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Movahed ZG, Mansouri K, Mohsen AH, Matin MM. Bone marrow mesenchymal stem cells enrich breast cancer stem cell population via targeting metabolic pathways. Med Oncol 2025; 42:90. [PMID: 40045066 DOI: 10.1007/s12032-025-02632-5] [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: 10/26/2024] [Accepted: 02/13/2025] [Indexed: 03/29/2025]
Abstract
The role of cancer cell metabolic reprogramming in the formation and maintenance of cancer stem cells (CSCs) has been well established. This reprogramming involves alterations in the metabolic pathways of cancer cells, leading to the acquisition of stem cell-like properties such as self-renewal and differentiation. This study aimed to investigate the potential effects of bone marrow mesenchymal stem cells (BM-MSCs) on the enrichment of breast CSCs. Exosomes (Exo) and conditioned media (CM) were isolated from BM-MSCs for use in this experimental study. The impact of BM-MSCs-Exo and BM-MSCs-CM on the expression of stemness genes NANOG and OCT-4, as well as CD24 and CD44 markers, was assessed in MCF-7 and MDA-MB-231 cell cultures to identify CSCs. Furthermore, the effects of BM-MSCs-Exo and BM-MSCs-CM on cancer cell metabolism were evaluated by examining changes in glycolysis, the pentose phosphate pathway (PPP), and amino acid profiles. Additionally, the influence of BM-MSCs-Exo and BM-MSCs-CM on tumor growth in vivo was also investigated. The analysis of stemness marker expression in cells treated with BM-MSCs-Exo and BM-MSCs-CM revealed an increase in stemness characteristics compared to the control group. Furthermore, the examination of changes in cell metabolism following these treatments showed alterations in glycolysis, PPP, and amino acid metabolism pathways. Additionally, it was demonstrated that BM-MSCs-Exo and BM-MSCs-CM can promote tumor growth in mice following transplantation of 4T1 cells. These findings suggest that BM-MSCs-Exo and BM-MSCs-CM can enrich the population of CSCs in MCF-7 and MDA-MB-231 cells by targeting metabolic pathways, however, further studies are required to elicit the exact mechanisms of these phenomena.
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Affiliation(s)
- Zahra Ghanbari Movahed
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Bākhtarān, Iran
| | - Kamran Mansouri
- Medical Biology Research Center, Health Technology Institute, School of Medicine, Kermanshah University of Medical Sciences, P.O. Box 67145-1673, Bākhtarān, Iran.
| | - Ali Hamrahi Mohsen
- Institute of Biochemistry and Biophysics, Faculty of Science, University of Tehran, Tehran, Iran
| | - Maryam M Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
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Cohen-Hagai K, Kuchuk E, Matalon ST, Benchetrit S, Zitman-Gal T. Exosomes Derived from Dialysis Patients' Serum Enhance Endothelial-Mesenchymal Transition and Calcification in Endothelial Cells. KIDNEY360 2025; 6:351-360. [PMID: 39899380 PMCID: PMC11970854 DOI: 10.34067/kid.0000000678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 12/06/2024] [Indexed: 02/05/2025]
Abstract
Key Points Vascular calcification (VC) is an independent risk factor of cardiovascular disease in patients with ESKD. We found that exosomes derived from serum of dialysis patients with VC induced endothelial–mesenchymal transition and thus contribute to calcification. The complex interplay between exosomes from dialysis patients with VC and endothelial cells highlights the critical need for therapeutic strategies. Background Vascular calcification (VC) is prevalent among patients with ESKD. Exosomes, small extracellular vesicles actively secreted by cells, contain proteins, nucleic acids, lipids, and other bioactive substances and are considered major mediators of cell–cell interactions. Endothelial–mesenchymal transition (EndMT) has been observed in a variety of pathological conditions, such as abnormal shear stress, vascular damage, and chronic inflammation. The aim of this research was to assess the effects of serum-derived exosomes from ESKD patients with VC on the induction of EndMT in endothelial cells (ECs) and their potential role in accelerating VC. Methods Twenty patients on hemodialysis with VC and ten healthy volunteers were recruited. Cardiac and brain VCs were assessed among patients with ESKD treated with dialysis. Serum samples were obtained at dialysis initiation for exosome isolation. Human umbilical vein ECs were treated with 100 µ g/ml exosomes for 24–96 hours. At the end of incubation, cells were collected for mRNA and protein analysis. Results Exosomes isolated from dialysis patients with VC induced EndMT in human umbilical vein ECs. After 24 hours, endothelial markers CD31 and vascular endothelial-cadherin were decreased (31% and 51%, respectively; P < 0.001) and the mesenchymal proteins Vimentin and N -cadherin were increased (283% and 156%, respectively; P < 0.001), compared with healthy exosomes. After 96 hours of incubation, expression of genes essential for osteoblast differentiation, including the bone morphogenetic genes (BMP2, BMPR2, BMP4, and BMP9), and the transcription factor RUNX2 were significantly elevated. Conclusions Exosomes derived from the serum of dialysis patients with VC induced EndMT and contributed to calcification. The vicious cycle highlighted the intricate interplay between exosomes, ECs, and VC, emphasizing the critical necessity for therapeutic strategies to disrupt this pathway and mitigate calcification advancement.
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Affiliation(s)
- Keren Cohen-Hagai
- Department of Nephrology and Hypertension, Meir Medical Center, Kfar Saba, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Eran Kuchuk
- Department of Nephrology and Hypertension, Meir Medical Center, Kfar Saba, Israel
| | - Shelly Tartakover Matalon
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
- Autoimmune Research Laboratory, Meir Medical Center, Kfar Saba, Israel
| | - Sydney Benchetrit
- Department of Nephrology and Hypertension, Meir Medical Center, Kfar Saba, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Tali Zitman-Gal
- Department of Nephrology and Hypertension, Meir Medical Center, Kfar Saba, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
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Song J, Ye X, Xiao H. Liquid biopsy entering clinical practice: Past discoveries, current insights, and future innovations. Crit Rev Oncol Hematol 2025; 207:104613. [PMID: 39756526 DOI: 10.1016/j.critrevonc.2025.104613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/22/2024] [Accepted: 01/02/2025] [Indexed: 01/07/2025] Open
Abstract
In recent years, liquid biopsy has gained prominence as an emerging biomarker in cancer research, providing critical insights into tumor biology and metastasis. Technological advancements have enabled its integration into clinical practice, with ongoing trials demonstrating encouraging outcomes. Key applications of liquid biopsy include early cancer detection, cancer staging, prognosis evaluation, and real-time monitoring of tumor progression to optimize treatment decisions. In this review, we present a comprehensive conceptual framework for liquid biopsy, discuss the challenges in its research and clinical application, and highlight its significant potential in identifying therapeutic targets and resistance mechanisms across various cancer types. Furthermore, we explore the emerging role of liquid biopsy-based multicancer screening, which has shown promising advancements. Looking ahead, standardization, multi-omics coanalysis, and the advancement of precision medicine and personalized treatments are expected to drive the future development and integration of liquid biopsy into routine clinical workflows, enhancing cancer diagnosis and treatment management.
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Affiliation(s)
- Jinghan Song
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiong Ye
- School of Clinical Medicine, Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Hui Xiao
- Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Liu L, Liu W, Han Z, Shan Y, Xie Y, Wang J, Qi H, Xu Q. Extracellular Vesicles-in-Hydrogel (EViH) targeting pathophysiology for tissue repair. Bioact Mater 2025; 44:283-318. [PMID: 39507371 PMCID: PMC11539077 DOI: 10.1016/j.bioactmat.2024.10.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 10/08/2024] [Accepted: 10/17/2024] [Indexed: 11/08/2024] Open
Abstract
Regenerative medicine endeavors to restore damaged tissues and organs utilizing biological approaches. Utilizing biomaterials to target and regulate the pathophysiological processes of injured tissues stands as a crucial method in propelling this field forward. The Extracellular Vesicles-in-Hydrogel (EViH) system amalgamates the advantages of extracellular vesicles (EVs) and hydrogels, rendering it a prominent biomaterial in regenerative medicine with substantial potential for clinical translation. This review elucidates the development and benefits of the EViH system in tissue regeneration, emphasizing the interaction and impact of EVs and hydrogels. Furthermore, it succinctly outlines the pathophysiological characteristics of various types of tissue injuries such as wounds, bone and cartilage injuries, cardiovascular diseases, nerve injuries, as well as liver and kidney injuries, underscoring how EViH systems target these processes to address related tissue damage. Lastly, it explores the challenges and prospects in further advancing EViH-based tissue regeneration, aiming to impart a comprehensive understanding of EViH. The objective is to furnish a thorough overview of EViH in enhancing regenerative medicine applications and to inspire researchers to devise innovative tissue engineering materials for regenerative medicine.
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Affiliation(s)
- Lubin Liu
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Wei Liu
- Department of Emergency Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266003, China
| | - Zeyu Han
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Yansheng Shan
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Yutong Xie
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Jialu Wang
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Hongzhao Qi
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Quanchen Xu
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
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Cipa J, Endzelins E, Abols A, Romanchikova N, Line A, Jenster GW, Mozolevskis G, Rimsa R. Elucidating Extracellular Vesicle Isolation Kinetics via an Integrated Off-Stoichiometry Thiol-Ene and Cyclic Olefin Copolymer Microfluidic Device. Polymers (Basel) 2024; 16:3579. [PMID: 39771431 PMCID: PMC11678796 DOI: 10.3390/polym16243579] [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: 11/29/2024] [Revised: 12/15/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Extracellular vesicles (EVs) are promising biomarkers for diagnosing complex diseases such as cancer and neurodegenerative disorders. Yet, their clinical application is hindered by challenges in isolating cancer-derived EVs efficiently due to their broad size distribution in biological samples. This study introduces a microfluidic device fabricated using off-stoichiometry thiol-ene and cyclic olefin copolymer, addressing the absorption limitations of polydimethylsiloxane (PDMS). The device streamlines a standard laboratory assay into a semi-automated microfluidic chip, integrating sample mixing and magnetic particle separation. Using the microfluidic device, the binding kinetics between EVs and anti-CD9 nanobodies were measured for the first time. Based on the binding kinetics, already after 10 min the EV capture was saturated and comparable to standard laboratory assays, offering a faster alternative to antibody-based immunomagnetic protocols. Furthermore, this study reveals the binding kinetics of EVs to anti-CD9 nanobodies for the first time. Our findings demonstrate the potential of the microfluidic device to enhance clinical diagnostics by offering speed and reducing manual labor without compromising accuracy.
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Affiliation(s)
- Janis Cipa
- Institute of Solid State Physics, University of Latvia, 8 Kengaraga Str., LV-1063 Riga, Latvia; (J.C.); (G.M.)
- Cellbox Labs LLC, 8 Kengaraga Str., LV-1063 Riga, Latvia;
| | - Edgars Endzelins
- Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, LV-1067 Riga, Latvia; (E.E.); (N.R.); (A.L.)
| | - Arturs Abols
- Cellbox Labs LLC, 8 Kengaraga Str., LV-1063 Riga, Latvia;
- Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, LV-1067 Riga, Latvia; (E.E.); (N.R.); (A.L.)
| | - Nadezda Romanchikova
- Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, LV-1067 Riga, Latvia; (E.E.); (N.R.); (A.L.)
| | - Aija Line
- Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, LV-1067 Riga, Latvia; (E.E.); (N.R.); (A.L.)
| | - Guido W. Jenster
- Department of Urology, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands;
| | - Gatis Mozolevskis
- Institute of Solid State Physics, University of Latvia, 8 Kengaraga Str., LV-1063 Riga, Latvia; (J.C.); (G.M.)
- Cellbox Labs LLC, 8 Kengaraga Str., LV-1063 Riga, Latvia;
| | - Roberts Rimsa
- Institute of Solid State Physics, University of Latvia, 8 Kengaraga Str., LV-1063 Riga, Latvia; (J.C.); (G.M.)
- Cellbox Labs LLC, 8 Kengaraga Str., LV-1063 Riga, Latvia;
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Jiang A, Liu Y, He Z, Liu W, Yang Q, Fang Y, Zhu B, Wu X, Ye H, Ye B, Gao S, Qu L, Xu W, Luo P, Wang L. TDERS, an exosome RNA-derived signature predicts prognosis and immunotherapeutic response in clear cell renal cell cancer: a multicohort study. JOURNAL OF THE NATIONAL CANCER CENTER 2024; 4:382-394. [PMID: 39735439 PMCID: PMC11674438 DOI: 10.1016/j.jncc.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 06/08/2024] [Accepted: 07/23/2024] [Indexed: 12/31/2024] Open
Abstract
Background Tumor-derived exosomes are involved in tumor progression and immune invasion and might function as promising noninvasive approaches for clinical management. However, there are few reports on exosom-based markers for predicting the progression and adjuvant therapy response rate among patients with clear cell renal cell carcinoma (ccRCC). Methods The signatures differentially expressed in exosomes from tumor and normal tissues from ccRCC patients were correspondingly deregulated in ccRCC tissues. We adopted a two-step strategy, including Lasso and bootstrapping, to construct a novel risk stratification system termed the TDERS (Tumor-Derived Exosome-Related Risk Score). During the testing and validation phases, we leveraged multiple external datasets containing over 2000 RCC cases from eight cohorts and one inhouse cohort to evaluate the accuracy of the TDERS. In addition, enrichment analysis, immune infiltration signatures, mutation landscape and therapy sensitivity between the high and low TDERS groups were compared. Finally, the impact of TDERS on the tumor microenvironment (TME) was also analysed in our single-cell datasets. Results TDERS consisted of 12 mRNAs deregulated in both exosomes and tissues from patients with ccRCC. TDERS achieved satisfactory performance in both prognosis and immune checkpoint inhibitor (ICI) response across all ccRCC cohorts and other pathological types, since the average area under the curve (AUC) to predict 5-year overall survival (OS) was larger than 0.8 across the four cohorts. Patients in the TDERS high group were resistant to ICIs, while mercaptopurine might function as a promising agent for those patients. Patients with a high TDERS were characterized by coagulation and hypoxia, which induced hampered tumor antigen presentation and relative resistance to ICIs. In addition, single cells from 12 advanced samples validated this phenomenon since the interaction between dendritic cells and macrophages was limited. Finally, PLOD2, which is highly expressed in fibro- and epi‑tissue, could be a potential therapeutic target for ccRCC patients since inhibiting PLOD2 altered the malignant phenotype of ccRCC in vitro. Conclusion As a novel, non-invasive, and repeatable monitoring tool, the TDERS could work as a robust risk stratification system for patients with ccRCC and precisely inform treatment decisions about ICI therapy.
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Affiliation(s)
- Aimin Jiang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Ying Liu
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Ziwei He
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Wenqiang Liu
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Qiwei Yang
- Department of Urology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Urology, the Third Affiliated Hospital of Naval Military Medical University (Eastern Hepatobiliary Surgery Hospital), Shanghai, China
| | - Yu Fang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Baohua Zhu
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Xiaofeng Wu
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Huamao Ye
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Bicheng Ye
- School of Clinical Medicine, Medical College of Yangzhou Polytechnic College, Yangzhou, China
| | - Shunxiang Gao
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Le Qu
- Department of Urology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Wenhao Xu
- Department of Urology, Fudan University Shanghai Cancer Center, State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, and Human Phenome Institute, Fudan University, Shanghai, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Linhui Wang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
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Harding MA, Yavuz H, Gathmann A, Upson S, Swiatecka‐Urban A, Erdbrügger U. Uromodulin and the study of urinary extracellular vesicles. JOURNAL OF EXTRACELLULAR BIOLOGY 2024; 3:e70022. [PMID: 39582686 PMCID: PMC11583080 DOI: 10.1002/jex2.70022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 10/05/2024] [Accepted: 10/25/2024] [Indexed: 11/26/2024]
Abstract
Urinary extracellular vesicles (uEVs) are a promising substrate for discovering new biomarkers. In order to investigate the origin of uEVs and the cargo they carry, some types of downstream analysis of uEVs may require concentration and enrichment as well as removal of contaminating substances. Co-isolation of the abundant urinary protein uromodulin with uEVs can be a problem, and may interfere with some techniques, in particular with proteomic analysis tools. Methods of separating out uromodulin and its removal have also not been standardized. This review highlights aspects of uromodulin structure that makes it recalcitrant to separation from uEVs, summarizes frequently used techniques for uEV enrichment and how they affect uromodulin separation, and specific methods for uromodulin removal during preparation of uEVs. The necessity of uromodulin removal for various study endpoints is also examined.
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Affiliation(s)
- Michael A. Harding
- Division of Nephrology, Department of MedicineUniversity of VirginiaCharlottesvilleVirginiaUSA
| | - Hayrettin Yavuz
- Division of Pediatric Nephrology, Department of MedicineUniversity of VirginiaCharlottesvilleVirginiaUSA
| | | | - Samantha Upson
- Division of Nephrology, Department of MedicineUniversity of VirginiaCharlottesvilleVirginiaUSA
| | - Agnieszka Swiatecka‐Urban
- Division of Pediatric Nephrology, Department of MedicineUniversity of VirginiaCharlottesvilleVirginiaUSA
| | - Uta Erdbrügger
- Division of Nephrology, Department of MedicineUniversity of VirginiaCharlottesvilleVirginiaUSA
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Mehrvar A, Akbari M, Khosroshahi EM, Nekavand M, Mokhtari K, Baniasadi M, Aghababaian M, Karimi M, Amiri S, Moazen A, Maghsoudloo M, Alimohammadi M, Rahimzadeh P, Farahani N, Vaghar ME, Entezari M, Hashemi M. The impact of exosomes on bone health: A focus on osteoporosis. Pathol Res Pract 2024; 263:155618. [PMID: 39362132 DOI: 10.1016/j.prp.2024.155618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 10/05/2024]
Abstract
Osteoporosis is a widespread chronic condition. Although standard treatments are generally effective, they are frequently constrained by side effects and the risk of developing drug resistance. A promising area of research is the investigation of extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, which play a crucial role in bone metabolism. Exosomes, in particular, have shown significant potential in both the diagnosis and treatment of osteoporosis. EVs derived from osteoclasts, osteoblasts, mesenchymal stem cells, and other sources can influence bone metabolism, while exosomes from inflammatory and tumor cells may exacerbate bone loss, highlighting their dual role in osteoporosis pathology. This review offers a comprehensive overview of EV biogenesis, composition, and function in osteoporosis, focusing on their diagnostic and therapeutic potential. We examine the roles of various types of EVs and their cargo-proteins, RNAs, and lipids-in bone metabolism. Additionally, we explore the emerging applications of EVs as biomarkers and therapeutic agents, emphasizing the need for further research to address current challenges and enhance EV-based strategies for managing osteoporosis.
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Affiliation(s)
- Amir Mehrvar
- Assistant Professor, Department of Orthopedics, Taleghani Hospital Research Development Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadarian Akbari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrandokht Nekavand
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Midwifery, Faculty of nursing and midwifery, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Khatere Mokhtari
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Mojtaba Baniasadi
- Department of Orthopedic Surgery, Isfahan University of Medical Sciences, Isfahan, Iran; MD, Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Department of Orthopedic, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Majid Aghababaian
- Department of Orthopedic Surgery, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mansour Karimi
- MD, Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Department of Orthopedic, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shayan Amiri
- MD, Assistant Professor of Orthopaedic Surgery, Shohadaye Haftom-e-Tir Hospital, Department of Orthopedic, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Moazen
- Department of Orthopedics, Bone and Joint Reconstruction Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mazaher Maghsoudloo
- Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan 646000, PR China
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mohammad Eslami Vaghar
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of gynecology, Faculty of Medicine, Tehran Medical sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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9
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Zhu T, Fu H, Wang Z, Guo S, Zhang S. Identification of exosomal ceRNA networks as prognostic markers in clear cell renal cell carcinoma. Medicine (Baltimore) 2024; 103:e40167. [PMID: 39470474 PMCID: PMC11521039 DOI: 10.1097/md.0000000000040167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 10/01/2024] [Accepted: 10/02/2024] [Indexed: 10/30/2024] Open
Abstract
Aggressive clear cell renal cell carcinoma (ccRCC) has a bad prognosis. We seek new ccRCC biomarkers for diagnosis and treatment. We used exoRBase and The Cancer Genome Atlas Database to compare DEmRNAs, DEmiRNAs, DElncRNAs, and DEcircRNAs in ccRCC and normal renal tissues. CircRNAs and circRNAs targeting microRNAs (miRNAs) were anticipated and taken intersections, and several databases assessed the targeted link between common miRNAs and messenger RNAs (mRNAs). The Cancer Genome Atlas database was used to create a predictive mRNA signature that was validated in E-MTAB-1980. Finally, we examined competing endogenous RNA network miRNAs and long noncoding RNAs for ccRCC predictive biomarkers using overall survival analysis. We built the first competing endogenous RNA regulation network of circRNA-lncRNA-miRNA-mRNA and found that it substantially correlates with ccRCC prognosis. We unveiled ccRCC's posttranscriptional regulation mechanism in greater detail. Our findings identified novel biomarkers for ccRCC diagnosis, therapy, and prognosis.
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Affiliation(s)
- Tao Zhu
- Department of Urology, Weifang People’s Hospital, Weifang, Shandong Province, China
| | - Haizhu Fu
- Department of Urology, Shouguang Hospital of Traditional Chinese Medicine, Shouguang, Shandong Province, China
| | - Zhiqiang Wang
- Department of Urology, Shouguang Hospital of Traditional Chinese Medicine, Shouguang, Shandong Province, China
| | - Shanchun Guo
- RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA
| | - Shidong Zhang
- Department of Urology, Weifang People’s Hospital, Weifang, Shandong Province, China
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10
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Krotofil M, Tota M, Siednienko J, Donizy P. Emerging Paradigms in Cancer Metastasis: Ghost Mitochondria, Vasculogenic Mimicry, and Polyploid Giant Cancer Cells. Cancers (Basel) 2024; 16:3539. [PMID: 39456632 PMCID: PMC11506636 DOI: 10.3390/cancers16203539] [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: 09/03/2024] [Revised: 10/04/2024] [Accepted: 10/18/2024] [Indexed: 10/28/2024] Open
Abstract
The capacity of cancer cells to migrate from a primary tumor, disseminate throughout the body, and eventually establish secondary tumors is a fundamental aspect of metastasis. A detailed understanding of the cellular and molecular mechanisms underpinning this multifaceted process would facilitate the rational development of therapies aimed at treating metastatic disease. Although various hypotheses and models have been proposed, no single concept fully explains the mechanism of metastasis or integrates all observations and experimental findings. Recent advancements in metastasis research have refined existing theories and introduced new ones. This review evaluates several novel/emerging theories, focusing on ghost mitochondria (GM), vasculogenic mimicry (VM), and polyploid giant cancer cells (PGCCs).
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Affiliation(s)
- Mateusz Krotofil
- Department of Clinical and Experimental Pathology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland
| | - Maciej Tota
- Department of Clinical and Experimental Pathology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland
| | - Jakub Siednienko
- Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
| | - Piotr Donizy
- Department of Clinical and Experimental Pathology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland
- Department of Pathology and Clinical Cytology, Jan Mikulicz-Radecki University Hospital, 50-556 Wroclaw, Poland
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11
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Walter-Rodriguez B, Ricketts CJ, Linehan WM, Merino MJ. Evaluating the Urinary Exosome microRNA Profile of von Hippel Lindau Syndrome Patients with Clear Cell Renal Cell Carcinoma. Genes (Basel) 2024; 15:905. [PMID: 39062684 PMCID: PMC11276299 DOI: 10.3390/genes15070905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 07/05/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
INTRODUCTION Renal cell carcinoma is one of the ten more common malignant tumors worldwide, with a high incidence and mortality rate. Kidney cancer frequently presents at an advanced stage, and it is almost invariably fatal. Much progress has been made in identifying molecular targets for therapy in the hope of improving survival rates, but still, we have no good markers for early detection or progression of the disease. Von Hippel Lindau syndrome (VHL) is an autosomal dominant cancer hereditary syndrome in which affected individuals are at risk of developing bilateral and multifocal renal cell carcinomas (RCC) as well as other tumors. These patients provide an ideal platform to investigate the potential of urinary exosomal miRNA biomarkers in the early development of ccRCC, as these patients are regularly imaged and tumors are actively monitored until the tumor reaches 3 cm before surgical excision. This allows for pre- and post-surgical urine collection and comparison to excised tumor tissues. Studying different biomarkers in urine can provide comprehensive molecular profiling available to patients and physicians and can be a great source of additional tumor genetic information. METHODS Pre- and postoperative urine samples were obtained from a cohort of VHL patients undergoing surveillance and surgical excision of ccRCCs, and exosomes were extracted. MicroRNA-Seq analysis was performed on miRNA extracted from both urine-derived exosomes and FFPE material from excised ccRCCs. RESULTS MicroRNA-Seq analysis highlighted a significant difference in the urinary exosome-derived miRNA expression profiles between VHL patients and normal control individuals. This included decreased expression of the miR-320 family, such as miR-320a, known to be decreased in sporadic ccRCC and suppressed by the HIF1α transcription factor activated by the loss of the VHL gene. MiR-542-5p represented a potential marker of VHL-associated ccRCC that was lowly expressed in normal control urinary exosomes, significantly increased in the preoperative urinary exosomes of tumor-bearing VHL patients, and subsequently reduced to normal levels of expression after tumor excision. In concordance with this, the expression of miR-542-5p was increased in the VHL-associated ccRCC in comparison to the normal kidney. CONCLUSIONS This study shows the potential for miRNA profiling of exosomes from readily available biofluids to both distinguish VHL patient urine from normal control urine microRNAs and to provide biomarkers for the presence of VHL syndrome-associated ccRCC. Further validation studies are necessary to demonstrate the utility of urinary exosome-derived miRNAs as biomarkers in kidney cancer.
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Affiliation(s)
- Beatriz Walter-Rodriguez
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Christopher J. Ricketts
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (C.J.R.); (W.M.L.)
| | - W. Marston Linehan
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (C.J.R.); (W.M.L.)
| | - Maria J. Merino
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
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12
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Shi M, Jia JS, Gao GS, Hua X. Advances and challenges of exosome-derived noncoding RNAs for hepatocellular carcinoma diagnosis and treatment. Biochem Biophys Rep 2024; 38:101695. [PMID: 38560049 PMCID: PMC10979073 DOI: 10.1016/j.bbrep.2024.101695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 02/10/2024] [Accepted: 03/20/2024] [Indexed: 04/04/2024] Open
Abstract
Exosomes, also termed extracellular vesicles (EVs), are an important component of the tumor microenvironment (TME) and exert versatile effects on the molecular communications in the TME of hepatocellular carcinoma (HCC). Exosome-mediated intercellular communication is closely associated with the tumorigenesis and development of HCC. Exosomes can be extracted through ultracentrifugation and size exclusion, followed by molecular analysis through sequencing. Increasing studies have confirmed the important roles of exosome-derived ncRNAs in HCC, including tumorigenesis, progression, immune escape, and treatment resistance. Due to the protective membrane structure of exosomes, the ncRNAs carried by exosomes can evade degradation by enzymes in body fluids and maintain good expression stability. Thus, exosome-derived ncRNAs are highly suitable as biomarkers for the diagnosis and prognostic prediction of HCC, such as exosomal miR-21-5p, miR-221-3p and lncRNA-ATB. In addition, substantial studies revealed that the up-or down-regulation of exosome-derived ncRNAs had an important impact on HCC progression and response to treatment. Exosomal biomarkers, such as miR-23a, lncRNA DLX6-AS1, miR-21-5p, lncRNA TUC339, lncRNA HMMR-AS1 and hsa_circ_0004658, can reshape immune microenvironment by regulating M2-type macrophage polarization and then promote HCC development. Therefore, by controlling exosome biogenesis and modulating exosomal ncRNA levels, HCC may be inhibited or eliminated. In this current review, we summarized the recent findings on the role of exosomes in HCC progression and analyzed the relationship between exosome-derived ncRNAs and HCC diagnosis and treatment.
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Affiliation(s)
- Min Shi
- Department of Clinical Laboratory, Ningbo No.2 Hospital, Ningbo, Zhejiang, China
| | - Jun-Su Jia
- Department of Clinical Laboratory, Ningbo No.2 Hospital, Ningbo, Zhejiang, China
| | - Guo-Sheng Gao
- Department of Clinical Laboratory, Ningbo No.2 Hospital, Ningbo, Zhejiang, China
| | - Xin Hua
- Department of Clinical Laboratory, Ningbo No.2 Hospital, Ningbo, Zhejiang, China
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13
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Li Q, Zhan S, Yang X, Zhang Z, Sun N, Wang X, Kang J, Du R, Hong X, Yue M, Li X, Tang Y, Liu G, Liu Y, Liu D. Choline Phosphate-Grafted Nanozymes as Universal Extracellular Vesicle Probes for Bladder Cancer Detection. ACS NANO 2024; 18:16113-16125. [PMID: 38857428 DOI: 10.1021/acsnano.4c00280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2024]
Abstract
Urinary extracellular vesicles (uEVs) are regarded as highly promising liquid-biopsy biomarkers for the early diagnosis and prognosis of bladder cancer (BC). However, detection of uEVs remains technically challenging owing to their huge heterogeneity and ultralow abundance in real samples. We herein present a choline phosphate-grafted platinum nanozyme (Pt@CP) that acts as a universal EV probe for the construction of a high-throughput and high-sensitivity immunoassay, which allowed multiplex profiling of uEV protein markers for BC detection. With the Pt@CP-based immunoassays, three uEV protein markers (MUC-1, CCDC25, and GLUT1) were identified for BC, by which the BC cases (n = 48), cystitis patients (n = 27), and healthy donors (n = 24) were discriminated with high clinical sensitivity and specificity (area under curve = 98.3%). For the BC cases (n = 9) after surgery, the Pt@CP-based immunoassay could report the postoperative residual tumor that cannot be observed by cystoscopy, which is clinically significant for assessing BC recurrence. This work provides generally high sensitivity for EV detection, facilitating the discovery and clinical use of EV-based biomarkers.
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Affiliation(s)
- Qiang Li
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Saisong Zhan
- Key Laboratory of Inorganic-Organic Hybrid Functional Materials Chemistry, Ministry of Education, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, College of Chemistry, Tianjin Normal University, Tianjin 300387, China
| | - Xiaoqing Yang
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Zhaowei Zhang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Ning Sun
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Xiang Wang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Jingjing Kang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Rui Du
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Xiaoqin Hong
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Minghao Yue
- Department of Urology, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Xiaomin Li
- Medical and Hygienic Materials Research Institute, SINOPEC (Beijing) Research Institute of Chemical Industry Co., Ltd., Beijing 100013, China
| | - Yujing Tang
- Medical and Hygienic Materials Research Institute, SINOPEC (Beijing) Research Institute of Chemical Industry Co., Ltd., Beijing 100013, China
| | - Guangming Liu
- Department of Urology, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Yue Liu
- Key Laboratory of Inorganic-Organic Hybrid Functional Materials Chemistry, Ministry of Education, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, College of Chemistry, Tianjin Normal University, Tianjin 300387, China
| | - Dingbin Liu
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Recognition and Biosensing, Frontiers Science Centers for Cell Responses and New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
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14
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Zhand S, Liao J, Castorina A, Yuen ML, Ebrahimi Warkiani M, Cheng YY. Small Extracellular Vesicle-Derived Circular RNA hsa_circ_0007386 as a Biomarker for the Diagnosis of Pleural Mesothelioma. Cells 2024; 13:1037. [PMID: 38920665 PMCID: PMC11201843 DOI: 10.3390/cells13121037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 05/30/2024] [Accepted: 06/12/2024] [Indexed: 06/27/2024] Open
Abstract
Pleural mesothelioma (PM) is a highly aggressive tumor that is caused by asbestos exposure and lacks effective therapeutic regimens. Current procedures for PM diagnosis are invasive and can take a long time to reach a definitive result. Small extracellular vesicles (sEVs) have been identified as important communicators between tumor cells and their microenvironment via their cargo including circular RNAs (circRNAs). CircRNAs are thermodynamically stable, highly conserved, and have been found to be dysregulated in cancer. This study aimed to identify potential biomarkers for PM diagnosis by investigating the expression of specific circRNA gene pattern (hsa_circ_0007386) in cells and sEVs using digital polymerase chain reaction (dPCR). For this reason, 5 PM, 14 non-PM, and one normal mesothelial cell line were cultured. The sEV was isolated from the cells using the gold standard ultracentrifuge method. The RNA was extracted from both cells and sEVs, cDNA was synthesized, and dPCR was run. Results showed that hsa_circ_0007386 was significantly overexpressed in PM cell lines and sEVs compared to non-PM and normal mesothelial cell lines (p < 0.0001). The upregulation of hsa_circ_0007386 in PM highlights its potential as a diagnostic biomarker. This study underscores the importance and potential of circRNAs and sEVs as cancer diagnostic tools.
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Affiliation(s)
- Sareh Zhand
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Jiayan Liao
- Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Alessandro Castorina
- Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Man-Lee Yuen
- Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Majid Ebrahimi Warkiani
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia
- Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
- Institute of Molecular Medicine, Sechenov First Moscow State University, Moscow 119991, Russia
| | - Yuen-Yee Cheng
- Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia
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15
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Yang Z, Zhang X, Zhan N, Lin L, Zhang J, Peng L, Qiu T, Luo Y, Liu C, Pan C, Hu J, Ye Y, Jiang Z, Liu X, Sun M, Zhang Y. Exosome-related lncRNA score: A value-based individual treatment strategy for predicting the response to immunotherapy in clear cell renal cell carcinoma. Cancer Med 2024; 13:e7308. [PMID: 38808948 PMCID: PMC11135019 DOI: 10.1002/cam4.7308] [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: 03/20/2024] [Revised: 04/26/2024] [Accepted: 05/07/2024] [Indexed: 05/30/2024] Open
Abstract
BACKGROUND Exosomes play a crucial role in intercellular communication in clear cell renal cell carcinoma (ccRCC), while the long non-coding RNAs (lncRNAs) are implicated in tumorigenesis and progression. AIMS The purpose of this study is to construction a exosomes-related lncRNA score and a ceRNA network to predict the response to immunotherapy and potential targeted drug in ccRCC. METHODS Data of ccRCC patients were obtained from the TCGA database. Pearson correlation analysis was used to identify eExosomes-related lncRNAs (ERLRs) from Top10 exosomes-related genes that have been screened. The entire cohort was randomly divided into a training cohort and a validation cohort in equal scale. LASSO regression and multivariate cox regression was used to construct the ERLRs-based score. Differences in clinicopathological characteristics, immune microenvironment, immune checkpoints, and drug susceptibility between the high- and low-risk groups were also investigated. Finally, the relevant ceRNA network was constructed by machine learning to analyze their potential targets in immunotherapy and drug use of ccRCC patients. RESULTS A score consisting of 4ERLRs was identified, and patients with higher ERLRs-based score tended to have a worse prognosis than those with lower ERLRs-based score. ROC curves and multivariate Cox regression analysis demonstrated that the score could be considered as a risk factor for prognosis in both training and validation cohorts. Moreover, patients with high scores are predisposed to experience poor overall survival, a larger prevalence of advanced stage (III-IV), a greater tumor mutational burden, a higher infiltration of immunosuppressive cells, and a greater likelihood of responding favorably to immunotherapy. The importance of EMX2OS was determined by mechanical learning, and the ceRNA network was constructed, and EMX2OS may be a potential therapeutic target, possibly exerting its function through the EMX2OS/hsa-miR-31-5p/TLN2 axis. CONCLUSIONS Based on machine learning, a novel ERLRs-based score was constructed for predicting the survival of ccRCC patients. The ERLRs-based score is a promising potential independent prognostic factor that is closely correlated with the immune microenvironment and clinicopathological characteristics. Meanwhile, we screened out key lncRNAEMX2OS and identified the EMX2OS/hsa-miR-31-5p/TLN2 axis, which may provide new clues for the targeted therapy of ccRCC.
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Affiliation(s)
- Zhan Yang
- Department of UrologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Xiaoting Zhang
- Stomatology Hospital, School of StomatologyZhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang ProvinceHangzhouZhejiang ProvinceChina
| | - Ning Zhan
- Stomatology Hospital, School of StomatologyZhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang ProvinceHangzhouZhejiang ProvinceChina
| | - Lining Lin
- Stomatology Hospital, School of StomatologyZhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang ProvinceHangzhouZhejiang ProvinceChina
| | - Jingyu Zhang
- Stomatology Hospital, School of StomatologyZhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang ProvinceHangzhouZhejiang ProvinceChina
| | - Lianjie Peng
- Stomatology Hospital, School of StomatologyZhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang ProvinceHangzhouZhejiang ProvinceChina
| | - Tao Qiu
- Stomatology Hospital, School of StomatologyZhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang ProvinceHangzhouZhejiang ProvinceChina
| | - Yaxian Luo
- Stomatology Hospital, School of StomatologyZhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang ProvinceHangzhouZhejiang ProvinceChina
| | - Chundi Liu
- Stomatology Hospital, School of StomatologyZhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang ProvinceHangzhouZhejiang ProvinceChina
| | - Chaoran Pan
- Department of UrologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Junhao Hu
- Department of UrologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Yifan Ye
- Department of UrologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Zilong Jiang
- Department of UrologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Xinyu Liu
- Department of UrologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
| | - Mouyuan Sun
- Stomatology Hospital, School of StomatologyZhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang ProvinceHangzhouZhejiang ProvinceChina
| | - Yan Zhang
- Department of UrologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang ProvinceChina
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Deng J, Liu C, Sun J. DNA-Based Nanomaterials for Analysis of Extracellular Vesicles. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2303092. [PMID: 38016069 DOI: 10.1002/adma.202303092] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 07/21/2023] [Indexed: 11/30/2023]
Abstract
Extracellular vesicles (EVs) are cell-derived nanovesicles comprising a myriad of molecular cargo such as proteins and nucleic acids, playing essential roles in intercellular communication and physiological and pathological processes. EVs have received substantial attention as noninvasive biomarkers for disease diagnosis and prognosis. Owing to their ability to recognize protein and nucleic acid targets, DNA-based nanomaterials with excellent programmability and modifiability provide a promising tool for the sensitive and accurate detection of molecular cargo carried by EVs. In this perspective, recent advancements in EV analysis using a variety of DNA-based nanomaterials are summarized, which can be broadly classified into three categories: linear DNA probes, DNA nanostructures, and hybrid DNA nanomaterials. The design, construction, advantages, and disadvantages of different types of DNA nanomaterials, as well as their performance for detecting EVs are reviewed. The challenges and opportunities in the field of EV analysis by DNA nanomaterials are also discussed.
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Affiliation(s)
- Jinqi Deng
- Beijing Engineering Research Center for BioNanotechnology, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, National Center for Nanoscience and Technology, Beijing, 100190, China
- School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chao Liu
- Beijing Engineering Research Center for BioNanotechnology, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, National Center for Nanoscience and Technology, Beijing, 100190, China
- School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jiashu Sun
- Beijing Engineering Research Center for BioNanotechnology, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, National Center for Nanoscience and Technology, Beijing, 100190, China
- School of Future Technology, University of Chinese Academy of Sciences, Beijing, 100049, China
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17
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Pszczołowska M, Walczak K, Miśków W, Antosz K, Batko J, Kurpas D, Leszek J. Chronic Traumatic Encephalopathy as the Course of Alzheimer's Disease. Int J Mol Sci 2024; 25:4639. [PMID: 38731858 PMCID: PMC11083609 DOI: 10.3390/ijms25094639] [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: 03/19/2024] [Revised: 04/15/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
This editorial investigates chronic traumatic encephalopathy (CTE) as a course of Alzheimer's disease (AD). CTE is a debilitating neurodegenerative disease that is the result of repeated mild traumatic brain injury (TBI). Many epidemiological studies show that experiencing a TBI in early or middle life is associated with an increased risk of dementia later in life. Chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD) present a series of similar neuropathological features that were investigated in this work like recombinant tau into filaments or the accumulation and aggregation of Aβ protein. However, these two conditions differ from each other in brain-blood barrier damage. The purpose of this review was to evaluate information about CTE and AD from various articles, focusing especially on new therapeutic possibilities for the improvement in cognitive skills.
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Affiliation(s)
- Magdalena Pszczołowska
- Faculty of Medicine, Wroclaw Medical University, Ludwika Pasteura 1, 50-367 Wrocław, Poland; (M.P.)
| | - Kamil Walczak
- Faculty of Medicine, Wroclaw Medical University, Ludwika Pasteura 1, 50-367 Wrocław, Poland; (M.P.)
| | - Weronika Miśków
- Faculty of Medicine, Wroclaw Medical University, Ludwika Pasteura 1, 50-367 Wrocław, Poland; (M.P.)
| | - Katarzyna Antosz
- Faculty of Medicine, Wroclaw Medical University, Ludwika Pasteura 1, 50-367 Wrocław, Poland; (M.P.)
| | - Joanna Batko
- Faculty of Medicine, Wroclaw Medical University, Ludwika Pasteura 1, 50-367 Wrocław, Poland; (M.P.)
| | - Donata Kurpas
- Faculty of Health Sciences, Wroclaw Medical University, Ul. Kazimierza Bartla 5, 51-618 Wrocław, Poland
| | - Jerzy Leszek
- Clinic of Psychiatry, Department of Psychiatry, Wroclaw Medical University, Ludwika Pasteura 10, 50-367 Wrocław, Poland
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18
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Yin C, Liufu C, Zhu T, Ye S, Jiang J, Wang M, Wang Y, Shi B. Bladder Cancer in Exosomal Perspective: Unraveling New Regulatory Mechanisms. Int J Nanomedicine 2024; 19:3677-3695. [PMID: 38681092 PMCID: PMC11048230 DOI: 10.2147/ijn.s458397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 04/06/2024] [Indexed: 05/01/2024] Open
Abstract
Bladder cancer, a prevalent malignant neoplasm of the urinary tract, exhibits escalating morbidity and mortality rates. Current diagnosis standards rely on invasive and costly cystoscopy and histopathology, underscoring the urgency for non-invasive, high-throughput, and cost-effective novel diagnostic techniques to ensure timely detection and standardized treatment. Recent years have witnessed the rise of exosome research in bladder cancer studies. Exosomes contain abundant bioactive molecules that can help elucidate the intricate mechanisms underlying bladder cancer pathogenesis and metastasis. Exosomes hold potential as biomarkers for early bladder cancer diagnosis while also serving as targeted drug delivery vehicles to enhance treatment efficacy and mitigate adverse effects. Furthermore, exosome analyses offer insights into the complex molecular signaling networks implicated in bladder cancer progression, revealing novel therapeutic targets. This review provides a comprehensive overview of prevalent exosome isolation techniques and highlights the promising clinical utility of exosomes in both diagnostic and therapeutic applications in bladder cancer management.
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Affiliation(s)
- Cong Yin
- Department of Urology, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, People’s Republic of China
- Shenzhen University Health Science Center, Shenzhen, People’s Republic of China
| | - Cen Liufu
- Department of Urology, Peking University Shenzhen Hospital, Institute of Urology, Shenzhen PKU-HKUST Medical Center, Shenzhen, People’s Republic of China
- Shantou University Medical College, Shantou, Guangdong, People’s Republic of China
| | - Tao Zhu
- Department of Urology, Peking University Shenzhen Hospital, Institute of Urology, Shenzhen PKU-HKUST Medical Center, Shenzhen, People’s Republic of China
- Shantou University Medical College, Shantou, Guangdong, People’s Republic of China
| | - Shuai Ye
- Department of Urology, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, People’s Republic of China
- Shenzhen University Health Science Center, Shenzhen, People’s Republic of China
| | - Jiahao Jiang
- Department of Urology, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, People’s Republic of China
- Clinical College of Anhui Medical University, Shenzhen, People’s Republic of China
| | - Mingxia Wang
- Department of Urology, Peking University Shenzhen Hospital, Institute of Urology, Shenzhen PKU-HKUST Medical Center, Shenzhen, People’s Republic of China
| | - Yan Wang
- Department of Urology, Peking University Shenzhen Hospital, Institute of Urology, Shenzhen PKU-HKUST Medical Center, Shenzhen, People’s Republic of China
| | - Bentao Shi
- Department of Urology, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, People’s Republic of China
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19
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Joshi N, Garapati K, Ghose V, Kandasamy RK, Pandey A. Recent progress in mass spectrometry-based urinary proteomics. Clin Proteomics 2024; 21:14. [PMID: 38389064 PMCID: PMC10885485 DOI: 10.1186/s12014-024-09462-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 02/12/2024] [Indexed: 02/24/2024] Open
Abstract
Serum or plasma is frequently utilized in biomedical research; however, its application is impeded by the requirement for invasive sample collection. The non-invasive nature of urine collection makes it an attractive alternative for disease characterization and biomarker discovery. Mass spectrometry-based protein profiling of urine has led to the discovery of several disease-associated biomarkers. Proteomic analysis of urine has not only been applied to disorders of the kidney and urinary bladder but also to conditions affecting distant organs because proteins excreted in the urine originate from multiple organs. This review provides a progress update on urinary proteomics carried out over the past decade. Studies summarized in this review have expanded the catalog of proteins detected in the urine in a variety of clinical conditions. The wide range of applications of urine analysis-from characterizing diseases to discovering predictive, diagnostic and prognostic markers-continues to drive investigations of the urinary proteome.
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Affiliation(s)
- Neha Joshi
- Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Kishore Garapati
- Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Vivek Ghose
- Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India
| | - Richard K Kandasamy
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, 55905, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Akhilesh Pandey
- Institute of Bioinformatics, International Technology Park, Bangalore, 560066, India.
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, 55905, USA.
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
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20
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Fang F, Yang J, Wang J, Li T, Wang E, Zhang D, Liu X, Zhou C. The role and applications of extracellular vesicles in osteoporosis. Bone Res 2024; 12:4. [PMID: 38263267 PMCID: PMC10806231 DOI: 10.1038/s41413-023-00313-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/13/2023] [Accepted: 11/28/2023] [Indexed: 01/25/2024] Open
Abstract
Osteoporosis is a widely observed condition characterized by the systemic deterioration of bone mass and microarchitecture, which increases patient susceptibility to fragile fractures. The intricate mechanisms governing bone homeostasis are substantially impacted by extracellular vesicles (EVs), which play crucial roles in both pathological and physiological contexts. EVs derived from various sources exert distinct effects on osteoporosis. Specifically, EVs released by osteoblasts, endothelial cells, myocytes, and mesenchymal stem cells contribute to bone formation due to their unique cargo of proteins, miRNAs, and cytokines. Conversely, EVs secreted by osteoclasts and immune cells promote bone resorption and inhibit bone formation. Furthermore, the use of EVs as therapeutic modalities or biomaterials for diagnosing and managing osteoporosis is promising. Here, we review the current understanding of the impact of EVs on bone homeostasis, including the classification and biogenesis of EVs and the intricate regulatory mechanisms of EVs in osteoporosis. Furthermore, we present an overview of the latest research progress on diagnosing and treating osteoporosis by using EVs. Finally, we discuss the challenges and prospects of translational research on the use of EVs in osteoporosis.
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Affiliation(s)
- Fei Fang
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Jie Yang
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Jiahe Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Tiantian Li
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Erxiang Wang
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Demao Zhang
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Xiaoheng Liu
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China.
| | - Chenchen Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
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21
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Wang HC, Yin WX, Jiang M, Han JY, Kuai XW, Sun R, Sun YF, Ji JL. Function and biomedical implications of exosomal microRNAs delivered by parenchymal and nonparenchymal cells in hepatocellular carcinoma. World J Gastroenterol 2023; 29:5435-5451. [PMID: 37900996 PMCID: PMC10600808 DOI: 10.3748/wjg.v29.i39.5435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/13/2023] [Accepted: 10/16/2023] [Indexed: 10/19/2023] Open
Abstract
Small extracellular vesicles (exosomes) are important components of the tumor microenvironment. They are small membrane-bound vesicles derived from almost all cell types and play an important role in intercellular communication. Exosomes transmit biological molecules obtained from parent cells, such as proteins, lipids, and nucleic acids, and are involved in cancer development. MicroRNAs (miRNAs), the most abundant contents in exosomes, are selectively packaged into exosomes to carry out their biological functions. Recent studies have revealed that exosome-delivered miRNAs play crucial roles in the tumorigenesis, progression, and drug resistance of hepatocellular carcinoma (HCC). In addition, exosomes have great industrial prospects in the diagnosis, treatment, and prognosis of patients with HCC. This review summarized the composition and function of exosomal miRNAs of different cell origins in HCC and highlighted the association between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC. Finally, we described the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC.
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Affiliation(s)
- Hai-Chen Wang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Wen-Xuan Yin
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Meng Jiang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Jia-Yi Han
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Xing-Wang Kuai
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Rui Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Yu-Feng Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Ju-Ling Ji
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
- Department of Pathology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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22
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Daneshdoust D, Yin M, Luo M, Sundi D, Dang Y, Lee C, Li J, Liu X. Conditional Reprogramming Modeling of Bladder Cancer for Clinical Translation. Cells 2023; 12:1714. [PMID: 37443748 PMCID: PMC10341071 DOI: 10.3390/cells12131714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/09/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
The use of advanced preclinical models has become increasingly important in drug development. This is particularly relevant in bladder cancer, where the global burden of disease is quite high based on prevalence and a relatively high rate of lethality. Predictive tools to select patients who will be responsive to invasive or morbid therapies (chemotherapy, radiotherapy, immunotherapy, and/or surgery) are largely absent. Patient-derived and clinically relevant models including patient-derived xenografts (PDX), organoids, and conditional reprogramming (CR) of cell cultures efficiently generate numerous models and are being used in both basic and translational cancer biology. These CR cells (CRCs) can be reprogrammed to maintain a highly proliferative state and reproduce the genomic and histological characteristics of the parental tissue. Therefore, CR technology may be a clinically relevant model to test and predict drug sensitivity, conduct gene profile analysis and xenograft research, and undertake personalized medicine. This review discusses studies that have utilized CR technology to conduct bladder cancer research.
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Affiliation(s)
- Danyal Daneshdoust
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
| | - Ming Yin
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
- Department of Medicine, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
| | - Mingjue Luo
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
| | - Debasish Sundi
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
- Department of Urology, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
| | - Yongjun Dang
- Center for Novel Target and Therapeutic Intervention, Chongqing Medical University, Chongqing 400016, China
| | - Cheryl Lee
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
- Department of Urology, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
| | - Jenny Li
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
| | - Xuefeng Liu
- Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA (M.L.)
- Departments of Pathology, Urology and Radiation Oncology, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA
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23
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Jordaens S, Oeyen E, Willems H, Ameye F, De Wachter S, Pauwels P, Mertens I. Protein Biomarker Discovery Studies on Urinary sEV Fractions Separated with UF-SEC for the First Diagnosis and Detection of Recurrence in Bladder Cancer Patients. Biomolecules 2023; 13:932. [PMID: 37371512 DOI: 10.3390/biom13060932] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/26/2023] [Accepted: 05/30/2023] [Indexed: 06/29/2023] Open
Abstract
Urinary extracellular vesicles (EVs) are an attractive source of bladder cancer biomarkers. Here, a protein biomarker discovery study was performed on the protein content of small urinary EVs (sEVs) to identify possible biomarkers for the primary diagnosis and recurrence of non-muscle-invasive bladder cancer (NMIBC). The sEVs were isolated by ultrafiltration (UF) in combination with size-exclusion chromatography (SEC). The first part of the study compared healthy individuals with NMIBC patients with a primary diagnosis. The second part compared tumor-free patients with patients with a recurrent NMIBC diagnosis. The separated sEVs were in the size range of 40 to 200 nm. Based on manually curated high quality mass spectrometry (MS) data, the statistical analysis revealed 69 proteins that were differentially expressed in these sEV fractions of patients with a first bladder cancer tumor vs. an age- and gender-matched healthy control group. When the discriminating power between healthy individuals and first diagnosis patients is taken into account, the biomarkers with the most potential are MASP2, C3, A2M, CHMP2A and NHE-RF1. Additionally, two proteins (HBB and HBA1) were differentially expressed between bladder cancer patients with a recurrent diagnosis vs. tumor-free samples of bladder cancer patients, but their biological relevance is very limited.
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Affiliation(s)
- Stephanie Jordaens
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, 2610 Wilrijk, Belgium
| | - Eline Oeyen
- Health Unit, Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium
- Centre for Proteomics (CfP), University of Antwerp, 2020 Antwerp, Belgium
| | - Hanny Willems
- Health Unit, Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium
| | - Filip Ameye
- Department of Urology, AZ Maria Middelares, 9000 Ghent, Belgium
| | - Stefan De Wachter
- Department of Urology, Antwerp University Hospital (UZA), 2650 Edegem, Belgium
| | - Patrick Pauwels
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, 2610 Wilrijk, Belgium
- Laboratory of Pathological Anatomy, Antwerp University Hospital (UZA), 2650 Edegem, Belgium
| | - Inge Mertens
- Health Unit, Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium
- Centre for Proteomics (CfP), University of Antwerp, 2020 Antwerp, Belgium
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24
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Beetler DJ, Di Florio DN, Bruno KA, Ikezu T, March KL, Cooper LT, Wolfram J, Fairweather D. Extracellular vesicles as personalized medicine. Mol Aspects Med 2023; 91:101155. [PMID: 36456416 PMCID: PMC10073244 DOI: 10.1016/j.mam.2022.101155] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 10/14/2022] [Accepted: 10/26/2022] [Indexed: 11/29/2022]
Abstract
Extracellular vesicles (EVs) are released from all cells in the body, forming an important intercellular communication network that contributes to health and disease. The contents of EVs are cell source-specific, inducing distinct signaling responses in recipient cells. The specificity of EVs and their accumulation in fluid spaces that are accessible for liquid biopsies make them highly attractive as potential biomarkers and therapies for disease. The duality of EVs as favorable (therapeutic) or unfavorable (pathological) messengers is context dependent and remains to be fully determined in homeostasis and various disease states. This review describes the use of EVs as biomarkers, drug delivery vehicles, and regenerative therapeutics, highlighting examples involving viral infections, cancer, and neurological diseases. There is growing interest to provide personalized therapy based on individual patient and disease characteristics. Increasing evidence suggests that EV biomarkers and therapeutic approaches are ideal for personalized medicine due to the diversity and multifunctionality of EVs.
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Affiliation(s)
- Danielle J Beetler
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN, 55902, USA; Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Damian N Di Florio
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN, 55902, USA; Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Katelyn A Bruno
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, 32224, USA; Center for Regenerative Medicine, University of Florida, Gainesville, FL, 32611, USA; Division of Cardiology, University of Florida, Gainesville, FL, 32611, USA
| | - Tsuneya Ikezu
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Keith L March
- Center for Regenerative Medicine, University of Florida, Gainesville, FL, 32611, USA; Division of Cardiology, University of Florida, Gainesville, FL, 32611, USA
| | - Leslie T Cooper
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Joy Wolfram
- School of Chemical Engineering, The University of Queensland, Brisbane, QLD, 4072, Australia; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - DeLisa Fairweather
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN, 55902, USA; Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, 32224, USA; Department of Environmental Health Sciences and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
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25
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Rickard BP, Overchuk M, Chappell VA, Kemal Ruhi M, Sinawang PD, Nguyen Hoang TT, Akin D, Demirci U, Franco W, Fenton SE, Santos JH, Rizvi I. Methods to Evaluate Changes in Mitochondrial Structure and Function in Cancer. Cancers (Basel) 2023; 15:2564. [PMID: 37174030 PMCID: PMC10177605 DOI: 10.3390/cancers15092564] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 04/25/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Mitochondria are regulators of key cellular processes, including energy production and redox homeostasis. Mitochondrial dysfunction is associated with various human diseases, including cancer. Importantly, both structural and functional changes can alter mitochondrial function. Morphologic and quantifiable changes in mitochondria can affect their function and contribute to disease. Structural mitochondrial changes include alterations in cristae morphology, mitochondrial DNA integrity and quantity, and dynamics, such as fission and fusion. Functional parameters related to mitochondrial biology include the production of reactive oxygen species, bioenergetic capacity, calcium retention, and membrane potential. Although these parameters can occur independently of one another, changes in mitochondrial structure and function are often interrelated. Thus, evaluating changes in both mitochondrial structure and function is crucial to understanding the molecular events involved in disease onset and progression. This review focuses on the relationship between alterations in mitochondrial structure and function and cancer, with a particular emphasis on gynecologic malignancies. Selecting methods with tractable parameters may be critical to identifying and targeting mitochondria-related therapeutic options. Methods to measure changes in mitochondrial structure and function, with the associated benefits and limitations, are summarized.
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Affiliation(s)
- Brittany P. Rickard
- Curriculum in Toxicology & Environmental Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Marta Overchuk
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, and North Carolina State University, Raleigh, NC 27695, USA
| | - Vesna A. Chappell
- Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - Mustafa Kemal Ruhi
- Institute of Biomedical Engineering, Boğaziçi University, Istanbul 34684, Turkey
| | - Prima Dewi Sinawang
- Canary Center at Stanford for Cancer Early Detection, Department of Radiology, School of Medicine, Palo Alto, CA 94304, USA
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
| | - Tina Thuy Nguyen Hoang
- Department of Biomedical Engineering, University of Massachusetts Lowell, Lowell, MA 01854, USA
| | - Demir Akin
- Canary Center at Stanford for Cancer Early Detection, Department of Radiology, School of Medicine, Palo Alto, CA 94304, USA
- Center for Cancer Nanotechnology Excellence for Translational Diagnostics (CCNE-TD), School of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Utkan Demirci
- Canary Center at Stanford for Cancer Early Detection, Department of Radiology, School of Medicine, Palo Alto, CA 94304, USA
| | - Walfre Franco
- Department of Biomedical Engineering, University of Massachusetts Lowell, Lowell, MA 01854, USA
| | - Suzanne E. Fenton
- Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - Janine H. Santos
- Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - Imran Rizvi
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, and North Carolina State University, Raleigh, NC 27695, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
- Center for Environmental Health and Susceptibility, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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26
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Abstract
Exosomes are nanoscale vesicles derived from endocytosis, formed by fusion of multivesicular bodies with membranes and secreted into the extracellular matrix or body fluids. Many studies have shown that exosomes can be present in a variety of biological fluids, such as plasma, urine, saliva, amniotic fluid, ascites, and sweat, and most types of cells can secrete exosomes. Exosomes play an important role in many aspects of human development, including immunity, cardiovascular diseases, neurodegenerative diseases, and neoplasia. Urine can be an alternative to blood or tissue samples as a potential source of disease biomarkers because of its simple, noninvasive, sufficient, and stable characteristics. Therefore, urinary exosomes have valuable potential for early screening, monitoring disease progression, prognosis, and treatment. The method for isolating urinary exosomes has been perfected, and exosome proteomics is widely used. Therefore, we review the potential use of urinary exosomes for disease diagnosis and summarize the related literature.
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Affiliation(s)
- Yizhao Wang
- Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
| | - Man Zhang
- Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
- Clinical Laboratory Medicine, Peking University Ninth School of Clinical Medicine, Beijing, China
- Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, China
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27
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Kort-Mascort J, Flores-Torres S, Peza-Chavez O, Jang JH, Pardo LA, Tran SD, Kinsella J. Decellularized ECM hydrogels: prior use considerations, applications, and opportunities in tissue engineering and biofabrication. Biomater Sci 2023; 11:400-431. [PMID: 36484344 DOI: 10.1039/d2bm01273a] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Tissue development, wound healing, pathogenesis, regeneration, and homeostasis rely upon coordinated and dynamic spatial and temporal remodeling of extracellular matrix (ECM) molecules. ECM reorganization and normal physiological tissue function, require the establishment and maintenance of biological, chemical, and mechanical feedback mechanisms directed by cell-matrix interactions. To replicate the physical and biological environment provided by the ECM in vivo, methods have been developed to decellularize and solubilize tissues which yield organ and tissue-specific bioactive hydrogels. While these biomaterials retain several important traits of the native ECM, the decellularizing process, and subsequent sterilization, and solubilization result in fragmented, cleaved, or partially denatured macromolecules. The final product has decreased viscosity, moduli, and yield strength, when compared to the source tissue, limiting the compatibility of isolated decellularized ECM (dECM) hydrogels with fabrication methods such as extrusion bioprinting. This review describes the physical and bioactive characteristics of dECM hydrogels and their role as biomaterials for biofabrication. In this work, critical variables when selecting the appropriate tissue source and extraction methods are identified. Common manual and automated fabrication techniques compatible with dECM hydrogels are described and compared. Fabrication and post-manufacturing challenges presented by the dECM hydrogels decreased mechanical and structural stability are discussed as well as circumvention strategies. We further highlight and provide examples of the use of dECM hydrogels in tissue engineering and their role in fabricating complex in vitro 3D microenvironments.
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Affiliation(s)
| | | | - Omar Peza-Chavez
- Department of Bioengineering, McGill University, Montreal, Quebec, Canada.
| | - Joyce H Jang
- Department of Bioengineering, McGill University, Montreal, Quebec, Canada.
| | | | - Simon D Tran
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Quebec, Canada
| | - Joseph Kinsella
- Department of Bioengineering, McGill University, Montreal, Quebec, Canada.
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28
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Musatova OE, Rubtsov YP. Effects of glioblastoma-derived extracellular vesicles on the functions of immune cells. Front Cell Dev Biol 2023; 11:1060000. [PMID: 36960410 PMCID: PMC10028257 DOI: 10.3389/fcell.2023.1060000] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 02/22/2023] [Indexed: 03/09/2023] Open
Abstract
Glioblastoma is the most aggressive variant of glioma, the tumor of glial origin which accounts for 80% of brain tumors. Glioblastoma is characterized by astoundingly poor prognosis for patients; a combination of surgery, chemo- and radiotherapy used for clinical treatment of glioblastoma almost inevitably results in rapid relapse and development of more aggressive and therapy resistant tumor. Recently, it was demonstrated that extracellular vesicles produced by glioblastoma (GBM-EVs) during apoptotic cell death can bind to surrounding cells and change their phenotype to more aggressive. GBM-EVs participate also in establishment of immune suppressive microenvironment that protects glioblastoma from antigen-specific recognition and killing by T cells. In this review, we collected present data concerning characterization of GBM-EVs and study of their effects on different populations of the immune cells (T cells, macrophages, dendritic cells, myeloid-derived suppressor cells). We aimed at critical analysis of experimental evidence in order to conclude whether glioblastoma-derived extracellular vesicles are a major factor in immune evasion of this deadly tumor. We summarized data concerning potential use of GBM-EVs for non-invasive diagnostics of glioblastoma. Finally, the applicability of approaches aimed at blocking of GBM-EVs production or their fusion with target cells for treatment of glioblastoma was analyzed.
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Affiliation(s)
- Oxana E. Musatova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, RAS, Moscow, Russia
| | - Yury P. Rubtsov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, RAS, Moscow, Russia
- N.N.Blokhin Russian Cancer Research Center, Ministry of Health of the Russian Federation, Moscow, Russia
- *Correspondence: Yury P. Rubtsov,
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29
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Wei X, Cai L, Chen H, Shang L, Zhao Y, Sun W. Noninvasive Multiplexed Analysis of Bladder Cancer-Derived Urine Exosomes via Janus Magnetic Microspheres. Anal Chem 2022; 94:18034-18041. [PMID: 36519619 DOI: 10.1021/acs.analchem.2c04408] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Bladder cancer greatly endangers human health, and its early diagnosis is of vital importance. Exosomes, which contain proteins and nucleic acids related to their source cells, are expected to be an emerging biomarker for bladder cancer detection. Here, we propose a novel system for multiplexed analysis of bladder cancer-derived urine exosomes based on Janus magnetic microspheres as barcoded microcarriers. The microcarriers are constructed by droplet-templated coassembly of colloidal silica nanoparticles and magnetic nanoparticles under a magnetic field. The microcarriers possess one hemisphere with structural color and the other hemisphere with magneto-responsiveness. Benefiting from the unique structure, these Janus microcarriers could serve as barcodes and could move controllably in a sample solution, thus realizing the multiplex detection of exosomes with high sensitivity. Notably, the present platform is noninvasive since a urine specimen, as an ideal source of bladder cancer-derived exosomes, is employed as the sample solution. This feature, together with the good sensitivity, specificity, low sample consumption, and easy operation, indicates the great potential of the platform for bladder cancer diagnosis in clinical applications.
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Affiliation(s)
- Xiaowei Wei
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou325027, China.,Laboratory Medicine Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing210011, China
| | - Lijun Cai
- Department of Clinical Laboratory, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing210096, China
| | - Hanxu Chen
- Department of Clinical Laboratory, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing210096, China
| | - Luoran Shang
- Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-Laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai200032, China
| | - Yuanjin Zhao
- Department of Clinical Laboratory, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing210096, China
| | - Weijian Sun
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou325027, China
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30
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Kanao E, Wada S, Nishida H, Kubo T, Tanigawa T, Imami K, Shimoda A, Umezaki K, Sasaki Y, Akiyoshi K, Adachi J, Otsuka K, Ishihama Y. Classification of Extracellular Vesicles Based on Surface Glycan Structures by Spongy-like Separation Media. Anal Chem 2022; 94:18025-18033. [PMID: 36511577 DOI: 10.1021/acs.analchem.2c04391] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Extracellular vesicles (EVs) are lipid bilayer vesicles that enclose various biomolecules. EVs hold promise as sensitive biomarkers to detect and monitor various diseases. However, they have heterogeneous molecular compositions. The compositions of EVs from identical donor cells obtained using the same purification methods may differ, which is a significant obstacle for elucidating objective biological functions. Herein, the potential of a novel lectin-based affinity chromatography (LAC) method to classify EVs based on their glycan structures is demonstrated. The proposed method utilizes a spongy-like monolithic polymer (spongy monolith, SPM), which consists of poly(ethylene-co-glycidyl methacrylate) with continuous micropores and allows an efficient in situ protein reaction with epoxy groups. Two distinct lectins with different specificities, Sambucus sieboldiana agglutinin and concanavalin A, are effectively immobilized on SPM without impacting the binding activity. Moreover, high recovery rates of liposomal nanoparticles as a model of EVs are achieved due to the large flow-through pores (>10 μm) of SPM compared to a typical agarose gel. Finally, lectin-immobilized SPMs are employed to classify EVs based on the surface glycan structures and demonstrate different subpopulations by proteome profiling. This is the first approach to clarify the variation of protein contents in EVs by the difference of surface glycans via lectin immobilized media.
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Affiliation(s)
- Eisuke Kanao
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto606-8501, Japan.,National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka567-0085, Japan
| | - Shuntaro Wada
- Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto615-8510, Japan
| | - Hiroshi Nishida
- National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka567-0085, Japan
| | - Takuya Kubo
- Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto615-8510, Japan
| | - Tetsuya Tanigawa
- Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto615-8510, Japan
| | - Koshi Imami
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto606-8501, Japan.,Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama332-0012, Japan
| | - Asako Shimoda
- Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto615-8510, Japan
| | - Kaori Umezaki
- Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto615-8510, Japan
| | - Yoshihiro Sasaki
- Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto615-8510, Japan
| | - Kazunari Akiyoshi
- Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto615-8510, Japan
| | - Jun Adachi
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto606-8501, Japan.,National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka567-0085, Japan
| | - Koji Otsuka
- Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto615-8510, Japan
| | - Yasushi Ishihama
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto606-8501, Japan.,National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka567-0085, Japan
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31
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Al-Awsi GRL, Jasim SA, Fakri Mustafa Y, Alhachami FR, Ziyadullaev S, Kandeel M, Abulkassim R, Sivaraman R, M Hameed N, Mireya Romero Parra R, Karampoor S, Mirzaei R. The role of miRNA-128 in the development and progression of gastrointestinal and urogenital cancer. Future Oncol 2022; 18:4209-4231. [PMID: 36519554 DOI: 10.2217/fon-2022-0574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 11/24/2022] [Indexed: 12/23/2022] Open
Abstract
Increasing data have shown the significance of various miRNAs in malignancy. In this regard, parallel to its biological role in normal tissues, miRNA-128 (miR-128) has been found to play an essential immunomodulatory function in the process of cancer initiation and development. The occurrence of the aberrant expression of miR-128 in tumors and the unique properties of miRNAs raise the prospect of their use as biomarkers and the next generation of molecular anticancer therapies. The function of miR-128 in malignancies such as breast, prostate, colorectal, gastric, pancreatic, esophageal, cervical, ovarian and bladder cancers and hepatocellular carcinoma is discussed in this review. Finally, the effect of exosomal miR-128 on cancer resistance to therapeutics and cancer immunotherapy in certain malignancies is highlighted.
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Affiliation(s)
| | - Saade Abdalkareem Jasim
- Department of Medical Laboratory Techniques, Al-maarif University College, Al-Anbar-Ramadi, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Firas Rahi Alhachami
- Department of Radiology, College of Health & Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | - Shukhrat Ziyadullaev
- No. 1 Department of Internal Diseases, Vice-rector for Scientific Affairs & Innovations, Samarkand State Medical University, Amir Temur Street 18, Samarkand, Uzbekistan
| | - Mahmoud Kandeel
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Hofuf, Al-Ahsa, 31982, Saudi Arabia
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelshikh University, Kafrelshikh, 33516, Egypt
| | | | - R Sivaraman
- Department of Mathematics, Dwaraka Doss Goverdhan Doss Vaishnav College, Arumbakkam, University of Madras, Chennai, India
| | - Noora M Hameed
- Anesthesia Techniques, Al-Nisour University College, Iraq
| | | | - Sajad Karampoor
- Gastrointestinal & Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Department of Medical Biotechnology, Venom & Biotherapeutics Molecules Lab, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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32
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Localized DNA tetrahedrons assisted catalytic hairpin assembly for the rapid and sensitive profiling of small extracellular vesicle-associated microRNAs. J Nanobiotechnology 2022; 20:503. [PMID: 36457020 PMCID: PMC9714172 DOI: 10.1186/s12951-022-01700-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 11/08/2022] [Indexed: 12/05/2022] Open
Abstract
The profiling of small extracellular vesicle-associated microRNAs (sEV-miRNAs) plays a vital role in cancer diagnosis and monitoring. However, detecting sEV-miRNAs with low expression in clinical samples remains challenging. Herein, we propose a novel electrochemical biosensor using localized DNA tetrahedron-assisted catalytic hairpin assembly (LDT-CHA) for sEV-miRNA determination. The LDT-CHA contained localized DNA tetrahedrons with CHA substrates, leveraging an efficient localized reaction to enable sensitive and rapid sEV-miRNA measurement. Based on the LDT-CHA, the proposed platform can quantitatively detect sEV-miRNA down to 25 aM in 30 min with outstanding specificity. For accurate diagnosis of gastric cancer patients, a combination of LDT-CHA and a panel of four sEV-miRNAs (sEV-miR-1246, sEV-miR-21, sEV-miR-183-5P, and sEV-miR-142-5P) was employed in a gastric cancer cohort. Compared with diagnosis with single sEV-miRNA, the proposed platform demonstrated a higher accuracy of 88.3% for early gastric tumor diagnoses with higher efficiency (AUC: 0.883) and great potential for treatment monitoring. Thus, this study provides a promising method for the bioanalysis and determination of the clinical applications of LDT-CHA.
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33
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Qian H, Shao X, Zhang H, Wang Y, Liu S, Pan J, Xue W. Diagnosis of urogenital cancer combining deep learning algorithms and surface-enhanced Raman spectroscopy based on small extracellular vesicles. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2022; 281:121603. [PMID: 35868057 DOI: 10.1016/j.saa.2022.121603] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/02/2022] [Accepted: 07/04/2022] [Indexed: 06/15/2023]
Abstract
PURPOSE To identify and compare the capacities of serum and serum-derived small extracellular vesicles (EV) in diagnosis of common urogenital cancer combining Surface-enhanced Raman spectroscopy (SERS) and Convolutional Neural Networks (CNN). MATERIALS AND METHODS We collected serum samples from 32 patients with prostate cancer (PCa), 33 patients with renal cell cancer (RCC) and 30 patients with bladder cancer (BCa) as well as 35 healthy control (HC), which were thereafter used to enrich extracellular vesicles by ultracentrifuge. Label-free SERS was utilized to collect Raman spectra from serum and matched EV samples. We constructed CNN models to process SERS data for classification of malignant patients and healthy controls (HCs). RESULTS We collected 650 and 1206 spectra from serum and serum-derived EV, respectively. CNN models of EV spectra revealed high testing accuracies of 79.3%, 78.7% and 74.2% in diagnosis of PCa, RCC and BCa, respectively. In comparison, serum SERS-based CNN model had testing accuracies of 73.0%, 71.1%, 69.2% in PCa, RCC and BCa, respectively. Moreover, CNN models based on EV SERS data show significantly higher diagnostic capacities than matched serum CNN models with the area under curve (AUC) of 0.80, 0.88 and 0.74 in diagnosis of PCa, RCC and BCa, respectively. CONCLUSION Deep learning-based SERS analysis of EV has great potentials in diagnosis of urologic cancer outperforming serum SERS analysis, providing a novel tool in cancer screening.
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Affiliation(s)
- Hongyang Qian
- Department of Urology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Xiaoguang Shao
- Department of Urology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Heng Zhang
- Key Laboratory of Specialty Fiber Optics and Optical Access Networks, Joint International Research Laboratory of Specialty Fiber Optics and Advanced Communication, Shanghai Institute for Advanced Communication and Data Science, Shanghai University, Shanghai, People's Republic of China
| | - Yan Wang
- Department of Urology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Shupeng Liu
- Key Laboratory of Specialty Fiber Optics and Optical Access Networks, Joint International Research Laboratory of Specialty Fiber Optics and Advanced Communication, Shanghai Institute for Advanced Communication and Data Science, Shanghai University, Shanghai, People's Republic of China
| | - Jiahua Pan
- Department of Urology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
| | - Wei Xue
- Department of Urology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
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34
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Ebrahimi N, Faghihkhorasani F, Fakhr SS, Moghaddam PR, Yazdani E, Kheradmand Z, Rezaei-Tazangi F, Adelian S, Mobarak H, Hamblin MR, Aref AR. Tumor-derived exosomal non-coding RNAs as diagnostic biomarkers in cancer. Cell Mol Life Sci 2022; 79:572. [PMID: 36308630 PMCID: PMC11802992 DOI: 10.1007/s00018-022-04552-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 09/02/2022] [Accepted: 09/04/2022] [Indexed: 12/24/2022]
Abstract
Almost all clinical oncologists agree that the discovery of reliable, accessible, and non-invasive biomarkers is necessary to decrease cancer mortality. It is possible to employ reliable biomarkers to diagnose cancer in the early stages, predict the patient prognosis, follow up the response to treatment, and estimate the risk of disease recurrence with high sensitivity and specificity. Extracellular vesicles (EVs), especially exosomes, have been the focus of translational research to develop such biomarkers over the past decade. The abundance and distribution of exosomes in bodily fluids, including serum, saliva, and urine, as well as their ability to transport various biomolecules (nucleic acids, proteins, and lipids) derived from their parent cells, make exosomes reliable, accessible, and potent biomarkers for diagnosis and follow-up of solid and hematopoietic tumors. In addition, exosomes play a vital role in various cellular processes, including tumor progression, by participating in intercellular communication. Although these advantages underline the high potential of tumor-derived exosomes as diagnostic biomarkers, the lack of standardized effective methods for their isolation, identification, and precise characterization makes their application challenging in clinical settings. We discuss the importance of non-coding RNAs (ncRNAs) in cellular processes, and the role of tumor-derived exosomes containing ncRNAs as potential biomarkers in several types of cancer. In addition, the advantages and challenges of these studies for translation into clinical applications are covered.
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Affiliation(s)
- Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
| | | | - Siavash Seifollahy Fakhr
- Division of Biotechnology, Faculty of Applied Ecology, Agricultural Sciences and Biotechnology, Campus, Hamar, Norway
| | - Parichehr Roozbahani Moghaddam
- Department of Molecular Genetics, Faculty of Science, Tonekabon Branch, Islamic Azad University, Tehran, Mazandaran, Iran
| | - Elnaz Yazdani
- Department of Biology, Faculty of Science, University of Isfahan, Isfahan, Iran
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Zahra Kheradmand
- Department of Agriculture, Islamic Azad University Maragheh Branch, Maragheh, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Samaneh Adelian
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Halimeh Mobarak
- Clinical Pathologist, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa.
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
- Translational Medicine Group, Xsphera Biosciences, 6 Tide Street, Boston, MA, 02210, USA.
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35
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Lee J, Park HS, Han SR, Kang YH, Mun JY, Shin DW, Oh HW, Cho YK, Lee MS, Park J. Alpha-2-macroglobulin as a novel diagnostic biomarker for human bladder cancer in urinary extracellular vesicles. Front Oncol 2022; 12:976407. [PMID: 36176383 PMCID: PMC9513419 DOI: 10.3389/fonc.2022.976407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/17/2022] [Indexed: 11/13/2022] Open
Abstract
Extracellular vesicles (EVs) derived from urine are promising tools for the diagnosis of urogenital cancers. Urinary EVs (uEVs) are considered potential biomarkers for bladder cancer (BC) because urine is in direct contact with the BC tumor microenvironment and thus reflects the current state of the disease. However, challenges associated with the effective isolation and analysis of uEVs complicate the clinical detection of uEV-associated protein biomarkers. Herein, we identified uEV-derived alpha-2-macroglobulin (a2M) as a novel diagnostic biomarker for BC through comparative analysis of uEVs obtained from patients with BC pre- and post-operation using an antibody array. Furthermore, enzyme-linked immunosorbent assay of uEVs isolated from patients with BC (n=60) and non-cancer control subjects (n=23) validated the significant upregulation of a2M expression in patient uEVs (p<0.0001). There was no significant difference in whole urine a2M levels between patients with BC and controls (p=0.317). We observed that compared to classical differential centrifugation, ExoDisc, a centrifugal microfluidic tangential flow filtration device, was a significantly more effective separation method for uEV protein analysis. We expect that our approach for EV analysis will provide an efficient route for the identification of clinically meaningful uEV-based biomarkers for cancer diagnosis.
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Affiliation(s)
- Jisu Lee
- Department of Microbiology and Immunology, Eulji University School of Medicine, Daejeon, South Korea
| | - Hyun Sik Park
- Department of Urology, Eulji University Hospital, Eulji University School of Medicine, Daejeon, South Korea
| | - Seung Ro Han
- Department of Microbiology and Immunology, Eulji University School of Medicine, Daejeon, South Korea
- Eulji Biomedical Science Research Institute, Eulji University School of Medicine, Daejeon, South Korea
| | - Yun Hee Kang
- Department of Microbiology and Immunology, Eulji University School of Medicine, Daejeon, South Korea
- Eulji Biomedical Science Research Institute, Eulji University School of Medicine, Daejeon, South Korea
| | - Ji Young Mun
- Neural Circuit Research Group, Korea Brain Research Institute, Daegu, South Korea
| | - Dong Wook Shin
- Department of Family Medicine/Supportive Care Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hyun-Woo Oh
- Core Facility Management Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
| | - Yoon-Kyoung Cho
- Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan, South Korea
- Center for Soft and Living Matter, Institute for Basic Science (IBS), Ulsan, South Korea
| | - Myung-Shin Lee
- Department of Microbiology and Immunology, Eulji University School of Medicine, Daejeon, South Korea
- Eulji Biomedical Science Research Institute, Eulji University School of Medicine, Daejeon, South Korea
- *Correspondence: Myung-Shin Lee, ; Jinsung Park,
| | - Jinsung Park
- Department of Urology, Eulji University Hospital, Eulji University School of Medicine, Daejeon, South Korea
- Department of Urology, Uijeongbu Eulji Medical Center, Eulji University, Uijeongbu-si, South Korea
- *Correspondence: Myung-Shin Lee, ; Jinsung Park,
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Xin W, Qin Y, Lei P, Zhang J, Yang X, Wang Z. From cerebral ischemia towards myocardial, renal, and hepatic ischemia: Exosomal miRNAs as a general concept of intercellular communication in ischemia-reperfusion injury. MOLECULAR THERAPY - NUCLEIC ACIDS 2022; 29:900-922. [PMID: 36159596 PMCID: PMC9464648 DOI: 10.1016/j.omtn.2022.08.032] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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He X, Tian F, Guo F, Zhang F, Zhang H, Ji J, Zhao L, He J, Xiao Y, Li L, Wei C, Huang C, Li Y, Zhang F, Yang B, Ye H, Wang F. Circulating exosomal mRNA signatures for the early diagnosis of clear cell renal cell carcinoma. BMC Med 2022; 20:270. [PMID: 36002886 PMCID: PMC9404613 DOI: 10.1186/s12916-022-02467-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 07/04/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND There are no proven tumor biomarkers for the early diagnosis of clear cell renal cell carcinoma (ccRCC) thus far. This study aimed to identify novel biomarkers of ccRCC based on exosomal mRNA (emRNA) profiling and develop emRNA-based signatures for the early detection of ccRCC. METHODS Four hundred eighty-eight participants, including 226 localized ccRCCs, 73 patients with benign renal masses, and 189 healthy controls, were recruited. Circulating emRNA sequencing was performed in 12 ccRCCs and 22 healthy controls in the discovery phase. The candidate emRNAs were evaluated with 108 ccRCCs and 70 healthy controls in the test and training phases. The emRNA-based signatures were developed by logistic regression analysis and validated with additional cohorts of 106 ccRCCs, 97 healthy controls, and 73 benign individuals. RESULTS Five emRNAs, CUL9, KMT2D, PBRM1, PREX2, and SETD2, were identified as novel potential biomarkers of ccRCC. We further developed an early diagnostic signature that comprised KMT2D and PREX2 and a differential diagnostic signature that comprised CUL9, KMT2D, and PREX2 for RCC detection. The early diagnostic signature displayed high accuracy in distinguishing ccRCCs from healthy controls, with areas under the receiver operating characteristic curve (AUCs) of 0.836 and 0.830 in the training and validation cohorts, respectively. The differential diagnostic signature also showed great performance in distinguishing ccRCCs from benign renal masses (AUC = 0.816), including solid masses (AUC = 0.810) and cystic masses (AUC = 0.832). CONCLUSIONS We established and validated novel emRNA-based signatures for the early detection of ccRCC and differential diagnosis of uncertain renal masses. These signatures could be promising and noninvasive biomarkers for ccRCC detection and thus improve the prognosis of ccRCC patients.
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Affiliation(s)
- Xing He
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), 168 Changhai Road, Shanghai, 200433, China
| | - Feng Tian
- Department of Urology, The Eighth People's Hospital of Shanghai, 8 Caobao Road, Shanghai, 200235, China
| | - Fei Guo
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), 168 Changhai Road, Shanghai, 200433, China
| | - Fangxing Zhang
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Huiyong Zhang
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Jin Ji
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), 168 Changhai Road, Shanghai, 200433, China
| | - Lin Zhao
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), 168 Changhai Road, Shanghai, 200433, China
| | - Jingyi He
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), 168 Changhai Road, Shanghai, 200433, China
| | - Yutian Xiao
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), 168 Changhai Road, Shanghai, 200433, China
| | - Longman Li
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Chunmeng Wei
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Caihong Huang
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Yexin Li
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Feng Zhang
- Department of Urology, The Eighth People's Hospital of Shanghai, 8 Caobao Road, Shanghai, 200235, China
| | - Bo Yang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), 168 Changhai Road, Shanghai, 200433, China.
| | - Huamao Ye
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), 168 Changhai Road, Shanghai, 200433, China.
| | - Fubo Wang
- Center for Genomic and Personalized Medicine, Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China.
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Urinary extracellular vesicle mRNA analysis of sodium chloride cotransporter in hypertensive patients under different conditions. J Hum Hypertens 2022:10.1038/s41371-022-00744-3. [PMID: 35978099 DOI: 10.1038/s41371-022-00744-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 07/19/2022] [Accepted: 07/27/2022] [Indexed: 11/09/2022]
Abstract
Urinary extracellular vesicles (UEV) mainly derive from cells of the urogenital tract and their cargo (proteins, nucleic acids, lipids, etc.) reflects their cells of origin. Na chloride cotransporter (NCC) is expressed at the kidney level in the distal convoluted tubule, is involved in salt reabsorption, and is the target of the diuretic thiazides. NCC protein has been recognized and quantified in UEV in previous studies; however, UEV NCC mRNA has never been studied. This study aimed to identify and analyze NCC mRNA levels in primary aldosteronism (PA). The rationale for this investigation stems from previous observations regarding NCC (protein) as a possible biomarker for the diagnosis of PA. To evaluate modulations in the expression of NCC, we analyzed NCC mRNA levels in UEV in PA and essential hypertensive (EH) patients under different conditions, that is, before and after saline infusion, anti-aldosterone pharmacological treatment, and adrenal surgery. NCC mRNA was measured by RT-qPCR in all the samples and was regulated by volume expansion. Its response to mineralocorticoid receptor antagonist was correlated with renin, and it was increased in PA patients after adrenalectomy. NCC mRNA is evaluable in UEV and it can provide insights into the pathophysiology of distal convolute tubule in different clinical conditions including PA.
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39
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Identification of Transferrin Receptor 1 (TfR1) Overexpressed in Lung Cancer Cells, and Internalization of Magnetic Au-CoFe2O4 Core-Shell Nanoparticles Functionalized with Its Ligand in a Cellular Model of Small Cell Lung Cancer (SCLC). Pharmaceutics 2022; 14:pharmaceutics14081715. [PMID: 36015341 PMCID: PMC9413248 DOI: 10.3390/pharmaceutics14081715] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/27/2022] [Accepted: 08/02/2022] [Indexed: 11/26/2022] Open
Abstract
Lung cancer is, currently, one of the main malignancies causing deaths worldwide. To date, early prognostic and diagnostic markers for small cell lung cancer (SCLC) have not been systematically and clearly identified, so most patients receive standard treatment. In the present study, we combine quantitative proteomics studies and the use of magnetic core-shell nanoparticles (mCSNP’s), first to identify a marker for lung cancer, and second to functionalize the nanoparticles and their possible application for early and timely diagnosis of this and other types of cancer. In the present study, we used label-free mass spectrometry in combination with an ion-mobility approach to identify 220 proteins with increased abundance in small cell lung cancer (SCLC) cell lines. Our attention was focused on cell receptors for their potential application as mCSNP’s targets; in this work, we report the overexpression of Transferrin Receptor (TfR1) protein, also known as Cluster of Differentiation 71 (CD71) up to a 30-fold increase with respect to the control cell. The kinetics of endocytosis, evaluated by a flow cytometry methodology based on fluorescence quantification, demonstrated that receptors were properly activated with the transferrin supported on the magnetic core-shell nanoparticles. Our results are important in obtaining essential information for monitoring the disease and/or choosing better treatments, and this finding will pave the way for future synthesis of nanoparticles including chemotherapeutic drugs for lung cancer treatments.
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Bragina VA, Khomyakova E, Orlov AV, Znoyko SL, Mochalova EN, Paniushkina L, Shender VO, Erbes T, Evtushenko EG, Bagrov DV, Lavrenova VN, Nazarenko I, Nikitin PI. Highly Sensitive Nanomagnetic Quantification of Extracellular Vesicles by Immunochromatographic Strips: A Tool for Liquid Biopsy. NANOMATERIALS (BASEL, SWITZERLAND) 2022; 12:1579. [PMID: 35564289 PMCID: PMC9101557 DOI: 10.3390/nano12091579] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/18/2022] [Accepted: 05/02/2022] [Indexed: 01/27/2023]
Abstract
Extracellular vesicles (EVs) are promising agents for liquid biopsy-a non-invasive approach for the diagnosis of cancer and evaluation of therapy response. However, EV potential is limited by the lack of sufficiently sensitive, time-, and cost-efficient methods for their registration. This research aimed at developing a highly sensitive and easy-to-use immunochromatographic tool based on magnetic nanoparticles for EV quantification. The tool is demonstrated by detection of EVs isolated from cell culture supernatants and various body fluids using characteristic biomarkers, CD9 and CD81, and a tumor-associated marker-epithelial cell adhesion molecules. The detection limit of 3.7 × 105 EV/µL is one to two orders better than the most sensitive traditional lateral flow system and commercial ELISA kits. The detection specificity is ensured by an isotype control line on the test strip. The tool's advantages are due to the spatial quantification of EV-bound magnetic nanolabels within the strip volume by an original electronic technique. The inexpensive tool, promising for liquid biopsy in daily clinical routines, can be extended to other relevant biomarkers.
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Affiliation(s)
- Vera A. Bragina
- Prokhorov General Physics Institute of the Russian Academy of Sciences, 38 Vavilov St., 119991 Moscow, Russia; (V.A.B.); (E.K.); (A.V.O.); (S.L.Z.); (E.N.M.)
| | - Elena Khomyakova
- Prokhorov General Physics Institute of the Russian Academy of Sciences, 38 Vavilov St., 119991 Moscow, Russia; (V.A.B.); (E.K.); (A.V.O.); (S.L.Z.); (E.N.M.)
| | - Alexey V. Orlov
- Prokhorov General Physics Institute of the Russian Academy of Sciences, 38 Vavilov St., 119991 Moscow, Russia; (V.A.B.); (E.K.); (A.V.O.); (S.L.Z.); (E.N.M.)
- Moscow Institute of Physics and Technology, 9 Institutskii per., 141700 Dolgoprudny, Russia
| | - Sergey L. Znoyko
- Prokhorov General Physics Institute of the Russian Academy of Sciences, 38 Vavilov St., 119991 Moscow, Russia; (V.A.B.); (E.K.); (A.V.O.); (S.L.Z.); (E.N.M.)
| | - Elizaveta N. Mochalova
- Prokhorov General Physics Institute of the Russian Academy of Sciences, 38 Vavilov St., 119991 Moscow, Russia; (V.A.B.); (E.K.); (A.V.O.); (S.L.Z.); (E.N.M.)
- Sirius University of Science and Technology, 1 Olympic Ave., 354340 Sochi, Russia
| | - Liliia Paniushkina
- Institute for Infection Prevention and Hospital Epidemiology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (L.P.); (I.N.)
| | - Victoria O. Shender
- Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, 1a Malaya Pirogovskaya St., 119992 Moscow, Russia; (V.O.S.); (V.N.L.)
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 16/10 Miklukho-Maklaya St., 117997 Moscow, Russia
| | - Thalia Erbes
- Department of Obstetrics and Gynecology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany;
| | - Evgeniy G. Evtushenko
- Lomonosov Moscow State University, 1 Leninskie Gory, 119991 Moscow, Russia; (E.G.E.); (D.V.B.)
| | - Dmitry V. Bagrov
- Lomonosov Moscow State University, 1 Leninskie Gory, 119991 Moscow, Russia; (E.G.E.); (D.V.B.)
| | - Victoria N. Lavrenova
- Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency, 1a Malaya Pirogovskaya St., 119992 Moscow, Russia; (V.O.S.); (V.N.L.)
- Lomonosov Moscow State University, 1 Leninskie Gory, 119991 Moscow, Russia; (E.G.E.); (D.V.B.)
| | - Irina Nazarenko
- Institute for Infection Prevention and Hospital Epidemiology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (L.P.); (I.N.)
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Petr I. Nikitin
- Prokhorov General Physics Institute of the Russian Academy of Sciences, 38 Vavilov St., 119991 Moscow, Russia; (V.A.B.); (E.K.); (A.V.O.); (S.L.Z.); (E.N.M.)
- National Research Nuclear University MEPhI (Moscow Engineering Physics Institute), 31 Kashirskoe Shosse, 115409 Moscow, Russia
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Microfluidic Platforms for the Isolation and Detection of Exosomes: A Brief Review. MICROMACHINES 2022; 13:mi13050730. [PMID: 35630197 PMCID: PMC9147043 DOI: 10.3390/mi13050730] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 02/06/2023]
Abstract
Extracellular vesicles (EVs) are a group of communication organelles enclosed by a phospholipid bilayer, secreted by all types of cells. The size of these vesicles ranges from 30 to 1000 nm, and they contain a myriad of compounds such as RNA, DNA, proteins, and lipids from their origin cells, offering a good source of biomarkers. Exosomes (30 to 100 nm) are a subset of EVs, and their importance in future medicine is beyond any doubt. However, the lack of efficient isolation and detection techniques hinders their practical applications as biomarkers. Versatile and cutting-edge platforms are required to detect and isolate exosomes selectively for further clinical analysis. This review paper focuses on lab-on-chip devices for capturing, detecting, and isolating extracellular vesicles. The first part of the paper discusses the main characteristics of different cell-derived vesicles, EV functions, and their clinical applications. In the second part, various microfluidic platforms suitable for the isolation and detection of exosomes are described, and their performance in terms of yield, sensitivity, and time of analysis is discussed.
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Emerging function and clinical significance of extracellular vesicle noncoding RNAs in lung cancer. Mol Ther Oncolytics 2022; 24:814-833. [PMID: 35317517 PMCID: PMC8908047 DOI: 10.1016/j.omto.2022.02.016] [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] [Indexed: 02/07/2023] Open
Abstract
Lung cancer (LC) is a commonly diagnosed cancer with an unsatisfactory prognosis. Extracellular vesicles (EVs) are lipid bilayer-delimited particles that mediate cell-cell communication by transporting various biomacromolecules, such as nucleic acids, proteins, and lipids. Noncoding RNAs (ncRNAs), including microRNAs, circular RNAs, and long noncoding RNAs, are important noncoding transcripts that play critical roles in a variety of physiological and pathological processes, especially in cancer. ncRNAs have been verified to be packaged into EVs and transported between LC cells and stromal cells, regulating multiple LC malignant phenotypes, such as proliferation, migration, invasion, epithelial-mesenchymal transition, metastasis, and treatment resistance. Additionally, EVs can be detected in various body fluids and are associated with the stage, grade, and metastasis of LC. Herein, we summarize the biological characteristics and functions of EV ncRNAs in the biological processes of LC, focusing on their potential to serve as diagnostic and prognostic biomarkers of LC as well as their probable role in the clinical treatment of LC. EV ncRNAs provide a new perspective for understanding the mechanism underlying LC pathogenesis and development, which might benefit numerous LC patients in the future.
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Millan C, Prause L, Vallmajo‐Martin Q, Hensky N, Eberli D. Extracellular Vesicles from 3D Engineered Microtissues Harbor Disease-Related Cargo Absent in EVs from 2D Cultures. Adv Healthc Mater 2022; 11:e2002067. [PMID: 33890421 DOI: 10.1002/adhm.202002067] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 04/05/2021] [Indexed: 12/13/2022]
Abstract
Engineered microtissues that recapitulate key properties of the tumor microenvironment can induce clinically relevant cancer phenotypes in vitro. However, their effect on molecular cargo of secreted extracellular vesicles (EVs) has not yet been investigated. Here, the impact of hydrogel-based 3D engineered microtissues on EVs secreted by benign and malignant prostate cells is assessed. Compared to 2D cultures, yield of EVs per cell is significantly increased for cancer cells cultured in 3D. Whole transcriptome sequencing and proteomics of 2D-EV and 3D-EV samples reveal stark contrasts in molecular cargo. For one cell type in particular, LNCaP, enrichment is observed exclusively in 3D-EVs of GDF15, FASN, and TOP1, known drivers of prostate cancer progression. Using imaging flow cytometry in a novel approach to validate a putative EV biomarker, colocalization in single EVs of GDF15 with CD9, a universal EV marker, is demonstrated. Finally, in functional assays it is observed that only 3D-EVs, unlike 2D-EVs, confer increased invasiveness and chemoresistance to cells in 2D. Collectively, this study highlights the value of engineered 3D microtissue cultures for the study of bona fide EV cargoes and their potential to identify biomarkers that are not detectable in EVs secreted by cells cultured in standard 2D conditions.
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Affiliation(s)
- Christopher Millan
- Laboratory for Urologic Oncology and Stem Cell Therapy University Hospital Zürich Wagistr. 21 Schlieren 8952 Switzerland
- CellSpring AG Breitensteinstr. 31 Zürich 8037 Switzerland
| | - Lukas Prause
- Laboratory for Urologic Oncology and Stem Cell Therapy University Hospital Zürich Wagistr. 21 Schlieren 8952 Switzerland
- Kantonsspital Aarau Urologie, Tellstr. 25 Aarau 5001 Switzerland
| | | | - Natalie Hensky
- Laboratory for Urologic Oncology and Stem Cell Therapy University Hospital Zürich Wagistr. 21 Schlieren 8952 Switzerland
| | - Daniel Eberli
- Laboratory for Urologic Oncology and Stem Cell Therapy University Hospital Zürich Wagistr. 21 Schlieren 8952 Switzerland
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Veuthey L, Aliotta A, Bertaggia Calderara D, Pereira Portela C, Alberio L. Mechanisms Underlying Dichotomous Procoagulant COAT Platelet Generation-A Conceptual Review Summarizing Current Knowledge. Int J Mol Sci 2022; 23:2536. [PMID: 35269679 PMCID: PMC8910683 DOI: 10.3390/ijms23052536] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/19/2022] [Accepted: 02/21/2022] [Indexed: 12/23/2022] Open
Abstract
Procoagulant platelets are a subtype of activated platelets that sustains thrombin generation in order to consolidate the clot and stop bleeding. This aspect of platelet activation is gaining more and more recognition and interest. In fact, next to aggregating platelets, procoagulant platelets are key regulators of thrombus formation. Imbalance of both subpopulations can lead to undesired thrombotic or bleeding events. COAT platelets derive from a common pro-aggregatory phenotype in cells capable of accumulating enough cytosolic calcium to trigger specific pathways that mediate the loss of their aggregating properties and the development of new adhesive and procoagulant characteristics. Complex cascades of signaling events are involved and this may explain why an inter-individual variability exists in procoagulant potential. Nowadays, we know the key agonists and mediators underlying the generation of a procoagulant platelet response. However, we still lack insight into the actual mechanisms controlling this dichotomous pattern (i.e., procoagulant versus aggregating phenotype). In this review, we describe the phenotypic characteristics of procoagulant COAT platelets, we detail the current knowledge on the mechanisms of the procoagulant response, and discuss possible drivers of this dichotomous diversification, in particular addressing the impact of the platelet environment during in vivo thrombus formation.
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Affiliation(s)
| | | | | | | | - Lorenzo Alberio
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland; (L.V.); (A.A.); (D.B.C.); (C.P.P.)
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Cappello F, Fais S. Extracellular vesicles in cancer pros and cons: the importance of the evidence-based medicine. Semin Cancer Biol 2022; 86:4-12. [DOI: 10.1016/j.semcancer.2022.01.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 01/18/2022] [Accepted: 01/28/2022] [Indexed: 12/17/2022]
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Correll VL, Otto JJ, Risi CM, Main BP, Boutros PC, Kislinger T, Galkin VE, Nyalwidhe JO, Semmes OJ, Yang L. Optimization of small extracellular vesicle isolation from expressed prostatic secretions in urine for in-depth proteomic analysis. J Extracell Vesicles 2022; 11:e12184. [PMID: 35119778 PMCID: PMC8815402 DOI: 10.1002/jev2.12184] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 11/22/2021] [Accepted: 12/22/2021] [Indexed: 01/23/2023] Open
Abstract
The isolation and subsequent molecular analysis of extracellular vesicles (EVs) derived from patient samples is a widely used strategy to understand vesicle biology and to facilitate biomarker discovery. Expressed prostatic secretions in urine are a tumor proximal fluid that has received significant attention as a source of potential prostate cancer (PCa) biomarkers for use in liquid biopsy protocols. Standard EV isolation methods like differential ultracentrifugation (dUC) co-isolate protein contaminants that mask lower-abundance proteins in typical mass spectrometry (MS) protocols. Further complicating the analysis of expressed prostatic secretions, uromodulin, also known as Tamm-Horsfall protein (THP), is present at high concentrations in urine. THP can form polymers that entrap EVs during purification, reducing yield. Disruption of THP polymer networks with dithiothreitol (DTT) can release trapped EVs, but smaller THP fibres co-isolate with EVs during subsequent ultracentrifugation. To resolve these challenges, we describe here a dUC method that incorporates THP polymer reduction and alkaline washing to improve EV isolation and deplete both THP and other common protein contaminants. When applied to human expressed prostatic secretions in urine, we achieved relative enrichment of known prostate and prostate cancer-associated EV-resident proteins. Our approach provides a promising strategy for global proteomic analyses of urinary EVs.
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Affiliation(s)
- Vanessa L. Correll
- Leroy T. Canoles Jr. Cancer Research CenterEastern Virginia Medical SchoolNorfolkVirginiaUSA
| | - Joseph J. Otto
- Leroy T. Canoles Jr. Cancer Research CenterEastern Virginia Medical SchoolNorfolkVirginiaUSA
| | - Cristina M. Risi
- Department of Physiological SciencesEastern Virginia Medical SchoolNorfolkVirginiaUSA
| | - Brian P. Main
- Leroy T. Canoles Jr. Cancer Research CenterEastern Virginia Medical SchoolNorfolkVirginiaUSA
| | - Paul C. Boutros
- Department of Medical BiophysicsUniversity of TorontoTorontoCanada
- Department of Pharmacology and ToxicologyUniversity of TorontoTorontoCanada
- Department of Human GeneticsUniversity of CaliforniaLos AngelesCaliforniaUSA
- Department of UrologyUniversity of CaliforniaLos AngelesCaliforniaUSA
- Institute for Precision HealthUniversity of CaliforniaLos AngelesCaliforniaUSA
- Jonsson Comprehensive Cancer CenterUniversity of CaliforniaLos AngelesCaliforniaUSA
| | - Thomas Kislinger
- Department of Medical BiophysicsUniversity of TorontoTorontoCanada
- Princess Margaret Cancer CentreUniversity Health NetworkTorontoCanada
| | - Vitold E. Galkin
- Department of Physiological SciencesEastern Virginia Medical SchoolNorfolkVirginiaUSA
| | - Julius O. Nyalwidhe
- Leroy T. Canoles Jr. Cancer Research CenterEastern Virginia Medical SchoolNorfolkVirginiaUSA
- Department of Microbiology and Molecular Cell BiologyEastern Virginia Medical SchoolNorfolkVirginiaUSA
| | - O. John Semmes
- Leroy T. Canoles Jr. Cancer Research CenterEastern Virginia Medical SchoolNorfolkVirginiaUSA
- Department of Microbiology and Molecular Cell BiologyEastern Virginia Medical SchoolNorfolkVirginiaUSA
| | - Lifang Yang
- Leroy T. Canoles Jr. Cancer Research CenterEastern Virginia Medical SchoolNorfolkVirginiaUSA
- Department of Microbiology and Molecular Cell BiologyEastern Virginia Medical SchoolNorfolkVirginiaUSA
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Ekström K, Crescitelli R, Pétursson HI, Johansson J, Lässer C, Olofsson Bagge R. Characterization of surface markers on extracellular vesicles isolated from lymphatic exudate from patients with breast cancer. BMC Cancer 2022; 22:50. [PMID: 35012489 PMCID: PMC8744234 DOI: 10.1186/s12885-021-08870-w] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 10/11/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Breast cancer is the most common cancer, and the leading cause of cancer-related deaths, among females world-wide. Recent research suggests that extracellular vesicles (EVs) play a major role in the development of breast cancer metastasis. Axillary lymph node dissection (ALND) is a procedure in patients with known lymph node metastases, and after surgery large amounts of serous fluid are produced from the axilla. The overall aim was to isolate and characterize EVs from axillary serous fluid, and more specifically to determine if potential breast cancer biomarkers could be identified. METHODS Lymphatic drain fluid was collected from 7 patients with breast cancer the day after ALND. EVs were isolated using size exclusion chromatography, quantified and detected by nanoparticle tracking analysis, electron microscopy, nano flow cytometry and western blot. The expression of 37 EV surface proteins was evaluated by flow cytometry using the MACSPlex Exosome kit. RESULTS Lymphatic drainage exudate retrieved after surgery from all 7 patients contained EVs. The isolated EVs were positive for the typical EV markers CD9, CD63, CD81 and Flotillin-1 while albumin was absent, indicating low contamination from blood proteins. In total, 24 different EV surface proteins were detected. Eleven of those proteins were detected in all patients, including the common EV markers CD9, CD63 and CD81, cancer-related markers CD24, CD29, CD44 and CD146, platelet markers CD41b, CD42a and CD62p as well as HLA-DR/DP/DQ. Furthermore, CD29 and CD146 were enriched in Her2+ patients compared to patients with Her2- tumors. CONCLUSIONS Lymphatic drainage exudate retrieved from breast cancer patients after surgery contains EVs that can be isolated using SEC isolation. The EVs have several cancer-related markers including CD24, CD29, CD44 and CD146, proteins of potential interest as biomarkers as well as to increase the understanding of the mechanisms of cancer biology.
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Affiliation(s)
- Karin Ekström
- Sahlgrenska Center for Cancer Research and Wallenberg Centre for Molecular and Translational Medicine, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
| | - Rossella Crescitelli
- Sahlgrenska Center for Cancer Research and Wallenberg Centre for Molecular and Translational Medicine, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Hafsteinn Ingi Pétursson
- Sahlgrenska Center for Cancer Research and Wallenberg Centre for Molecular and Translational Medicine, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Junko Johansson
- Sahlgrenska Center for Cancer Research and Wallenberg Centre for Molecular and Translational Medicine, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Cecilia Lässer
- Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Roger Olofsson Bagge
- Sahlgrenska Center for Cancer Research and Wallenberg Centre for Molecular and Translational Medicine, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
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Akbar A, Malekian F, Baghban N, Kodam SP, Ullah M. Methodologies to Isolate and Purify Clinical Grade Extracellular Vesicles for Medical Applications. Cells 2022; 11:186. [PMID: 35053301 PMCID: PMC8774122 DOI: 10.3390/cells11020186] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
The use of extracellular vesicles (EV) in nano drug delivery has been demonstrated in many previous studies. In this study, we discuss the sources of extracellular vesicles, including plant, salivary and urinary sources which are easily available but less sought after compared with blood and tissue. Extensive research in the past decade has established that the breadth of EV applications is wide. However, the efforts on standardizing the isolation and purification methods have not brought us to a point that can match the potential of extracellular vesicles for clinical use. The standardization can open doors for many researchers and clinicians alike to experiment with the proposed clinical uses with lesser concerns regarding untraceable side effects. It can make it easier to identify the mechanism of therapeutic benefits and to track the mechanism of any unforeseen effects observed.
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Affiliation(s)
- Asma Akbar
- Institute for Immunity and Transplantation, Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Palo Alto, CA 94304, USA; (A.A.); (F.M.); (N.B.); (S.P.K.)
| | - Farzaneh Malekian
- Institute for Immunity and Transplantation, Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Palo Alto, CA 94304, USA; (A.A.); (F.M.); (N.B.); (S.P.K.)
| | - Neda Baghban
- Institute for Immunity and Transplantation, Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Palo Alto, CA 94304, USA; (A.A.); (F.M.); (N.B.); (S.P.K.)
| | - Sai Priyanka Kodam
- Institute for Immunity and Transplantation, Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Palo Alto, CA 94304, USA; (A.A.); (F.M.); (N.B.); (S.P.K.)
| | - Mujib Ullah
- Institute for Immunity and Transplantation, Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Palo Alto, CA 94304, USA; (A.A.); (F.M.); (N.B.); (S.P.K.)
- Department of Cancer Immunology, Genentech Inc., South San Francisco, CA 94080, USA
- Molecular Medicine Department of Medicine, Stanford University, Palo Alto, CA 94304, USA
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Yu W, Li S, Guan X, Zhang N, Xie X, Zhang K, Bai Y. Higher yield and enhanced therapeutic effects of exosomes derived from MSCs in hydrogel-assisted 3D culture system for bone regeneration. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2022; 133:112646. [DOI: 10.1016/j.msec.2022.112646] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/09/2021] [Accepted: 01/03/2022] [Indexed: 02/07/2023]
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50
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Bernardino RMM, Leão R, Henrique R, Pinheiro LC, Kumar P, Suravajhala P, Beck HC, Carvalho AS, Matthiesen R. Extracellular Vesicle Proteome in Prostate Cancer: A Comparative Analysis of Mass Spectrometry Studies. Int J Mol Sci 2021; 22:13605. [PMID: 34948404 PMCID: PMC8707426 DOI: 10.3390/ijms222413605] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/15/2021] [Accepted: 12/15/2021] [Indexed: 12/24/2022] Open
Abstract
Molecular diagnostics based on discovery research holds the promise of improving screening methods for prostate cancer (PCa). Furthermore, the congregated information prompts the question whether the urinary extracellular vesicles (uEV) proteome has been thoroughly explored, especially at the proteome level. In fact, most extracellular vesicles (EV) based biomarker studies have mainly targeted plasma or serum. Therefore, in this study, we aim to inquire about possible strategies for urinary biomarker discovery particularly focused on the proteome of urine EVs. Proteomics data deposited in the PRIDE archive were reanalyzed to target identifications of potential PCa markers. Network analysis of the markers proposed by different prostate cancer studies revealed moderate overlap. The recent throughput improvements in mass spectrometry together with the network analysis performed in this study, suggest that a larger standardized cohort may provide potential biomarkers that are able to fully characterize the heterogeneity of PCa. According to our analysis PCa studies based on urinary EV proteome presents higher protein coverage compared to plasma, plasma EV, and voided urine proteome. This together with a direct interaction of the prostate gland and urethra makes uEVs an attractive option for protein biomarker studies. In addition, urinary proteome based PCa studies must also evaluate samples from bladder and renal cancers to assess specificity for PCa.
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Affiliation(s)
- Rui Miguel Marques Bernardino
- Computational and Experimental Biology Group, Chronic Diseases Research Centre (CEDOC), NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal;
- Urology Department, Centro Hospitalar e Universitário de Lisboa Central, 1169-050 Lisbon, Portugal;
| | - Ricardo Leão
- Faculty of Medicine, University of Coimbra, 3000-370 Coimbra, Portugal;
| | - Rui Henrique
- Pathology Department, Instituto Português de Oncologia, 4200-072 Porto, Portugal;
| | - Luis Campos Pinheiro
- Urology Department, Centro Hospitalar e Universitário de Lisboa Central, 1169-050 Lisbon, Portugal;
| | - Prashant Kumar
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India;
- Somaiya Institute of Research and Consultancy (SIRAC), Somaiya Vidyavihar University (SVU), Vidyavihar, Mumbai 400077, India
| | - Prashanth Suravajhala
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri Campus, Clappana P.O., Kollam 690525, India;
| | - Hans Christian Beck
- Centre for Clinical Proteomics, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, 5000 Odense, Denmark;
| | - Ana Sofia Carvalho
- Computational and Experimental Biology Group, Chronic Diseases Research Centre (CEDOC), NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal;
| | - Rune Matthiesen
- Computational and Experimental Biology Group, Chronic Diseases Research Centre (CEDOC), NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal;
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