growth, immune evasion, metastasis, drug resistance, and angiogenesis. This type of MSC, known as cancer-associated mesenchymal stem/stromal cells (CA-MSCs (interacts with tumor/non-tumor cells in the TME and affects their function by producing cytokines, chemokines, and various growth factors to facilitate tumor cell migration, survival, proliferation, and tumor progression. Considering that the effect of different cells on each other in the TME is a multi-faceted relationship, it is essential to discover the role of these relationships for targeting in tumor therapy. Due to the immunomodulatory role and the tissue repair characteristic of MSCs, these cells can help tumor growth from different aspects. CA-MSCs indirectly suppress antitumor immune response through several mechanisms, including decreasing dendritic cells (DCs) antigen presentation potential, disrupting natural killer (NK) cell differentiation, inducing immunoinhibitory subsets like tumor-associated macrophages (TAMs) and Treg cells, and immune checkpoint expression to reduce effector T cell antitumor responses. Therefore, if these cells can be targeted for treatment so that their population decreases, we can hope for the treatment and improvement of the tumor conditions. Also, various studies show that CA-MSCs in the TME can affect other vital aspects of a tumor, including cell proliferation, drug resistance, angiogenesis, and tumor cell invasion and metastasis. In this review article, we will discuss in detail some of the mechanisms by which CA-MSCs suppress the innate and adaptive immune systems and other mechanisms related to tumor progression.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Mirsanei
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arezou Khosrojerdi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Nasim Rahmani-Kukia
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Neda Heidari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ardeshir Abbasi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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13
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Gschwendtberger T, Thau-Habermann N, von der Ohe J, Luo T, Hass R, Petri S. Protective effects of EVs/exosomes derived from permanently growing human MSC on primary murine ALS motor neurons. Neurosci Lett 2023; 816:137493. [PMID: 37774774 DOI: 10.1016/j.neulet.2023.137493] [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: 06/15/2023] [Revised: 08/29/2023] [Accepted: 09/19/2023] [Indexed: 10/01/2023]
Abstract
In recent years, the neuroprotective potential of mesenchymal stroma-/stem-like cells (MSC) as well as of MSC-derived extracellular vesicles (EVs) like exosomes has been intensively explored. This included preclinical evaluation regarding treatment of neurodegenerative disorders such as the fatal motor neuron disease amyotrophic Lateral Sclerosis (ALS). Several studies have reported that MSC-derived exosomes can stimulate tissue regeneration and reduce inflammation. MSC release EVs and trophic factors and thereby modify cell-to-cell communication. These cell-free products may protect degenerating motor neurons (MNs) and represent a potential therapeutic approach for ALS. In the present study we investigated the effects of exosomes derived from a permanently growing MSC line on both, wild type and ALS (SOD1G93A transgenic) primary motor neurons. Following application in a normal and stressed environment we could demonstrate beneficial effects of MSC exosomes on neurite growth and morphology indicating the potential for further preclinical evaluation and clinical therapeutic development. Investigation of gene expression profiles detected transcripts of several antioxidant and anti-inflammatory genes in MSC exosomes. Characterization of their microRNA (miRNA) content revealed miRNAs capable of regulating antioxidant and anti-apoptotic pathways.
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Affiliation(s)
- Thomas Gschwendtberger
- Department of Neurology, Hannover Medical School, Hannover 30625, Germany; Center for Systems Neuroscience (ZSN), Hannover, Germany
| | | | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover 30625, Germany
| | - Tianjiao Luo
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover 30625, Germany
| | - Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover 30625, Germany.
| | - Susanne Petri
- Department of Neurology, Hannover Medical School, Hannover 30625, Germany; Center for Systems Neuroscience (ZSN), Hannover, Germany.
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14
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Slama Y, Ah-Pine F, Khettab M, Arcambal A, Begue M, Dutheil F, Gasque P. The Dual Role of Mesenchymal Stem Cells in Cancer Pathophysiology: Pro-Tumorigenic Effects versus Therapeutic Potential. Int J Mol Sci 2023; 24:13511. [PMID: 37686315 PMCID: PMC10488262 DOI: 10.3390/ijms241713511] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells involved in numerous physiological events, including organogenesis, the maintenance of tissue homeostasis, regeneration, or tissue repair. MSCs are increasingly recognized as playing a major, dual, and complex role in cancer pathophysiology through their ability to limit or promote tumor progression. Indeed, these cells are known to interact with the tumor microenvironment, modulate the behavior of tumor cells, influence their functions, and promote distant metastasis formation through the secretion of mediators, the regulation of cell-cell interactions, and the modulation of the immune response. This dynamic network can lead to the establishment of immunoprivileged tissue niches or the formation of new tumors through the proliferation/differentiation of MSCs into cancer-associated fibroblasts as well as cancer stem cells. However, MSCs exhibit also therapeutic effects including anti-tumor, anti-proliferative, anti-inflammatory, or anti-oxidative effects. The therapeutic interest in MSCs is currently growing, mainly due to their ability to selectively migrate and penetrate tumor sites, which would make them relevant as vectors for advanced therapies. Therefore, this review aims to provide an overview of the double-edged sword implications of MSCs in tumor processes. The therapeutic potential of MSCs will be reviewed in melanoma and lung cancers.
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Affiliation(s)
- Youssef Slama
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Franck Ah-Pine
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service d’Anatomie et Cytologie Pathologiques, CHU de La Réunion sites SUD—Saint-Pierre, Avenue François Mitterrand, 97448 Saint-Pierre Cedex, La Réunion, France
| | - Mohamed Khettab
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
- Service d’Oncologie Médicale, CHU de La Réunion sites SUD—Saint-Pierre, Avenue François Mitterrand, 97448 Saint-Pierre Cedex, La Réunion, France
| | - Angelique Arcambal
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Mickael Begue
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Fabien Dutheil
- Service de Radiothérapie, Clinique Sainte-Clotilde, Groupe Clinifutur, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France; (M.B.); (F.D.)
- Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France;
| | - Philippe Gasque
- Unité de Recherche Études Pharmaco-Immunologiques (EPI), Université de La Réunion, CHU de La Réunion, Allée des Topazes, 97400 Saint-Denis, La Réunion, France; (F.A.-P.); (M.K.); (P.G.)
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15
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Hennigan K, Lavik E. Nature vs. Manmade: Comparing Exosomes and Liposomes for Traumatic Brain Injury. AAPS J 2023; 25:83. [PMID: 37610471 DOI: 10.1208/s12248-023-00849-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 08/08/2023] [Indexed: 08/24/2023] Open
Abstract
Traumatic brain injury (TBI) of all severities is a significant public health burden, causing a range of effects that can lead to death or a diminished quality of life. Liposomes and mesenchymal stem cell-derived exosomes are two drug delivery agents with potential to be leveraged in the treatment of TBI by increasing the efficacy of drug therapies as well as having additional therapeutic effects. They exhibit several physical similarities, but key differences affect their performances as nanocarriers. Liposomes can be produced commercially at scale, and liposomes achieve higher encapsulation efficiency. Meanwhile, the intrinsic cargo and targeting moieties of exosomes, which liposomes lack, give exosomes a greater ability to facilitate neural regeneration, and exosomes do not trigger the infusion reactions that liposomes can. However, there are concerns about both exosomes and liposomes regarding interactions with tumors. The same routes of administration can be used for both exosomes and liposomes, resulting in somewhat different distribution throughout the body. While the effect of the nanocarrier type on accumulation in the brain is not concrete, targeting leads to increased accumulation of both exosomes and liposomes in the brain, upon which on-demand release can be used for both drug deliverers. Although neither have been applied to TBI in humans, preclinical trials have shown their immense potential, as have clinical trials pertaining to other brain injuries and conditions. While questions remain, research thus far shows that the various differences make exosomes a better choice of nanocarrier for TBI.
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Affiliation(s)
- Kate Hennigan
- Marriotts Ridge High School, Ellicott City, Maryland, 21042, USA
| | - Erin Lavik
- University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, Maryland, 21250, USA.
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16
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Feng Q, Zhang Y, Fang Y, Kong X, He Z, Ji J, Yang X, Zhai G. Research progress of exosomes as drug carriers in cancer and inflammation. J Drug Target 2023; 31:335-353. [PMID: 36543743 DOI: 10.1080/1061186x.2022.2162059] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Extracellular vesicles (EVs) could be produced by most cells and play an important role in disease development. As a subtype of EVs, exosomes exhibit suitable size, rich surface markers and diverse contents, making them more appealing as potential drug carriers. Compared with traditional synthetic nanoparticles, exosomes possess superior biocompatibility and much lower immunogenicity. This work reviewed the most up-to-date research progress of exosomes as carriers for nucleic acids, proteins and small molecule drugs for cancer and inflammation management. The drug loading strategies and potential cellular uptake behaviour of exosomes are highlighted, trying to provide reference for future exosome design and application.
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Affiliation(s)
- Qixiang Feng
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
| | - Yu Zhang
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
| | - Yuelin Fang
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
| | - Xinru Kong
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
| | - Zhijing He
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
| | - Jianbo Ji
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
| | - Xiaoye Yang
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
| | - Guangxi Zhai
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, P.R. China
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17
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Cell-Free Therapies: The Use of Cell Extracts to Mitigate Irradiation-Injured Salivary Glands. BIOLOGY 2023; 12:biology12020305. [PMID: 36829582 PMCID: PMC9953449 DOI: 10.3390/biology12020305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/17/2023]
Abstract
Radiotherapy is a standard treatment for head and neck cancer patients worldwide. However, millions of patients who received radiotherapy consequently suffer from xerostomia because of irreversible damage to salivary glands (SGs) caused by irradiation (IR). Current treatments for IR-induced SG hypofunction only provide temporary symptom alleviation but do not repair the damaged SG, thus resulting in limited treatment efficacy. Therefore, there has recently been a growing interest in regenerative treatments, such as cell-free therapies. This review aims to summarize cell-free therapies for IR-induced SG, with a particular emphasis on utilizing diverse cell extract (CE) administrations. Cell extract is a group of heterogeneous mixtures containing multifunctional inter-cellular molecules. This review discusses the current knowledge of CE's components and efficacy. We propose optimal approaches to improve cell extract treatment from multiple perspectives (e.g., delivery routes, preparation methods, and other details regarding CE administration). In addition, the advantages and limitations of CE treatment are systematically discussed by comparing it to other cell-free (such as conditioned media and exosomes) and cell-based therapies. Although a comprehensive identification of the bioactive factors within CEs and their mechanisms of action have yet to be fully understood, we propose cell extract therapy as an effective, practical, user-friendly, and safe option to conventional therapies in IR-induced SG.
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18
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Mesenchymal Stem Cells and Their Exocytotic Vesicles. Int J Mol Sci 2023; 24:ijms24032085. [PMID: 36768406 PMCID: PMC9916886 DOI: 10.3390/ijms24032085] [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: 12/28/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 01/21/2023] Open
Abstract
Mesenchymal stem cells (MSCs), as a kind of pluripotent stem cells, have attracted much attention in orthopedic diseases, geriatric diseases, metabolic diseases, and sports functions due to their osteogenic potential, chondrogenic differentiation ability, and adipocyte differentiation. Anti-inflammation, anti-fibrosis, angiogenesis promotion, neurogenesis, immune regulation, and secreted growth factors, proteases, hormones, cytokines, and chemokines of MSCs have been widely studied in liver and kidney diseases, cardiovascular and cerebrovascular diseases. In recent years, many studies have shown that the extracellular vesicles of MSCs have similar functions to MSCs transplantation in all the above aspects. Here we review the research progress of MSCs and their exocrine vesicles in recent years.
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19
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Jafarinia M, Farrokhi MR, Ganjalikhani Hakemi M, Cho WC. The role of miRNAs from mesenchymal stem/stromal cells-derived extracellular vesicles in neurological disorders. Hum Cell 2023; 36:62-75. [PMID: 36261702 DOI: 10.1007/s13577-022-00813-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/12/2022] [Indexed: 01/07/2023]
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells with immunomodulatory effects that have been attempted as a possible treatment for neurologic disorders. Since currently available drugs for neurologic disorders are limited, special attention has been paid to MSCs. With the ability to differentiate into neural cells, it has been shown that MSCs exert their effects in a paracrine manner by producing extracellular vesicles (EVs). Extracellular vesicles are small vesicles with a size of 30-1000 nm that are released by cells, such as MSCs, T cells, B cells, etc. EVs contain various molecules, including proteins, lipids, mRNAs, and microRNAs (miRNAs). In recent years, the administration of EVs in models of neurological disorders has been shown to improve neurological dysfunctions. miRNAs from MSC-EVs as one of the important mediators which regulate various genes and reduce neuropathological change have been identified in different neurological disorders. Here, we review the effects of EVs miRNAs from MSCs on different neurological disorders and their potential applications.
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Affiliation(s)
- Morteza Jafarinia
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Majid Reza Farrokhi
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Neurosurgery, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mazdak Ganjalikhani Hakemi
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
- Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong SAR, China.
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20
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Zhou Q, Wei S, Wang H, Li Y, Fan S, Cao Y, Wang C. T cell-derived exosomes in tumor immune modulation and immunotherapy. Front Immunol 2023; 14:1130033. [PMID: 37153615 PMCID: PMC10157026 DOI: 10.3389/fimmu.2023.1130033] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/27/2023] [Indexed: 05/09/2023] Open
Abstract
Exosomes are nanoscale vesicles secreted by most cells and have a phospholipid bilayer structure. Exosomes contain DNA, small RNA, proteins, and other substances that can carry proteins and nucleic acids and participate in communication between cells. T cells are an indispensable part of adaptive immunity, and the functions of T cell-derived exosomes have been widely studied. In the more than three decades since the discovery of exosomes, several studies have revealed that T cell-derived exosomes play a novel role in cell-to-cell signaling, especially in the tumor immune response. In this review, we discuss the function of exosomes derived from different T cell subsets, explore applications in tumor immunotherapy, and consider the associated challenges.
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Affiliation(s)
- Qiujun Zhou
- Department of First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Shenyu Wei
- Department of Hepato-Pancreato-Biliary Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Hui Wang
- Department of First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuanyuan Li
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Shasha Fan
- Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Yi Cao
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Chenglei Wang
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- *Correspondence: Chenglei Wang,
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21
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Pallares-Rusiñol A, Bernuz M, Moura SL, Fernández-Senac C, Rossi R, Martí M, Pividori MI. Advances in exosome analysis. Adv Clin Chem 2022; 112:69-117. [PMID: 36642486 DOI: 10.1016/bs.acc.2022.09.002] [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] [Indexed: 12/24/2022]
Abstract
There is growing demand for novel biomarkers that detect early stage disease as well as monitor clinical management and therapeutic strategies. Exosome analysis could provide the next advance in attaining that goal. Exosomes are membrane encapsulated biologic nanometric-sized particles of endocytic origin which are released by all cell types. Unfortunately, exosomes are exceptionally challenging to characterize with current technologies. Exosomes are between 30 and 200nm in diameter, a size that makes them out of the sensitivity range to most cell-oriented sorting or analysis platforms, i.e., traditional flow cytometers. The most common methods for targeting exosomes to date typically involve purification followed by the characterization and the specific determination of their cargo. The whole procedure is time consuming, requiring thus skilled personnel as well as laboratory facilities and benchtop instrumentation. The most relevant methodology for exosome isolation, characterization and quantification is addressed in this chapter, including the most up-to-date approaches to explore the potential usefulness of exosomes as biomarkers in liquid biopsies and in advanced nanomedicine.
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Affiliation(s)
- Arnau Pallares-Rusiñol
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Mireia Bernuz
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Silio Lima Moura
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Carolina Fernández-Senac
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Rosanna Rossi
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Mercè Martí
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - María Isabel Pividori
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain.
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22
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Dittmar T, Hass R. Extracellular Events Involved in Cancer Cell-Cell Fusion. Int J Mol Sci 2022; 23:16071. [PMID: 36555709 PMCID: PMC9784959 DOI: 10.3390/ijms232416071] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/13/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Fusion among different cell populations represents a rare process that is mediated by both intrinsic and extracellular events. Cellular hybrid formation is relayed by orchestrating tightly regulated signaling pathways that can involve both normal and neoplastic cells. Certain important cell merger processes are often required during distinct organismal and tissue development, including placenta and skeletal muscle. In a neoplastic environment, however, cancer cell fusion can generate new cancer hybrid cells. Following survival during a subsequent post-hybrid selection process (PHSP), the new cancer hybrid cells express different tumorigenic properties. These can include elevated proliferative capacity, increased metastatic potential, resistance to certain therapeutic compounds, and formation of cancer stem-like cells, all of which characterize significantly enhanced tumor plasticity. However, many parts within this multi-step cascade are still poorly understood. Aside from intrinsic factors, cell fusion is particularly affected by extracellular conditions, including an inflammatory microenvironment, viruses, pH and ionic stress, hypoxia, and exosome signaling. Accordingly, the present review article will primarily highlight the influence of extracellular events that contribute to cell fusion in normal and tumorigenic tissues.
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Affiliation(s)
- Thomas Dittmar
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Str. 10, 58448 Witten, Germany
| | - Ralf Hass
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany
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23
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Kitaeva KV, Chulpanova DS, Zhuravleva MN, Filin IY, Deviatiiarov RM, Ballard-Reisch AC, Rizvanov AA, Solovyeva VV. Characteristics and Resistance to Cisplatin of Human Neuroblastoma Cells Co-Cultivated with Immune and Stromal Cells. Bioengineering (Basel) 2022; 9:655. [PMID: 36354566 PMCID: PMC9687654 DOI: 10.3390/bioengineering9110655] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/21/2022] [Accepted: 11/03/2022] [Indexed: 12/03/2023] Open
Abstract
We investigated the features of the morphology and cytokine profiles of neuroblastoma SH-SY5Y cells, bone marrow-derived mesenchymal stromal/stem cells (BM-MSCs), and peripheral blood mononuclear cells (PBMCs) in double (BM-MSCs + SH-SY5Y cells) and triple (BM-MSCs + SH-SY5Y cells + PBMCs) co-cultures incubated on plastic and Matrigel. Cells in the co-cultures communicated by vesicular transport and by exchanging membrane and cytoplasmic components. The cytokine profile of double and triple co-cultures incubated on Matrigel and plastic had differences and showed the highest concentration of a number of chemokines/cytokines, such as CXCL8/IL-8, I-TAC/CXCL11, IP10/CXCL10, MDC/CCL22, MIP-1α/CCL3, IL-1β, ENA-78/CXCL5, Gro-α/CXCL1, MCP-1/CCL2, TERC/CCL25, CXCL8/IL-8, and IL-6. High concentrations of inflammatory chemokines/cytokines in the conditioned medium of triple co-culture form a chronic inflammation, which brings the presented co-cultivation system closer to a natural tumor. Triple co-cultures were more resistant to cisplatin (CDDP) than the double- and monoculture of SH-SY5Y. The mRNA levels of BCL2, BCL2L1, RAC1, CAV1, CASP3, and BAX genes were changed in cells after co-culturing and CDDP treatment in double and triple co-cultures. The expression of the BCL2, BAX, CAV1, and CASP3 proteins in SH-SY5Y cells after the triple co-culture and CAV1 and BAX protein expression in SH-SY5Y cells after the double co-culture were determined. This study demonstrated the nature of the cellular interactions between components of tumor niche and the intercellular influence on chemoresistance observed in our tumor model, which should enable the development of novel test systems for anti-tumor agents.
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Affiliation(s)
| | | | | | | | | | | | | | - Valeriya V. Solovyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
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Gilazieva Z, Chulpanova D, Ponomarev A, Filin I, Garanina E, Rizvanov A, Solovyeva V. Comparative Analysis of Natural and Cytochalasin B-Induced Membrane Vesicles from Tumor Cells and Mesenchymal Stem Cells. Curr Issues Mol Biol 2022; 44:5363-5378. [PMID: 36354675 PMCID: PMC9688684 DOI: 10.3390/cimb44110363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 04/15/2025] Open
Abstract
To date, there are numerous protocols for the isolation of extracellular vesicles (EVs). Depending on the isolation method, it is possible to obtain vesicles with different characteristics, enriched with specific groups of proteins, DNA and RNA, which affect similar types of cells in the opposite way. Therefore, it is important to study and compare methods of vesicle isolation. Moreover, the differences between the EVs derived from tumor and mesenchymal stem cells are still poorly understood. This article compares EVs from human glioblastoma cells and mesenchymal stem cells (MSCs) obtained by two different methods, ultracentrifugation and cytochalasin B-mediated induction. The size of the vesicles, the presence of the main EV markers, the presence of nuclear and mitochondrial components, and the molecular composition of the vesicles were determined. It has been shown that EVs obtained by both ultracentrifugation and cytochalasin B treatment have similar features, contain particles of endogenous and membrane origin and can interact with monolayer cultures of tumor cells.
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Affiliation(s)
| | | | | | | | | | | | - Valeriya Solovyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
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25
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Castillo-Sanchez R, Churruca-Schuind A, Martinez-Ival M, Salazar EP. Cancer-associated Fibroblasts Communicate with Breast Tumor Cells Through Extracellular Vesicles in Tumor Development. Technol Cancer Res Treat 2022; 21:15330338221131647. [PMID: 36222020 PMCID: PMC9558853 DOI: 10.1177/15330338221131647] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Breast cancer is the leading cause of cancer death among women worldwide. In solid tumors, the microenvironment plays a critical role in tumor development, and it has been described a communication between the different cell types that conform the stroma, including fibroblasts, pericytes, adipocytes, immune cells and cancer-associated fibroblasts. Intercellular communication is bidirectional, complex, multifactorial and is mediated by the secretion of molecules and extracellular vesicles. The extracellular vesicles are vesicles limited by two membranes that are secreted by normal and cancer cells into the extracellular space. Extracellular vesicle cargo is complex and includes proteins, miRNAs, DNA and lipids, and their composition is specific to their parent cells. Extracellular vesicles are taken up for neighboring or distant cells. Particularly, extracellular vesicles from breast cancer cells are taken up for fibroblasts and it induces the activation of fibroblasts into cancer-associated fibroblasts. Interestingly, cancer associated fibroblasts release extracellular vesicles that are taken up for breast cancer cells and promote migration, invasion, proliferation, epithelial-mesenchymal transition, changes in metabolism, chemoresistance, evasion of immune system and remodeling of extracellular matrix. In addition, the enrichment of specific cargos in extracellular vesicles of breast cancer patients has been suggested to be used as biomarkers of the disease. Here we review the current literature about the intercommunication between tumor cells and cancer associated fibroblasts through extracellular vesicles in breast cancer.
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Affiliation(s)
| | | | | | - Eduardo Perez Salazar
- Eduardo Perez Salazar, PhD, Departamento de
Biologia Celular, Cinvestav-IPN, Av. IPN # 2508, Mexico City 07360, Mexico.
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Lucotti S, Kenific CM, Zhang H, Lyden D. Extracellular vesicles and particles impact the systemic landscape of cancer. EMBO J 2022; 41:e109288. [PMID: 36052513 PMCID: PMC9475536 DOI: 10.15252/embj.2021109288] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 02/16/2022] [Accepted: 03/23/2022] [Indexed: 11/09/2022] Open
Abstract
Intercellular cross talk between cancer cells and stromal and immune cells is essential for tumor progression and metastasis. Extracellular vesicles and particles (EVPs) are a heterogeneous class of secreted messengers that carry bioactive molecules and that have been shown to be crucial for this cell-cell communication. Here, we highlight the multifaceted roles of EVPs in cancer. Functionally, transfer of EVP cargo between cells influences tumor cell growth and invasion, alters immune cell composition and function, and contributes to stromal cell activation. These EVP-mediated changes impact local tumor progression, foster cultivation of pre-metastatic niches at distant organ-specific sites, and mediate systemic effects of cancer. Furthermore, we discuss how exploiting the highly selective enrichment of molecules within EVPs has profound implications for advancing diagnostic and prognostic biomarker development and for improving therapy delivery in cancer patients. Altogether, these investigations into the role of EVPs in cancer have led to discoveries that hold great promise for improving cancer patient care and outcome.
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Affiliation(s)
- Serena Lucotti
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Candia M Kenific
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Haiying Zhang
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - David Lyden
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
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27
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Lin Z, Wu Y, Xu Y, Li G, Li Z, Liu T. Mesenchymal stem cell-derived exosomes in cancer therapy resistance: recent advances and therapeutic potential. Mol Cancer 2022; 21:179. [PMID: 36100944 PMCID: PMC9468526 DOI: 10.1186/s12943-022-01650-5] [Citation(s) in RCA: 154] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 08/30/2022] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stromal cells that can be obtained from various human tissues and organs. They can differentiate into a wide range of cell types, including osteoblasts, adipocytes and chondrocytes, thus exhibiting great potential in regenerative medicine. Numerous studies have indicated that MSCs play critical roles in cancer biology. The crosstalk between tumour cells and MSCs has been found to regulate many tumour behaviours, such as proliferation, metastasis and epithelial-mesenchymal transition (EMT). Multiple lines of evidence have demonstrated that MSCs can secrete exosomes that can modulate the tumour microenvironment and play important roles in tumour development. Notably, very recent works have shown that mesenchymal stem cell-derived exosomes (MSC-derived exosomes) are critically involved in cancer resistance to chemotherapy agents, targeted-therapy drugs, radiotherapy and immunotherapy. In this review, we systematically summarized the emerging roles and detailed molecular mechanisms of MSC-derived exosomes in mediating cancer therapy resistance, thus providing novel insights into the clinical applications of MSC-derived exosomes in cancer management.
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Composition, Biogenesis, and Role of Exosomes in Tumor Development. Stem Cells Int 2022; 2022:8392509. [PMID: 36117723 PMCID: PMC9481374 DOI: 10.1155/2022/8392509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 08/14/2022] [Accepted: 08/26/2022] [Indexed: 11/30/2022] Open
Abstract
The role of exosomes and their mechanism of action at the tumor site have received increasing attention. These microvesicles are produced by a wide range of cells including mesenchymal stem cells (MSCs) and immune cells. In particular, tumor cells release remarkable amounts of exosomes which spread to distant organs through the blood and enhance the possibility of tumor metastasis. In spite of results on tumor promoting properties, there are reports demonstrating the tumor inhibiting effects of exosomes depending on the type of the tumor and cell source. This review aims to have a comprehensive appraisal on the biogenesis, composition, and isolation of exosomes and then highlights the current knowledge of their role in cancer progression or inhibition by special focusing on MSC's exosomes (MSC-EXOs).
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29
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Műzes G, Sipos F. Mesenchymal Stem Cell-Derived Secretome: A Potential Therapeutic Option for Autoimmune and Immune-Mediated Inflammatory Diseases. Cells 2022; 11:2300. [PMID: 35892597 PMCID: PMC9367576 DOI: 10.3390/cells11152300] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 07/16/2022] [Accepted: 07/26/2022] [Indexed: 02/05/2023] Open
Abstract
Immune-mediated inflammatory diseases (IMIDs) encompass several entities such as "classic" autoimmune disorders or immune-mediated diseases with autoinflammatory characteristics. Adult stem cells including mesenchymal stem cells (MSCs) are by far the most commonly used type in clinical practice. However, due to the possible side effects of MSC-based treatments, there is an increase in interest in the MSC-secretome (containing large extracellular vesicles, microvesicles, and exosomes) as an alternative therapeutic option in IMIDs. A wide spectrum of MSC-secretome-related biological activities has been proven thus far including anti-inflammatory, anti-apoptotic, and immunomodulatory properties. In comparison with MSCs, the secretome is less immunogenic but exerts similar biological actions, so it can be considered as an ideal cell-free therapeutic alternative. Additionally, since the composition of the MSC-secretome can be engineered, for a future perspective, it could also be viewed as part of a potential delivery system within nanomedicine, allowing us to specifically target dysfunctional cells or tissues. Although many encouraging results from pre-clinical studies have recently been obtained that strongly support the application of the MSC-secretome in IMIDs, human studies with MSC-secretome administration are still in their infancy. This article reviews the immunomodulatory effects of the MSC-secretome in IMIDs and provides insight into the interpretation of its beneficial biological actions.
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Affiliation(s)
- Györgyi Műzes
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, Szentkirályi Street 46, 1088 Budapest, Hungary;
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30
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Sipos F, Műzes G. Disagreements in the therapeutic use of mesenchymal stem cell-derived secretome. World J Stem Cells 2022; 14:365-371. [PMID: 35949398 PMCID: PMC9244954 DOI: 10.4252/wjsc.v14.i6.365] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 03/15/2022] [Accepted: 05/27/2022] [Indexed: 02/06/2023] Open
Abstract
In a recent article, the authors provide a detailed summary of the characteristics and biological functions of mesenchymal stem cells (MSCs), as well as a discussion on the potential mechanisms of action of MSC-based therapies. They describe the morphology, biogenesis, and current isolation techniques of exosomes, one of the most important fractions of the MSC-derived secretome. They also summarize the characteristics of MSC-derived exosomes and highlight their functions and therapeutic potential for tissue/organ regeneration and for kidney, liver, cardiovascular, neurological, and musculoskeletal diseases, as well as cutaneous wound healing. Despite the fact that MSCs are regarded as an important pillar of regenerative medicine, their regenerative potential has been demonstrated to be limited in a number of pathological conditions. The negative effects of MSC-based cell therapy have heightened interest in the therapeutic use of MSC-derived secretome. On the other hand, MSC-derived exosomes and microvesicles possess the potential to have a significant impact on disease development, including cancer. MSCs can interact with tumor cells and promote mutual exchange and induction of cellular markers by exchanging secretome. Furthermore, enzymes secreted into and activated within exosomes can result in tumor cells acquiring new properties. As a result, therapeutic applications of MSC-derived secretomes must be approached with extreme caution.
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Affiliation(s)
- Ferenc Sipos
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest 1088, Hungary.
| | - Györgyi Műzes
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest 1088, Hungary
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31
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Gilazieva Z, Ponomarev A, Rizvanov A, Solovyeva V. The Dual Role of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Carcinogenesis. BIOLOGY 2022; 11:biology11060813. [PMID: 35741334 PMCID: PMC9220333 DOI: 10.3390/biology11060813] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 02/07/2023]
Abstract
Simple Summary Extracellular vesicles (EVs) are membrane structures that play the role of intermediaries between tumor cells and the tumor microenvironment (TME) because they have the ability to transport lipids, transcription factors, mRNA, and proteins. Mesenchymal stem cells (MSCs) are a major component of the TME and may have different effects on tumor progression using EVs. This review includes information about various studies which have reported that EVs from MSCs can have either antitumor or pro-tumor effects, depending on both the tumor type and developmental stage. It provides an overview of the published data on EV MSCs and their effect on tumor cells. In addition, the use of EV MSCs for the development of new methods for treating oncological diseases is described. Abstract Mesenchymal stem cells (MSCs) are a major component of the tumor microenvironment (TME) and play an important role in tumor progression. MSCs remodel the extracellular matrix, participate in the epithelial–mesenchymal transition, promote the spread of metastases, and inhibit antitumor immune responses in the TME; however, there are also data pertaining to the antitumor effects of MSCs. MSCs activate the cell death mechanism by modulating the expression of proteins involved in the regulation of the cell cycle, angiogenesis receptors, and proapoptotic proteins. One of the main ways in which MSCs and TME interact is through the production of extracellular vesicles (EVs) by cells. Currently, data on the effects of both MSCs and their EVs on tumor cells are rather contradictory. Various studies have reported that EVs from MSCs can have either antitumor or pro-tumor effects, depending on both the tumor type and developmental stage. In this review, we discuss published data on EV MSCs and their effect on tumor cells. The molecular composition of vesicles obtained from MSCs is also presented in the review. In addition, the use of EV MSCs for the development of new methods for treating oncological diseases is described.
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32
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Frisbie L, Buckanovich RJ, Coffman L. Carcinoma Associated Mesenchymal Stem/Stromal Cells - Architects of the Pro-tumorigenic tumor microenvironment. Stem Cells 2022; 40:705-715. [PMID: 35583414 PMCID: PMC9406606 DOI: 10.1093/stmcls/sxac036] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 05/12/2022] [Indexed: 11/13/2022]
Abstract
The interaction between tumor cells and non-malignant hosts cells within the tumor microenvironment (TME) is critical to the pathophysiology of cancer. These non-malignant host cells, consisting of a variety of stromal, immune and endothelial cells, engage in a complex bidirectional crosstalk with the malignant tumor cells. Mesenchymal stem/stromal cells (MSCs) are one of these host cells, and they play a critical role in directing the formation and function of the entire TME. These MSCs are epigenetically reprogrammed by cancer cells to assume a strongly pro-tumorigenic phenotype and are referred to as carcinoma-associated mesenchymal stem/stromal cells (CA-MSCs). Studies over the last decade demonstrate that CA-MSCs not only directly interact with cancer cells to promote tumor growth and metastasis, but also orchestrate the formation of the TME. CA-MSCs can differentiate into virtually all stromal sub-lineages present in the TME, including pro-tumorigenic cancer associated fibroblasts (CAF), myofibroblasts, and adipocytes. CA-MSCs and the CAFs they produce, secrete much of the extracellular matrix in the TME. Furthermore, CA-MSC secreted factors promote angiogenesis, and recruit immunosuppressive myeloid cells effectively driving tumor immune exclusion. Thus CA-MSCs impact nearly every aspect of the TME. Despite their influence on cancer biology, as CA-MSCs represent a heterogenous population without a single definitive marker, significant confusion remains regarding the origin and proper identification CA-MSCs. This review will focus on the impact of CA-MSCs on cancer progression and metastasis and the ongoing work on CA-MSC identification, nomenclature and mechanism of action.
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Affiliation(s)
- Len Frisbie
- Department of Integrative Systems Biology, University of Pittsburgh, Pittsburgh, PA
| | - Ronald J Buckanovich
- Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA.,Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, PA
| | - Lan Coffman
- Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA.,Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, PA
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33
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SIPOS FERENC, MŰZES GYÖRGYI. Controversies in therapeutic application of mesenchymal stem cell-derived secretome. BIOCELL 2022; 46:903-906. [DOI: 10.32604/biocell.2022.018200] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/30/2021] [Indexed: 02/05/2023]
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Liao CM, Luo T, von der Ohe J, de Juan Mora B, Schmitt R, Hass R. Human MSC-Derived Exosomes Reduce Cellular Senescence in Renal Epithelial Cells. Int J Mol Sci 2021; 22:13562. [PMID: 34948355 PMCID: PMC8709122 DOI: 10.3390/ijms222413562] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/10/2021] [Accepted: 12/14/2021] [Indexed: 12/23/2022] Open
Abstract
Cellular senescence of renal tubular cells is associated with chronic diseases and age-related kidney disorders. Therapies to antagonize senescence are, therefore, explored as novel approaches in nephropathy. Exosomes derived from human mesenchymal stroma-/stem-like cells (MSC) entail the transfer of multiple bioactive molecules, exhibiting profound regenerative potential in various tissues, including therapeutic effects in kidney diseases. Here, we first demonstrate that exosomes promote proliferation and reduce senescence in aged MSC cultures. For potential therapeutic perspectives in organ rejuvenation, we used MSC-derived exosomes to antagonize senescence in murine kidney primary tubular epithelial cells (PTEC). Exosome treatment efficiently reduced senescence while diminishing the transcription of senescence markers and senescence-associated secretory phenotype (SASP) factors. Concomitantly, we observed less DNA damage foci and more proliferating cells. These data provide new information regarding the therapeutic property of MSC exosomes in the development of renal senescence, suggesting a contribution to a new chapter of regenerative vehicles in senotherapy.
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Affiliation(s)
- Chieh Ming Liao
- Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany; (C.M.L.); (B.d.J.M.); (R.S.)
| | - Tianjiao Luo
- Biochemistry and Tumor Biology Lab, Department of Gynecology and Obstetrics, Hannover Medical School, 30625 Hannover, Germany; (T.L.); (J.v.d.O.)
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Gynecology and Obstetrics, Hannover Medical School, 30625 Hannover, Germany; (T.L.); (J.v.d.O.)
| | - Blanca de Juan Mora
- Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany; (C.M.L.); (B.d.J.M.); (R.S.)
| | - Roland Schmitt
- Department of Nephrology and Hypertension, Hannover Medical School, 30625 Hannover, Germany; (C.M.L.); (B.d.J.M.); (R.S.)
| | - Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Gynecology and Obstetrics, Hannover Medical School, 30625 Hannover, Germany; (T.L.); (J.v.d.O.)
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Zhao LX, Zhang K, Shen BB, Li JN. Mesenchymal stem cell-derived exosomes for gastrointestinal cancer. World J Gastrointest Oncol 2021; 13:1981-1996. [PMID: 35070036 PMCID: PMC8713327 DOI: 10.4251/wjgo.v13.i12.1981] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/15/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) malignancies, a series of malignant conditions originating from the digestive system, include gastric cancer, hepatocellular carcinoma, pancreatic cancer, and colorectal cancer. GI cancers have been regarded as the leading cancer-related cause of death in recent years. Therefore, it is essential to develop effective treatment strategies for GI malignancies. Mesenchymal stem cells (MSCs), a type of distinct non-hematopoietic stem cells and an important component of the tumor microenvironment, play important roles in regulating GI cancer development and progression through multiple mechanisms, such as secreting cytokines and direct interactions. Currently, studies are focusing on the anti-cancer effect of MSCs on GI malignancies. However, the effects and functional mechanisms of MSC-derived exosomes on GI cancer are less studied. MSC-derived exosomes can regulate GI tumor growth, drug response, metastasis, and invasion through transplanting proteins and miRNA to tumor cells to activate the specific signal pathway. Besides, the MSC-derived exosomes are also seen as an important drug delivery system and have shown potential in anti-cancer treatment. This study aims to summarize the effect and biological functions of MSC-derived exosomes on the development of GI cancers and discuss their possible clinical applications for the treatment of GI malignancies.
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Affiliation(s)
- Lin-Xian Zhao
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Kai Zhang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Bing-Bing Shen
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Jian-Nan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
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Role and Function of T Cell-Derived Exosomes and Their Therapeutic Value. Mediators Inflamm 2021; 2021:8481013. [PMID: 34803518 PMCID: PMC8604589 DOI: 10.1155/2021/8481013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 12/20/2022] Open
Abstract
Exosomes are membrane-bound extracellular vesicles that are produced in the endosomal compartment of most eukaryotic cells. Containing proteins, RNA, and DNA, exosomes mediate intercellular communication between different cell types by transferring their contents and thus are involved in numerous physiological and pathological processes. T cells are an indispensable part of adaptive immunity, and the functions of T cell-derived exosomes have been widely studied. In the more than three decades since the discovery of exosomes, several studies have revealed that T cell-derived exosomes play a novel role in cell-to-cell signaling, especially in inflammatory responses, autoimmunity, and infectious diseases. In this review, we will summarize the function of T cell-derived exosomes and their therapeutic potential.
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Raudenska M, Balvan J, Masarik M. Crosstalk between autophagy inhibitors and endosome-related secretory pathways: a challenge for autophagy-based treatment of solid cancers. Mol Cancer 2021; 20:140. [PMID: 34706732 PMCID: PMC8549397 DOI: 10.1186/s12943-021-01423-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 09/11/2021] [Indexed: 01/18/2023] Open
Abstract
Autophagy is best known for its role in organelle and protein turnover, cell quality control, and metabolism. The autophagic machinery has, however, also adapted to enable protein trafficking and unconventional secretory pathways so that organelles (such as autophagosomes and multivesicular bodies) delivering cargo to lysosomes for degradation can change their mission from fusion with lysosomes to fusion with the plasma membrane, followed by secretion of the cargo from the cell. Some factors with key signalling functions do not enter the conventional secretory pathway but can be secreted in an autophagy-mediated manner.Positive clinical results of some autophagy inhibitors are encouraging. Nevertheless, it is becoming clear that autophagy inhibition, even within the same cancer type, can affect cancer progression differently. Even next-generation inhibitors of autophagy can have significant non-specific effects, such as impacts on endosome-related secretory pathways and secretion of extracellular vesicles (EVs). Many studies suggest that cancer cells release higher amounts of EVs compared to non-malignant cells, which makes the effect of autophagy inhibitors on EVs secretion highly important and attractive for anticancer therapy. In this review article, we discuss how different inhibitors of autophagy may influence the secretion of EVs and summarize the non-specific effects of autophagy inhibitors with a focus on endosome-related secretory pathways. Modulation of autophagy significantly impacts not only the quantity of EVs but also their content, which can have a deep impact on the resulting pro-tumourigenic or anticancer effect of autophagy inhibitors used in the antineoplastic treatment of solid cancers.
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Affiliation(s)
- Martina Raudenska
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic
- Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00, Brno, Czech Republic
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic
| | - Jan Balvan
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic
- Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00, Brno, Czech Republic
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic
| | - Michal Masarik
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic.
- Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00, Brno, Czech Republic.
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic.
- BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, CZ-252 50, Vestec, Czech Republic.
- Center for Advanced Functional Nanorobots, Department of Inorganic Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology in Prague, Technická 5, CZ-166 28, Prague, Czech Republic.
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Luo T, von der Ohe J, Hass R. MSC-Derived Extracellular Vesicles in Tumors and Therapy. Cancers (Basel) 2021; 13:5212. [PMID: 34680359 PMCID: PMC8533755 DOI: 10.3390/cancers13205212] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 10/15/2021] [Indexed: 12/24/2022] Open
Abstract
Exosomes derived from mesenchymal stroma-/stem-like cells (MSCs) as part of extracellular vesicles are considered cell-free biocompatible nanovesicles that promote repair activities of damaged tissues or organs by exhibiting low immunogenic and cytotoxic effects. Contributions to regenerative activities include wound healing, maintenance of stem cell niches, beneficial regenerative effects in various diseases, and reduction of senescence. However, the mode of action in MSC-derived exosomes strongly depends on the biological content like different regulatory microRNAs that are determined by the tissue origin of MSCs. In tumors, MSCs use indirect and direct pathways in a communication network to interact with cancer cells. This leads to mutual functional changes with the acquisition of an aberrant tumor-associated MSC phenotype accompanied by altered cargo in the exosomes. Consequently, MSC-derived exosomes either from normal tissue-originating MSCs or from aberrant tumor-associated MSCs can confer different actions on tumor development. These processes exhibiting tumor-inhibitory and tumor-supportive effects with a focus on exosome microRNA content will be discriminated and discussed within this review.
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Affiliation(s)
| | | | - Ralf Hass
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany; (T.L.); (J.v.d.O.)
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The Role of MSCs and Cell Fusion in Tissue Regeneration. Int J Mol Sci 2021; 22:ijms222010980. [PMID: 34681639 PMCID: PMC8535885 DOI: 10.3390/ijms222010980] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/04/2021] [Accepted: 10/05/2021] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is concerned with the investigation of therapeutic agents that can be used to promote the process of regeneration after injury or in different diseases. Mesenchymal stem/stromal cells (MSCs) and their secretome—including extracellular vesicles (EVs) are of great interest, due to their role in tissue regeneration, immunomodulatory capacity and low immunogenicity. So far, clinical studies are not very conclusive as they show conflicting efficacies regarding the use of MSCs. An additional process possibly involved in regeneration might be cell fusion. This process occurs in both a physiological and a pathophysiological context and can be affected by immune response due to inflammation. In this review the role of MSCs and cell fusion in tissue regeneration is discussed.
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Hass R, von der Ohe J, Dittmar T. Cancer Cell Fusion and Post-Hybrid Selection Process (PHSP). Cancers (Basel) 2021; 13:4636. [PMID: 34572863 PMCID: PMC8470238 DOI: 10.3390/cancers13184636] [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: 08/17/2021] [Revised: 09/10/2021] [Accepted: 09/10/2021] [Indexed: 12/17/2022] Open
Abstract
Fusion of cancer cells either with other cancer cells (homotypic fusion) in local vicinity of the tumor tissue or with other cell types (e.g., macrophages, cancer-associated fibroblasts (CAFs), mesenchymal stromal-/stem-like cells (MSC)) (heterotypic fusion) represents a rare event. Accordingly, the clinical relevance of cancer-cell fusion events appears questionable. However, enhanced tumor growth and/or development of certain metastases can originate from cancer-cell fusion. Formation of hybrid cells after cancer-cell fusion requires a post-hybrid selection process (PHSP) to cope with genomic instability of the parental nuclei and reorganize survival and metabolic functionality. The present review dissects mechanisms that contribute to a PHSP and resulting functional alterations of the cancer hybrids. Based upon new properties of cancer hybrid cells, the arising clinical consequences of the subsequent tumor heterogeneity after cancer-cell fusion represent a major therapeutic challenge. However, cellular partners during cancer-cell fusion such as MSC within the tumor microenvironment or MSC-derived exosomes may provide a suitable vehicle to specifically address and deliver anti-tumor cargo to cancer cells.
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Affiliation(s)
- Ralf Hass
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Thomas Dittmar
- Institute of Immunology, Center of Biomedical Education and Research (ZABF), Witten/Herdecke University, 58448 Witten, Germany
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Weng Z, Zhang B, Wu C, Yu F, Han B, Li B, Li L. Therapeutic roles of mesenchymal stem cell-derived extracellular vesicles in cancer. J Hematol Oncol 2021; 14:136. [PMID: 34479611 PMCID: PMC8414028 DOI: 10.1186/s13045-021-01141-y] [Citation(s) in RCA: 218] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/16/2021] [Indexed: 02/08/2023] Open
Abstract
Extracellular vesicles (EVs) are cell-derived membrane structures enclosing proteins, lipids, RNAs, metabolites, growth factors, and cytokines. EVs have emerged as essential intercellular communication regulators in multiple physiological and pathological processes. Previous studies revealed that mesenchymal stem cells (MSCs) could either support or suppress tumor progression in different cancers by paracrine signaling via MSC-derived EVs. Evidence suggested that MSC-derived EVs could mimic their parental cells, possessing pro-tumor and anti-tumor effects, and inherent tumor tropism. Therefore, MSC-derived EVs can be a cell-free cancer treatment alternative. This review discusses different insights regarding MSC-derived EVs' roles in cancer treatment and summarizes bioengineered MSC-derived EVs’ applications as safe and versatile anti-tumor agent delivery platforms. Meanwhile, current hurdles of moving MSC-derived EVs from bench to bedside are also discussed.
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Affiliation(s)
- Zhijie Weng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bowen Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Comfort Care Dental Center, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chenzhou Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Fanyuan Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bo Han
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Comfort Care Dental Center, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bo Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
| | - Longjiang Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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Storti G, Scioli MG, Kim BS, Terriaca S, Fiorelli E, Orlandi A, Cervelli V. Mesenchymal Stem Cells in Adipose Tissue and Extracellular Vesicles in Ovarian Cancer Patients: A Bridge toward Metastatic Diffusion or a New Therapeutic Opportunity? Cells 2021; 10:cells10082117. [PMID: 34440886 PMCID: PMC8392703 DOI: 10.3390/cells10082117] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/09/2021] [Accepted: 08/16/2021] [Indexed: 12/24/2022] Open
Abstract
Ovarian cancer is one of the deadliest malignancies among women. Approximately 75% of the patients with ovarian cancer are diagnosed with advanced disease that already has metastasis, particularly to the omentum. The omentum constitutes the ideal soil for ovarian cancer metastasis due to a complex intraperitoneal milieu that favors and supports the whole metastatic process. Adipose-derived stem/stromal cells (ADSCs) are part of this microenvironment and foster tumor progression via sustained paracrine secretion, including extracellular vesicles (EVs). Nonetheless, the preferential relationship between ADSCs, ADSC-derived EVs, and ovarian cancer cells could be exploited to use ADSCs and EVs as a vehicle for anti-cancer therapies. This review will analyze the strict relations between tumor progression, metastatic disease, and adipose tissue with its staminal components. In addition, we will describe the crosstalk and biologic relationship between ADSCs and tumor cells, the role of EVs in intercellular communication, the establishment of drug resistance, metastatic capacity, and ovarian cancer progression. We will analyze the new therapeutic opportunities in treating ovarian cancer offered by ADSCs and EVs as a vehicle for therapeutic molecules to target precisely tumor cells and limit the systemic adverse effects. Finally, we will discuss the limitations of these therapeutic approaches.
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Affiliation(s)
- Gabriele Storti
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, Tor Vergata University of Rome, 00133 Rome, Italy;
- Correspondence: ; Tel.: +39-06-23188514; Fax: +39-06-23188466
| | - Maria Giovanna Scioli
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, Tor Vergata University of Rome, 00133 Rome, Italy; (M.G.S.); (S.T.); (E.F.); (A.O.)
| | - Bong-Sung Kim
- Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, 8091 Zurich, Switzerland;
| | - Sonia Terriaca
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, Tor Vergata University of Rome, 00133 Rome, Italy; (M.G.S.); (S.T.); (E.F.); (A.O.)
| | - Elena Fiorelli
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, Tor Vergata University of Rome, 00133 Rome, Italy; (M.G.S.); (S.T.); (E.F.); (A.O.)
| | - Augusto Orlandi
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, Tor Vergata University of Rome, 00133 Rome, Italy; (M.G.S.); (S.T.); (E.F.); (A.O.)
| | - Valerio Cervelli
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, Tor Vergata University of Rome, 00133 Rome, Italy;
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Liu M, Yang Y, Zhao B, Yang Y, Wang J, Shen K, Yang X, Hu D, Zheng G, Han J. Exosomes Derived From Adipose-Derived Mesenchymal Stem Cells Ameliorate Radiation-Induced Brain Injury by Activating the SIRT1 Pathway. Front Cell Dev Biol 2021; 9:693782. [PMID: 34395427 PMCID: PMC8358610 DOI: 10.3389/fcell.2021.693782] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/12/2021] [Indexed: 12/11/2022] Open
Abstract
Objective Studies have shown that the therapeutic effects of mesenchymal stem cells (MSCs) are mediated in a paracrine manner, mainly through extracellular vesicles such as exosomes. Here, we designed a study to investigate whether exosomes derived from adipose-derived mesenchymal stem cells (ADMSC-Exos) had protective effects in a rat model of radiation-induced brain injury and in microglia. Methods Male adult Sprague-Dawley (SD) rats were randomly divided into three groups: the control group, the radiation group (30 Gy), and the radiation + exosomes group (30 Gy + 100 ug exosomes). Meanwhile, microglia were divided into four groups: the control group, the radiation group (10 Gy), the radiation + exosomes group (10 Gy + 4 ug exosomes), and radiation + exosomes + EX527 group (10 Gy + 4 ug exosomes + 100 nM EX527). Tissue samples and the levels of oxidative stress and inflammatory factors in each group were compared. Results Statistical analysis showed that after irradiation, ADMSC-Exos intervention in vivo significantly reduced the levels of caspase-3, malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), and promoted the recovery of superoxide dismutase (SOD), catalase (CAT), IL-4, and IL-10. Moreover, ADMSC-Exos intervention inhibited microglial infiltration and promoted the expression of SIRT1. Furthermore, the results in vitro showed that the above effects of ADMSC-Exos could be reversed by SIRT-1 inhibitor EX527. Conclusion This study demonstrated that ADMSC-Exos exerted protective effects against radiation-induced brain injury by reducing oxidative stress, inflammation and microglial infiltration via activating the SIRT1 pathway. ADMSC-Exos may serve as a promising therapeutic tool for radiation-induced brain injury.
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Affiliation(s)
- Mengdong Liu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Yunshu Yang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Bin Zhao
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Yuefan Yang
- Department of Biomedical Engineering, Air Force Military Medical University, Xi'an, China.,Department of Neurosurgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Jing Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Kuo Shen
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Xuekang Yang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Dahai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Guoxu Zheng
- State key laboratory of Cancer Biology, Department of Immunology, Air Force Military Medical University, Xi'an, China
| | - Juntao Han
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
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Liu T, Hooda J, Atkinson JM, Whiteside TL, Oesterreich S, Lee AV. Exosomes in Breast Cancer - Mechanisms of Action and Clinical Potential. Mol Cancer Res 2021; 19:935-945. [PMID: 33627501 PMCID: PMC8178200 DOI: 10.1158/1541-7786.mcr-20-0952] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 01/04/2021] [Accepted: 02/19/2021] [Indexed: 12/24/2022]
Abstract
Extracellular vesicles (EV) are a heterogeneous group of cell-derived membrane vesicles comprising apoptotic bodies, microvesicles, and small EVs also called as exosomes. Exosomes when initially identified were considered as a waste product but the advancement in research techniques have provided insight into the important roles of exosomes in cell-cell communication, various biological processes and diseases, including cancer. As an important component of EVs, exosomes contain various biomolecules such as miRNAs, lipids, and proteins that largely reflect the characteristics of their parent cells. Notably, cancer cells generate and secrete many more exosomes than normal cells. A growing body of evidence suggests that exosomes, as mediators of intercellular cross-talk, play a role in tumorigenesis, cancer cell invasion, angiogenesis, tumor microenvironment (TME) formation, and cancer metastasis. As we gain more insights into the association between exosomes and cancer, the potential of exosomes for clinical use is becoming more intriguing. This review is focused on the role of exosomes in breast cancer, in terms of breast cancer biology, mechanism of action, potential as biomarkers, and therapeutic opportunities.
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Affiliation(s)
- Tiantong Liu
- Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Womens Research Institute, Pittsburgh, Pennsylvania
- School of Medicine, Tsinghua University, Beijing, China
| | - Jagmohan Hooda
- Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Womens Research Institute, Pittsburgh, Pennsylvania
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jennifer M Atkinson
- Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Womens Research Institute, Pittsburgh, Pennsylvania
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Theresa L Whiteside
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Steffi Oesterreich
- Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Womens Research Institute, Pittsburgh, Pennsylvania
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Adrian V Lee
- Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Womens Research Institute, Pittsburgh, Pennsylvania.
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Li X, Liu Y, Zheng S, Zhang T, Wu J, Sun Y, Zhang J, Liu G. Role of exosomes in the immune microenvironment of ovarian cancer. Oncol Lett 2021; 21:377. [PMID: 33777201 PMCID: PMC7988709 DOI: 10.3892/ol.2021.12638] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 01/27/2021] [Indexed: 12/12/2022] Open
Abstract
Exosomes are excretory vesicles that can deliver a variety of bioactive cargo molecules to the extracellular environment. Accumulating evidence demonstrates exosome participation in intercellular communication, immune response, inflammatory response and they even play an essential role in affecting the tumor immune microenvironment. The role of exosomes in the immune microenvironment of ovarian cancer is mainly divided into suppression and stimulation. On one hand exosomes can stimulate the innate and adaptive immune systems by activating dendritic cells (DCs), natural killer cells and T cells, allowing these immune cells exert an antitumorigenic effect. On the other hand, ovarian cancer-derived exosomes initiate cross-talk with immunosuppressive effector cells, which subsequently cause immune evasion; one of the hallmarks of cancer. Exosomes induce the polarization of macrophages in M2 phenotype and induce apoptosis of lymphocytes and DCs. Exosomes further activate additional immunosuppressive effector cells (myeloid-derived suppressor cells and regulatory T cells) that induce fibroblasts to differentiate into cancer-associated fibroblasts. Exosomes also induce the tumorigenicity of mesenchymal stem cells to exert additional immune suppression. Furthermore, besides mediating the intercellular communication, exosomes carry microRNAs (miRNAs), proteins and lipids to the tumor microenvironment, which collectively promotes ovarian cancer cells to proliferate, invade and tumors to metastasize. Studying proteins, lipids and miRNAs carried by exosomes could potentially be used as an early diagnostic marker of ovarian cancer for designing treatment strategies.
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Affiliation(s)
- Xiao Li
- Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Yang Liu
- Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Shuangshuang Zheng
- Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Tianyu Zhang
- Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Jing Wu
- Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Yue Sun
- Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Jingzi Zhang
- Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Guoyan Liu
- Department of Gynecology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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Fang G, Lu H, Aboulkheyr Es H, Wang D, Liu Y, Warkiani ME, Lin G, Jin D. Unidirectional intercellular communication on a microfluidic chip. Biosens Bioelectron 2021; 175:112833. [PMID: 33288428 DOI: 10.1016/j.bios.2020.112833] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/29/2020] [Accepted: 11/17/2020] [Indexed: 12/15/2022]
Abstract
Cell co-culture serves as a standard method to study intercellular communication. However, random diffusion of signal molecules during co-culture may arouse crosstalk among different types of cells and hide directive signal-target responses. Here, a microfluidic chip is proposed to study unidirectional intercellular communication by spatially controlling the flow of the signal molecules. The chip contains two separated chambers connected by two channels where the culture media flows oppositely. A zigzag signal-blocking channel is designed to study the function of a specific signal. The chip is applied to study the unidirectional communication between tumor cells and stromal cells. It shows that the expression of α-smooth muscle actin (a marker of cancer-associated fibroblast (CAF)) of both MRC-5 fibroblasts and mesenchymal stem cells can be up-regulated only by the secreta from invasive MDA-MB-231 cells, but not from non-invasive MCF-7 cells. The proliferation of the tumor cells can be improved by the stromal cells. Moreover, transforming growth factor beta 1 is found as one of the main factors for CAF transformation via the signal-blocking function. The chip achieves unidirectional cell communication along X-axis, signal concentration gradient along Y-axis and 3D cell culture along Z-axis, which provides a useful tool for cell communication studies.
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Affiliation(s)
- Guocheng Fang
- Institute for Biomedical Materials and Devices, School of Mathematical and Physical Sciences, University of Technology Sydney, Broadway Ultimo, Sydney, NSW, 2007, Australia
| | - Hongxu Lu
- Institute for Biomedical Materials and Devices, School of Mathematical and Physical Sciences, University of Technology Sydney, Broadway Ultimo, Sydney, NSW, 2007, Australia.
| | - Hamidreza Aboulkheyr Es
- School of Biomedical Engineering, University of Technology Sydney, Broadway Ultimo, Sydney, NSW, 2007, Australia
| | - Dejiang Wang
- Institute for Biomedical Materials and Devices, School of Mathematical and Physical Sciences, University of Technology Sydney, Broadway Ultimo, Sydney, NSW, 2007, Australia
| | - Yuan Liu
- Institute for Biomedical Materials and Devices, School of Mathematical and Physical Sciences, University of Technology Sydney, Broadway Ultimo, Sydney, NSW, 2007, Australia
| | - Majid Ebrahimi Warkiani
- School of Biomedical Engineering, University of Technology Sydney, Broadway Ultimo, Sydney, NSW, 2007, Australia
| | - Gungun Lin
- Institute for Biomedical Materials and Devices, School of Mathematical and Physical Sciences, University of Technology Sydney, Broadway Ultimo, Sydney, NSW, 2007, Australia
| | - Dayong Jin
- Institute for Biomedical Materials and Devices, School of Mathematical and Physical Sciences, University of Technology Sydney, Broadway Ultimo, Sydney, NSW, 2007, Australia; UTS-SUSTech Joint Research Centre for Biomedical Materials & Devices, Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, China.
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Galgaro BC, Beckenkamp LR, van den M Nunnenkamp M, Korb VG, Naasani LIS, Roszek K, Wink MR. The adenosinergic pathway in mesenchymal stem cell fate and functions. Med Res Rev 2021; 41:2316-2349. [PMID: 33645857 DOI: 10.1002/med.21796] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/02/2021] [Accepted: 02/17/2021] [Indexed: 12/18/2022]
Abstract
Mesenchymal stem cells (MSCs) play an important role in tissue homeostasis and damage repair through their ability to differentiate into cells of different tissues, trophic support, and immunomodulation. These properties made them attractive for clinical applications in regenerative medicine, immune disorders, and cell transplantation. However, despite multiple preclinical and clinical studies demonstrating beneficial effects of MSCs, their native identity and mechanisms of action remain inconclusive. Since its discovery, the CD73/ecto-5'-nucleotidase is known as a classic marker for MSCs, but its role goes far beyond a phenotypic characterization antigen. CD73 contributes to adenosine production, therefore, is an essential component of purinergic signaling, a pathway composed of different nucleotides and nucleosides, which concentrations are finely regulated by the ectoenzymes and receptors. Thus, purinergic signaling controls pathophysiological functions such as proliferation, migration, cell fate, and immune responses. Despite the remarkable progress already achieved in considering adenosinergic pathway as a therapeutic target in different pathologies, its role is not fully explored in the context of the therapeutic functions of MSCs. Therefore, in this review, we provide an overview of the role of CD73 and adenosine-mediated signaling in the functions ascribed to MSCs, such as homing and proliferation, cell differentiation, and immunomodulation. Additionally, we will discuss the pathophysiological role of MSCs, via CD73 and adenosine, in different diseases, as well as in tumor development and progression. A better understanding of the adenosinergic pathway in the regulation of MSCs functions will help to provide improved therapeutic strategies applicable in regenerative medicine.
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Affiliation(s)
- Bruna C Galgaro
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Liziane R Beckenkamp
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Martha van den M Nunnenkamp
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Vitória G Korb
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Liliana I S Naasani
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Katarzyna Roszek
- Department of Biochemistry, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Toruń, Poland
| | - Márcia R Wink
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
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Liang L, Zhao L, Wang Y, Wang Y. Treatment for Hepatocellular Carcinoma Is Enhanced When Norcantharidin Is Encapsulated in Exosomes Derived from Bone Marrow Mesenchymal Stem Cells. Mol Pharm 2021; 18:1003-1013. [PMID: 33527831 DOI: 10.1021/acs.molpharmaceut.0c00976] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Mesenchymal stem cell-derived exosomes (MSC-Exos) have potential as drug-delivery vehicles and exhibit great promise for hepatocellular carcinoma (HCC) therapy. Here, we consider bone mesenchymal stem cell-derived exosomes (BMSC-Exos) as drug carriers to encase anticancer drug norcantharidin (NCTD) and explore their potential therapeutic effects against HCC. NCTD was loaded into purified exosomes from BMSCs via electroporation, and an in vitro drug release study showed that BMSC-Exos-NCTD provided a continuous and slow release of the drug. A series of in vitro and in vivo pharmacodynamic evaluations based on the HCC cell line HepG2 were conducted. The results showed that the BMSC-Exos-NCTD delivery system effectively promoted cellular uptake, induced cell cycle arrest, reduced tumor cell proliferation, increased apoptosis, and exerted obvious in vivo antitumor effects compared with the NCTD treatment alone, with BMSC-Exos-NCTD showing more significant antitumor effects. Furthermore, the in vivo detection results of the homing effect using the probe Cy5.5 showed that the BMSC-Exos carrier has an in situ homing effect on the tumor sites of HCC in mice. Moreover, BMSC-Exos-NCTD did not show body toxicity. Excitedly, BMSC-Exos-NCTD repaired damaged liver tissues in liver sections; specifically, the experimental effectiveness of the exosomes on the normal liver cell line L02 indicated that the damaged liver cells were repaired by the exosomes, as reflected by the increase in cellular proliferation and the inhibition of liver cell oxidation. Our results suggest that BMSC-Exos, as drug carriers with specific functions, have great potential in the HCC treatment in combination with anticancer drugs.
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Affiliation(s)
- Leyi Liang
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Ling Zhao
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Ying Wang
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Wang
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China
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49
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Cohen O, Betzer O, Elmaliach-Pnini N, Motiei M, Sadan T, Cohen-Berkman M, Dagan O, Popovtzer A, Yosepovich A, Barhom H, Michaeli S, Popovtzer R. 'Golden' exosomes as delivery vehicles to target tumors and overcome intratumoral barriers: in vivo tracking in a model for head and neck cancer. Biomater Sci 2021; 9:2103-2114. [PMID: 33475633 DOI: 10.1039/d0bm01735c] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Exosomes are promising vectors for anti-tumor therapy, due to their biocompatibility, low immunogenicity, and innate ability to interact with target cells. However, promoting clinical application of exosome-based therapeutics requires elucidation of key issues, including exosome biodistribution, tumor targeting and accumulation, and the ability to overcome tumor barriers that limit the penetration of various nano-carriers and drugs. Here, we examined these parameters in exosomes derived from mesenchymal stem cells (MSC-exo) and from the A431 squamous cell carcinoma line (A431-exo), which both have potential use in cancer therapy. Using our novel technique combining gold nanoparticle (GNP) labeling of exosomes and non-invasive computed tomography imaging (CT), we longitudinally and quantitatively tracked the two intravenously-injected exosome types in A431 tumor-bearing mice. CT imaging up to 48 h and subsequent ex vivo analysis revealed tumor homing abilities of both exosome types, yet there was significantly higher tumor accumulation of MSC-exo as compared to A431-exo. Moreover, MSC-exo demonstrated the ability to penetrate the tumor and distribute throughout its bulk, while non-encapsulated GNPs remained concentrated at the tumor periphery. Histological analysis showed penetration of MSC-exo not only into the tumor tissue, but also into tumor cell cytoplasm. While the proportion of biodistribution between organs at 48 h was similar for both exosome types, more rapid clearance was indicated for A431-exo. Thus, our findings demonstrate an effect of exosome type on tumor targeting abilities and biodistribution, and suggest that MSC-exo may have superior abilities for tumor-targeted therapy.
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Affiliation(s)
- Oded Cohen
- Department of Otolaryngology, Head and Neck Surgery, Kaplan Medical Center, Rehovot, Israel, affiliated to the Hebrew University, Jerusalem, Israel
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50
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Hass R, von der Ohe J, Ungefroren H. Impact of the Tumor Microenvironment on Tumor Heterogeneity and Consequences for Cancer Cell Plasticity and Stemness. Cancers (Basel) 2020; 12:3716. [PMID: 33322354 PMCID: PMC7764513 DOI: 10.3390/cancers12123716] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/08/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022] Open
Abstract
Tumor heterogeneity is considered the major cause of treatment failure in current cancer therapies. This feature of solid tumors is not only the result of clonal outgrowth of cells with genetic mutations, but also of epigenetic alterations induced by physical and chemical signals from the tumor microenvironment (TME). Besides fibroblasts, endothelial and immune cells, mesenchymal stroma/stem-like cells (MSCs) and tumor-associated macrophages (TAMs) intimately crosstalk with cancer cells and can exhibit both anti- and pro-tumorigenic effects. MSCs can alter cancer cellular phenotypes to increase cancer cell plasticity, eventually resulting in the generation of cancer stem cells (CSCs). The shift between different phenotypic states (phenotype switching) of CSCs is controlled via both genetic programs, such as epithelial-mesenchymal transdifferentiation or retrodifferentiation, and epigenetic alterations triggered by signals from the TME, like hypoxia, spatial heterogeneity or stromal cell-derived chemokines. Finally, we highlight the role of spontaneous cancer cell fusion with various types of stromal cells. i.e., MSCs in shaping CSC plasticity. A better understanding of cell plasticity and phenotype shifting in CSCs is a prerequisite for exploiting this phenomenon to reduce tumor heterogeneity, thereby improving the chance for therapy success.
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Affiliation(s)
- Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Hendrik Ungefroren
- First Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Germany;
- Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
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