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Xu C, Xu X, Huang Y, Shang S, Ma L. RNA methylation: A new promising biomaker in cancer liquid biopsy. Biochim Biophys Acta Rev Cancer 2025; 1880:189337. [PMID: 40315965 DOI: 10.1016/j.bbcan.2025.189337] [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: 01/24/2025] [Revised: 04/24/2025] [Accepted: 04/25/2025] [Indexed: 05/04/2025]
Abstract
RNA methylation is a vital epigenetic modification that regulates gene expression by influencing RNA processes such as transcription, degradation, translation, and transport. Aberrant methylation, including modifications like m6A, m5C, m1A, m7G, and m3C, is closely linked to tumorigenesis and progression. Liquid biopsy, a non-invasive technique analyzing tumor markers in body fluids, offers significant potential for early diagnosis and dynamic monitoring. In this context, RNA methylation, due to its tumor-specific properties, is emerging as a valuable marker. However, significant challenges remain in its clinical application. This review explores the roles of RNA methylation in cancer, recent advances in detection technologies, and its potential as a liquid biopsy marker in tumor management. It highlights its promising applications in cancer diagnosis, prognosis, and personalized treatment in the era of precision oncology.
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Affiliation(s)
- Chenxin Xu
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xin Xu
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Yiwen Huang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Shuang Shang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Lifang Ma
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
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Tiszbein K, Koss-Mikołajczyk I, Martysiak-Żurowska D. Unlocking the Secrets of Human Milk: Isolation and Characterization of Extracellular Vesicles. Adv Nutr 2025; 16:100430. [PMID: 40288493 DOI: 10.1016/j.advnut.2025.100430] [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: 01/27/2025] [Revised: 04/11/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025] Open
Abstract
Extracellular vesicles from human milk (HMEVs) are crucial for neonatal development, immune modulation, and protection against pathogens. However, the lack of standardized isolation and characterization protocols poses significant challenges. This review aims to evaluate and compare various methods for the isolation and characterization of HMEVs, highlighting their effectiveness and potential applications. Preliminary purification steps, including the removal of cells, fat globules, and casein micelles, enhance the purity of isolated HMEVs. We categorized isolation methods into density-based, size-based, and affinity-based techniques. Density-based methods include differential and density gradient ultracentrifugation. Size-based methods encompass polymer precipitation, membrane filtration, electrophoretic filtration, size exclusion chromatography, and microfluidics. Affinity-based methods involve immunoisolation using antibodies specific to HMEV surface proteins. Characterization techniques discussed include flow cytometry, dynamic light scattering, nanoparticle tracking analysis, tunable resistive pulse sensing, electron microscopy, atomic force microscopy, confocal microscopy, western blotting, ELISA, and lateral flow immunoassay systems. Differential ultracentrifugation, considered the "gold standard," provides high purity but is time-consuming. Density gradient ultracentrifugation offers precise separation. Size-based methods like polyethylene glycol precipitation and membrane filtration are simple and fast. Electrophoretic filtration and microfluidics provide precise control of sample flow. Affinity-based methods are highly specific but costly. Advanced characterization techniques provide comprehensive insights into HMEV properties and functions. Standardizing isolation protocols and employing advanced characterization techniques are essential for advancing HMEV research. Future studies should focus on understanding the molecular mechanisms of HMEVs, exploring the impact of maternal health, and developing targeted delivery technologies. These efforts will enhance the therapeutic potential of HMEVs in neonatal care and contribute to personalized nutritional interventions.
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Rawat S, Arora S, Dhondale MR, Khadilkar M, Kumar S, Agrawal AK. Stability Dynamics of Plant-Based Extracellular Vesicles Drug Delivery. J Xenobiot 2025; 15:55. [PMID: 40278160 PMCID: PMC12028407 DOI: 10.3390/jox15020055] [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: 01/11/2025] [Revised: 03/25/2025] [Accepted: 04/07/2025] [Indexed: 04/26/2025] Open
Abstract
Plant-based extracellular vesicles (PBEVs) have been recognized for their wide range of applications in drug delivery however, the extent of their medicinal applicability depends on how well they are preserved and stored. Assessing their physicochemical properties, such as size, particle concentration, shape, and the activity of their cargo, forms the foundation for determining their stability during storage. Moreover, the evaluation of PBEVs is essential to ensure both safety and efficacy, which are critical for advancing their clinical development. Maintaining the biological activity of EVs during storage is a challenging task, similar to the preservation of cells and other cell-derived products like proteins. However, despite limited studies, it is expected that storing drug-loaded EVs may present fewer challenges compared to cell-based therapies, although some limitations are inevitable. This article provides a comprehensive overview of current knowledge on PBEVs preservation and storage methods, particularly focusing on their role as drug carriers. PBEVs hold promise as potential candidates for oral drug administration due to their effective intestinal absorption and ability to withstand both basic and acidic environments. However, maintaining their preservation and stability during storage is critical. Moreover, this review centers on the isolation, characterization, and storage of PBEVs, exploring the potential advantages they offer. Furthermore, it highlights key areas that require further research to overcome existing challenges and enhance the development of effective preservation and storage methods for therapeutic EVs.
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Affiliation(s)
- Satyavati Rawat
- Department of Botany, Kurukshetra University, Kurukshetra 136119, Haryana, India;
| | - Sanchit Arora
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India; (S.A.); (M.R.D.); (M.K.)
| | - Madhukiran R. Dhondale
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India; (S.A.); (M.R.D.); (M.K.)
| | - Mansi Khadilkar
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India; (S.A.); (M.R.D.); (M.K.)
| | - Sanjeev Kumar
- Department of Dravyaguna, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India;
| | - Ashish Kumar Agrawal
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India; (S.A.); (M.R.D.); (M.K.)
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Yin H, Zhang M, Zhang Y, Zhang X, Zhang X, Zhang B. Liquid biopsies in cancer. MOLECULAR BIOMEDICINE 2025; 6:18. [PMID: 40108089 PMCID: PMC11923355 DOI: 10.1186/s43556-025-00257-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 02/14/2025] [Accepted: 02/23/2025] [Indexed: 03/22/2025] Open
Abstract
Cancer ranks among the most lethal diseases worldwide. Tissue biopsy is currently the primary method for the diagnosis and biological analysis of various solid tumors. However, this method has some disadvantages related to insufficient tissue specimen collection and intratumoral heterogeneity. Liquid biopsy is a noninvasive approach for identifying cancer-related biomarkers in peripheral blood, which allows for repetitive sampling across multiple time points. In the field of liquid biopsy, representative biomarkers include circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosomes. Many studies have evaluated the prognostic and predictive roles of CTCs and ctDNA in various solid tumors. Although these studies have limitations, the results of most studies appear to consistently demonstrate the correlations of high CTC counts and ctDNA mutations with lower survival rates in cancer patients. Similarly, a reduction in CTC counts throughout therapy may be a potential prognostic indicator related to treatment response in advanced cancer patients. Moreover, the biochemical characteristics of CTCs and ctDNA can provide information about tumor biology as well as resistance mechanisms against targeted therapy. This review discusses the current clinical applications of liquid biopsy in cancer patients, emphasizing its possible utility in outcome prediction and treatment decision-making.
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Affiliation(s)
- Hang Yin
- The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Manjie Zhang
- The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Yu Zhang
- Dalian Medical University, Dalian, 116000, China
| | - Xuebing Zhang
- The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Xia Zhang
- Dalian Fifth People's Hospital, Dalian, 116000, China.
| | - Bin Zhang
- The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China.
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Peng Z, Liu Y, Ma H, Xiao S, Au-Yeung A, Zhang L, Zeng Q, Guo Y. Characterization of extracellular vesicles released from Prochlorococcus MED4 at the steady state and under a light-dark cycle. Philos Trans R Soc Lond B Biol Sci 2025; 380:20230339. [PMID: 39842488 PMCID: PMC11753881 DOI: 10.1098/rstb.2023.0339] [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: 09/26/2023] [Revised: 04/20/2024] [Accepted: 05/28/2024] [Indexed: 01/24/2025] Open
Abstract
Bacterial extracellular vesicles (EVs) are vesicles secreted by bacteria into the extracellular environment. Containing DNA, RNA and proteins, EVs are implicated to mediate intercellular communications. The marine cyanobacterium Prochlorococcus, the most abundant photosynthetic organism in marine ecosystems, has been shown to generate EVs continuously during cell growth. However, biogenesis and functions of EVs released by Prochlorococcus remain largely unclear. Here, we isolated and characterized EVs released by Prochlorococcus MED4 culture. We found that the majority of MED4 EVs are elliptical and enriched with specific proteins performing particular cellular functions. The light-dark cycle has been demonstrated to affect the cell cycle of Prochlorococcus, with cell division occurring at night time. Interestingly, we found that the net production of MED4 EVs was faster during the night time. Moreover, we revealed that MED4 EVs that are released or absorbed in the night time are enriched with distinct proteins, suggesting the release and absorbance of EVs are influenced by the diel cycle. We found that inhibiting cell division decreased the net production of MED4 EVs during the night time, suggesting that cell division is important for the biogenesis of MED4 EVs. These analyses provide novel insights into biogenesis and functions of EVs released from bacteria.This article is part of the Theo Murphy meeting issue 'Circadian rhythms in infection and immunity'.
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Affiliation(s)
- Ziqing Peng
- Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Yaxin Liu
- Department of Ocean Science, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Haiying Ma
- Department of Biomedical Sciences, and Tung Biomedical Sciences Center, City University of Hong Kong, Hong Kong, China
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China
| | - Shiwei Xiao
- Department of Ocean Science, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Allan Au-Yeung
- Department of Biomedical Sciences, and Tung Biomedical Sciences Center, City University of Hong Kong, Hong Kong, China
| | - Liang Zhang
- Department of Biomedical Sciences, and Tung Biomedical Sciences Center, City University of Hong Kong, Hong Kong, China
- Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, 518057, China
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Futian Research Institute, Shenzhen, China
| | - Qinglu Zeng
- Department of Ocean Science, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Yusong Guo
- Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China
- Hong Kong University of Science and Technology Shenzhen Research Institute, Shenzhen, China
- Thrust of Bioscience and Biomedical Engineering, Hong Kong University of Science and Technology, Guangzhou, China
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Mensah GA, Williams A, Khatkar P, Kim Y, Erickson J, Duverger A, Branscome H, Patil K, Chaudhry H, Wu Y, Kutsch O, Kashanchi F. Effect of Kinases in Extracellular Vesicles from HIV-1-Infected Cells on Bystander Cells. Cells 2025; 14:119. [PMID: 39851547 PMCID: PMC11763833 DOI: 10.3390/cells14020119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 01/06/2025] [Accepted: 01/10/2025] [Indexed: 01/26/2025] Open
Abstract
As of 2023, there were 39.9 million people living with Human Immunodeficiency Virus type 1 (HIV-1). Although great strides have been made in treatment options for HIV-1, and our understanding of the HIV-1 life cycle has vastly improved since the start of this global health crisis, a functional cure remains elusive. One of the main barriers to a cure is latency, which allows the virus to persist despite combined antiretroviral therapy (cART). Recently, we have found that exosomes, which are small, membrane-enclosed particles released by virtually all cell types and known to mediate intercellular communication, caused an increase in RNA Polymerase II loading onto the HIV-1 promoter. This resulted in the production of both short- and long-length viral transcripts in infected cells under cART. This current study examines the effects of exosome-associated kinases on bystander cells. The phospho-kinase profiling of exosomes revealed differences in the kinase payload of exosomes derived from uninfected and HIV-1-infected cells, with CDK10, GSK3β, and MAPK8 having the largest concentration differences. These kinases were shown to be biologically active and capable of phosphorylating substrates, and they modulated changes in the cell cycle dynamics of exposed cells. Given the relevance of such effects for the immune response, our results implicate exosome-associated kinases as new possible key contributors to HIV-1 pathogenesis that affect bystander cells. These findings may guide new therapeutic avenues to improve the current antiretroviral treatment regimens.
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Affiliation(s)
- Gifty A. Mensah
- Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA; (G.A.M.); (A.W.); (P.K.); (Y.K.); (J.E.); (H.B.); (K.P.); (H.C.)
| | - Anastasia Williams
- Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA; (G.A.M.); (A.W.); (P.K.); (Y.K.); (J.E.); (H.B.); (K.P.); (H.C.)
| | - Pooja Khatkar
- Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA; (G.A.M.); (A.W.); (P.K.); (Y.K.); (J.E.); (H.B.); (K.P.); (H.C.)
| | - Yuriy Kim
- Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA; (G.A.M.); (A.W.); (P.K.); (Y.K.); (J.E.); (H.B.); (K.P.); (H.C.)
| | - James Erickson
- Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA; (G.A.M.); (A.W.); (P.K.); (Y.K.); (J.E.); (H.B.); (K.P.); (H.C.)
| | - Alexandra Duverger
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (A.D.); (O.K.)
| | - Heather Branscome
- Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA; (G.A.M.); (A.W.); (P.K.); (Y.K.); (J.E.); (H.B.); (K.P.); (H.C.)
| | - Kajal Patil
- Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA; (G.A.M.); (A.W.); (P.K.); (Y.K.); (J.E.); (H.B.); (K.P.); (H.C.)
| | - Hafsa Chaudhry
- Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA; (G.A.M.); (A.W.); (P.K.); (Y.K.); (J.E.); (H.B.); (K.P.); (H.C.)
| | - Yuntao Wu
- National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA;
| | - Olaf Kutsch
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (A.D.); (O.K.)
| | - Fatah Kashanchi
- Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA; (G.A.M.); (A.W.); (P.K.); (Y.K.); (J.E.); (H.B.); (K.P.); (H.C.)
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Huang C, Li J, Xie Z, Hu X, Huang Y. Relationship between exosomes and cancer: formation, diagnosis, and treatment. Int J Biol Sci 2025; 21:40-62. [PMID: 39744442 PMCID: PMC11667803 DOI: 10.7150/ijbs.95763] [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: 02/27/2024] [Accepted: 11/02/2024] [Indexed: 01/11/2025] Open
Abstract
Exosomes are a member of extracellular vesicles. However, their biological characteristics differ from those of other vesicles, and recently, their powerful functions as information molecules, biomarkers, and carriers have been demonstrated. Malignancies are the leading cause of high morbidity and mortality worldwide. The cure rate of malignancies can be improved by improving early screening rates and therapy. Moreover, a close correlation between exosomes and malignancies has been observed. An in-depth study of exosomes can provide new methods for diagnosing and treating tumors. Therefore, this study aimed to review, sort, and summarize such achievements, and present ideas and opinions on the application of exosomes in tumor treatment.
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Affiliation(s)
- Chen Huang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jiajin Li
- Sichuan university, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Zichuan Xie
- Sichuan university, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Xiangjun Hu
- Sichuan university, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Yan Huang
- Health Management Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
- State Key Laboratory of Respiratory Health and Multimorbidity, China
- Research Laboratory for Prediction and Evaluation of Chronic Diseases in the Elderly, National Clinical Research Center for Geriatric Diseases, China
- General Practice Research Institute, West China Hospital, Sichuan University, Chengdu, China
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Blancas-Zugarazo SS, Langley E, Hidalgo-Miranda A. Exosomal lncRNAs as regulators of breast cancer chemoresistance and metastasis and their potential use as biomarkers. Front Oncol 2024; 14:1419808. [PMID: 39148900 PMCID: PMC11324554 DOI: 10.3389/fonc.2024.1419808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 07/16/2024] [Indexed: 08/17/2024] Open
Abstract
Breast cancer is the most common cancer in women and the leading cause of female deaths by cancer in the world worldwide. Hence, understanding the molecular mechanisms associated with breast cancer development and progression, including drug resistance and breast cancer metastasis, is essential for achieving the best management of breast cancer patients. Cancer-related long noncoding RNAs have been shown to be involved in the regulation of each stage of breast cancer progression. Additionally, exosomes are extracellular microvesicles that are central to intercellular communication and play an important role in tumorigenesis. Exosomes can be released from primary tumor cells into the bloodstream and transmit cellular signals to distant body sites. In this work, we review the findings regarding the cellular mechanisms regulated by exosomal lncRNAs that are essentials to chemoresistance development and metastasis of breast cancer. Likewise, we evaluate the outcomes of the potential clinical use of exosomal lncRNAs as breast cancer biomarkers to achieve personalized management of the patients. This finding highlights the importance of transcriptomic analysis of exosomal lncRNAs to understand the breast cancer tumorigenesis as well as to improve the clinical tests available for this disease.
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Affiliation(s)
- Sugela Susana Blancas-Zugarazo
- Cátedras CONAHCYT (Consejo Nacional de Humanidades Ciencia y Tecnología) - Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Elizabeth Langley
- Laboratorio de Cáncer Hormono Regulado, Instituto Nacional de Cancerología (INCAN), Mexico City, Mexico
| | - Alfredo Hidalgo-Miranda
- Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
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Lenart M, Siemińska I, Szatanek R, Mordel A, Szczepanik A, Rubinkiewicz M, Siedlar M, Baj-Krzyworzeka M. Identification of miRNAs Present in Cell- and Plasma-Derived Extracellular Vesicles-Possible Biomarkers of Colorectal Cancer. Cancers (Basel) 2024; 16:2464. [PMID: 39001526 PMCID: PMC11240749 DOI: 10.3390/cancers16132464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 06/29/2024] [Accepted: 07/04/2024] [Indexed: 07/16/2024] Open
Abstract
Globally, an increasing prevalence of colorectal cancer (CRC) prompts a need for the development of new methods for early tumor detection. MicroRNAs (also referred to as miRNAs) are short non-coding RNA molecules that play a pivotal role in the regulation of gene expression. MiRNAs are effectively transferred to extracellular vesicle (EVs) membrane sacs commonly released by cells. Our study aimed to examine the expression of miRNAs in four CRC cell lines and EVs derived from them (tumor EVs) in comparison to the normal colon epithelium cell line and its EVs. EVs were isolated by ultracentrifugation from the culture supernatant of SW480, SW620, SW1116, HCT116 and normal CCD841CoN cell lines and characterized according to the MISEV2023 guidelines. MiRNAs were analyzed by small RNA sequencing and validated by quantitative PCR. The performed analysis revealed 22 common miRNAs highly expressed in CRC cell lines and effectively transferred to tumor EVs, including miR-9-5p, miR-182-5p, miR-196b-5p, miR-200b-5p, miR-200c-3p, miR-425-5p and miR-429, which are associated with development, proliferation, invasion and migration of colorectal cancer cells, as well as in vesicle maturation and transport-associated pathways. In parallel, normal cells expressed miRNAs, such as miR-369 and miR-143, which play a role in proinflammatory response and tumor suppression. The analysis of selected miRNAs in plasma-derived EVs and tumor samples from CRC patients showed the similarity of miRNA expression profile between the patients' samples and CRC cell lines. Moreover, miR-182-5p, miR-196-5p, miR-425-5p and miR-429 were detected in several EV samples isolated from patients' plasma. Our results suggest that miR-182-5p, miR-196b-5p and miR-429 are differentially expressed between EVs from CRC patients and healthy donors, which might have clinical implications.
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Affiliation(s)
- Marzena Lenart
- Department of Clinical Immunology, Medical College, Jagiellonian University, 30-663 Krakow, Poland
| | - Izabela Siemińska
- Department of Clinical Immunology, Medical College, Jagiellonian University, 30-663 Krakow, Poland
- Institute of Veterinary Sciences, University Center of Veterinary Medicine JU-AU, University of Agriculture in Krakow, 30-059 Krakow, Poland
| | - Rafał Szatanek
- Department of Clinical Immunology, Medical College, Jagiellonian University, 30-663 Krakow, Poland
| | - Anna Mordel
- Department of Clinical Immunology, University Children's Hospital of Cracow, 30-663 Krakow, Poland
| | - Antoni Szczepanik
- Third Department of Surgery, Faculty of Medicine, Jagiellonian University Medical College, 31-202 Krakow, Poland
| | - Mateusz Rubinkiewicz
- Second Department of Surgery, Jagiellonian University Medical College, 30-688 Krakow, Poland
| | - Maciej Siedlar
- Department of Clinical Immunology, Medical College, Jagiellonian University, 30-663 Krakow, Poland
| | - Monika Baj-Krzyworzeka
- Department of Clinical Immunology, Medical College, Jagiellonian University, 30-663 Krakow, Poland
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10
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Almeida PP, Moraes JA, Barja-Fidalgo TC, Renovato-Martins M. Extracellular vesicles as modulators of monocyte and macrophage function in tumors. AN ACAD BRAS CIENC 2024; 96:e20231212. [PMID: 38922279 DOI: 10.1590/0001-3765202420231212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 02/17/2024] [Indexed: 06/27/2024] Open
Abstract
The tumor microenvironment (TME) harbors several cell types, such as tumor cells, immune cells, and non-immune cells. These cells communicate through several mechanisms, such as cell-cell contact, cytokines, chemokines, and extracellular vesicles (EVs). Tumor-derived vesicles are known to have the ability to modulate the immune response. Monocytes are a subset of circulating innate immune cells and play a crucial role in immune surveillance, being recruited to tissues where they differentiate into macrophages. In the context of tumors, it has been observed that tumor cells can attract monocytes to the TME and induce their differentiation into tumor-associated macrophages with a pro-tumor phenotype. Tumor-derived EVs have emerged as essential structures mediating this process. Through the transfer of specific molecules and signaling factors, tumor-derived EVs can shape the phenotype and function of monocytes, inducing the expression of cytokines and molecules by these cells, thus modulating the TME towards an immunosuppressive environment.
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Affiliation(s)
- Palloma P Almeida
- Universidade Federal Fluminense, Departamento de Biologia Celular e Molecular, Instituto de Biologia, Laboratório de Inflamação e Metabolismo, Rua Professor Marcos Waldemar de Freitas Reis, s/n, 24020-140 Niterói, RJ, Brazil
- Universidade Federal do Rio de Janeiro, Instituto de Ciências Biomédicas, Laboratório de Biologia Redox, Av. Carlos Chagas Filho, 373, Prédio do ICB - Anexo B1F3, Ilha do Fundão, 21941-902 Rio de Janeiro, RJ, Brazil
- Universidade do Estado do Rio de Janeiro, Departamento de Biologia Celular, Instituto de Biologia Roberto Alcantara Gomes - IBRAG, Laboratório de Farmacologia Celular e Molecular, Av. 28 de setembro, 87, 20551-030 Rio de Janeiro, RJ, Brazil
| | - João Alfredo Moraes
- Universidade Federal do Rio de Janeiro, Instituto de Ciências Biomédicas, Laboratório de Biologia Redox, Av. Carlos Chagas Filho, 373, Prédio do ICB - Anexo B1F3, Ilha do Fundão, 21941-902 Rio de Janeiro, RJ, Brazil
| | - Thereza Christina Barja-Fidalgo
- Universidade do Estado do Rio de Janeiro, Departamento de Biologia Celular, Instituto de Biologia Roberto Alcantara Gomes - IBRAG, Laboratório de Farmacologia Celular e Molecular, Av. 28 de setembro, 87, 20551-030 Rio de Janeiro, RJ, Brazil
| | - Mariana Renovato-Martins
- Universidade Federal Fluminense, Departamento de Biologia Celular e Molecular, Instituto de Biologia, Laboratório de Inflamação e Metabolismo, Rua Professor Marcos Waldemar de Freitas Reis, s/n, 24020-140 Niterói, RJ, Brazil
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Di Niro L, Linders AC, Glynn T, Pegtel DM, Siderius M, Crudden C, Smit MJ. G protein-coupled receptors: a gateway to targeting oncogenic EVs? EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2024; 5:233-248. [PMID: 39698539 PMCID: PMC11648488 DOI: 10.20517/evcna.2024.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/29/2024] [Accepted: 05/14/2024] [Indexed: 12/20/2024]
Abstract
Dysregulated intercellular communication is a key feature driving cancer progression. Recently, extracellular vesicles (EVs) have added a new channel to this dense communication network. Despite solid evidence that EVs are central mediators of dysregulated signaling in onco-pathological settings, this has yet to be translated into clinically actionable strategies. The heterogeneity of EV cargo molecules, plasticity of biogenesis routes, and large overlap with their role in physiological communication, complicate a potential targeting strategy. However, recent work has linked EV biology to perhaps the "most druggable" proteins - G protein-coupled receptors (GPCRs). GPCR targeting accounts for ~60% of drugs in development and more than a third of all currently approved drugs, spanning almost all areas of medicine. Although several GPCRs have been linked to cancer initiation and progression, relatively few agents have made it into oncological regimes, suggesting that their potential is underexploited. Herein, we examine the molecular mechanisms linking GPCRs to EV communication in cancer settings. We propose that GPCRs hold potential in the search for EV-targeting in oncology.
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Affiliation(s)
- Lotte Di Niro
- Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam, Amsterdam 1081 HV, The Netherlands
| | - Amber C. Linders
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam 1081 HV, The Netherlands
| | - Thomas Glynn
- Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam, Amsterdam 1081 HV, The Netherlands
| | - D. Michiel Pegtel
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam 1081 HV, The Netherlands
| | - Marco Siderius
- Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam, Amsterdam 1081 HV, The Netherlands
| | - Caitrin Crudden
- Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam, Amsterdam 1081 HV, The Netherlands
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam 1081 HV, The Netherlands
| | - Martine J. Smit
- Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam, Amsterdam 1081 HV, The Netherlands
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12
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De Sota RE, Quake SR, Sninsky JJ, Toden S. Decoding bioactive signals of the RNA secretome: the cell-free messenger RNA catalogue. Expert Rev Mol Med 2024; 26:e12. [PMID: 38682644 PMCID: PMC11140549 DOI: 10.1017/erm.2024.12] [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: 08/08/2023] [Revised: 01/18/2024] [Accepted: 03/18/2024] [Indexed: 05/01/2024]
Abstract
Despite gene-expression profiling being one of the most common methods to evaluate molecular dysregulation in tissues, the utilization of cell-free messenger RNA (cf-mRNA) as a blood-based non-invasive biomarker analyte has been limited compared to other RNA classes. Recent advancements in low-input RNA-sequencing and normalization techniques, however, have enabled characterization as well as accurate quantification of cf-mRNAs allowing direct pathological insights. The molecular profile of the cell-free transcriptome in multiple diseases has subsequently been characterized including, prenatal diseases, neurological disorders, liver diseases and cancers suggesting this biological compartment may serve as a disease agnostic platform. With mRNAs packaged in a myriad of extracellular vesicles and particles, these signals may be used to develop clinically actionable, non-invasive disease biomarkers. Here, we summarize the recent scientific developments of extracellular mRNA, biology of extracellular mRNA carriers, clinical utility of cf-mRNA as disease biomarkers, as well as proposed functions in cell and tissue pathophysiology.
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Affiliation(s)
- Rhys E. De Sota
- Superfluid Dx., 259 E Grand Avenue, South San Francisco, CA 94080, USA
| | - Stephen R. Quake
- Department of Bioengineering and Department of Applied Physics, Stanford University, Stanford, CA, USA
- Chan Zuckerberg Biohub, San Francisco, CA, USA
| | - John J. Sninsky
- Superfluid Dx., 259 E Grand Avenue, South San Francisco, CA 94080, USA
| | - Shusuke Toden
- Superfluid Dx., 259 E Grand Avenue, South San Francisco, CA 94080, USA
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13
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Dellar ER, Hill C, Carter DRF, Baena‐Lopez LA. Oxidative stress-induced changes in the transcriptomic profile of extracellular vesicles. JOURNAL OF EXTRACELLULAR BIOLOGY 2024; 3:e150. [PMID: 38938847 PMCID: PMC11080704 DOI: 10.1002/jex2.150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 03/04/2024] [Accepted: 04/04/2024] [Indexed: 06/29/2024]
Abstract
Extracellular vesicles (EVs) have been proposed to play dual roles in cellular homeostasis, functioning both to remove unwanted intracellular molecules, and to enable communication between cells as a means of modulating cellular responses in different physiological and pathological scenarios. EVs contain a broad range of cargoes, including multiple biotypes of RNA, which can vary depending on the cell status, and may function as signalling molecules. In this study, we carried out comparative transcriptomic analysis of Drosophila EVs and cells, demonstrating that the RNA profile of EVs is distinct from cells and shows dose-dependent changes in response to oxidative stress. We identified a high abundance of snoRNAs in EVs, alongside an enrichment of intronic and untranslated regions (UTRs) of mRNAs under stress. We also observed an increase in the relative abundance of either aberrant or modified mRNAs under stress. These findings suggest that EVs may function both for the elimination of specific cellular RNAs, and for the incorporation of RNAs that may hold signalling potential.
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Affiliation(s)
- Elizabeth R. Dellar
- Sir William Dunn School of PathologyUniversity of OxfordOxfordUK
- Department of Biological and Medical SciencesOxford Brookes UniversityOxfordUK
- Nuffield Department of Clinical NeurosciencesUniversity of OxfordOxfordUK
| | - Claire Hill
- Sir William Dunn School of PathologyUniversity of OxfordOxfordUK
- Centre for Public HealthQueen's University BelfastBelfastUK
| | - David R. F. Carter
- Department of Biological and Medical SciencesOxford Brookes UniversityOxfordUK
- Evox Therapeutics LimitedOxford Science ParkOxfordUK
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14
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Wang X, Song D, Zhu B, Jin Y, Cai C, Wang Z. Urinary exosomal mRNA as a biomarker for the diagnosis of bladder cancer. Anticancer Drugs 2024; 35:362-370. [PMID: 38385960 PMCID: PMC10919263 DOI: 10.1097/cad.0000000000001571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 12/20/2023] [Indexed: 02/23/2024]
Abstract
OBJECTIVE To study the diagnostic value of mRNA expression in urinary exocrine body in bladder cancer. METHODS From February 2022 to December 2022, 60 patients diagnosed with bladder cancer by pathology in the Department of Urology, Affiliated Hospital of Chengde Medical University were selected as the case group. In total, 40 healthy subjects receiving physical examinations were selected as the control group. 100 mL of morning urine samples were collected from the subjects in both groups based on the same standard. Three subjects were randomly selected from each group. Urinary exosomes were extracted by differential ultracentrifugation. High-throughput sequencing (RNA-seq) was used to detect mRNA expression profiles in urinary exosomes and identify differentially expressed genes. Bioinformatic analysis was performed to predict major biological functions of differentially expressed genes and related signaling pathways. RT-PCR validated expression levels of differentially expressed genes in urinary exosomes between the two groups. ROC curves evaluated the diagnostic value of differential genes for bladder cancer. Spearman's correlation analysis determined correlations between differentially expressed genes and the occurrence of bladder cancer. ROC curves speculated the diagnostic value of using combined differentially expressed genes. RESULTS Compared with normal subjects, there were 189 significantly differentially expressed genes in urinary exosomes of bladder cancer patients, including 33 up-regulated and 156 down-regulated. According to go and kyoto encyclopedia of genes and genomes (KEGG) analysis, the above differentially expressed genes may participate in the occurrence and development of bladder cancer through the MAPK pathway, PPAP signaling pathway, PI3K Akt signaling pathway and Hippo signaling pathway, affect protein and lipid metabolism, RNase activity, polysaccharide synthesis, signal transduction and other biological processes, and participate in cell proliferation, death, movement and adhesion, as well as cell differentiation and signal transduction. RT-PCR verified that the expression of tmeff1, SDPR, ACBD7, SCG2 and COL6A2 in the two groups of samples was statistically significant ( P < 0.05). The ROC curve showed that the area under curve area under the curve of the five differential genes were 0.6934, 0.7746, 0.7239, 0.6396 and 0.6610, respectively. The sensitivity was 42.11%, 64.86%, 47.37%, 73.53% and 76.47%, and the specificity was 90%, 81.36%, 96.36%, 61.02% and 58.18%, respectively. Spearman correlation analysis showed that tmeff1, SDPR and acbd7 were associated with the occurrence of bladder cancer. The ROC curve of the combined diagnosis of the three and the two combined diagnoses suggested that the area under the curve of the combined diagnosis of SDPR and acbd7 was 0.7945, the sensitivity was 89.09%, and the specificity was 60.53%. CONCLUSION The gene expression profile in urinary exosomes of bladder cancer patients has changed significantly, and the differential genes may play an important biological role in the occurrence and development of bladder cancer. The combined detection of urinary exosome SDPR and ACBD7 has a certain diagnostic value for bladder cancer.
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Affiliation(s)
- Xinying Wang
- Department of Urinary Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Dianbin Song
- Department of Urinary Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Baoxing Zhu
- Department of Urinary Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Yang Jin
- Department of Urinary Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Caisen Cai
- Department of Urinary Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Zhiyong Wang
- Department of Urinary Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, China
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15
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Huang Z, Liu X, Guo Q, Zhou Y, Shi L, Cai Q, Tang S, Ouyang Q, Zheng J. Extracellular vesicle-mediated communication between CD8 + cytotoxic T cells and tumor cells. Front Immunol 2024; 15:1376962. [PMID: 38562940 PMCID: PMC10982391 DOI: 10.3389/fimmu.2024.1376962] [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: 01/26/2024] [Accepted: 03/05/2024] [Indexed: 04/04/2024] Open
Abstract
Tumors pose a significant global public health challenge, resulting in numerous fatalities annually. CD8+ T cells play a crucial role in combating tumors; however, their effectiveness is compromised by the tumor itself and the tumor microenvironment (TME), resulting in reduced efficacy of immunotherapy. In this dynamic interplay, extracellular vesicles (EVs) have emerged as pivotal mediators, facilitating direct and indirect communication between tumors and CD8+ T cells. In this article, we provide an overview of how tumor-derived EVs directly regulate CD8+ T cell function by carrying bioactive molecules they carry internally and on their surface. Simultaneously, these EVs modulate the TME, indirectly influencing the efficiency of CD8+ T cell responses. Furthermore, EVs derived from CD8+ T cells exhibit a dual role: they promote tumor immune evasion while also enhancing antitumor activity. Finally, we briefly discuss current prevailing approaches that utilize functionalized EVs based on tumor-targeted therapy and tumor immunotherapy. These approaches aim to present novel perspectives for EV-based tumor treatment strategies, demonstrating potential for advancements in the field.
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Affiliation(s)
- Zeyu Huang
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xuehui Liu
- Department of Medicinal Chemistry, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Qinghao Guo
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yihang Zhou
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Linlin Shi
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Qingjin Cai
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Shupei Tang
- Department of Shigatse Branch, Xinqiao Hospital, Third Military Medical University, Shigatse, China
| | - Qin Ouyang
- Department of Medicinal Chemistry, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Ji Zheng
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
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16
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Petrova T, Kalinina O, Aquino A, Grigoryev E, Dubashynskaya NV, Zubkova K, Kostareva A, Golovkin A. Topographic Distribution of miRNAs (miR-30a, miR-223, miR-let-7a, miR-let-7f, miR-451, and miR-486) in the Plasma Extracellular Vesicles. Noncoding RNA 2024; 10:15. [PMID: 38392970 PMCID: PMC10892389 DOI: 10.3390/ncrna10010015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/27/2024] [Accepted: 02/04/2024] [Indexed: 02/25/2024] Open
Abstract
There are many articles on the quantitative analysis of miRNAs contained in a population of EVs of different sizes under various physiological and pathological conditions. For such analysis, it is important to correctly quantify the miRNA contents of EVs. It should be considered that quantification is skewed depending on the isolation protocol, and different miRNAs are degraded by nucleases with different efficiencies. In addition, it is important to consider the contribution of miRNAs coprecipitating with the EVs population, because the amount of miRNAs in the EVs population under study is skewed without appropriate enzymatic treatment. By studying a population of EVs from the blood plasma of healthy donors, we found that the absolute amount of miRNA inside the vesicles is commensurate with the amount of the same type of miRNA adhered to the outside of the EVs. The inside/outside ratio ranged from 1.02 to 2.64 for different investigated miRNAs. According to our results, we propose the hypothesis that high occupancy of miRNAs on the outer surface of EVs influence on the transporting RNA repertoire no less than the inner cargo received from the host cell.
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Affiliation(s)
- Tatiana Petrova
- Almazov National Medical Research Centre, 197341 St. Petersburg, Russia; (T.P.); (O.K.); (A.A.); (K.Z.); (A.K.)
| | - Olga Kalinina
- Almazov National Medical Research Centre, 197341 St. Petersburg, Russia; (T.P.); (O.K.); (A.A.); (K.Z.); (A.K.)
| | - Arthur Aquino
- Almazov National Medical Research Centre, 197341 St. Petersburg, Russia; (T.P.); (O.K.); (A.A.); (K.Z.); (A.K.)
| | - Evgeniy Grigoryev
- St. Petersburg State University, Research Park, 199034 St. Petersburg, Russia;
| | - Natallia V. Dubashynskaya
- Institute of Macromolecular Compounds of the Russian Academy of Sciences, 199004 St. Petersburg, Russia;
| | - Kseniya Zubkova
- Almazov National Medical Research Centre, 197341 St. Petersburg, Russia; (T.P.); (O.K.); (A.A.); (K.Z.); (A.K.)
| | - Anna Kostareva
- Almazov National Medical Research Centre, 197341 St. Petersburg, Russia; (T.P.); (O.K.); (A.A.); (K.Z.); (A.K.)
| | - Alexey Golovkin
- Almazov National Medical Research Centre, 197341 St. Petersburg, Russia; (T.P.); (O.K.); (A.A.); (K.Z.); (A.K.)
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Ghodasara A, Raza A, Wolfram J, Salomon C, Popat A. Clinical Translation of Extracellular Vesicles. Adv Healthc Mater 2023; 12:e2301010. [PMID: 37421185 DOI: 10.1002/adhm.202301010] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/03/2023] [Indexed: 07/10/2023]
Abstract
Extracellular vesicles (EVs) occur in a variety of bodily fluids and have gained recent attraction as natural materials due to their bioactive surfaces, internal cargo, and role in intercellular communication. EVs contain various biomolecules, including surface and cytoplasmic proteins; and nucleic acids that are often representative of the originating cells. EVs can transfer content to other cells, a process that is thought to be important for several biological processes, including immune responses, oncogenesis, and angiogenesis. An increased understanding of the underlying mechanisms of EV biogenesis, composition, and function has led to an exponential increase in preclinical and clinical assessment of EVs for biomedical applications, such as diagnostics and drug delivery. Bacterium-derived EV vaccines have been in clinical use for decades and a few EV-based diagnostic assays regulated under Clinical Laboratory Improvement Amendments have been approved for use in single laboratories. Though, EV-based products are yet to receive widespread clinical approval from national regulatory agencies such as the United States Food and Drug Administration (USFDA) and European Medicine Agency (EMA), many are in late-stage clinical trials. This perspective sheds light on the unique characteristics of EVs, highlighting current clinical trends, emerging applications, challenges and future perspectives of EVs in clinical use.
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Affiliation(s)
- Aayushi Ghodasara
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4102, Australia
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, The University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4029, Australia
| | - Aun Raza
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4102, Australia
| | - Joy Wolfram
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, 4072, Australia
- The School of Chemical Engineering, The University of Queensland, Brisbane, QLD, 4072, Australia
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA
| | - Carlos Salomon
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, The University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4029, Australia
- Department of Research, Postgraduate and Further Education (DIPEC), Falcuty of Health Sciences, University of Alba, Santiago, 8320000, Chile
| | - Amirali Popat
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4102, Australia
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18
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Babula A, Gałuszka-Bulaga A, Węglarczyk K, Siedlar M, Baj-Krzyworzeka M. CD44‑hyaluronan axis plays a role in the interactions between colon cancer‑derived extracellular vesicles and human monocytes. Oncol Lett 2023; 26:413. [PMID: 37600336 PMCID: PMC10436155 DOI: 10.3892/ol.2023.13999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 07/17/2023] [Indexed: 08/22/2023] Open
Abstract
During tumor progression, monocytes circulating in the blood or infiltrating tissue may be exposed to tumor-derived extracellular vesicles (TEVs). The first stage of such interactions involves binding of TEVs to the surface of monocytes, followed by their internalization. The present study examines the role of CD44 molecules in the interactions between monocytes and EVs derived from colon cancer cell lines (HCT116 and SW1116). The efficiency of the attachment and engulfment of TEVs by monocytes is linked to the number of TEVs and time of exposure/interaction. The two investigated TEVs, TEVsHCT116 and TEVsSW1116, originating from HCT116 and SW1116 cells, respectively, differ in hyaluronan (HA) cargo, which reflects HA secretion by parental cancer cells. HA-rich TEVsHCT116 are internalized more effectively in comparison with HA-low TEVsSW1116. Blocking of CD44 molecules on monocytes by anti-CD44 monoclonal antibody significantly decreased the engulfment of TEVsHCT116 but not that of TEVsSW1116 after 30 min contact, suggesting the involvement of the HA-CD44 axis. The three subsets of monocytes, classical, intermediate and non-classical, characterized by gradual changes in the expression of CD14 and CD16 markers, also differ in the expression of CD44. The highest expression of CD44 molecules was observed in the intermediate monocyte subset. Blocking of CD44 molecules decreased the internalization of HA-rich TEVs in all three subsets, which is associated with CD44 expression level. It was hypothesized that HA carried by TEVs, potentially as a component of the 'corona' coating, may facilitate the interaction between subsets of monocytes and TEVs, which may influence the fate of TEVs (such as the rate of TEVs adhesion and engulfment) and change monocyte activity.
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Affiliation(s)
- Aneta Babula
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Kraków, Poland
- Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, 31-530 Kraków, Poland
| | - Adrianna Gałuszka-Bulaga
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Kraków, Poland
| | - Kazimierz Węglarczyk
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Kraków, Poland
| | - Maciej Siedlar
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Kraków, Poland
| | - Monika Baj-Krzyworzeka
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Kraków, Poland
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19
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Wang J, Chen HC, Sheng Q, Dawson TR, Coffey RJ, Patton JG, Weaver AM, Shyr Y, Liu Q. Systematic Assessment of Small RNA Profiling in Human Extracellular Vesicles. Cancers (Basel) 2023; 15:3446. [PMID: 37444556 PMCID: PMC10340377 DOI: 10.3390/cancers15133446] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/22/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
MOTIVATION Extracellular vesicles (EVs) are produced and released by most cells and are now recognized to play a role in intercellular communication through the delivery of molecular cargo, including proteins, lipids, and RNA. Small RNA sequencing (small RNA-seq) has been widely used to characterize the small RNA content in EVs. However, there is a lack of a systematic assessment of the quality, technical biases, RNA composition, and RNA biotypes enrichment for small RNA profiling of EVs across cell types, biofluids, and conditions. METHODS We collected and reanalyzed small RNA-seq datasets for 2756 samples from 83 studies involving 55 with EVs only and 28 with both EVs and matched donor cells. We assessed their quality by the total number of reads after adapter trimming, the overall alignment rate to the host and non-host genomes, and the proportional abundance of total small RNA and specific biotypes, such as miRNA, tRNA, rRNA, and Y RNA. RESULTS We found that EV extraction methods varied in their reproducibility in isolating small RNAs, with effects on small RNA composition. Comparing proportional abundances of RNA biotypes between EVs and matched donor cells, we discovered that rRNA and tRNA fragments were relatively enriched, but miRNAs and snoRNA were depleted in EVs. Except for the export of eight miRNAs being context-independent, the selective release of most miRNAs into EVs was study-specific. CONCLUSION This work guides quality control and the selection of EV isolation methods and enhances the interpretation of small RNA contents and preferential loading in EVs.
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Affiliation(s)
- Jing Wang
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (J.W.); (H.-C.C.); (Q.S.)
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Hua-Chang Chen
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (J.W.); (H.-C.C.); (Q.S.)
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Quanhu Sheng
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (J.W.); (H.-C.C.); (Q.S.)
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - T. Renee Dawson
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; (T.R.D.); (R.J.C.); (A.M.W.)
- Center for Extracellular Vesicle Research, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Robert J. Coffey
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; (T.R.D.); (R.J.C.); (A.M.W.)
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - James G. Patton
- Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA;
| | - Alissa M. Weaver
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; (T.R.D.); (R.J.C.); (A.M.W.)
- Center for Extracellular Vesicle Research, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Yu Shyr
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (J.W.); (H.-C.C.); (Q.S.)
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Qi Liu
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (J.W.); (H.-C.C.); (Q.S.)
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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20
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Arena GO, Forte S, Abdouh M, Vanier C, Corbeil D, Lorico A. Horizontal Transfer of Malignant Traits and the Involvement of Extracellular Vesicles in Metastasis. Cells 2023; 12:1566. [PMID: 37371036 PMCID: PMC10297028 DOI: 10.3390/cells12121566] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/31/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Metastases are responsible for the vast majority of cancer deaths, yet most therapeutic efforts have focused on targeting and interrupting tumor growth rather than impairing the metastatic process. Traditionally, cancer metastasis is attributed to the dissemination of neoplastic cells from the primary tumor to distant organs through blood and lymphatic circulation. A thorough understanding of the metastatic process is essential to develop new therapeutic strategies that improve cancer survival. Since Paget's original description of the "Seed and Soil" hypothesis over a hundred years ago, alternative theories and new players have been proposed. In particular, the role of extracellular vesicles (EVs) released by cancer cells and their uptake by neighboring cells or at distinct anatomical sites has been explored. Here, we will outline and discuss these alternative theories and emphasize the horizontal transfer of EV-associated biomolecules as a possibly major event leading to cell transformation and the induction of metastases. We will also highlight the recently discovered intracellular pathway used by EVs to deliver their cargoes into the nucleus of recipient cells, which is a potential target for novel anti-metastatic strategies.
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Affiliation(s)
- Goffredo O. Arena
- Department of Surgery, McGill University, Montréal, QC H3A 0G4, Canada;
- Fondazione Istituto G. Giglio, 90015 Cefalù, Italy
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy;
| | - Stefano Forte
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy;
| | - Mohamed Abdouh
- Cancer Research Program, Research Institute, McGill University Health Centre, Montréal, QC H3A 0G4, Canada;
| | - Cheryl Vanier
- Touro University Nevada College of Medicine, Henderson, NV 89014, USA;
| | - Denis Corbeil
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, 01307 Dresden, Germany;
| | - Aurelio Lorico
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy;
- Touro University Nevada College of Medicine, Henderson, NV 89014, USA;
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21
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Hill C, Dellar ER, Baena‐Lopez LA. Caspases help to spread the message via extracellular vesicles. FEBS J 2023; 290:1954-1972. [PMID: 35246932 PMCID: PMC10952732 DOI: 10.1111/febs.16418] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/10/2022] [Accepted: 03/03/2022] [Indexed: 11/27/2022]
Abstract
Cell-cell communication is an essential aspect of multicellular life, key for coordinating cell proliferation, growth, and death in response to environmental changes. Whilst caspases are well-known for facilitating apoptotic and pyroptotic cell death, several recent investigations are uncovering new roles for these enzymes in biological scenarios requiring long-range intercellular signalling mediated by extracellular vesicles (EVs). EVs are small membrane-bound nanoparticles released from cells that may carry and deliver cargo between distant cells, thus helping to coordinate their behaviour. Intriguingly, there is emerging evidence indicating a key contribution of caspases in the biogenesis of EVs, the selection of their cargo content, and EV uptake/function in recipient cells. Here, we discuss the latest findings supporting the interplay between caspases and EVs, and the biological relevance of this molecular convergence for cellular signalling, principally in non-apoptotic scenarios.
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Affiliation(s)
- Claire Hill
- Sir William Dunn School of PathologyUniversity of OxfordUK
| | - Elizabeth R. Dellar
- Sir William Dunn School of PathologyUniversity of OxfordUK
- Nuffield Department of Clinical NeurosciencesUniversity of OxfordUK
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22
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Lopez K, Lai SWT, Lopez Gonzalez EDJ, Dávila RG, Shuck SC. Extracellular vesicles: A dive into their role in the tumor microenvironment and cancer progression. Front Cell Dev Biol 2023; 11:1154576. [PMID: 37025182 PMCID: PMC10071009 DOI: 10.3389/fcell.2023.1154576] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 03/10/2023] [Indexed: 04/08/2023] Open
Abstract
Extracellular vesicles (EVs) encompass a diverse set of membrane-derived particles released from cells and are found in numerous biological matrices and the extracellular space. Specific classes of EVs include apoptotic bodies, exosomes, and microvesicles, which vary in their size, origin, membrane protein expression, and interior cargo. EVs provide a mechanism for shuttling cargo between cells, which can influence cell physiology by transporting proteins, DNA, and RNA. EVs are an abundant component of the tumor microenvironment (TME) and are proposed to drive tumor growth and progression by communicating between fibroblasts, macrophages, and tumor cells in the TME. The cargo, source, and type of EV influences the pro- or anti-tumoral role of these molecules. Therefore, robust EV isolation and characterization techniques are required to ensure accurate elucidation of their association with disease. Here, we summarize different EV subclasses, methods for EV isolation and characterization, and a selection of current clinical trials studying EVs. We also review key studies exploring the role and impact of EVs in the TME, including how EVs mediate intercellular communication, drive cancer progression, and remodel the TME.
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23
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Zafari R, Razi S, Rezaei N. The role of dendritic cells in neuroblastoma: Implications for immunotherapy. Immunobiology 2022; 227:152293. [DOI: 10.1016/j.imbio.2022.152293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 09/09/2022] [Accepted: 10/19/2022] [Indexed: 11/26/2022]
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24
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Kaczmarek M, Baj-Krzyworzeka M, Bogucki Ł, Dutsch-Wicherek M. HPV-Related Cervical Cancer and Extracellular Vesicles. Diagnostics (Basel) 2022; 12:2584. [PMID: 36359429 PMCID: PMC9689649 DOI: 10.3390/diagnostics12112584] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/21/2022] [Accepted: 10/23/2022] [Indexed: 11/03/2023] Open
Abstract
Cervical cancer is the fourth most common type of cancer in females worldwide. Infection with a human papillomavirus is crucial to the etiopathogenesis of cervical cancer. The natural trajectory of HPV infection comprises HPV acquisition, HPV persistence versus clearance, and progression to precancer and invasive cancer. The majority of HPV infections are cleared and controlled by the immune system within 2 years, but some infections may become quiescent or undetectable. The persistence of high-risk HPV infection for a longer period of time enhances the risk of malignant transformation of infected cells; however, the mechanisms responsible for the persistence of infection are not yet well-understood. It is estimated that 10-15% of infections do persist, and the local microenvironment is now recognized as an important cofactor promoting infection maintenance. Extracellular vesicles (EVs) are small membrane vesicles derived from both normal cells and cancer cells. EVs contain various proteins, such as cytoskeletal proteins, adhesion molecules, heat shock proteins, major histocompatibility complex, and membrane fusion proteins. EVs derived from HPV-infected cells also contain viral proteins and nucleic acids. These biologically active molecules are transferred via EVs to target cells, constituting a kind of cell-to-cell communication. The viral components incorporated into EVs are transmitted independently of the production of infectious virions. This mode of transfer makes EVs a perfect vector for viruses and their components. EVs participate in both physiological and pathological conditions; they have also been identified as one of the mediators involved in cancer metastasis. This review discusses the potential role of EVs in remodeling the cervical cancer microenvironment which may be crucial to tumor development and the acquisition of metastatic potential. EVs are promising as potential biomarkers in cervical cancer.
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Affiliation(s)
- Magdalena Kaczmarek
- Department of Endoscopic Otorhinolaryngology, Centre of Postgraduate Medical Education (CMKP), 01-813 Warsaw, Poland
| | - Monika Baj-Krzyworzeka
- Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, 30-663 Kraków, Poland
| | - Łukasz Bogucki
- Department of Endoscopic Otorhinolaryngology, Centre of Postgraduate Medical Education (CMKP), 01-813 Warsaw, Poland
| | - Magdalena Dutsch-Wicherek
- Department of Endoscopic Otorhinolaryngology, Centre of Postgraduate Medical Education (CMKP), 01-813 Warsaw, Poland
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25
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Ma Q, Beal JR, Song X, Bhurke A, Bagchi IC, Bagchi MK. Extracellular Vesicles Secreted by Mouse Decidual Cells Carry Critical Information for the Establishment of Pregnancy. Endocrinology 2022; 163:6758297. [PMID: 36219207 PMCID: PMC9761388 DOI: 10.1210/endocr/bqac165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Indexed: 11/19/2022]
Abstract
The mouse decidua secretes many factors that act in a paracrine/autocrine manner to critically control uterine decidualization, neovascularization, and tissue remodeling that ensure proper establishment of pregnancy. The precise mechanisms that dictate intercellular communications among the uterine cells during early pregnancy remain unknown. We recently reported that conditional deletion of the gene encoding the hypoxia-inducible transcription factor 2 alpha (Hif2α) in mouse uterus led to infertility. Here, we report that HIF2α in mouse endometrial stromal cells (MESCs) acts via the cellular trafficking regulator RAB27b to control the secretion of extracellular vesicles (EVs) during decidualization. We also found that Hif2α-regulated pathways influence the biogenesis of EVs. Proteomic analysis of EVs secreted by decidualizing MESCs revealed that they harbor a wide variety of protein cargoes whose composition changed as the decidualization process progressed. The EVs enhanced the differentiation capacity of MESCs and the production of angiogenic factors by these cells. We also established that matrix metalloproteinase-2, a prominent EV cargo protein, modulates uterine remodeling during decidualization. Collectively, our results support the concept that EVs are central to the mechanisms by which the decidual cells communicate with each other and other cell types within the uterus to facilitate successful establishment of pregnancy.
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Affiliation(s)
- Qiuyan Ma
- Department of Molecular and Integrative Physiology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
| | - Jacob R Beal
- Department of Molecular and Integrative Physiology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
| | - Xiangning Song
- Department of Molecular and Integrative Physiology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
| | - Arpita Bhurke
- Carle Woese Institute of Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
| | - Indrani C Bagchi
- Correspondence: Indrani C. Bagchi, PhD, Departments of Comparative Biosciences, University of Illinois, Urbana-Champaign, Urbana, IL, USA. ; or Milan K. Bagchi, PhD, Departments of Molecular and Integrative Physiology, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
| | - Milan K Bagchi
- Correspondence: Indrani C. Bagchi, PhD, Departments of Comparative Biosciences, University of Illinois, Urbana-Champaign, Urbana, IL, USA. ; or Milan K. Bagchi, PhD, Departments of Molecular and Integrative Physiology, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
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26
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Stępień EŁ, Rząca C, Moskal P. Radiovesicolomics-new approach in medical imaging. Front Physiol 2022; 13:996985. [DOI: 10.3389/fphys.2022.996985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
This review introduce extracellular vesicles (EVs) to a molecular imaging field. The idea of modern analyses based on the use of omics studies, using high-throughput methods to characterize the molecular content of a single biological system, vesicolomics seems to be the new approach to collect molecular data about EV content, to find novel biomarkers or therapeutic targets. The use of various imaging techniques, including those based on radionuclides as positron emission tomography (PET) or single photon emission computed tomography (SPECT), combining molecular data on EVs, opens up the new space for radiovesicolomics—a new approach to be used in theranostics.
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27
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Xu J, Cao W, Wang P, Liu H. Tumor-Derived Membrane Vesicles: A Promising Tool for Personalized Immunotherapy. Pharmaceuticals (Basel) 2022; 15:ph15070876. [PMID: 35890175 PMCID: PMC9318328 DOI: 10.3390/ph15070876] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 11/16/2022] Open
Abstract
Tumor-derived membrane vesicles (TDMVs) are non-invasive, chemotactic, easily obtained characteristics and contain various tumor-borne substances, such as nucleic acid and proteins. The unique properties of tumor cells and membranes make them widely used in drug loading, membrane fusion and vaccines. In particular, personalized vectors prepared using the editable properties of cells can help in the design of personalized vaccines. This review focuses on recent research on TDMV technology and its application in personalized immunotherapy. We elucidate the strengths and challenges of TDMVs to promote their application from theory to clinical practice.
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Affiliation(s)
- Jiabin Xu
- School of Stomatology, Xuzhou Medical University, Xuzhou 221004, China; (J.X.); (P.W.)
- Affiliated Stomatological Hospital of Xuzhou Medical University, Xuzhou 221004, China
| | - Wenqiang Cao
- Zhuhai Jinan Selenium Source Nanotechnology Co., Ltd., Jinan University, Zhuhai 519000, China;
| | - Penglai Wang
- School of Stomatology, Xuzhou Medical University, Xuzhou 221004, China; (J.X.); (P.W.)
- Affiliated Stomatological Hospital of Xuzhou Medical University, Xuzhou 221004, China
| | - Hong Liu
- Zhuhai Jinan Selenium Source Nanotechnology Co., Ltd., Jinan University, Zhuhai 519000, China;
- Correspondence:
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28
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Subudhi PD, Bihari C, Sarin SK, Baweja S. Emerging Role of Edible Exosomes-Like Nanoparticles (ELNs) as Hepatoprotective Agents. Nanotheranostics 2022; 6:365-375. [PMID: 35795340 PMCID: PMC9254361 DOI: 10.7150/ntno.70999] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 05/24/2022] [Indexed: 11/07/2022] Open
Abstract
Liver diseases are responsible for over 2 million deaths each year and the number is rapidly increasing. There is a strong link between edibles, gut microbiota, liver fat and the liver damage. There are very limited therapeutic options for treatment specifically for Alcoholic liver disease (ALD) and Non-Alcoholic liver disease (NAFLD). Recently, identified Edible Exosomes-like nanoparticles (ELNs) are plant derived membrane bound particles, released by microvesicular bodies for cellular communication and regulate immune responses against many pathogens. Many studies have identified their role as hepatoprotective agent as they carry bioactive material as cargoes which are transferred to recipient cells and affect various biological functions in liver. They are also known to carry specific miRNA, which increases the copy number of beneficial bacteria and the production of lactic acid metabolites in gut and hence restrains from liver injury through portal vein. Few in-vitro studies also have been reported about the anti-inflammatory, anti-oxidant and detoxification properties of ELNs which again protects the liver. The properties such as small size, biocompatibility, stability, low toxicity and non-immunogenicity make ELNs as a better therapeutic option. But, till now, studies on the effect of ELNs as therapeutics are still at its infancy yet promising. Here we discuss about the isolation, characterization, their role in maintaining the gut microbiome and liver homeostasis. Also, we give an outline about the latest advances in ELNs modifications, its biological effects, limitations and we propose the future prospective of ELNs as therapeutics.
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Affiliation(s)
- P Debishree Subudhi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, Delhi, India
| | - Chhagan Bihari
- Department of Pathology, Institute of Liver and Biliary Sciences, Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Delhi, India
| | - Sukriti Baweja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, Delhi, India
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29
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Avalos PN, Forsthoefel DJ. An Emerging Frontier in Intercellular Communication: Extracellular Vesicles in Regeneration. Front Cell Dev Biol 2022; 10:849905. [PMID: 35646926 PMCID: PMC9130466 DOI: 10.3389/fcell.2022.849905] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/28/2022] [Indexed: 12/12/2022] Open
Abstract
Regeneration requires cellular proliferation, differentiation, and other processes that are regulated by secreted cues originating from cells in the local environment. Recent studies suggest that signaling by extracellular vesicles (EVs), another mode of paracrine communication, may also play a significant role in coordinating cellular behaviors during regeneration. EVs are nanoparticles composed of a lipid bilayer enclosing proteins, nucleic acids, lipids, and other metabolites, and are secreted by most cell types. Upon EV uptake by target cells, EV cargo can influence diverse cellular behaviors during regeneration, including cell survival, immune responses, extracellular matrix remodeling, proliferation, migration, and differentiation. In this review, we briefly introduce the history of EV research and EV biogenesis. Then, we review current understanding of how EVs regulate cellular behaviors during regeneration derived from numerous studies of stem cell-derived EVs in mammalian injury models. Finally, we discuss the potential of other established and emerging research organisms to expand our mechanistic knowledge of basic EV biology, how injury modulates EV biogenesis, cellular sources of EVs in vivo, and the roles of EVs in organisms with greater regenerative capacity.
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Affiliation(s)
- Priscilla N. Avalos
- Department of Cell Biology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
| | - David J. Forsthoefel
- Department of Cell Biology, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
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30
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Frommeyer TC, Gilbert MM, Brittain GV, Wu T, Nguyen TQ, Rohan CA, Travers JB. UVB-Induced Microvesicle Particle Release and Its Effects on the Cutaneous Microenvironment. Front Immunol 2022; 13:880850. [PMID: 35603177 PMCID: PMC9120817 DOI: 10.3389/fimmu.2022.880850] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/04/2022] [Indexed: 12/14/2022] Open
Abstract
Ultraviolet B radiation (UVB) has profound effects on human skin that results in a broad spectrum of immunological local and systemic responses and is the major cause of skin carcinogenesis. One important area of study in photobiology is how UVB is translated into effector signals. As the skin is exposed to UVB light, subcellular microvesicle particles (MVP), a subtype of bioactive extracellular vesicles, are released causing a variety of local and systemic immunological effects. In this review, we highlight keratinocyte MVP release in keratinocytes in response to UVB. Specifically, Platelet-activating factor receptor agonists generated by UVB result in MVP released from keratinocytes. The downstream effects of MVP release include the ability of these subcellular particles to transport agents including the glycerophosphocholine-derived lipid mediator Platelet-activating factor (PAF). Moreover, even though UVB is only absorbed in the epidermis, it appears that PAF release from MVPs also mediates systemic immunosuppression and enhances tumor growth and metastasis. Tumor cells expressing PAF receptors can use this mechanism to evade chemotherapy responses, leading to treatment resistance for advanced cancers such as melanoma. Furthermore, novel pharmacological agents provide greater insight into the UVB-induced immune response pathway and a potential target for pharmacological intervention. This review outlines the need to more clearly elucidate the mechanism linking UVB-irradiation with the cutaneous immune response and its pathological manifestations. An improved understanding of this process can result in new insights and treatment strategies for UVB-related disorders from carcinogenesis to photosensitivity.
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Affiliation(s)
- Timothy C. Frommeyer
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
| | - Michael M. Gilbert
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
| | - Garrett V. Brittain
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
| | - Tongfan Wu
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
| | - Trang Q. Nguyen
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
| | - Craig A. Rohan
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
- Department of Dermatology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
- Department of Medicine, Dayton Veterans Administration Medical Center, Dayton, OH, United States
| | - Jeffrey B. Travers
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
- Department of Dermatology, Boonshoft School of Medicine at Wright State University, Dayton, OH, United States
- Department of Medicine, Dayton Veterans Administration Medical Center, Dayton, OH, United States
- *Correspondence: Jeffrey B. Travers,
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31
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Dellar ER, Hill C, Melling GE, Carter DR, Baena‐Lopez LA. Unpacking extracellular vesicles: RNA cargo loading and function. JOURNAL OF EXTRACELLULAR BIOLOGY 2022; 1:e40. [PMID: 38939528 PMCID: PMC11080855 DOI: 10.1002/jex2.40] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/30/2022] [Accepted: 04/05/2022] [Indexed: 06/29/2024]
Abstract
Extracellular vesicles (EVs) are a heterogeneous group of membrane-enclosed structures produced by prokaryotic and eukaryotic cells. EVs carry a range of biological cargoes, including RNA, protein, and lipids, which may have both metabolic significance and signalling potential. EV release has been suggested to play a critical role in maintaining intracellular homeostasis by eliminating unnecessary biological material from EV producing cells, and as a delivery system to enable cellular communication between both neighbouring and distant cells without physical contact. In this review, we give an overview of what is known about the relative enrichment of the different types of RNA that have been associated with EVs in the most recent research efforts. We then examine the selective and non-selective incorporation of these different RNA biotypes into EVs, the molecular systems of RNA sorting into EVs that have been elucidated so far, and the role of this process in EV-producing cells. Finally, we also discuss the model systems providing evidence for EV-mediated delivery of RNA to recipient cells, and the implications of this evidence for the relevance of this RNA delivery process in both physiological and pathological scenarios.
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Affiliation(s)
- Elizabeth R. Dellar
- Department of Biological and Medical SciencesOxford Brookes UniversityGipsy LaneOxfordUK
- Sir William Dunn School of PathologyUniversity of OxfordSouth Parks RoadOxfordUK
- Nuffield Department of Clinical NeurosciencesJohn Radcliffe HospitalUniversity of OxfordOxfordUK
| | - Claire Hill
- Sir William Dunn School of PathologyUniversity of OxfordSouth Parks RoadOxfordUK
| | - Genevieve E. Melling
- Department of Biological and Medical SciencesOxford Brookes UniversityGipsy LaneOxfordUK
- Institute of Clinical SciencesSchool of Biomedical SciencesCollege of Medical and Dental SciencesUniversity of BirminghamEdgbastonBirminghamUK
| | - David R.F Carter
- Department of Biological and Medical SciencesOxford Brookes UniversityGipsy LaneOxfordUK
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32
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Sun H, Bhandari K, Burrola S, Wu J, Ding WQ. Pancreatic Ductal Cell-Derived Extracellular Vesicles Are Effective Drug Carriers to Enhance Paclitaxel's Efficacy in Pancreatic Cancer Cells through Clathrin-Mediated Endocytosis. Int J Mol Sci 2022; 23:4773. [PMID: 35563165 PMCID: PMC9099870 DOI: 10.3390/ijms23094773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/22/2022] [Accepted: 04/22/2022] [Indexed: 11/25/2022] Open
Abstract
Chemo-resistance challenges the clinical management of pancreatic ductal adenocarcinoma (PDAC). A limited admittance of chemotherapeutics to PDAC tissues is a key obstacle in chemotherapy of the malignancy. An enhanced uptake of drugs into PDAC cells is required for a more effective treatment. Extracellular vesicles (EVs), especially small EVs (sEVs), have emerged as drug carriers for delivering chemotherapeutics due to their low immunogenicity and propensity for homing toward tumor cells. The present study evaluated sEVs derived from six different human cell lines as carriers for paclitaxel (PTX). The encapsulation of the chemotherapeutics was achieved using incubation, sonication and electroporation. The cytotoxicity of the EV drugs was evaluated by MTS assay. While sonication led to a higher efficiency of drug loading than incubation and electroporation, PTX loaded through incubation with HPNE-derived sEVs (HI-PTX) was the most efficacious in killing PDAC cells. Furthermore, HI-PTX was taken up by PDAC cells more efficiently than other EV drugs, implying that the efficacy of HI-PTX is associated with its efficient uptake. This was supported by the observation that the cytotoxicity and uptake of HI-PTX is mediated via the clathrin-dependent endocytosis. Our results indicate that the hTERT-HPNE cell-derived EVs are effective drug carriers to enhance paclitaxel's efficacy in PDAC cells.
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Affiliation(s)
- Haoyao Sun
- Department of Radiation Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, China;
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (K.B.); (S.B.)
| | - Kritisha Bhandari
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (K.B.); (S.B.)
| | - Stephanie Burrola
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (K.B.); (S.B.)
| | - Jinchang Wu
- Department of Radiation Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, China;
| | - Wei-Qun Ding
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (K.B.); (S.B.)
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33
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Hu Y, Sun Y, Wan C, Dai X, Wu S, Lo PC, Huang J, Lovell JF, Jin H, Yang K. Microparticles: biogenesis, characteristics and intervention therapy for cancers in preclinical and clinical research. J Nanobiotechnology 2022; 20:189. [PMID: 35418077 PMCID: PMC9006557 DOI: 10.1186/s12951-022-01358-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/08/2022] [Indexed: 12/24/2022] Open
Abstract
Extracellular vesicles (EVs), spherical biological vesicles, mainly contain nucleic acids, proteins, lipids and metabolites for biological information transfer between cells. Microparticles (MPs), a subtype of EVs, directly emerge from plasma membranes, and have gained interest in recent years. Specific cell stimulation conditions, such as ultraviolet and X-rays irradiation, can induce the release of MPs, which are endowed with unique antitumor functionalities, either for therapeutic vaccines or as direct antitumor agents. Moreover, the size of MPs (100–1000 nm) and their spherical structures surrounded by a lipid bilayer membrane allow MPs to function as delivery vectors for bioactive antitumor compounds, with favorable phamacokinetic behavior, immunostimulatory activity and biological function, without inherent carrier-specific toxic side effects. In this review, the mechanisms underlying MP biogenesis, factors that influence MP production, properties of MP membranes, size, composition and isolation methods of MPs are discussed. Additionally, the applications and mechanisms of action of MPs, as well as the main hurdles for their applications in cancer management, are introduced.
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Affiliation(s)
- Yan Hu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yajie Sun
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chao Wan
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaomeng Dai
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Shuhui Wu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Pui-Chi Lo
- Department of Biomedical Sciences, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong kong, China
| | - Jing Huang
- College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China
| | - Jonathan F Lovell
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, 14260, USA
| | - Honglin Jin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China.
| | - Kunyu Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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34
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Ahmad S, Srivastava RK, Singh P, Naik UP, Srivastava AK. Role of Extracellular Vesicles in Glia-Neuron Intercellular Communication. Front Mol Neurosci 2022; 15:844194. [PMID: 35493327 PMCID: PMC9043804 DOI: 10.3389/fnmol.2022.844194] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 02/23/2022] [Indexed: 11/13/2022] Open
Abstract
Cross talk between glia and neurons is crucial for a variety of biological functions, ranging from nervous system development, axonal conduction, synaptic transmission, neural circuit maturation, to homeostasis maintenance. Extracellular vesicles (EVs), which were initially described as cellular debris and were devoid of biological function, are now recognized as key components in cell-cell communication and play a critical role in glia-neuron communication. EVs transport the proteins, lipids, and nucleic acid cargo in intercellular communication, which alters target cells structurally and functionally. A better understanding of the roles of EVs in glia-neuron communication, both in physiological and pathological conditions, can aid in the discovery of novel therapeutic targets and the development of new biomarkers. This review aims to demonstrate that different types of glia and neuronal cells secrete various types of EVs, resulting in specific functions in intercellular communications.
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Affiliation(s)
- Shahzad Ahmad
- Department of Medical Elementology and Toxicology, Jamia Hamdard University, New Delhi, India
| | - Rohit K. Srivastava
- Department of Pediatric Surgery, Texas Children’s Hospital, Houston, TX, United States
- M.E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States
| | - Pratibha Singh
- Department of Biochemistry and Cell Biology, Biosciences Research Collaborative, Rice University, Houston, TX, United States
| | - Ulhas P. Naik
- Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Cardeza Foundation for Hematologic Research, Philadelphia, PA, United States
| | - Amit K. Srivastava
- Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Cardeza Foundation for Hematologic Research, Philadelphia, PA, United States
- *Correspondence: Amit K. Srivastava,
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Tani A, Tomiyasu H, Asada H, Lin CS, Goto-Koshino Y, Ohno K, Tsujimoto H. Changes in gene expression profiles and cytokine secretions in peripheral monocytes by treatment with small extracellular vesicles derived from a canine lymphoma cell line. J Vet Med Sci 2022; 84:712-719. [PMID: 35387951 PMCID: PMC9177395 DOI: 10.1292/jvms.21-0506] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Interactions between tumor and immune cells within the tumor microenvironment play an important role in tumor progression, and small extracellular vesicles (EVs) derived from these tumor
cells have been shown to exert immunomodulatory effects on various immune cells, including macrophages and lymphocytes. Although the immunomodulatory effects of small EVs derived from human
cancer cells have been intensively investigated, few studies have investigated the effects of lymphoma-derived small EVs on macrophages in both human and veterinary medicine. Here, we
evaluated the effects of canine lymphoma-derived small EVs on canine primary monocytes, which are the major source of macrophages in neoplastic tissues. Comprehensive gene expression
analysis of these treated monocytes revealed their distinct activation via the Toll-like receptor (TLR) and NF-κβ signaling pathways. In addition, treatment with lymphoma small EVs increased
the secretion of MCP-1, which induces the infiltration and migration of monocytes and lymphocytes in neoplastic and cancer tissues. The results of this study indicate that canine lymphoma
small EVs activate monocytes, possibly through the activation of TLR and NF-κβ signaling pathways, and induce monocytes to secrete of MCP-1, which might contribute to immune cell
infiltration within the tumor microenvironment.
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Affiliation(s)
- Akiyoshi Tani
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Hirotaka Tomiyasu
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Hajime Asada
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo.,Present address: Department of Urology, Northwestern University
| | - Chen-Si Lin
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University
| | - Yuko Goto-Koshino
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Koichi Ohno
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo
| | - Hajime Tsujimoto
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo
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Yang L, Patel KD, Rathnam C, Thangam R, Hou Y, Kang H, Lee KB. Harnessing the Therapeutic Potential of Extracellular Vesicles for Biomedical Applications Using Multifunctional Magnetic Nanomaterials. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2104783. [PMID: 35132796 PMCID: PMC9344859 DOI: 10.1002/smll.202104783] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 01/12/2022] [Indexed: 04/14/2023]
Abstract
Extracellular vesicles (e.g., exosomes) carrying various biomolecules (e.g., proteins, lipids, and nucleic acids) have rapidly emerged as promising platforms for many biomedical applications. Despite their enormous potential, their heterogeneity in surfaces and sizes, the high complexity of cargo biomolecules, and the inefficient uptake by recipient cells remain critical barriers for their theranostic applications. To address these critical issues, multifunctional nanomaterials, such as magnetic nanomaterials, with their tunable physical, chemical, and biological properties, may play crucial roles in next-generation extracellular vesicles (EV)-based disease diagnosis, drug delivery, tissue engineering, and regenerative medicine. As such, one aims to provide cutting-edge knowledge pertaining to magnetic nanomaterials-facilitated isolation, detection, and delivery of extracellular vesicles and their associated biomolecules. By engaging the fields of extracellular vesicles and magnetic nanomaterials, it is envisioned that their properties can be effectively combined for optimal outcomes in biomedical applications.
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Affiliation(s)
- Letao Yang
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Kapil D. Patel
- Department of Materials Science and Engineering, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Christopher Rathnam
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Ramar Thangam
- Department of Materials Science and Engineering, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Yannan Hou
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Heemin Kang
- Department of Materials Science and Engineering, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Ki-Bum Lee
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123 Bevier Road, Pis cataway, NJ 08854, USA
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Fan B, Gu J, Wu J, Sun Y, Huang R, Shen H, Zhang X, Li Z. Circulating Abnormal Extracellular Vesicles: Their Mechanism for Crossing Blood-Brain Barrier, Effects on Central Nervous System and Detection Methods. J Biomed Nanotechnol 2022; 18:640-659. [PMID: 35715917 DOI: 10.1166/jbn.2022.3293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Central nervous system (CNS) diseases are difficult to treat and harmful. Many CNS diseases are secondary to peripheral diseases, such as tumor brain metastases (BMS), viral infections and inflammation of the brain, and their pathogenic factors travel through the circulatory system to the brain, eventually leading to lesions. Extracellular vesicles (EVs) play an important role in this process. Recent studies have shown that, extracellular EVs can effectively cross the blood- brain barrier (BBB) through endocytosis and they transmit molecular signals in cell-to-cell communication. Abnormal EVs produced in the lesion portion transport pathogenic factors, including miRNAs, proteins, and virions into the CNS. These pathogenic factors participate in cellular pathways to interfere with homeostasis or are themselves pathogens that directly damage CNS. In addition, different or specific pathological molecules in EVs are potential disease markers. We herein reviewed pathways through which the abnormal EVs cross BBB and adverse effects of abnormal exosomes. We also and summarized their existing detection techniques, so as to provide basis for prevention and early diagnosis of secondary diseases.
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Affiliation(s)
- Boyue Fan
- Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, 210008, China
| | - Jiaqi Gu
- Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, 210008, China
| | - Jie Wu
- Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, 210008, China
| | - Yifan Sun
- Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, 210008, China
| | - Rongrong Huang
- Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, 210008, China
| | - Han Shen
- Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, 210008, China
| | - Xu Zhang
- Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, 210008, China
| | - Zhiyang Li
- Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, 210008, China
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Hosseini K, Ranjbar M, Pirpour Tazehkand A, Asgharian P, Montazersaheb S, Tarhriz V, Ghasemnejad T. Evaluation of exosomal non-coding RNAs in cancer using high-throughput sequencing. J Transl Med 2022; 20:30. [PMID: 35033106 PMCID: PMC8760667 DOI: 10.1186/s12967-022-03231-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 01/05/2022] [Indexed: 12/13/2022] Open
Abstract
Clinical oncologists need more reliable and non-invasive diagnostic and prognostic biomarkers to follow-up cancer patients. However, the existing biomarkers are often invasive and costly, emphasizing the need for the development of biomarkers to provide convenient and precise detection. Extracellular vesicles especially exosomes have recently been the focus of translational research to develop non-invasive and reliable biomarkers for several diseases such as cancers, suggesting as a valuable source of tumor markers. Exosomes are nano-sized extracellular vesicles secreted by various living cells that can be found in all body fluids including serum, urine, saliva, cerebrospinal fluid, and ascites. Different molecular and genetic contents of their origin such as nucleic acids, proteins, lipids, and glycans in a stable form make exosomes a promising approach for various cancers' diagnoses, prediction, and follow-up in a minimally invasive manner. Since exosomes are used by cancer cells for intercellular communication, they play a critical role in the disease process, highlighting the importance of their use as clinically relevant biomarkers. However, regardless of the advantages that exosome-based diagnostics have, they suffer from problems regarding their isolation, detection, and characterization of their contents. This study reviews the history and biogenesis of exosomes and discusses non-coding RNAs (ncRNAs) and their potential as tumor markers in different types of cancer, with a focus on next generation sequencing (NGS) as a detection method. Moreover, the advantages and challenges associated with exosome-based diagnostics are also presented.
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Affiliation(s)
- Kamran Hosseini
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Ranjbar
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Pirpour Tazehkand
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parina Asgharian
- Department of Pharmacognosy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Montazersaheb
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahideh Tarhriz
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Tohid Ghasemnejad
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
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Balzanelli MG, Distratis P, Lazzaro R, D’Ettorre E, Nico A, Inchingolo F, Dipalma G, Tomassone D, Serlenga EM, Dalagni G, Ballini A, Nguyen KCD, Isacco CG. New Translational Trends in Personalized Medicine: Autologous Peripheral Blood Stem Cells and Plasma for COVID-19 Patient. J Pers Med 2022; 12:85. [PMID: 35055400 PMCID: PMC8778886 DOI: 10.3390/jpm12010085] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/29/2021] [Accepted: 01/04/2022] [Indexed: 02/04/2023] Open
Abstract
The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), still remains a severe threat. At the time of writing this paper, the second infectious wave has caused more than 280,000 deaths all over the world. Italy was one of the first countries involved, with more than 200,000 people reported as infected and 30,000 deaths. There are no specific treatments for COVID-19 and the vaccine still remains somehow inconclusive. The world health community is trying to define and share therapeutic protocols in early and advanced clinical stages. However, numbers remain critical with a serious disease rate of 14%, ending with sepsis, acute respiratory distress syndrome (ARDS), multiple organ failure (MOF) and vascular and thromboembolic findings. The mortality rate was estimated within 2-3%, and more than double that for individuals over 65 years old; almost one patient in three dies in the Intensive Care Unit (ICU). Efforts for effective solutions are underway with multiple lines of investigations, and health authorities have reported success treating infected patients with donated plasma from survivors of the illness, the proposed benefit being protective antibodies formed by the survivors. Plasma transfusion, blood and stem cells, either autologous or allograft transplantation, are not novel therapies, and in this short paper, we propose therapeutic autologous plasma and peripheral blood stem cells as a possible treatment for fulminant COVID-19 infection.
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Affiliation(s)
- Mario Giosuè Balzanelli
- SET-118, Department of Pre-Hospital and Emergency, SG Giuseppe Moscati Hospital, 74010 Taranto, Italy; (M.G.B.); (P.D.); (R.L.)
| | - Pietro Distratis
- SET-118, Department of Pre-Hospital and Emergency, SG Giuseppe Moscati Hospital, 74010 Taranto, Italy; (M.G.B.); (P.D.); (R.L.)
| | - Rita Lazzaro
- SET-118, Department of Pre-Hospital and Emergency, SG Giuseppe Moscati Hospital, 74010 Taranto, Italy; (M.G.B.); (P.D.); (R.L.)
| | - Ernesto D’Ettorre
- Department of Pneumology, SG Giuseppe Moscati Hospital, 74010 Taranto, Italy; (E.D.); (A.N.); (G.D.)
| | - Andrea Nico
- Department of Pneumology, SG Giuseppe Moscati Hospital, 74010 Taranto, Italy; (E.D.); (A.N.); (G.D.)
| | - Francesco Inchingolo
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (F.I.); (G.D.)
| | - Gianna Dipalma
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (F.I.); (G.D.)
| | - Diego Tomassone
- Foundation of Physics Research Center, Celico, 87100 Cosenza, Italy;
| | | | - Giancarlo Dalagni
- Department of Pneumology, SG Giuseppe Moscati Hospital, 74010 Taranto, Italy; (E.D.); (A.N.); (G.D.)
| | - Andrea Ballini
- School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
| | | | - Ciro Gargiulo Isacco
- SET-118, Department of Pre-Hospital and Emergency, SG Giuseppe Moscati Hospital, 74010 Taranto, Italy; (M.G.B.); (P.D.); (R.L.)
- American Stem Cells Hospital, Ho Chi Minh 70000, Vietnam;
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Whittle K, Kao S, Clarke S, Grau GE, Hosseini-Beheshti E. Exploring the role of extracellular vesicles and their protein cargo in lung cancer metastasis: a review. Crit Rev Oncol Hematol 2022; 171:103603. [DOI: 10.1016/j.critrevonc.2022.103603] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 01/17/2022] [Accepted: 01/18/2022] [Indexed: 12/12/2022] Open
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Kumar S, Kumar P, Kodidela S, Duhart B, Cernasev A, Nookala A, Kumar A, Singh UP, Bissler J. Racial Health Disparity and COVID-19. J Neuroimmune Pharmacol 2021; 16:729-742. [PMID: 34499313 PMCID: PMC8426163 DOI: 10.1007/s11481-021-10014-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023]
Abstract
The infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and resultant coronavirus diseases-19 (COVID-19) disproportionally affects minorities, especially African Americans (AA) compared to the Caucasian population. The AA population is disproportionally affected by COVID-19, in part, because they have high prevalence of underlying conditions such as obesity, diabetes, and hypertension, which are known to exacerbate not only kidney diseases, but also COVID-19. Further, a decreased adherence to COVID-19 guidelines among tobacco smokers could result in increased infection, inflammation, reduced immune response, and lungs damage, leading to more severe form of COVID-19. As a result of high prevalence of underlying conditions that cause kidney diseases in the AA population coupled with tobacco smoking make the AA population vulnerable to severe form of both COVID-19 and kidney diseases. In this review, we describe how tobacco smoking interact with SARS-CoV-2 and exacerbates SARS-CoV-2-induced kidney diseases including renal failure, especially in the AA population. We also explore the role of extracellular vesicles (EVs) in COVID-19 patients who smoke tobacco. EVs, which play important role in tobacco-mediated pathogenesis in infectious diseases, have also shown to be important in COVID-19 pathogenesis and organ injuries including kidney. Further, we explore the potential role of EVs in biomarker discovery and therapeutics, which may help to develop early diagnosis and treatment of tobacco-induced renal injury in COVID-19 patients, respectively.
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Affiliation(s)
- Santosh Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA.
| | - Prashant Kumar
- Department of Pediatrics, University of Tennessee Health Science Center and Le Bonheur Children's Hospital, Memphis, TN, USA
| | - Sunitha Kodidela
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Benjamin Duhart
- Department of Clinical Pharmacy and Translational Science, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - Alina Cernasev
- Department of Clinical Pharmacy and Translational Science, University of Tennessee Health Sciences Center, Nashville, TN, USA
| | | | - Asit Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Udai P Singh
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - John Bissler
- Department of Pediatrics, University of Tennessee Health Science Center and Le Bonheur Children's Hospital, Memphis, TN, USA.
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Giovannelli P, Di Donato M, Galasso G, Monaco A, Licitra F, Perillo B, Migliaccio A, Castoria G. Communication between cells: exosomes as a delivery system in prostate cancer. Cell Commun Signal 2021; 19:110. [PMID: 34772427 PMCID: PMC8586841 DOI: 10.1186/s12964-021-00792-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 10/03/2021] [Indexed: 02/08/2023] Open
Abstract
Despite the considerable efforts in screening and diagnostic protocols, prostate cancer still represents the second leading cause of cancer-related death in men. Many patients with localized disease and low risk of recurrence have a favourable outcome. In a substantial proportion of patients, however, the disease progresses and becomes aggressive. The mechanisms that promote prostate cancer progression remain still debated. Many findings point to the role of cross-communication between prostate tumor cells and their surrounding microenvironment during the disease progression. Such a connection fosters survival, proliferation, angiogenesis, metastatic spreading and drug-resistance of prostate cancer. Recent years have seen a profound interest in understanding the way by which prostate cancer cells communicate with the surrounding cells in the microenvironment. In this regard, direct cell-to-cell contacts and soluble factors have been identified. Increasing evidence indicates that PC cells communicate with the surrounding cells through the release of extracellular vesicles, mainly the exosomes. By directly acting in stromal or prostate cancer epithelial cells, exosomes represent a critical intercellular communication system. By querying the public database ( https://pubmed.ncbi.nlm.nih.gov ) for the past 10 years, we have found more than four hundred papers. Among them, we have extrapolated the most relevant about the role of exosomes in prostate cancer malignancy and progression. Emerging data concerning the use of these vesicles in diagnostic management and therapeutic guidance of PC patients are also presented. Video Abstract.
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Affiliation(s)
- Pia Giovannelli
- Dipartimento di Medicina di Precisione, Università Della Campania ‘L. Vanvitelli’, Via L. De Crecchio, 7, 80138 Naples, Italy
| | - Marzia Di Donato
- Dipartimento di Medicina di Precisione, Università Della Campania ‘L. Vanvitelli’, Via L. De Crecchio, 7, 80138 Naples, Italy
| | - Giovanni Galasso
- Dipartimento di Medicina di Precisione, Università Della Campania ‘L. Vanvitelli’, Via L. De Crecchio, 7, 80138 Naples, Italy
| | - Alessandra Monaco
- Dipartimento di Medicina di Precisione, Università Della Campania ‘L. Vanvitelli’, Via L. De Crecchio, 7, 80138 Naples, Italy
| | - Fabrizio Licitra
- Dipartimento di Medicina di Precisione, Università Della Campania ‘L. Vanvitelli’, Via L. De Crecchio, 7, 80138 Naples, Italy
| | - Bruno Perillo
- Istituto di Scienze dell’Alimentazione, C.N.R., 83100 Avellino, Italy
| | - Antimo Migliaccio
- Dipartimento di Medicina di Precisione, Università Della Campania ‘L. Vanvitelli’, Via L. De Crecchio, 7, 80138 Naples, Italy
| | - Gabriella Castoria
- Dipartimento di Medicina di Precisione, Università Della Campania ‘L. Vanvitelli’, Via L. De Crecchio, 7, 80138 Naples, Italy
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Zhu S, Li S, Yi M, Li N, Wu K. Roles of Microvesicles in Tumor Progression and Clinical Applications. Int J Nanomedicine 2021; 16:7071-7090. [PMID: 34703228 PMCID: PMC8536885 DOI: 10.2147/ijn.s325448] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 10/08/2021] [Indexed: 12/20/2022] Open
Abstract
Microvesicles are extracellular vesicles with diameter ranging from 100 to 1000 nm that are secreted by tumor cells or other cells in the tumor microenvironment. A growing number of studies demonstrate that tumor-derived microvesicles are involved in tumor initiation and progression, as well as drug resistance. In addition, tumor-derived microvesicles carry a variety of immunogenic molecules and inhibit tumor response to immunotherapy; therefore, they can be exploited for use in tumor vaccines. Moreover, because of their high stability, tumor-derived microvesicles extracted from body fluids can be used as biomarkers for cancer diagnosis or assessment of prognosis. Tumor-derived microvesicles can also be deployed to reverse drug resistance of tumor regenerative cells, or to deliver chemotherapeutic drugs and oncolytic adenovirus for the treatment of cancer patients. This review summarizes the general characteristics of tumor-derived microvesicles, focusing on their biological characteristics, their involvement in tumor progression, and their clinical applications.
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Affiliation(s)
- Shuangli Zhu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Shiyu Li
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Ning Li
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, People's Republic of China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.,Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, People's Republic of China
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McMillen P, Oudin MJ, Levin M, Payne SL. Beyond Neurons: Long Distance Communication in Development and Cancer. Front Cell Dev Biol 2021; 9:739024. [PMID: 34621752 PMCID: PMC8491768 DOI: 10.3389/fcell.2021.739024] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022] Open
Abstract
Cellular communication is important in all aspects of tissue and organism functioning, from the level of single cells, two discreet populations, and distant tissues of the body. Long distance communication networks integrate individual cells into tissues to maintain a complex organism during development, but when communication between cells goes awry, disease states such as cancer emerge. Herein we discuss the growing body of evidence suggesting that communication methods known to be employed by neurons, also exist in other cell types. We identify three major areas of long-distance communication: bioelectric signaling, tunneling nanotubes (TNTs), and macrophage modulation of networks, and draw comparisons about how these systems operate in the context of development and cancer. Bioelectric signaling occurs between cells through exchange of ions and tissue-level electric fields, leading to changes in biochemical gradients and molecular signaling pathways to control normal development and tumor growth and invasion in cancer. TNTs transport key morphogens and other cargo long distances, mediating electrical coupling, tissue patterning, and malignancy of cancer cells. Lastly macrophages maintain long distance signaling networks through trafficking of vesicles during development, providing communication relays and priming favorable microenvironments for cancer metastasis. By drawing comparisons between non-neural long distance signaling in the context of development and cancer we aim to encourage crosstalk between the two fields to cultivate new hypotheses and potential therapeutic strategies.
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Affiliation(s)
- Patrick McMillen
- Department of Biology, Allen Discovery Center, Tufts University, Medford, MA, United States
| | - Madeleine J Oudin
- Department of Biomedical Engineering, Tufts University, Medford, MA, United States
| | - Michael Levin
- Department of Biology, Allen Discovery Center, Tufts University, Medford, MA, United States
| | - Samantha L Payne
- Department of Biomedical Engineering, Tufts University, Medford, MA, United States
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Prieto-Vila M, Yoshioka Y, Ochiya T. Biological Functions Driven by mRNAs Carried by Extracellular Vesicles in Cancer. Front Cell Dev Biol 2021; 9:620498. [PMID: 34527665 PMCID: PMC8435577 DOI: 10.3389/fcell.2021.620498] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 07/30/2021] [Indexed: 12/15/2022] Open
Abstract
Extracellular vesicles (EVs), including exosomes and microvesicles, are extracellular nanovesicles released by most cells. EVs play essential roles in intercellular communication via the transport of a large variety of lipids, proteins, and nucleic acids to recipient cells. Nucleic acids are the most commonly found molecules inside EVs, and due to their small size, microRNAs and other small RNAs are the most abundant nucleic acids. However, longer molecules, such as messenger RNAs (mRNAs), have also been found. mRNAs encapsulated within EVs have been shown to be transferred to recipient cells and translated into proteins, altering the behavior of the cells. Secretion of EVs is maintained not only through multiple normal physiological conditions but also during aberrant pathological conditions, including cancer. Recently, the mRNAs carried by EVs in cancer have attracted great interest due to their broad roles in tumor progression and microenvironmental remodeling. This review focuses on the biological functions driven by mRNAs carried in EVs in cancer, which include supporting tumor progression by activating cancer cell growth, migration, and invasion; inducing microenvironmental remodeling via hypoxia, angiogenesis, and immunosuppression; and promoting modulation of the microenvironment at distant sites for the generation of a premetastatic niche, collectively inducing metastasis. Furthermore, we describe the potential use of mRNAs carried by EVs as a noninvasive diagnostic tool and novel therapeutic approach.
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Affiliation(s)
| | | | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
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Luquero A, Vilahur G, Crespo J, Badimon L, Borrell‐Pages M. Microvesicles carrying LRP5 induce macrophage polarization to an anti-inflammatory phenotype. J Cell Mol Med 2021; 25:7935-7947. [PMID: 34288375 PMCID: PMC8358886 DOI: 10.1111/jcmm.16723] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 05/19/2021] [Accepted: 05/29/2021] [Indexed: 12/12/2022] Open
Abstract
Microvesicles (MV) contribute to cell-to-cell communication through their transported proteins and nucleic acids. MV, released into the extracellular space, exert paracrine regulation by modulating cellular responses after interaction with near and far target cells. MV are released at high concentrations by activated inflammatory cells. Different subtypes of human macrophages have been characterized based on surface epitopes being CD16+ macrophages associated with anti-inflammatory phenotypes. We have previously shown that low-density lipoprotein receptor-related protein 5 (LRP5), a member of the LDLR family that participates in lipid homeostasis, is expressed in macrophage CD16+ with repair and survival functions. The goal of our study was to characterize the cargo and tentative function of macrophage-derived MV, whether LRP5 is delivered into MV and whether these MV are able to induce inflammatory cell differentiation to a specific CD16- or CD16+ phenotype. We show, for the first time, that lipid-loaded macrophages release MV containing LRP5. LDL loading induces increased expression of macrophage pro-inflammatory markers and increased release of MV containing pro-inflammatory markers. Conditioning of fresh macrophages with MV released by Lrp5-silenced macrophages induced the transcription of inflammatory genes and reduced the transcription of anti-inflammatory genes. Thus, MV containing LRP5 induce anti-inflammatory phenotypes in macrophages.
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Affiliation(s)
- Aureli Luquero
- Cardiovascular Program ICCCIR‐Hospital de la Santa Creu i Sant PauIIB‐Sant PauBarcelonaSpain
| | - Gemma Vilahur
- Cardiovascular Program ICCCIR‐Hospital de la Santa Creu i Sant PauIIB‐Sant PauBarcelonaSpain
- CIBER‐CVInstituto de Salud Carlos IIIMadridSpain
| | - Javier Crespo
- Cardiovascular Program ICCCIR‐Hospital de la Santa Creu i Sant PauIIB‐Sant PauBarcelonaSpain
| | - Lina Badimon
- Cardiovascular Program ICCCIR‐Hospital de la Santa Creu i Sant PauIIB‐Sant PauBarcelonaSpain
- CIBER‐CVInstituto de Salud Carlos IIIMadridSpain
- Cardiovascular Research ChairUABBarcelonaSpain
| | - Maria Borrell‐Pages
- Cardiovascular Program ICCCIR‐Hospital de la Santa Creu i Sant PauIIB‐Sant PauBarcelonaSpain
- CIBER‐CVInstituto de Salud Carlos IIIMadridSpain
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Hur JY, Lee KY. Characteristics and Clinical Application of Extracellular Vesicle-Derived DNA. Cancers (Basel) 2021; 13:3827. [PMID: 34359729 PMCID: PMC8345206 DOI: 10.3390/cancers13153827] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/25/2021] [Accepted: 07/27/2021] [Indexed: 02/06/2023] Open
Abstract
Extracellular vesicles (EVs) carry RNA, proteins, lipids, and diverse biomolecules for intercellular communication. Recent studies have reported that EVs contain double-stranded DNA (dsDNA) and oncogenic mutant DNA. The advantage of EV-derived DNA (EV DNA) over cell-free DNA (cfDNA) is the stability achieved through the encapsulation in the lipid bilayer of EVs, which protects EV DNA from degradation by external factors. The existence of DNA and its stability make EVs a useful source of biomarkers. However, fundamental research on EV DNA remains limited, and many aspects of EV DNA are poorly understood. This review examines the known characteristics of EV DNA, biogenesis of DNA-containing EVs, methylation, and next-generation sequencing (NGS) analysis using EV DNA for biomarker detection. On the basis of this knowledge, this review explores how EV DNA can be incorporated into diagnosis and prognosis in clinical settings, as well as gene transfer of EV DNA and its therapeutic potential.
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Affiliation(s)
- Jae Young Hur
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul 05030, Korea;
- Department of Pathology, Konkuk University Medical Center, Seoul 05030, Korea
| | - Kye Young Lee
- Precision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul 05030, Korea;
- Department of Pulmonary Medicine, Konkuk University School of Medicine, Seoul 05030, Korea
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48
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Hussain Z, Nigri J, Tomasini R. The Cellular and Biological Impact of Extracellular Vesicles in Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13123040. [PMID: 34207163 PMCID: PMC8235245 DOI: 10.3390/cancers13123040] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/11/2021] [Accepted: 06/14/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The increased incidence and global failure of ongoing therapies project pancreatic cancer as the second deadliest cancer worldwide. While our knowledge of pancreatic cancer cells’ abilities and specificities has drastically improved based on multi-scaled omics, one must consider that much more remains to be uncovered on the role and impact of stromal cells and the established network of communication with tumor cells. This review article discusses how tumor cells communicate with the various cells composing the stroma and its implication in tumor cells’ abilities, PDA (pancreatic ductal adenocarcinoma) carcinogenesis and therapeutic response. We will focus on extracellular vesicles-mediated crosstalk and how this multifaceted dialogue impacts both cellular compartments and its subsequent impact on PDA biology. Abstract Deciphering the interactions between tumor and stromal cells is a growing field of research to improve pancreatic cancer-associated therapies and patients’ care. Indeed, while accounting for 50 to 90% of the tumor mass, many pieces of evidence reported that beyond their structural role, the non-tumoral cells composing the intra-tumoral microenvironment influence tumor cells’ proliferation, metabolism, cell death and resistance to therapies, among others. Simultaneously, tumor cells can influence non-tumoral neighboring or distant cells in order to shape a tumor-supportive and immunosuppressive environment as well as influencing the formation of metastatic niches. Among intercellular modes of communication, extracellular vesicles can simultaneously transfer the largest variety of signals and were recently reported as key effectors of cell–cell communication in pancreatic cancer, from its development to its evolution as well as its ability to resist available treatments. This review focuses on extracellular vesicles-mediated communication between different cellular components of pancreatic tumors, from the modulation of cellular activities and abilities to their biological and physiological relevance. Taking into consideration the intra-tumoral microenvironment and its extracellular-mediated crosstalk as main drivers of pancreatic cancer development should open up new therapeutic windows.
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Tomita T, Kato M, Mishima T, Matsunaga Y, Sanjo H, Ito KI, Minagawa K, Matsui T, Oikawa H, Takahashi S, Takao T, Iwai N, Mino T, Takeuchi O, Maru Y, Hiratsuka S. Extracellular mRNA transported to the nucleus exerts translation-independent function. Nat Commun 2021; 12:3655. [PMID: 34135341 PMCID: PMC8208975 DOI: 10.1038/s41467-021-23969-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 05/27/2021] [Indexed: 12/19/2022] Open
Abstract
RNA in extracellular vesicles (EVs) are uptaken by cells, where they regulate fundamental cellular functions. EV-derived mRNA in recipient cells can be translated. However, it is still elusive whether “naked nonvesicular extracellular mRNA” (nex-mRNA) that are not packed in EVs can be uptaken by cells and, if so, whether they have any functions in recipient cells. Here, we show the entrance of nex-mRNA in the nucleus, where they exert a translation-independent function. Human nex-interleukin-1β (IL1β)-mRNA outside cells proved to be captured by RNA-binding zinc finger CCCH domain containing protein 12D (ZC3H12D)-expressing human natural killer (NK) cells. ZC3H12D recruited to the cell membrane binds to the 3′-untranslated region of nex-IL1β-mRNA and transports it to the nucleus. The nex-IL1β-mRNA in the NK cell nucleus upregulates antiapoptotic gene expression, migration activity, and interferon-γ production, leading to the killing of cancer cells and antimetastasis in mice. These results implicate the diverse actions of mRNA. Nonvesicular extracellular RNA (nex-RNA) that are not packed in extracellular vesicles is detected outside the cell, but it is poorly understood. Here the authors report that nex-RNA is captured by a zinc finger protein and transported to the nucleus to enhance antimetastatic characters of the cell.
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Affiliation(s)
- Takeshi Tomita
- Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, School of Medicine, Matsumoto, Nagano, Japan.,Department of Biochemistry and Molecular Biology, Shinshu University, School of Medicine, Matsumoto, Nagano, Japan
| | - Masayoshi Kato
- Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, School of Medicine, Matsumoto, Nagano, Japan.,Department of Biochemistry and Molecular Biology, Shinshu University, School of Medicine, Matsumoto, Nagano, Japan
| | - Taishi Mishima
- Department of Pharmacology, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan
| | - Yuta Matsunaga
- Department of Pharmacology, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan
| | - Hideki Sanjo
- Department of Molecular and Cellular Immunology, Shinshu University, School of Medicine, Matsumoto, Nagano, Japan
| | - Ken-Ichi Ito
- Division of Breast, Endocrine and Respiratory Surgery, Department of Surgery, Shinshu University, School of Medicine, Matsumoto, Nagano, Japan
| | - Kentaro Minagawa
- Department of Hematology/Oncology, Penn State College of Medicine, Hershey, PA, USA
| | - Toshimitsu Matsui
- Department of Hematology, Nishiwaki Municipal Hospital, Nishiwaki, Hyogo, Japan
| | - Hiroyuki Oikawa
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Japan
| | - Satoshi Takahashi
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Japan
| | - Toshifumi Takao
- Institute for Protein Research, Osaka University, Suita, Osaka, Japan
| | - Noriki Iwai
- Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takashi Mino
- Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Osamu Takeuchi
- Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshiro Maru
- Department of Pharmacology, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan.
| | - Sachie Hiratsuka
- Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, School of Medicine, Matsumoto, Nagano, Japan. .,Department of Biochemistry and Molecular Biology, Shinshu University, School of Medicine, Matsumoto, Nagano, Japan.
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50
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Chivero ET, Dagur RS, Peeples ES, Sil S, Liao K, Ma R, Chen L, Gurumurthy CB, Buch S, Hu G. Biogenesis, physiological functions and potential applications of extracellular vesicles in substance use disorders. Cell Mol Life Sci 2021; 78:4849-4865. [PMID: 33821293 PMCID: PMC10563196 DOI: 10.1007/s00018-021-03824-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/02/2021] [Accepted: 03/26/2021] [Indexed: 02/07/2023]
Abstract
Substance use disorder (SUD) is a growing health problem that affects several millions of people worldwide, resulting in negative socioeconomic impacts and increased health care costs. Emerging evidence suggests that extracellular vesicles (EVs) play a crucial role in SUD pathogenesis. EVs, including exosomes and microvesicles, are membrane-encapsulated particles that are released into the extracellular space by most types of cells. EVs are important players in mediating cell-to-cell communication through transfer of cargo such as proteins, lipids and nucleic acids. The EV cargo can alter the status of recipient cells, thereby contributing to both physiological and pathological processes; some of these play critical roles in SUD. Although the functions of EVs under several pathological conditions have been extensively reviewed, EV functions and potential applications in SUD remain less studied. In this review, we provide an overview of the current knowledge of the role of EVs in SUD, including alcohol, cocaine, heroin, marijuana, nicotine and opiate abuse. The review will focus on the biogenesis and cargo composition of EVs as well as the potential use of EVs as biomarkers of SUD or therapeutic targets in SUD.
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Affiliation(s)
- Ernest T Chivero
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.
| | - Raghubendra Singh Dagur
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68105, USA
| | - Eric S Peeples
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA
| | - Susmita Sil
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Ke Liao
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
- Cedars-Sinai Medical Center, Smidt Heart Institute, Los Angeles, CA, USA
| | - Rong Ma
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Liang Chen
- Department of Computer Science, College of Engineering, Shantou University, Shantou, Guangdong, China
- Key Laboratory of Intelligent Manufacturing Technology, Ministry of Education, Shantou University, Shantou, Guangdong, China
| | - Channabasavaiah B Gurumurthy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Shilpa Buch
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Guoku Hu
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.
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