|
1
|
Dlamini NH, Bridi A, da Silveira JC, Feugang JM. Unlocking Gamete Quality Through Extracellular Vesicles: Emerging Perspectives. BIOLOGY 2025; 14:198. [PMID: 40001966 PMCID: PMC11851576 DOI: 10.3390/biology14020198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 02/08/2025] [Accepted: 02/12/2025] [Indexed: 02/27/2025]
Abstract
Extracellular vesicles (EVs) are gaining recognition for their essential role in enhancing gamete quality and improving outcomes in assisted reproductive technologies. These nanosized particles, released by cells, carry proteins, lipids, and RNAs, facilitating critical cell communication and offering the potential to enhance gamete maturation and improve fertilization rates. Most research on males has concentrated on seminal plasma, a complex fluid produced by the testes and accessory glands vital in modulating sperm fertility potential. The components of seminal plasma significantly affect sperm functionality, embryo survival, and placental development, making this a prominent area of interest in reproductive biology. The EVs within seminal plasma contribute to maintaining sperm membrane stability, enhancing motility, and promoting capacitation, which may influence the female reproductive tract following mating. In females, EVs have been identified in both the follicular and uterine environments, where effective embryo-maternal communication is crucial. The oviduct epithelium supports gamete transport and early embryonic development, with EVs found in oviductal fluid playing a key role in reproductive processes. These EVs support the embryo's growth in the nutrient-rich uterine environment. These important studies underscore the significant role of EVs in transporting essential molecular compounds to gametes and embryos, leading to an enhanced understanding and potential manipulation of reproductive processes. This review aims to summarize the current research on the benefits of EVs in gamete manipulation and embryo development, highlighting their promising implications for reproductive health.
Collapse
Affiliation(s)
- Notsile H. Dlamini
- Department of Animal and Dairy Sciences, Mississippi State University, Starkville, MS 39759, USA;
| | - Alessandra Bridi
- University of the West of Santa Catarina, Xanxerê 89820-000, SC, Brazil;
| | | | - Jean M. Feugang
- Department of Animal and Dairy Sciences, Mississippi State University, Starkville, MS 39759, USA;
| |
Collapse
|
|
2
|
Wang N, Li J, Hu Z, Ngowi EE, Yan B, Qiao A. Exosomes: New Insights into the Pathogenesis of Metabolic Syndrome. BIOLOGY 2023; 12:1480. [PMID: 38132306 PMCID: PMC10740970 DOI: 10.3390/biology12121480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 11/19/2023] [Accepted: 11/21/2023] [Indexed: 12/23/2023]
Abstract
Exosomes are a subtype of extracellular vesicles (EVs) with a diameter of 30~150 nm (averaging ~100 nm) that are primarily produced through the endosomal pathway, and carry various components such as lipids, proteins, RNA, and other small molecular substances. Exosomes can mediate intercellular communication through the bioactive substances they carry, thus participating in different physiological activities. Metabolic syndrome (MS) is a disease caused by disturbances in the body's metabolism, mainly including insulin resistance (IR), diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), hyperlipidemia, and atherosclerosis (AS). Recent studies have shown that exosomes are closely related to the occurrence and development of MS. Exosomes can act as messengers to mediate signaling transductions between metabolic cells in the organism and play a bidirectional regulatory role in the MS process. This paper mainly reviews the components, biogenesis, biological functions and potential applications of exosomes, and exosomes involved in the pathogenesis of MS as well as their clinical significance in MS diagnosis.
Collapse
Affiliation(s)
- Ning Wang
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; (N.W.); (J.L.); (Z.H.); (E.E.N.)
| | - Jing Li
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; (N.W.); (J.L.); (Z.H.); (E.E.N.)
| | - Zixuan Hu
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; (N.W.); (J.L.); (Z.H.); (E.E.N.)
| | - Ebenezeri Erasto Ngowi
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; (N.W.); (J.L.); (Z.H.); (E.E.N.)
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 101408, China
- Department of Biological Sciences, Dar es Salaam University College of Education, Dar es Salaam 2329, Tanzania
| | - Baolong Yan
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China;
| | - Aijun Qiao
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; (N.W.); (J.L.); (Z.H.); (E.E.N.)
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
| |
Collapse
|
|
3
|
Altuna-Coy A, Ruiz-Plazas X, Arreaza-Gil V, Segarra-Tomás J, Chacón MR. In silico analysis of prognostic and diagnostic significance of target genes from prostate cancer cell lines derived exomicroRNAs. Cancer Cell Int 2023; 23:275. [PMID: 37978493 PMCID: PMC10655318 DOI: 10.1186/s12935-023-03123-1] [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: 08/03/2023] [Accepted: 11/02/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Cancer-secreted exovesicles are important for cell-to-cell communication by altering cancer-related signalling pathways. Exovesicles-derived miRNAs (exomiRNAs)-target genes can be useful for diagnostic and prognostic purposes. METHODS ExomiRNA from prostate cancer (PCa) cells (PC-3 and LNCaP) were quantified by qRT-PCR and compared to the healthy cell line RWPE-1 by using miRNome PCR 752 miRNAs Panel. MiRNet database was used to predict exomiRNA-target genes. ExomiRNA-target genes pathway functional enrichment was performed by using Reactome database and Enrichr platform. Protein-protein interaction analysis was carried out by using the STRING database. RNA target-gene sequencing data from The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) database was screened out in 465 PCa patients for candidate gene expression in prostate tumour (PT) tissue and non-pathologic prostate (N-PP) tissue. Signature gene candidates were statistically analysed for diagnosis and prognosis usefulness. RESULTS A total of 36 exomiRNAs were found downregulated when comparing PCa cells vs a healthy cell line; and when comparing PC-3 vs LNCaP, 14 miRNAs were found downregulated and 52 upregulated. Reactome pathway database revealed altered pathways and genes related to miRNA biosynthesis, miRNA-mediated gene silencing (TNRC6B and AGO1), and cell proliferation (CDK6), among others. Results showed that TNRC6B gene expression was up-regulated in PT tissue compared to N-PP (n = 52 paired samples) and could be useful for diagnostic purposes. Likewise, gene expression levels of CDK6, TNRC6B, and AGO1 were down-regulated in high-risk PT (n = 293) compared to low-risk PCa tissue counterparts (n = 172). When gene expression levels of CDK6, TNRC6B, and AGO1 were tested as a prognostic panel, the results showed that these improve the prognostic power of classical biomarkers. CONCLUSION ExomiRNAs-targets genes, TNRC6B, CDK6, and AGO1, showed a deregulated expression profile in PCa tissue and could be useful for PCa diagnosis and prognosis.
Collapse
Affiliation(s)
- Antonio Altuna-Coy
- Disease Biomarkers and Molecular Mechanisms Group, IISPV, Joan XXIII University Hospital, Universitat Rovira I Virgili, C/Dr. Mallafré Guasch, 4,, 43007, Tarragona, Spain
| | - Xavier Ruiz-Plazas
- Disease Biomarkers and Molecular Mechanisms Group, IISPV, Joan XXIII University Hospital, Universitat Rovira I Virgili, C/Dr. Mallafré Guasch, 4,, 43007, Tarragona, Spain
- Urology Unit, Joan XXIII University Hospital, Tarragona, Spain
| | - Verónica Arreaza-Gil
- Disease Biomarkers and Molecular Mechanisms Group, IISPV, Joan XXIII University Hospital, Universitat Rovira I Virgili, C/Dr. Mallafré Guasch, 4,, 43007, Tarragona, Spain
| | - José Segarra-Tomás
- Disease Biomarkers and Molecular Mechanisms Group, IISPV, Joan XXIII University Hospital, Universitat Rovira I Virgili, C/Dr. Mallafré Guasch, 4,, 43007, Tarragona, Spain
- Urology Unit, Joan XXIII University Hospital, Tarragona, Spain
| | - Matilde R Chacón
- Disease Biomarkers and Molecular Mechanisms Group, IISPV, Joan XXIII University Hospital, Universitat Rovira I Virgili, C/Dr. Mallafré Guasch, 4,, 43007, Tarragona, Spain.
| |
Collapse
|
|
4
|
Yasodha K, Lizha Mary L, Surajit P, Satish R. Exosomes from metastatic colon cancer cells drive the proliferation and migration of primary colon cancer through increased expression of cancer stem cell markers CD133 and DCLK1. Tissue Cell 2023; 84:102163. [PMID: 37487255 DOI: 10.1016/j.tice.2023.102163] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 07/03/2023] [Accepted: 07/11/2023] [Indexed: 07/26/2023]
Abstract
The exchange of biological material between the neighbouring cells is essential for homeostasis. In pathological conditions, such as cancer, the major challenge in cancer treatment is the abnormal expression of crucial proteins and miRNA exchanged between the cancer cells through extracellular vesicles called exosomes. Clinically, it has been noticed that the primary tumour and the distal metastases are interconnected and co-dependent. The exosomes are key factors responsible for preparing the pre-metastatic niche and communicating between the tumour and the distal metastatic site. Cancer stem cells (CSCs) are a subpopulation of cancer cells with self-renewal characteristics and are shown to be responsible for metastasis. This study aims to understand the effect of metastatic cell line-derived exosomes and their regulation of CSC marker expressions on primary colon cancer cell lines. We have identified that treatment of primary colon cancer cell lines with metastatic colon cancer cell-derived exosomes has significantly increased the proliferation, colony formation, cell migration, and invasion. In addition, there was a significant increase in the number and size of spheroids following the exosomes treatment. We found that this metastatic phenotype is due to the increased expression of CD133 and DCLK1 in primary colon cancer cells.
Collapse
Affiliation(s)
- K Yasodha
- Department of Genetic Engineering, School of Bio-Engineering, SRM Institute of Science and Technology, kattankulathur, Chengalpattu, Tamil Nadu 603203, India
| | - L Lizha Mary
- Department of Genetic Engineering, School of Bio-Engineering, SRM Institute of Science and Technology, kattankulathur, Chengalpattu, Tamil Nadu 603203, India
| | - Pathak Surajit
- Department of Allied Health Sciences. Chettinad Academy of Science and Technology, Kelambakkam, Kanchipuram, Tamil Nadu 603103, India
| | - R Satish
- Department of Genetic Engineering, School of Bio-Engineering, SRM Institute of Science and Technology, kattankulathur, Chengalpattu, Tamil Nadu 603203, India.
| |
Collapse
|
|
5
|
Cruz-Burgos M, Cortés-Ramírez SA, Losada-García A, Morales-Pacheco M, Martínez-Martínez E, Morales-Montor JG, Servín-Haddad A, Izquierdo-Luna JS, Rodríguez-Martínez G, Ramos-Godínez MDP, González-Covarrubias V, Cañavera-Constantino A, González-Ramírez I, Su B, Leong HS, Rodríguez-Dorantes M. Unraveling the Role of EV-Derived miR-150-5p in Prostate Cancer Metastasis and Its Association with High-Grade Gleason Scores: Implications for Diagnosis. Cancers (Basel) 2023; 15:4148. [PMID: 37627176 PMCID: PMC10453180 DOI: 10.3390/cancers15164148] [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: 06/24/2023] [Revised: 08/05/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
Metastasis remains the leading cause of mortality in prostate cancer patients. The presence of tumor cells in lymph nodes is an established prognostic indicator for several cancer types, such as melanoma, breast, oral, pancreatic, and cervical cancers. Emerging evidence highlights the role of microRNAs enclosed within extracellular vesicles as facilitators of molecular communication between tumors and metastatic sites in the lymph nodes. This study aims to investigate the potential diagnostic utility of EV-derived microRNAs in liquid biopsies for prostate cancer. By employing microarrays on paraffin-embedded samples, we characterized the microRNA expression profiles in metastatic lymph nodes, non-metastatic lymph nodes, and primary tumor tissues of prostate cancer. Differential expression of microRNAs was observed in metastatic lymph nodes compared to prostate tumors and non-metastatic lymph node tissues. Three microRNAs (miR-140-3p, miR-150-5p, and miR-23b-3p) were identified as differentially expressed between tissue and plasma samples. Furthermore, we evaluated the expression of these microRNAs in exosomes derived from prostate cancer cells and plasma samples. Intriguingly, high Gleason score samples exhibited the lowest expression of miR-150-5p compared to control samples. Pathway analysis suggested a potential regulatory role for miR-150-5p in the Wnt pathway and bone metastasis. Our findings suggest EV-derived miR-150-5p as a promising diagnostic marker for identifying patients with high-grade Gleason scores and detecting metastasis at an early stage.
Collapse
Affiliation(s)
- Marian Cruz-Burgos
- Laboratorio de Oncogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico; (M.C.-B.)
| | - Sergio A. Cortés-Ramírez
- Laboratorio de Oncogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico; (M.C.-B.)
| | - Alberto Losada-García
- Laboratorio de Oncogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico; (M.C.-B.)
| | - Miguel Morales-Pacheco
- Laboratorio de Oncogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico; (M.C.-B.)
| | - Eduardo Martínez-Martínez
- Laboratory of Cell Communication and Extracellular Vesicles, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico
| | | | - Alejandro Servín-Haddad
- Urology Department, Hospital General Dr. Manuel Gea Gonzalez, Mexico City 14080, Mexico; (J.G.M.-M.); (A.S.-H.)
| | | | - Griselda Rodríguez-Martínez
- Laboratorio de Oncogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico; (M.C.-B.)
| | | | | | | | - Imelda González-Ramírez
- Departamento de Atención a la Salud, Universidad Autónoma Metropolitana, Mexico City 14387, Mexico
| | - Boyang Su
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L7, Canada
- Biological Sciences Platform, Sunybrook Research Institute, Toronto, ON M4N 3M5, Canada
| | - Hon S. Leong
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L7, Canada
- Biological Sciences Platform, Sunybrook Research Institute, Toronto, ON M4N 3M5, Canada
| | - Mauricio Rodríguez-Dorantes
- Laboratorio de Oncogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico; (M.C.-B.)
| |
Collapse
|
|
6
|
Diao Y, Zhu B, Ding T, Li R, Li J, Yang L, Zhou L, Hao X, Liu J. Tumor-derived extracellular vesicle nucleic acids as promising diagnostic biomarkers for prostate cancer. Front Oncol 2023; 13:1201554. [PMID: 37456240 PMCID: PMC10338955 DOI: 10.3389/fonc.2023.1201554] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 06/14/2023] [Indexed: 07/18/2023] Open
Abstract
Liquid biopsy as a non-invasive method has a bright future in cancer diagnosis. Tumor-related extracellular vesicles (EVs) and their components (nucleic acids, proteins, and lipids) in biofluids may exert multiple functions in tumor growth, metastasis, immune escape, and angiogenesis. Among all the components, nucleic acids have attracted the most interest due to their simplicity of extraction and detection. In this review, the biological functions of EVs in prostate cancer (PCa) genesis and progression were summarized. Moreover, the diagnostic value of EV RNA markers found in clinical body fluid samples was reviewed, including their trends, challenging isolation methods, and diagnostic efficacy. Lastly, because relatively much progress has been made in PCa, studies on EV DNA markers are also discussed.
Collapse
|
|
7
|
Wang Y, Ren L, Bai H, Jin Q, Zhang L. Exosome-Autophagy Crosstalk in Enveloped Virus Infection. Int J Mol Sci 2023; 24:10618. [PMID: 37445802 DOI: 10.3390/ijms241310618] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 06/21/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Exosomes, which are extracellular vesicles (EVs) predominantly present in bodily fluids, participate in various physiological processes. Autophagy, an intracellular degradation mechanism, eliminates proteins and damaged organelles by forming double-membrane autophagosomes. These autophagosomes subsequently merge with lysosomes for target degradation. The interaction between autophagy and endosomal/exosomal pathways can occur at different stages, exerting significant influences on normal physiology and human diseases. The interplay between exosomes and the autophagy pathway is intricate. Exosomes exhibit a cytoprotective role by inducing intracellular autophagy, while autophagy modulates the biogenesis and degradation of exosomes. Research indicates that exosomes and autophagy contribute to the infection process of numerous enveloped viruses. Enveloped viruses, comprising viral nucleic acid, proteins, or virions, can be encapsulated within exosomes and transferred between cells via exosomal transport. Consequently, exosomes play a crucial role in the infection of certain viral diseases. This review presents recent findings on the interplay between exosomes and autophagy, as well as their implications in the infection of enveloped viruses, thereby offering valuable insights into the pathogenesis and vaccine research of enveloped virus infection.
Collapse
Affiliation(s)
- Yuqi Wang
- Key Lab for Zoonoses Research, College of Animal Sciences, Ministry of Education, Jilin University, Changchun 130062, China
| | - Linzhu Ren
- Key Lab for Zoonoses Research, College of Animal Sciences, Ministry of Education, Jilin University, Changchun 130062, China
| | - Haocheng Bai
- Key Lab for Zoonoses Research, College of Animal Sciences, Ministry of Education, Jilin University, Changchun 130062, China
| | - Qing Jin
- Key Lab for Zoonoses Research, College of Animal Sciences, Ministry of Education, Jilin University, Changchun 130062, China
| | - Liying Zhang
- Key Lab for Zoonoses Research, College of Animal Sciences, Ministry of Education, Jilin University, Changchun 130062, China
| |
Collapse
|
|
8
|
Bilal M, Javaid A, Amjad F, Youssif TA, Afzal S. An overview of prostate cancer (PCa) diagnosis: Potential role of miRNAs. Transl Oncol 2022; 26:101542. [PMID: 36148731 PMCID: PMC9493385 DOI: 10.1016/j.tranon.2022.101542] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/18/2022] [Accepted: 09/07/2022] [Indexed: 12/15/2022] Open
Abstract
Prostate cancer is the second most frequently diagnosed cancer among men worldwide, with the estimated sixth leading cause of cancer death. Despite major advancements in clinical biology and imaging, digital rectal examination (DRE), prostate-specific antigen (PSA), and biopsies indication remain the keystone for screening. Several kits are used to detect genomic changes and non-coding RNAs in the sample. However, its indication remains controversial for screening purposes. There is an urged need for non-invasive biomarkers to implement precision medicine. Recent research shows that miRNAs have an important role in the diagnostic, prognostic, and therapeutic agents as non-invasive biomarkers. Though prostate cancer data remains controversial in other cancer types, such as breast cancer, miR-21 expression is upregulated. Here, we reported a prolonged revision of miRNAs as prostate cancer prognostic, diagnostic, and predictive tools, including data on androgen receptor (AR) signaling, epithelial-mesenchymal transition (EMT) process, and cancer stem cells (CSCs) regulation. The combined utilization of miRNAs with other tests will help patients and clinicians to select the most appropriate personalized treatment and to avoid overdiagnosis and unnecessary biopsies. Future clinical applications of our reported novel miRNAs have a substantial role in the primary diagnosis of prostate cancer to help treatment decisions.
Collapse
Affiliation(s)
- Muhammad Bilal
- Department of Biotechnology, Graduate School of Engineering, Osaka University, Suita, Japan; SANKEN (The Institute of Scientific and Industrial Research), Osaka University, Ibaraki, Japan
| | - Aqsa Javaid
- Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Farhat Amjad
- Quaid-e-Azam Medical College, Bahawalpur, Pakistan
| | | | - Samia Afzal
- Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
| |
Collapse
|
|
9
|
Amin AH, Sharifi LMA, Kakhharov AJ, Opulencia MJC, Alsaikhan F, Bokov DO, Majdi HS, Jawad MA, Hammid AT, Shalaby MN, Mustafa YF, Siahmansouri H. Role of Acute Myeloid Leukemia (AML)-Derived exosomes in tumor progression and survival. Biomed Pharmacother 2022; 150:113009. [PMID: 35486974 DOI: 10.1016/j.biopha.2022.113009] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/17/2022] [Accepted: 04/19/2022] [Indexed: 02/07/2023] Open
Abstract
Acute myeloid leukemia (AML) is a quickly aggressive hematopoietic disorder that progress due to the accumulation and clonal expansion of immature myeloid cells. Despite the latest developments in AML treatment, repeated relapses and drug resistance remain one of the major challenges in treatment of leukemia. Currently, it is well known that the components of the tumor microenvironment such as cellular and non-cellular elements play a critical function in treatment failures of AML, also they are most common cause of complications including suppression of hematopoiesis. Exosomes are membrane-bound extracellular vesicles (EVs) that transfer signaling molecules and have attracted a large amount of attention due to their important role in inter-cellular communication in health and disease. Exosomes participate in the survival and chemoresistance of many leukemia through transferring their rich cargos of molecules including miRNAs, growth factors, and cytokines. The key producers of exosomes that mainly participate to AML pathogenesis are bone marrow mesenchymal stem cell (BMSCs) and AML cell themselves. These cells release an enormous number of exosomes that affect several target cells such as natural killer (NK) and hematopoietic stem cells to the development of leukemia proliferation and progression. In the present study, a comprehensive review of the literature has been done to briefly discuss the biology of exosomes and highlight the role of exosomes derived from AML in the progress of acute myeloid leukemia.
Collapse
Affiliation(s)
- Ali H Amin
- Deanship of Scientific Research, Umm Al-Qura University, Makkah, Saudi Arabia; Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | | | - Alisher Jamoliddinovich Kakhharov
- Department of Oncology and Medical Radiology, Tashkent State Dental Institute, Tashkent, Uzbekistan; Department of Oncology and Medical Radiology, Samarkand State Dental Institute, Samarkand, Uzbekistan.
| | | | - Fahad Alsaikhan
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow 119991, Russian Federation; Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, 2/14 Ustyinsky pr., Moscow 109240, Russian Federation
| | - Hasan Sh Majdi
- Department of Chemical Engineering and Petroleum Industries, Al-Mustaqbal University College, Babylon 51001, Iraq
| | | | - Ali Thaeer Hammid
- Computer Engineering Department, Imam Ja'afar Al-Sadiq University, Baghdad, Iraq
| | - Mohammed Nader Shalaby
- Biological Sciences and Sports Health Department, Faculty of Physical Education, Suez Canal University, Egypt
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Homayoon Siahmansouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
10
|
Follicular fluid-derived exosomal miR-143-3p/miR-155-5p regulate follicular dysplasia by modulating glycolysis in granulosa cells in polycystic ovary syndrome. Cell Commun Signal 2022; 20:61. [PMID: 35534864 PMCID: PMC9082924 DOI: 10.1186/s12964-022-00876-6] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/02/2022] [Indexed: 12/02/2022] Open
Abstract
Objective Polycystic ovary syndrome (PCOS) is characterized by follicular dysplasia. An insufficient glycolysis-derived energy supply of granulosa cells (GCs) is an important cause of follicular dysplasia in PCOS. Follicular fluid (FF) exosomal microRNAs (miRNAs) have been proven to regulate the function of GCs. In this study, exosomes extracted from clinical FF samples were used for transcriptome sequencing (RNA-seq) analysis, and a human ovarian granulocyte tumour cell line (KGN cells) was used for in vitro mechanistic studies. Methods and results In FF exosomal RNA-seq analysis, a decrease in glycolysis-related pathways was identified as an important feature of the PCOS group, and the differentially expressed miR-143-3p and miR-155-5p may be regulatory factors of glycolysis. By determining the effects of miR-143-3p and miR-155-5p on hexokinase (HK) 2, pyruvate kinase muscle isozyme M2 (PKM2), lactate dehydrogenase A (LDHA), pyruvate, lactate and apoptosis in KGN cells, we found that upregulated miR-143-3p expression in exosomes from the PCOS group inhibited glycolysis in KGN cells; knockdown of miR-143-3p significantly alleviated the decrease in glycolysis in KGN cells in PCOS. MiR-155-5p silencing attenuated glycolytic activation in KGN cells; overexpression of miR-155-5p significantly promoted glycolysis in KGN cells in PCOS. In this study, HK2 was found to be the mediator of miR-143-3p and miR-155-5p in FF-derived exosome-mediated regulation of glycolysis in KGN cells. Reduced glycolysis accelerated apoptosis of KGN cells, which mediated follicular dysplasia through ATP, lactate and apoptotic pathways. Conclusions In conclusion, these results indicate that miR-143-3p and miR-155-5p in FF-derived exosomes antagonistically regulate glycolytic-mediated follicular dysplasia of GCs in PCOS.
|
|
11
|
O'Brien K, Ughetto S, Mahjoum S, Nair AV, Breakefield XO. Uptake, functionality, and re-release of extracellular vesicle-encapsulated cargo. Cell Rep 2022; 39:110651. [PMID: 35417683 PMCID: PMC9074118 DOI: 10.1016/j.celrep.2022.110651] [Citation(s) in RCA: 109] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 08/06/2021] [Accepted: 03/18/2022] [Indexed: 12/19/2022] Open
Abstract
Extracellular vesicles (EVs) are membrane-encapsulated particles that carry genetically active and protein/lipid cargo that can affect the function of the recipient cell. A number of studies have described the effect of these vesicles on recipient cells and demonstrated their promise as therapeutic delivery vectors. Here we demonstrate functional delivery of EV-encapsulated RNA and protein cargo through use of luminescence and fluorescence reporters by combining organelle-targeted nanoluciferase with fluorescent proteins. We highlight a mechanism by which cells retain internalized cargo in the endosomal compartment for days, usually leading to content degradation. We also identify a mode through which recipient cells re-release internalized EVs intact after uptake. Highlighting these different fates of EVs in recipient cells sheds light on critical factors in steering functional cargo delivery and will ultimately allow more efficient use of EVs for therapeutic purposes.
Collapse
Affiliation(s)
- Killian O'Brien
- Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
| | - Stefano Ughetto
- Department of Oncology, University of Turin, 10060 Candiolo, TO, Italy
| | - Shadi Mahjoum
- Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Anil V Nair
- Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Xandra O Breakefield
- Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
12
|
Thinking Quantitatively of RNA-Based Information Transfer via Extracellular Vesicles: Lessons to Learn for the Design of RNA-Loaded EVs. Pharmaceutics 2021; 13:pharmaceutics13111931. [PMID: 34834346 PMCID: PMC8617734 DOI: 10.3390/pharmaceutics13111931] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/01/2021] [Accepted: 11/10/2021] [Indexed: 02/06/2023] Open
Abstract
Extracellular vesicles (EVs) are 50–1000 nm vesicles secreted by virtually any cell type in the body. They are expected to transfer information from one cell or tissue to another in a short- or long-distance way. RNA-based transfer of information via EVs at long distances is an interesting well-worn hypothesis which is ~15 years old. We review from a quantitative point of view the different facets of this hypothesis, ranging from natural RNA loading in EVs, EV pharmacokinetic modeling, EV targeting, endosomal escape and RNA delivery efficiency. Despite the unique intracellular delivery properties endowed by EVs, we show that the transfer of RNA naturally present in EVs might be limited in a physiological context and discuss the lessons we can learn from this example to design efficient RNA-loaded engineered EVs for biotherapies. We also discuss other potential EV mediated information transfer mechanisms, among which are ligand–receptor mechanisms.
Collapse
|
|
13
|
Kuracha MR, Thomas P, Tobi M, McVicker BL. Role of cell-free network communication in alcohol-associated disorders and liver metastasis. World J Gastroenterol 2021; 27:7080-7099. [PMID: 34887629 PMCID: PMC8613644 DOI: 10.3748/wjg.v27.i41.7080] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/02/2021] [Accepted: 09/30/2021] [Indexed: 02/06/2023] Open
Abstract
The aberrant use of alcohol is a major factor in cancer progression and metastasis. Contributing mechanisms include the systemic effects of alcohol and the exchange of bioactive molecules between cancerous and non-cancerous cells along the brain-gut-liver axis. Such interplay leads to changes in molecular, cellular, and biological functions resulting in cancer progression. Recent investigations have examined the role of extracellular vesicles (EVs) in cancer mechanisms in addition to their contribution as diagnostic biomarkers. Also, EVs are emerging as novel cell-free mediators in pathophysiological scenarios including alcohol-mediated gut microbiome dysbiosis and the release of nanosized EVs into the circulatory system. Interestingly, EVs in cancer patients are enriched with oncogenes, miRNA, lipids, and glycoproteins whose delivery into the hepatic microenvironment may be enhanced by the detrimental effects of alcohol. Proof-of-concept studies indicate that alcohol-associated liver disease is impacted by the effects of exosomes, including altered immune responses, reprogramming of stromal cells, and remodeling of the extracellular matrix. Moreover, the culmination of alcohol-related changes in the liver likely contributes to enhanced hepatic metastases and poor outcomes for cancer patients. This review summarizes the numerous aspects of exosome communications between organs with emphasis on the relationship of EVs in alcohol-associated diseases and cancer metastasis. The potential impact of EV cargo and release along a multi-organ axis is highly relevant to the promotion of tumorigenic mechanisms and metastatic disease. It is hypothesized that EVs target recipient tissues to initiate the formation of prometastatic niches and cancer progression. The study of alcohol-associated mechanisms in metastatic cancers is expected to reveal a better understanding of factors involved in the growth of secondary malignancies as well as novel approaches for therapeutic interventions.
Collapse
Affiliation(s)
- Murali R Kuracha
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Peter Thomas
- Department of Surgery, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Martin Tobi
- Research and Development Service, Detroit VAMC, Detroit, MI 48201, United States
- Department of Medicine, Central Michigan University College of Medicine, Detroit, MI 48201, United States
| | - Benita L McVicker
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Research Service, Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
| |
Collapse
|
|
14
|
Ghafour AA, Odemis DA, Tuncer SB, Kurt B, Saral MA, Erciyas SK, Erdogan OS, Celik B, Saip P, Yazici H. High expression level of miR-1260 family in the peripheral blood of patients with ovarian carcinoma. J Ovarian Res 2021; 14:131. [PMID: 34629107 PMCID: PMC8504092 DOI: 10.1186/s13048-021-00878-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 09/08/2021] [Indexed: 12/24/2022] Open
Abstract
The most common gynecologic cancers detected in women in Turkey are uterine cancer, ovarian cancer, and cervical cancer. These data reported that a mean of 3800 individuals were diagnosed with uterine cancer, 2790 were diagnosed with ovarian cancer, and 1950 were diagnosed with cervical cancer, and 400 individuals were diagnosed with other gynecologic cancers each year in Turkey. A mean of 14.270 individuals were detected to have been diagnosed with gynecologic cancers each year in the United States of America (USA). Ovarian cancer treatment is generally composed of chemotherapy, and surgery. In general, chemotherapy is administered after surgery. The identification of the molecular pathogenesis of ovarian cancer, and discovery of new moleculer biomarkers which facilitate the ovarian cancer treatment are required for an effective ovarian cancer treatment in clinics. miRNAs are reported to be the possible biologic indicators for various cancer types. We aimed to investigate 2 miRNAs which were suggested to have effect in ovarian cancer in our (previous) monozygotic twin study from miR-1260 microRNA family whose association with ovarian cancer yet has not been reported in the literature. We investigated the expression levels of miR-1260a, and miR-1260b miRNAs, in the peripheral blood lymphocytes of 150 familial and sporadic ovarian cancer patients, and of 100 healthy individuals of the control group who were matched for age, sex, and ethnicity with the patient group, and investigated their possible property of being a biologic indicator for ovarian cancer. The expression results of ovarian cancer patients were evaluated by comparison of the results of the control group in the study. The expression levels of miR-1260a, and miR-1260b in ovarian cancer patients were found highly increased compared with the levels in the control group. miR-1260a expression level in ovarian cancer patients was detected to have increased approximately 17 fold compared with the control group, and miR-1260b expression level in ovarian cancer patients was detected to have increased approximately 33 fold compared with the levels in the control group. The String Analyses showed that the miR-1260a was associated with the ribosomal protein family which was known to be effective in the translation stage of cell and that miR-1260b was associated with CHEK2 protein which was a member of the serine/threonine-protein kinase family. It should be investigated for larger cohorts in benign ovarian diseases and in different stages of patients receiving ovarian cancer treatment whether these two molecules are a noninvasive biomarker and therapeutic target to be used especially in the early diagnosis and prognosis of ovarian cancer in future.
Collapse
Affiliation(s)
- Arash Adamnejad Ghafour
- Division of Cancer Genetics, Department of Basic Oncology, Oncology Institute, Istanbul University, Fatih, 34093, Istanbul, Turkey.,Health Science Institute, Istanbul University, Fatih, 34093, Istanbul, Turkey
| | - Demet Akdeniz Odemis
- Division of Cancer Genetics, Department of Basic Oncology, Oncology Institute, Istanbul University, Fatih, 34093, Istanbul, Turkey
| | - Seref Bugra Tuncer
- Division of Cancer Genetics, Department of Basic Oncology, Oncology Institute, Istanbul University, Fatih, 34093, Istanbul, Turkey
| | - Busra Kurt
- Division of Cancer Genetics, Department of Basic Oncology, Oncology Institute, Istanbul University, Fatih, 34093, Istanbul, Turkey
| | - Mukaddes Avsar Saral
- Health Services Vocational School of Higher Education, T.C. Istanbul Aydin University, Sefakoy, Kucukcekmece, 34295, Istanbul, Turkey
| | - Seda Kilic Erciyas
- Division of Cancer Genetics, Department of Basic Oncology, Oncology Institute, Istanbul University, Fatih, 34093, Istanbul, Turkey
| | - Ozge Sukruoglu Erdogan
- Division of Cancer Genetics, Department of Basic Oncology, Oncology Institute, Istanbul University, Fatih, 34093, Istanbul, Turkey
| | - Betul Celik
- Division of Cancer Genetics, Department of Basic Oncology, Oncology Institute, Istanbul University, Fatih, 34093, Istanbul, Turkey
| | - Pinar Saip
- Department of Medical Oncology, Oncology Institute, Istanbul University, Fatih, 34093, Istanbul, Turkey
| | - Hulya Yazici
- Division of Cancer Genetics, Department of Basic Oncology, Oncology Institute, Istanbul University, Fatih, 34093, Istanbul, Turkey. .,Medical Biology and Genetics Department, Medical Faculty, Istanbul Arel University, Istanbul, Zeytiburnu, 34010, Turkey.
| |
Collapse
|
|
15
|
Baral H, Uchiyama A, Yokoyama Y, Sekiguchi A, Yamazaki S, Amalia SN, Inoue Y, Ogino S, Torii R, Hosoi M, Matsuzaki T, Motegi SI. Antifibrotic effects and mechanisms of mesenchymal stem cell-derived exosomes in a systemic sclerosis mouse model: Possible contribution of miR-196b-5p. J Dermatol Sci 2021; 104:39-47. [PMID: 34479773 DOI: 10.1016/j.jdermsci.2021.08.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 08/01/2021] [Accepted: 08/22/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Systemic sclerosis (SSc) is a connective tissue disorder characterized by the development of fibrosis in the skin and internal organs. Increasing evidence suggests that mesenchymal stem cells (MSCs) can be used to a treatment for fibrotic diseases. Recent studies have demonstrated that some of the biological effects of MSCs are due to the secretion of exosomes. However, the precise mechanisms underlying MSCs-derived exosomes in skin fibrosis are not well understood. OBJECTIVE We aimed to elucidate the effect of MSCs-derived exosomes on skin fibrosis in SSc and the mechanism underlying their inhibitory action on fibrosis. METHODS Exosome was collected from MSCs by ultracentrifugation method. We examined the suppressive effect of MSCs-derived exosome on skin fibrosis in bleomycin-induced SSc mouse model. Skin samples from the injected site were collected for further examination, and micro-RNA analysis of MSCs-derived exosome was performed. RESULTS Injection of MSCs-derived exosomes significantly inhibited bleomycin-induced dermal fibrosis in mice. MSCs-derived exosomes significantly reduced the amount of collagen and the number of α-SMA+ myofibroblasts and CD68+ macrophages in lesional skin. They also reduced the expression of type I collagen and TGF-β receptor 1 in fibroblasts in vitro. Moreover, micro-RNA analysis revealed that several microRNAs in MSCs-derived exosomes have antifibrotic potential. We confirmed that overexpression of miR-196b-5p in fibroblasts significantly suppressed collagen type I alpha 2 expression. CONCLUSION This study demonstrated that inhibition of collagen type I expression by miR-196b-5p in exosomes might be one of the mechanisms by which MSCs suppress skin fibrosis in an SSc mouse model.
Collapse
Affiliation(s)
- Hritu Baral
- Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Akihiko Uchiyama
- Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
| | - Yoko Yokoyama
- Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Akiko Sekiguchi
- Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Sahori Yamazaki
- Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Syahla Nisaa Amalia
- Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Yuta Inoue
- Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Sachiko Ogino
- Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Ryoko Torii
- Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Mari Hosoi
- Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Toshiyuki Matsuzaki
- Department of Anatomy and Cell Biology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Sei-Ichiro Motegi
- Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan
| |
Collapse
|
|
16
|
Martens‐Uzunova ES, Kusuma GD, Crucitta S, Lim HK, Cooper C, Riches JE, Azad A, Ochiya T, Boyle GM, Southey MC, Del Re M, Lim R, Ramm GA, Jenster GW, Soekmadji C. Androgens alter the heterogeneity of small extracellular vesicles and the small RNA cargo in prostate cancer. J Extracell Vesicles 2021; 10:e12136. [PMID: 34434533 PMCID: PMC8374107 DOI: 10.1002/jev2.12136] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 07/29/2021] [Accepted: 08/03/2021] [Indexed: 12/24/2022] Open
Abstract
Proliferation and survival of prostate cancer cells are driven by the androgen receptor (AR) upon binding to androgen steroid hormones. Manipulating the AR signalling axis is the focus for prostate cancer therapy; thus, it is crucial to understand the role of androgens and AR on extracellular vesicle (EV) secretion and cargo. In this study, we report that plasma-derived circulating vesicles consisting of CD9 and double-positive for CD9 and Prostate Specific Membrane Antigen (PSMA) are increased in patients with advanced metastatic prostate cancer, whereas double positives for CD9 and CD63 small extracellular vesicles (S-EVs) are significantly higher in patients with localised prostate cancer. Androgen manipulation by dihydrotestosterone (DHT) and the clinical antagonist enzalutamide (ENZ) altered the heterogeneity and size of CD9 positive S-EVs in AR expressing prostate cancer cells, while assessment of the total number and protein cargo of total S-EVs was unaltered across different treatment groups. Furthermore, hormone stimulation caused strong and specific effects on the small RNA cargo of S-EVs. A total of 543 small RNAs were found to be regulated by androgens including miR-19-3p and miR-361-5p. Analysis of S-EVs heterogeneity and small RNA cargo may provide clinical utility for prostate cancer and be informative to understand further the mechanism of resistance to androgen targeted therapy in castration-resistant prostate cancer.
Collapse
Affiliation(s)
- Elena S. Martens‐Uzunova
- Department of Urology, Erasmus MC, Cancer InstituteUniversity Medical Centre RotterdamRotterdamThe Netherlands
| | - Gina D. Kusuma
- The Ritchie Centre, Hudson Institute of Medical ResearchClaytonVictoriaAustralia
- Department of Obstetrics and GynaecologyMonash UniversityClaytonVictoriaAustralia
| | - Stefania Crucitta
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental MedicineUniversity Hospital of PisaPisaItaly
| | - Hong Kiat Lim
- Department of Cell and Molecular BiologyQIMR Berghofer Medical Research InstituteBrisbaneAustralia
| | - Crystal Cooper
- Central Analytical Research FacilityInstitute for Future EnvironmentsQueensland University of TechnologyBrisbaneAustralia
| | - James E. Riches
- Central Analytical Research FacilityInstitute for Future EnvironmentsQueensland University of TechnologyBrisbaneAustralia
| | - Arun Azad
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneParkvilleVictoriaAustralia
- Department of Medical OncologyPeter MacCallum Cancer CentreMelbourneAustralia
| | - Takahiro Ochiya
- Institute of Medical ScienceTokyo Medical UniversityTokyoJapan
| | - Glen M. Boyle
- Department of Cell and Molecular BiologyQIMR Berghofer Medical Research InstituteBrisbaneAustralia
- School of Biomedical Sciences, Faculty of MedicineUniversity of QueenslandBrisbaneAustralia
| | - Melissa C. Southey
- Genetic Epidemiology Laboratory, Department of PathologyThe University of MelbourneMelbourneAustralia
| | - Marzia Del Re
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental MedicineUniversity Hospital of PisaPisaItaly
| | - Rebecca Lim
- The Ritchie Centre, Hudson Institute of Medical ResearchClaytonVictoriaAustralia
- Department of Obstetrics and GynaecologyMonash UniversityClaytonVictoriaAustralia
| | - Grant A. Ramm
- Department of Cell and Molecular BiologyQIMR Berghofer Medical Research InstituteBrisbaneAustralia
- School of Biomedical Sciences, Faculty of MedicineUniversity of QueenslandBrisbaneAustralia
| | - Guido W. Jenster
- Department of Urology, Erasmus MC, Cancer InstituteUniversity Medical Centre RotterdamRotterdamThe Netherlands
| | - Carolina Soekmadji
- Department of Cell and Molecular BiologyQIMR Berghofer Medical Research InstituteBrisbaneAustralia
- School of Biomedical Sciences, Faculty of MedicineUniversity of QueenslandBrisbaneAustralia
| |
Collapse
|
|
17
|
Prostate Cancer Biomarkers: From diagnosis to prognosis and precision-guided therapeutics. Pharmacol Ther 2021; 228:107932. [PMID: 34174272 DOI: 10.1016/j.pharmthera.2021.107932] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/10/2021] [Accepted: 05/12/2021] [Indexed: 12/23/2022]
Abstract
Prostate cancer (PCa) is one of the most commonly diagnosed malignancies and among the leading causes of cancer-related death worldwide. It is a highly heterogeneous disease, ranging from remarkably slow progression or inertia to highly aggressive and fatal disease. As therapeutic decision-making, clinical trial design and outcome highly depend on the appropriate stratification of patients to risk groups, it is imperative to differentiate between benign versus more aggressive states. The incorporation of clinically valuable prognostic and predictive biomarkers is also potentially amenable in this process, in the timely prevention of metastatic disease and in the decision for therapy selection. This review summarizes the progress that has so far been made in the identification of the genomic events that can be used for the classification, prediction and prognostication of PCa, and as major targets for clinical intervention. We include an extensive list of emerging biomarkers for which there is enough preclinical evidence to suggest that they may constitute crucial targets for achieving significant advances in the management of the disease. Finally, we highlight the main challenges that are associated with the identification of clinically significant PCa biomarkers and recommend possible ways to overcome such limitations.
Collapse
|
|
18
|
Zhang Y, Ding N, Xie S, Ding Y, Huang M, Ding X, Jiang L. Identification of important extracellular vesicle RNA molecules related to sperm motility and prostate cancer. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2021; 2:104-126. [PMID: 39697534 PMCID: PMC11648515 DOI: 10.20517/evcna.2021.02] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/11/2021] [Accepted: 03/15/2021] [Indexed: 12/20/2024]
Abstract
Aim Many male diseases are associated with sperm quality, such as prostate cancer (PCa), oligospermia, and asthenospermia. Seminal plasma extracellular vesicles (SPEVs) play important roles in sperm function. In this study, we explored the specific RNA molecules in SPEVs that play an important role in sperm motility and found promising biomarkers of PCa in SPEVs. Methods Pigs have become an ideal model for human biomedical research. In this study, the whole transcriptome profiles of SPEVs of boars with high or low sperm motility were studied for the first time. Important long non-coding RNAs, microRNAs, and genes were identified through differentially expressed analysis and weighted correlation network analysis (WGCNA). In addition, we established a diagnosis model of PCa by differentially expressed miRNAs homologous with human. Results In total, 27 differentially expressed miRNAs, 106 differentially expressed lncRNAs, and 503 differentially expressed genes were detected between the groups. The results of WGCNA show one module was significantly associated with sperm motility (r = 0.98, FDR = 2 × 10-6). The value of highly homologous miRNAs for the diagnosis of PCa was assessed and the combination of hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-155-5p, and hsa-miR-378a-3p exhibited the highest sensitivity (AUC = 0.914). Interestingly, mRNA expression of SPEVs was mainly enriched in resting memory CD4 T cells and monocytes, and 33 cell marker genes of monocytes overlapped with the differentially expressed genes. Conclusion These data demonstrate that SPEVs of individuals with high and low sperm motility exhibit distinct transcriptional profiles, which provide valuable information for further research on diagnosis and molecular mechanism of diseases.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Li Jiang
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding & Reproduction, Ministry of Agriculture, College of Animal Science & Technology, China Agricultural University, Beijing 100193, China
| |
Collapse
|
|
19
|
Wu SC, Kuo PJ, Rau CS, Wu YC, Wu CJ, Lu TH, Lin CW, Tsai CW, Hsieh CH. Subpopulations of exosomes purified via different exosomal markers carry different microRNA contents. Int J Med Sci 2021; 18:1058-1066. [PMID: 33456364 PMCID: PMC7807189 DOI: 10.7150/ijms.52768] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/22/2020] [Indexed: 12/17/2022] Open
Abstract
The heterogeneity of exosome populations presents a great challenge to their study. The current study was designed to investigate the potential heterogeneity miRNA contents in circulating exosomes purified via different exosomal markers. In this study, exosomes from the serum of C57BL/6 mice after cecum ligation and perforation (CLP) or sham operation were isolated by precipitation using ExoQuick-TC and affinity purified with anti-Rab5b, anti-CD9, anti-CD31, and anti-CD44 antibodies using the Exo-Flow Exosome Capture kit to collect exosome subpopulations. RNA extracted from the exosomes isolated by ExoQuick-TC were profiled by next-generation sequencing (NGS). Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) was also employed to determine the expression profiles of four representative exosomal miRNAs (mmu-miR-486-5p, mmu-miR-10a-5p, mmu-miR-143-3p, and mmu-miR-25-3p) selected from the NGS analysis. The results revealed that the expression patterns of these miRNAs in exosomes isolated by ExoQuick-TC as determined by RT-qPCR and NGS were similar, showing upregulation of mmu-miR-10a-5p and mmu-miR-143-3p but downregulation of mmu-miR-25-3p and mmu-miR-486-5p following CLP when compared to the levels in exosomes from sham control mice. However, their expression levels in the antibody-captured exosome subpopulations varied. The miRNAs in the exosomes captured by anti-Rab5b or anti-CD9 antibodies were more similar to those isolated by ExoQuick-TC than to those captured by anti-CD44 antibodies. However, there were no significant differences in these four miRNAs in CD31-captured exosomes. This study demonstrated that purification with different exosomal markers allows the collection of different exosome subpopulations with various miRNA contents. The results of this study demonstrate the heterogeneity of circulating exosomes and suggest the importance of stratifying exosome subpopulations when using circulating exosomes as biomarkers or investigating exosome function. In addition, this study also emphasized the necessity of using a consistent exosome marker across different samples as detecting biomarkers.
Collapse
Affiliation(s)
- Shao-Chun Wu
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Pao-Jen Kuo
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Cheng-Shyuan Rau
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Yi-Chan Wu
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Chia-Jung Wu
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Tsu-Hsiang Lu
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Chia-Wei Lin
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Chia-Wen Tsai
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Ching-Hua Hsieh
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| |
Collapse
|
|
20
|
Zhu L, Sun HT, Wang S, Huang SL, Zheng Y, Wang CQ, Hu BY, Qin W, Zou TT, Fu Y, Shen XT, Zhu WW, Geng Y, Lu L, Jia HL, Qin LX, Dong QZ. Isolation and characterization of exosomes for cancer research. J Hematol Oncol 2020; 13:152. [PMID: 33168028 PMCID: PMC7652679 DOI: 10.1186/s13045-020-00987-y] [Citation(s) in RCA: 307] [Impact Index Per Article: 61.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023] Open
Abstract
Exosomes are a subset of extracellular vesicles that carry specific combinations of proteins, nucleic acids, metabolites, and lipids. Mounting evidence suggests that exosomes participate in intercellular communication and act as important molecular vehicles in the regulation of numerous physiological and pathological processes, including cancer development. Exosomes are released by various cell types under both normal and pathological conditions, and they can be found in multiple bodily fluids. Moreover, exosomes carrying a wide variety of important macromolecules provide a window into altered cellular or tissue states. Their presence in biological fluids renders them an attractive, minimally invasive approach for liquid biopsies with potential biomarkers for cancer diagnosis, prediction, and surveillance. Due to their biocompatibility and low immunogenicity and cytotoxicity, exosomes have potential clinical applications in the development of innovative therapeutic approaches. Here, we summarize recent advances in various technologies for exosome isolation for cancer research. We outline the functions of exosomes in regulating tumor metastasis, drug resistance, and immune modulation in the context of cancer development. Finally, we discuss prospects and challenges for the clinical development of exosome-based liquid biopsies and therapeutics.
Collapse
Affiliation(s)
- Le Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Hao-Ting Sun
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Shun Wang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Sheng-Lin Huang
- Institutes of Biomedical Sciences, Fudan University, 131 Dong An Road, Shanghai, 200032, China
- Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yan Zheng
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Chao-Qun Wang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Bei-Yuan Hu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Wei Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Tian-Tian Zou
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Yan Fu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Xiao-Tian Shen
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Wen-Wei Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Yan Geng
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Lu Lu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Hu-Liang Jia
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
- Institutes of Biomedical Sciences, Fudan University, 131 Dong An Road, Shanghai, 200032, China.
| | - Qiong-Zhu Dong
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
- Institutes of Biomedical Sciences, Fudan University, 131 Dong An Road, Shanghai, 200032, China.
| |
Collapse
|
|
21
|
Asgarpour K, Shojaei Z, Amiri F, Ai J, Mahjoubin-Tehran M, Ghasemi F, ArefNezhad R, Hamblin MR, Mirzaei H. Exosomal microRNAs derived from mesenchymal stem cells: cell-to-cell messages. Cell Commun Signal 2020; 18:149. [PMID: 32917227 PMCID: PMC7488404 DOI: 10.1186/s12964-020-00650-6] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 08/24/2020] [Indexed: 12/18/2022] Open
Abstract
Exosomes are extracellular vesicles characterized by their size, source, release mechanism and contents. MicroRNAs (miRNAs) are single stranded non-coding RNAs transcribed from DNA. Exosomes and miRNAs are widespread in eukaryotic cells, especially in mesenchymal stem cells (MSCs). MSCs are used for tissue regeneration, and also exert paracrine, anti-inflammatory and immunomodulatory effects. However, the use of MSCs is controversial, especially in the presence or after the remission of a tumor, due to their secretion of growth factors and their migration ability. Instead of intact MSCs, MSC-derived compartments or substances could be used as practical tools for diagnosis, follow up, management and monitoring of diseases. Herein, we discuss some aspects of exosomal miRNAs derived from MSCs in the progression, diagnosis and treatment of various diseases. Video Abstract.
Collapse
Affiliation(s)
- Kasra Asgarpour
- Department of Medicine, University of Western Ontario, London, Ontario, Canada
| | - Zahra Shojaei
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Amiri
- School of Allied Medical Sciences, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Jafar Ai
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine (SATM), Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Maryam Mahjoubin-Tehran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Faezeh Ghasemi
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Reza ArefNezhad
- Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 40 Blossom Street, Boston, MA, 02114, USA.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, IR, Iran.
| |
Collapse
|
|
22
|
Zebrowska A, Widlak P, Whiteside T, Pietrowska M. Signaling of Tumor-Derived sEV Impacts Melanoma Progression. Int J Mol Sci 2020; 21:ijms21145066. [PMID: 32709086 PMCID: PMC7404104 DOI: 10.3390/ijms21145066] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/14/2020] [Accepted: 07/15/2020] [Indexed: 12/12/2022] Open
Abstract
Small extracellular vesicles (sEV or exosomes) are nanovesicles (30–150 nm) released both in vivo and in vitro by most cell types. Tumor cells produce sEV called TEX and disperse them throughout all body fluids. TEX contain a cargo of proteins, lipids, and RNA that is similar but not identical to that of the “parent” producer cell (i.e., the cargo of exosomes released by melanoma cells is similar but not identical to exosomes released by melanocytes), possibly due to selective endosomal packaging. TEX and their role in cancer biology have been intensively investigated largely due to the possibility that TEX might serve as key component of a “liquid tumor biopsy.” TEX are also involved in the crosstalk between cancer and immune cells and play a key role in the suppression of anti-tumor immune responses, thus contributing to the tumor progression. Most of the available information about the TEX molecular composition and functions has been gained using sEV isolated from supernatants of cancer cell lines. However, newer data linking plasma levels of TEX with cancer progression have focused attention on TEX in the patients’ peripheral circulation as potential biomarkers of cancer diagnosis, development, activity, and response to therapy. Here, we consider the molecular cargo and functions of TEX as potential biomarkers of one of the most fatal malignancies—melanoma. Studies of TEX in plasma of patients with melanoma offer the possibility of an in-depth understanding of the melanoma biology and response to immune therapies. This review features melanoma cell-derived exosomes (MTEX) with special emphasis on exosome-mediated signaling between melanoma cells and the host immune system.
Collapse
Affiliation(s)
- Aneta Zebrowska
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-100 Gliwice, Poland; (A.Z.); (P.W.)
| | - Piotr Widlak
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-100 Gliwice, Poland; (A.Z.); (P.W.)
| | - Theresa Whiteside
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA;
- Department of Pathology, University of Pittsburgh School of Medicine Pittsburgh, Pittsburgh, PA 15261, USA
| | - Monika Pietrowska
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-100 Gliwice, Poland; (A.Z.); (P.W.)
- Correspondence: ; Tel.: +48-32-278-9627
| |
Collapse
|
|
23
|
Branscome H, Paul S, Yin D, El-Hage N, Agbottah ET, Zadeh MA, Liotta LA, Kashanchi F. Use of Stem Cell Extracellular Vesicles as a "Holistic" Approach to CNS Repair. Front Cell Dev Biol 2020; 8:455. [PMID: 32587858 PMCID: PMC7298153 DOI: 10.3389/fcell.2020.00455] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 05/15/2020] [Indexed: 12/20/2022] Open
Abstract
Neurodegeneration is a hallmark of many diseases and disorders of the central nervous system (CNS). High levels of neuroinflammation are often associated with irreparable damage to CNS cells due to the dysregulation of signaling cascades that are unable to restore a homeostatic balance. Due to the inherent complexity of the CNS, development of CNS-related therapeutics has met limited success. While stem cell therapy has been evaluated in the context of CNS repair, the mechanisms responsible for their functional properties have not been clearly defined. In recent years, there has been growing interest in the use of stem cell extracellular vesicles (EVs) for the treatment of various CNS pathologies as these vesicles are believed to mediate many of the functional effects associated with their donor stem cells. The potency of stem cell EVs is believed to be largely driven by their biological cargo which includes various types of RNAs, proteins, and cytokines. In this review, we describe the characteristic properties of stem cell EVs and summarize their reported neuroprotective and immunomodulatory functions. A special emphasis is placed on the identification of specific biological cargo, including proteins and non-coding RNA molecules, that have been found to be associated with stem cell EVs. Collectively, this review highlights the potential of stem cell EVs as an alternative to traditional stem cell therapy for the repair of cellular damage associated with diverse CNS pathologies.
Collapse
Affiliation(s)
- Heather Branscome
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
- American Type Culture Collection (ATCC), Manassas, VA, United States
| | - Siddhartha Paul
- American Type Culture Collection (ATCC) Cell Systems, Gaithersburg, MD, United States
| | - Dezhong Yin
- American Type Culture Collection (ATCC) Cell Systems, Gaithersburg, MD, United States
| | - Nazira El-Hage
- Department of Immunology and Nano-Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
| | - Emmanuel T. Agbottah
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
| | - Mohammad Asad Zadeh
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
| | - Lance A. Liotta
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, United States
| | - Fatah Kashanchi
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
| |
Collapse
|
|
24
|
Daßler-Plenker J, Küttner V, Egeblad M. Communication in tiny packages: Exosomes as means of tumor-stroma communication. Biochim Biophys Acta Rev Cancer 2020; 1873:188340. [PMID: 31926290 DOI: 10.1016/j.bbcan.2020.188340] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 01/06/2020] [Accepted: 01/06/2020] [Indexed: 02/08/2023]
Abstract
Tumor-derived exosomes are nano-sized vesicles acting as multi-signal devices influencing tumor growth at local and distant sites. Exosomes are derived from the endolysosomal compartment and can shuttle diverse biomolecules like nucleic acids (microRNAs and DNA fragments), lipids, proteins, and even pharmacological compounds from a donor cell to recipient cells. The transfer of cargo to recipient cells enables tumor-derived exosomes to influence diverse cellular functions like proliferation, cell survival, and migration in recipient cells, highlighting tumor-derived exosomes as important players in communication within the tumor microenvironment and at distant sites. In this review, we discuss the mechanisms associated with exosome biogenesis and cargo sorting. In addition, we highlight the communication of tumor-derived exosomes in the tumor microenvironment during different phases of tumor development, focusing on angiogenesis, immune escape mechanisms, drug resistance, and metastasis.
Collapse
Affiliation(s)
| | - Victoria Küttner
- Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA
| | - Mikala Egeblad
- Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
| |
Collapse
|
|
25
|
Wang J, Ni J, Beretov J, Thompson J, Graham P, Li Y. Exosomal microRNAs as liquid biopsy biomarkers in prostate cancer. Crit Rev Oncol Hematol 2019; 145:102860. [PMID: 31874447 DOI: 10.1016/j.critrevonc.2019.102860] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 12/16/2019] [Accepted: 12/16/2019] [Indexed: 12/21/2022] Open
Abstract
Prostate cancer (PCa) is the most commonly diagnosed solid-organ cancer in males. The PSA testing may cause overdiagnosis and overtreatment for PCa patients. There is an urgent need for new biomarkers with greater discriminative precision for diagnosis and risk-stratification, to select for prostate biopsy and treatment of PCa. Liquid biopsy is a promising field with the potential to provide comprehensive information on the genetic landscape at diagnosis and to track genomic evolution over time in order to tailor the therapeutic choices at all stages of PCa. Exosomes, containing RNAs, DNAs and proteins, have been shown to be involved in tumour progression and a rich potential source of tumour biomarkers, especially for profiling analysis of their miRNAs content. In this review, we summarise the exosomal miRNAs in PCa diagnosis, prognosis and management, and further discuss their possible technical challenges associated with isolating PCa-specific exosomes.
Collapse
Affiliation(s)
- Jingpu Wang
- St George and Sutherland Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia; Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia
| | - Jie Ni
- St George and Sutherland Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia; Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia
| | - Julia Beretov
- St George and Sutherland Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia; Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia; Anatomical Pathology, NSW Health Pathology, St. George Hospital, Kogarah, NSW, Australia
| | - James Thompson
- St George and Sutherland Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia; Department of Urology, St. George Hospital, Kogarah, NSW, Australia; Prostate Clinical Research Group, Kinghorn Cancer Centre, Darlinghurst, NSW, Australia
| | - Peter Graham
- St George and Sutherland Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia; Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia
| | - Yong Li
- St George and Sutherland Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia; Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia; School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
| |
Collapse
|
|
26
|
Thippabhotla S, Zhong C, He M. 3D cell culture stimulates the secretion of in vivo like extracellular vesicles. Sci Rep 2019; 9:13012. [PMID: 31506601 PMCID: PMC6736862 DOI: 10.1038/s41598-019-49671-3] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 08/29/2019] [Indexed: 12/18/2022] Open
Abstract
For studying cellular communications ex-vivo, a two-dimensional (2D) cell culture model is currently used as the “gold standard”. 2D culture models are also widely used in the study of RNA expression profiles from tumor cells secreted extracellular vesicles (EVs) for tumor biomarker discovery. Although the 2D culture system is simple and easily accessible, the culture environment is unable to represent in vivo extracellular matrix (ECM) microenvironment. Our study observed that 2D- culture derived EVs showed significantly different profiles in terms of secretion dynamics and essential signaling molecular contents (RNAs and DNAs), when compared to the three-dimensional (3D) culture derived EVs. By performing small RNA next-generation sequencing (NGS) analysis of cervical cancer cells and their EVs compared with cervical cancer patient plasma EV-derived small RNAs, we observed that 3D- culture derived EV small RNAs differ from their parent cell small RNA profile which may indicate a specific sorting process. Most importantly, the 3D- culture derived EV small RNA profile exhibited a much higher similarity (~96%) to in vivo circulating EVs derived from cervical cancer patient plasma. However, 2D- culture derived EV small RNA profile correlated better with only their parent cells cultured in 2D. On the other hand, DNA sequencing analysis suggests that culture and growth conditions do not affect the genomic information carried by EV secretion. This work also suggests that tackling EV molecular alterations secreted into interstitial fluids can provide an alternative, non-invasive approach for investigating 3D tissue behaviors at the molecular precision. This work could serve as a foundation for building precise models employed in mimicking in vivo tissue system with EVs as the molecular indicators or transporters. Such models could be used for investigating tumor biomarkers, drug screening, and understanding tumor progression and metastasis.
Collapse
Affiliation(s)
- Sirisha Thippabhotla
- Department of Electrical Engineering and Computer Science, University of Kansas, Lawrence, Kansas, 66045, USA
| | - Cuncong Zhong
- Department of Electrical Engineering and Computer Science, University of Kansas, Lawrence, Kansas, 66045, USA.,Bioengineering Research Center, University of Kansas, Lawrence, Kansas, 66045, USA
| | - Mei He
- Bioengineering Research Center, University of Kansas, Lawrence, Kansas, 66045, USA. .,Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, Kansas, 66045, USA. .,Department of Chemistry, University of Kansas, Lawrence, Kansas, 66045, USA.
| |
Collapse
|
|
27
|
Iliescu FS, Poenar DP, Yu F, Ni M, Chan KH, Cima I, Taylor HK, Cima I, Iliescu C. Recent advances in microfluidic methods in cancer liquid biopsy. BIOMICROFLUIDICS 2019; 13:041503. [PMID: 31431816 PMCID: PMC6697033 DOI: 10.1063/1.5087690] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 06/24/2019] [Indexed: 05/04/2023]
Abstract
Early cancer detection, its monitoring, and therapeutical prediction are highly valuable, though extremely challenging targets in oncology. Significant progress has been made recently, resulting in a group of devices and techniques that are now capable of successfully detecting, interpreting, and monitoring cancer biomarkers in body fluids. Precise information about malignancies can be obtained from liquid biopsies by isolating and analyzing circulating tumor cells (CTCs) or nucleic acids, tumor-derived vesicles or proteins, and metabolites. The current work provides a general overview of the latest on-chip technological developments for cancer liquid biopsy. Current challenges for their translation and their application in various clinical settings are discussed. Microfluidic solutions for each set of biomarkers are compared, and a global overview of the major trends and ongoing research challenges is given. A detailed analysis of the microfluidic isolation of CTCs with recent efforts that aimed at increasing purity and capture efficiency is provided as well. Although CTCs have been the focus of a vast microfluidic research effort as the key element for obtaining relevant information, important clinical insights can also be achieved from alternative biomarkers, such as classical protein biomarkers, exosomes, or circulating-free nucleic acids. Finally, while most work has been devoted to the analysis of blood-based biomarkers, we highlight the less explored potential of urine as an ideal source of molecular cancer biomarkers for point-of-care lab-on-chip devices.
Collapse
Affiliation(s)
- Florina S. Iliescu
- School of Applied Science, Republic Polytechnic, Singapore 738964, Singapore
| | - Daniel P. Poenar
- VALENS-Centre for Bio Devices and Signal Analysis, School of EEE, Nanyang Technological University, Singapore 639798, Singapore
| | - Fang Yu
- Singapore Institute of Manufacturing Technology, A*STAR, Singapore 138634, Singapore
| | - Ming Ni
- School of Biological Sciences and Engineering, Yachay Technological University, San Miguel de Urcuquí 100105, Ecuador
| | - Kiat Hwa Chan
- Division of Science, Yale-NUS College, Singapore 138527, Singapore
| | | | - Hayden K. Taylor
- Department of Mechanical Engineering, University of California, Berkeley, California 94720, USA
| | - Igor Cima
- DKFZ-Division of Translational Oncology/Neurooncology, German Cancer Consortium (DKTK), Heidelberg and University Hospital Essen, Essen 45147, Germany
| | | |
Collapse
|
|
28
|
Circulating microRNAs as potential diagnostic biomarkers and therapeutic targets in prostate cancer: Current status and future perspectives. J Cell Biochem 2019; 120:16316-16329. [DOI: 10.1002/jcb.29053] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Accepted: 02/04/2019] [Indexed: 12/19/2022]
|
|
29
|
Iliescu FS, Vrtačnik D, Neuzil P, Iliescu C. Microfluidic Technology for Clinical Applications of Exosomes. MICROMACHINES 2019; 10:mi10060392. [PMID: 31212754 PMCID: PMC6631586 DOI: 10.3390/mi10060392] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 06/06/2019] [Accepted: 06/07/2019] [Indexed: 02/07/2023]
Abstract
Exosomes, a type of nanovesicle, are distinct cellular entities specifically capable of carrying various cargos between cells. It has been hypothesized that exosomes, as an enriched source of biomolecules, may serve as biomarkers for various diseases. This review introduces general aspects of exosomes, presents the challenges in exosome research, discusses the potential of exosomes as biomarkers, and describes the contribution of microfluidic technology to enable their isolation and analysis for diagnostic and disease monitoring. Additionally, clinical applications of exosomes for diagnostic purposes are also summarized.
Collapse
Affiliation(s)
- Florina S Iliescu
- School of Applied Science, Republic Polytechnic Singapore, Singapore 738964, Singapore.
| | - Danilo Vrtačnik
- Laboratory of Microsensor Structures and Electronics, Faculty of Electrical Engineering, University of Ljubljana, SI-1000 Ljubljana, Slovenia.
| | - Pavel Neuzil
- Ministry of Education Key Laboratory of Micro/Nano Systems for Aerospace, School of Mechanical Engineering, Northwestern Polytechnical University, Xi'an 710072, China.
- Central European Institute of Technology, Brno University of Technology, Brno 613 00, Czech Republic.
- Department of Microelectronics, Faculty of Electrical Engineering, Brno University of Technology, Technická 3058/10, 61600 Brno, Czech Republic.
| | - Ciprian Iliescu
- Biomedical Institute for Global Health Research and Technology (BIGHEART), National University of Singapore, Singapore 117599, Singapore.
- Academy of Romanian Scientists, Bucharest 050094, Romania.
| |
Collapse
|
|
30
|
Kim KS, Park JI, Oh N, Cho HJ, Park JH, Park KS. ELK3 expressed in lymphatic endothelial cells promotes breast cancer progression and metastasis through exosomal miRNAs. Sci Rep 2019; 9:8418. [PMID: 31182803 PMCID: PMC6557839 DOI: 10.1038/s41598-019-44828-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 05/24/2019] [Indexed: 12/12/2022] Open
Abstract
Tumor-associated lymphatic vessels (LV) serve as a route of cancer dissemination through the prometastatic crosstalk between lymphatic endothelial cells (LECs) lining the LVs and cancer cells. Compared to blood endothelial cell-derived angiocrine factors, however, LEC-secreted factors in the tumor microenvironment and their roles in tumor metastasis are poorly understood. Here, we report that ELK3 expressed in LECs contributes to the dissemination of cancer cells during tumor growth by providing oncogenic miRNAs to tumor cells through exosomes. We found that conditioned medium from ELK3-suppressed LECs (LCM) lost its ability to promote the migration and invasion of breast cancer cells such as MDA-MB-231, Hs578T and BT20 in vitro. Suppression of ELK3 in LECs diminished the ability of LECs to promote tumor growth and metastasis of MDA-MB-231 in vivo. Exosomes derived from LECs significantly increased the migration and invasion of MDA-MB-231 in vitro, but ELK3 suppression significantly diminished the pro-oncogenic activity of exosomes from LECs. Based on the miRNA expression profiles of LECs and functional analysis, we identified miR-503-3p, miR-4269 and miR-30e-3p as downstream targets of ELK3 in LECs, which cause the above phenotype of cancer cells. These findings strongly suggest that ELK3 expressed in LECs is a major regulator that controls the communication between the tumor microenvironment and tumors to support cancer metastasis.
Collapse
Affiliation(s)
- Kwang-Soo Kim
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam-si, Republic of Korea
| | - Ji-In Park
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam-si, Republic of Korea
| | - Nuri Oh
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam-si, Republic of Korea
| | - Hyeon-Ju Cho
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam-si, Republic of Korea
| | - Ji-Hoon Park
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam-si, Republic of Korea
| | - Kyung-Soon Park
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam-si, Republic of Korea.
| |
Collapse
|
|
31
|
Duijvesz D, Rodriguez‐Blanco G, Hoogland AM, Verhoef EI, Dekker LJ, Roobol MJ, van Leenders GJLH, Luider TM, Jenster G. Differential tissue expression of extracellular vesicle-derived proteins in prostate cancer. Prostate 2019; 79:1032-1042. [PMID: 31018022 PMCID: PMC6594141 DOI: 10.1002/pros.23813] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 04/03/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND Proteomic profiling of extracellular vesicles (EVs) from prostate cancer (PCa) and normal prostate cell lines, led to the identification of new candidate PCa markers. These proteins included the nuclear exportin proteins XPO1 (also known as CRM1), the EV-associated PDCD6IP (also known as ALIX), and the previously published fatty acid synthase FASN. In this study, we investigated differences in expression of XPO1 and PDCD6IP on well-characterized prostate cancer cohorts using mass spectrometry and tissue microarray (TMA) immunohistochemistry to determine their diagnostic and prognostic value. METHODS Protein fractions from 67 tissue samples (n = 33 normal adjacent prostate [NAP] and n = 34 PCa) were analyzed by mass spectrometry (nano-LC-MS-MS). Label-free quantification of EVs was performed to identify differentially expressed proteins between PCa and NAP. Prognostic evaluation of the candidate markers was performed with a TMA, containing 481 radical prostatectomy samples. Samples were stained for the candidate markers and correlated with patient information and clinicopathological outcome. RESULTS XPO1 was higher expressed in PCa compared to NAP in the MS data analysis (P > 0.0001). PDCD6IP was not significantly higher expressed (P = 0.0501). High cytoplasmic XPO1 staining in the TMA immunohistochemistry, correlated in a multivariable model with high Gleason scores (P = 0.002) and PCa-related death (P = 0.009). CONCLUSION High expression of cytoplasmic XPO1 shows correlation with prostate cancer and has added clinical value in tissue samples. Furthermore, as an extracellular vesicles-associated protein, it might be a novel relevant liquid biomarker.
Collapse
Affiliation(s)
- Diederick Duijvesz
- Department of UrologyErasmus Medical CenterRotterdamThe Netherlands
- Department of UrologyCanisius Wilhelmina HospitalNijmegenThe Netherlands
| | | | - A. Marije Hoogland
- Department of PathologyErasmus Medical CenterRotterdamThe Netherlands
- Department of PathologyIsala ClinicsZwolleThe Netherlands
| | - Esther I. Verhoef
- Department of PathologyErasmus Medical CenterRotterdamThe Netherlands
| | - Lennard J. Dekker
- Department of NeurologyErasmus Medical CenterRotterdamThe Netherlands
| | | | | | - Theo M. Luider
- Department of NeurologyErasmus Medical CenterRotterdamThe Netherlands
| | - Guido Jenster
- Department of UrologyErasmus Medical CenterRotterdamThe Netherlands
| |
Collapse
|
|
32
|
Kamity R, Sharma S, Hanna N. MicroRNA-Mediated Control of Inflammation and Tolerance in Pregnancy. Front Immunol 2019; 10:718. [PMID: 31024550 PMCID: PMC6460512 DOI: 10.3389/fimmu.2019.00718] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 03/18/2019] [Indexed: 01/08/2023] Open
Abstract
Gestational age-dependent immune intolerance at the maternal-fetal interface might be a contributing factor to placental pathology and adverse pregnancy outcomes. Although the intrauterine setting is highly choreographed and considered to be a protective environment for the fetus, unscheduled inflammation might overwhelm the intrauterine milieu to cause a cascade of events leading to adverse pregnancy outcomes. The old paradigm of a sterile intrauterine microenvironment has been challenged, and altered microflora has been detected in gestational tissues and amniotic fluid in the absence of induction of significant inflammation. Is there a role for endotoxin tolerance at the maternal-fetal interface? Endotoxin tolerance is a phenomenon in which tissues or cells exposed to the bacterial product, particularly lipopolysaccharide, become less responsive to subsequent exposures accompanied by decreased expression of pro-inflammatory mediators. This could also be related to trained or experienced immunity that leads to the successful outcome of subsequent pregnancies. Adaptation to endotoxin tolerance or trained immunity might be critical in preventing rejection of the fetus by the maternal immune system and protecting the fetus from excessive maternal inflammatory responses to infectious agents; however, to date, the exact mechanisms contributing to the establishment and maintenance of tolerance at the maternal-fetal interface remain incompletely understood. There is now extensive evidence suggesting that microRNAs (miRNAs) play important roles in the maintenance of a healthy pregnancy. miRNAs not only circulate freely in extracellular fluids but are also packaged within extracellular vesicles (EVs) produced by various cells and tissues. The placenta is a known, abundant, and transient source of EVs; therefore, our proposed model suggests that repeated exposure to infectious agents induces a tolerant phenotype at the maternal-fetal interface mediated by specific miRNAs mostly contained within placental EVs. We hypothesize that impaired endotoxin tolerance or failed trained immunity at the maternal-fetal interface will result in a pathological inflammatory response contributing to early or late pregnancy maladies.
Collapse
Affiliation(s)
- Ranjith Kamity
- Women and Children Research Laboratory, Division of Neonatology, Department of Pediatrics, NYU Winthrop Hospital, Mineola, NY, United States
| | - Surendra Sharma
- Department of Pediatrics, Women and Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Nazeeh Hanna
- Women and Children Research Laboratory, Division of Neonatology, Department of Pediatrics, NYU Winthrop Hospital, Mineola, NY, United States
| |
Collapse
|
|
33
|
Qiu G, Zheng G, Ge M, Wang J, Huang R, Shu Q, Xu J. Mesenchymal stem cell-derived extracellular vesicles affect disease outcomes via transfer of microRNAs. Stem Cell Res Ther 2018; 9:320. [PMID: 30463593 PMCID: PMC6249826 DOI: 10.1186/s13287-018-1069-9] [Citation(s) in RCA: 204] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are adult stromal cells with the capacity to differentiate into multiple types of cells. MSCs represent an attractive option in regenerative medicine due to their multifaceted abilities for tissue repair, immunosuppression, and anti-inflammation. Recent studies demonstrate that MSCs exert their effects via paracrine activity, which is at least partially mediated by extracellular vesicles (EVs). MSC-derived EVs (MSC-EVs) could mimic the function of parental MSCs by transferring their components such as DNA, proteins/peptides, mRNA, microRNA (miRNA), lipids, and organelles to recipient cells. In this review, we aim to summarize the mechanism and role of miRNA transfer in mediating the effects of MSC-EVs in the models of human diseases. The first three sections of the review discuss the sorting of miRNAs into EVs, uptake of EVs by target cells, and functional transfer of miRNAs via EVs. Then, we describe the composition of miRNAs in MSC-EVs. Next, we provide the existing evidence that MSC-EVs affect the outcomes of renal, liver, heart, and brain diseases by transferring their miRNA contents. In conclusion, EV-mediated miRNA transfer plays an important role in disease-modulating capacity of MSCs.
Collapse
Affiliation(s)
- Guanguan Qiu
- Shaoxing Second Hospital, 123 Yanan Road, Shaoxing, 312000, Zhejiang, China
| | - Guoping Zheng
- Shaoxing Second Hospital, 123 Yanan Road, Shaoxing, 312000, Zhejiang, China
| | - Menghua Ge
- Shaoxing Second Hospital, 123 Yanan Road, Shaoxing, 312000, Zhejiang, China
| | - Jiangmei Wang
- The Children's Hospital of Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310051, Zhejiang, China
| | - Ruoqiong Huang
- The Children's Hospital of Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310051, Zhejiang, China
| | - Qiang Shu
- The Children's Hospital of Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310051, Zhejiang, China.
| | - Jianguo Xu
- Shaoxing Second Hospital, 123 Yanan Road, Shaoxing, 312000, Zhejiang, China. .,The First Affiliated Hospital of Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
| |
Collapse
|
|
34
|
Communication of prostate cancer cells with bone cells via extracellular vesicle RNA; a potential mechanism of metastasis. Oncogene 2018; 38:1751-1763. [PMID: 30353168 PMCID: PMC6372071 DOI: 10.1038/s41388-018-0540-5] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 09/11/2018] [Accepted: 09/25/2018] [Indexed: 12/20/2022]
Abstract
The role of extracellular vesicles (EVs) as vehicles for cell-to-cell communication between a tumour and its environment is a relatively new concept. The hypothesis that EVs may be critical in co-opting tissues by tumours to generate distant metastatic niches is particularly pertinent to prostate cancer (PCa), where metastatic-tropism to bone predominates over other tissue types. The potential role of EVs as a means of communication between PCa cells and cells of the bone stroma such as osteoblasts, is yet to be fully explored. In this study, we demonstrate that PCa cell EVs both enhance osteoblast viability and produce a significantly more supportive growth environment for PCa cells when grown in co-culture with EV-treated osteoblasts (p < 0.005). Characterisation of the RNA cargo of EVs produced by the bone-metastatic PCa cell line PC3, highlights the EV-RNA cargo is significantly enriched in genes relating to cell surface signalling, cell–cell interaction, and protein translation (p < 0.01). Using novel techniques to track RNA, we demonstrate the delivery of a set of PCa-RNAs to osteoblast via PCa-EVs and show the effect on osteoblast endogenous transcript abundance. Taken together, by using proof-of-concept studies we demonstrate for the first time the contribution of the RNA element of the PCa EV cargo, providing evidence to support PCa EV communication via RNA molecules as a potential novel route to mediate bone metastasis. We propose targeting PCa EVs could offer a potentially important preventative therapy for men at risk of metastatic PCa.
Collapse
|
|
35
|
Said R, Garcia-Mayea Y, Trabelsi N, Setti Boubaker N, Mir C, Blel A, Ati N, Paciucci R, Hernández-Losa J, Rammeh S, Derouiche A, Chebil M, LLeonart ME, Ouerhani S. Expression patterns and bioinformatic analysis of miR-1260a and miR-1274a in Prostate Cancer Tunisian patients. Mol Biol Rep 2018; 45:2345-2358. [PMID: 30250996 DOI: 10.1007/s11033-018-4399-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 09/21/2018] [Indexed: 12/12/2022]
Abstract
Currently, microRNAs (miRs) represent great biomarkers in cancer due to their stability and their potential role in diagnosis, prognosis and therapy. This study aims to evaluate the expression levels of miRs-1260 and -1274a in prostate cancer (PC) samples and to identify their eventual targets by using bioinformatic analysis. In this project, we evaluated the expression status of miRs-1260 and -1274a in 86 PC patients and 19 controls by using real-time quantitative PCR and 2-ΔΔCt method. Moreover, we retrieved validated and predicted targets of miRs from several datasets by using the "multiMir" R/Bioconductor package. We have found that miRs-1260 and -1274a were over-expressed in PC patients compared to controls (p < 1 × 10-5). Moreover ROC curve for miRs-1260 and 1274a showed a good performance to distinguish between controls group and PC samples with an area under the ROC curve of 0.897 and 0.784 respectively. However, no significant association could be shown between these two miRs and clinical parameters such as PSA levels, Gleason score, tumor stage, D'Amico classification, lymph node metastasis statues, tumor recurrence, metastasis status and progression after a minimum of 5 years follow-up. Finally, a bioinformatic analysis revealed the association between these two miRs and several targets implicated in prostate cancer initiation pathways.
Collapse
Affiliation(s)
- Rahma Said
- Laboratory of Protein Engineering and Bio-active Molecules, National Institute of Applied Science and Technology - University of Carthage, Tunis, Tunisia
- Faculty of Sciences of Bizerte, University of Carthage, Tunis, Tunisia
| | - Yoelsis Garcia-Mayea
- Biomedical Research in Cancer Stem Cells Group, Pathology Department, Vall d'Hebron Research Institute (VHIR), Passeig Vall d´Hebron 119-129, 08035, Barcelona, Spain
| | - Nesrine Trabelsi
- Laboratory of Protein Engineering and Bio-active Molecules, National Institute of Applied Science and Technology - University of Carthage, Tunis, Tunisia
| | - Nouha Setti Boubaker
- Laboratory of Protein Engineering and Bio-active Molecules, National Institute of Applied Science and Technology - University of Carthage, Tunis, Tunisia
| | - Cristina Mir
- Biomedical Research in Cancer Stem Cells Group, Pathology Department, Vall d'Hebron Research Institute (VHIR), Passeig Vall d´Hebron 119-129, 08035, Barcelona, Spain
| | - Ahlem Blel
- Pathology Anatomy and Cytology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | - Nidhal Ati
- Urology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | - Rosanna Paciucci
- Biomedical Research Group of Urology, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Javier Hernández-Losa
- Biomedical Research in Cancer Stem Cells Group, Pathology Department, Vall d'Hebron Research Institute (VHIR), Passeig Vall d´Hebron 119-129, 08035, Barcelona, Spain
| | - Soumaya Rammeh
- Pathology Anatomy and Cytology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | - Amine Derouiche
- Urology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | - Mohamed Chebil
- Urology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | - Matilde E LLeonart
- Biomedical Research in Cancer Stem Cells Group, Pathology Department, Vall d'Hebron Research Institute (VHIR), Passeig Vall d´Hebron 119-129, 08035, Barcelona, Spain
- Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain
| | - Slah Ouerhani
- Laboratory of Protein Engineering and Bio-active Molecules, National Institute of Applied Science and Technology - University of Carthage, Tunis, Tunisia.
| |
Collapse
|
|
36
|
Than UT, Guanzon D, Broadbent JA, Leavesley DI, Salomon C, Parker TJ. Differential Expression of Keratinocyte-Derived Extracellular Vesicle Mirnas Discriminate Exosomes From Apoptotic Bodies and Microvesicles. Front Endocrinol (Lausanne) 2018; 9:535. [PMID: 30258405 PMCID: PMC6143807 DOI: 10.3389/fendo.2018.00535] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 08/22/2018] [Indexed: 01/07/2023] Open
Abstract
Extracellular vesicles (EVs) are mammalian cell-derived nano-scale structures enclosed by a lipid bilayer that were previously considered to be cell debris with little biological value. However, EVs are now recognized to possess biological function, acting as a packaging, transport and delivery mechanisms by which functional molecules (i.e., miRNAs) can be transferred to target cells over some distance. To examine the miRNA from keratinocyte-derived EVs, we isolated three distinct populations of EVs from both HaCaT and primary human keratinocytes (PKCs) and characterized their biophysical, biochemical and functional features by using microscopy, immunoblotting, nanoparticle tracking, and next generation sequencing. We identified 1,048; 906; and 704 miRNAs, respectively, in apoptotic bodies (APs), microvesicles (MVs) and exosomes (EXs) released from HaCaT, and 608; 506; and 622 miRNAs in APs, MVs and EXs released from PKCs. In which, there were 623 and 437 identified miRNAs common to three HaCaT-derived EVs and PKC-derived EVs, respectively. In addition, we found hundreds of exosomal miRNAs that were previously un-reported. Differences in the abundance levels of the identified EV miRNAs could discriminate between the three EV populations. These data contribute substantially to knowledge within the EV-identified miRNA database, especially with regard to keratinocyte-derived EV miRNA content.
Collapse
Affiliation(s)
- Uyen T.T. Than
- Tissue Repair and Translational Physiology Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Australia
- Faculty of Health, School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, Australia
- Wound Management Innovation Cooperative Research Centre, West End, QLD, Australia
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec International Hospital, Ha Noi, Vietnam
| | - Dominic Guanzon
- Tissue Repair and Translational Physiology Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Australia
- Faculty of Health, School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, Australia
- Wound Management Innovation Cooperative Research Centre, West End, QLD, Australia
- Institute of Medical Biology–Agency for Science, Technology and Research, Singapore, Singapore
| | - James A. Broadbent
- Faculty of Health, School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, Australia
| | - David I. Leavesley
- Faculty of Health, School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, Australia
- Institute of Medical Biology–Agency for Science, Technology and Research, Singapore, Singapore
| | - Carlos Salomon
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, QLD, Australia
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción, Concepción, Chile
| | - Tony J. Parker
- Tissue Repair and Translational Physiology Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Australia
- Faculty of Health, School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, Australia
| |
Collapse
|
|
37
|
Nowak I, Boratyn E, Durbas M, Horwacik I, Rokita H. Exogenous expression of miRNA-3613-3p causes APAF1 downregulation and affects several proteins involved in apoptosis in BE(2)-C human neuroblastoma cells. Int J Oncol 2018; 53:1787-1799. [PMID: 30066861 DOI: 10.3892/ijo.2018.4509] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 07/02/2018] [Indexed: 11/05/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of small non‑coding RNAs involved in post‑transcriptional gene regulation. Furthermore, dysregulation of miRNA expression is an important factor in the pathogenesis of neuroblastoma. Our previous study identified that overexpression of monocyte chemoattractant protein‑induced protein 1 protein led to a significant downregulation of a novel miRNA molecule, miRNA‑3613‑3p. In the present study, the potential involvement of miRNA‑3613‑3p in the cell biology of neuroblastoma was investigated. It was identified that the expression of miRNA‑3613‑3p varies among a range of human neuroblastoma cell lines. As the delineation of the functions of a miRNA requires the identification of its target genes, seven putative mRNAs that may be regulated by miRNA‑3613‑3p were selected. Furthermore, it was identified that overexpression of miRNA‑3613‑3p causes significant downregulation of several genes exhibiting tumor suppressive potential [encoding apoptotic protease‑activating factor 1 (APAF1), Dicer, DNA fragmentation factor subunit β, von Hippel‑Lindau protein and neurofibromin 1] in BE(2)‑C human neuroblastoma cells. APAF1 mRNA was the most significantly decreased transcript in the cells with miRNA‑3613‑3p overexpression. In accordance with the aforementioned results, the downregulation of cleaved caspase-9 and lack of activation of executive caspases in BE(2)‑C cells following miRNA‑3613‑3p overexpression was observed. The results of the present study suggest a potential underlying molecular mechanism of apoptosis inhibition via APAF1 downregulation in human neuroblastoma BE(2)‑C cells with miRNA‑3613‑3p overexpression.
Collapse
Affiliation(s)
- Iwona Nowak
- Laboratory of Molecular Genetics and Virology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
| | - Elżbieta Boratyn
- Laboratory of Molecular Genetics and Virology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
| | - Małgorzata Durbas
- Laboratory of Molecular Genetics and Virology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
| | - Irena Horwacik
- Laboratory of Molecular Genetics and Virology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
| | - Hanna Rokita
- Laboratory of Molecular Genetics and Virology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
| |
Collapse
|
|
38
|
Lee J, Kwon MH, Kim JA, Rhee WJ. Detection of exosome miRNAs using molecular beacons for diagnosing prostate cancer. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2018; 46:S52-S63. [PMID: 30033809 DOI: 10.1080/21691401.2018.1489263] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Prostate cancer is the fifth leading cause of cancer-related deaths among males worldwide. However, the biomarker for diagnosing prostate cancer that is used currently has limitations that must be overcome. Recently, several studies have demonstrated that the cancer liquid biopsy can be implemented by using exosome miRNAs. However, the current methods for the detection of exosome miRNAs are time-consuming, expensive, and laborious. Thus, we investigated a novel method for diagnosing prostate cancer that involves the use of molecular beacons for the in situ detection of miRNAs in exosomes from prostate cancer cells. We chose miRNA-375 and miRNA-574-3p as the target miRNAs for prostate cancer, and these markers in exosomes produced by prostate cancer cells including DU145 and PC-3 were successfully detected using molecular beacons. High fluorescent signals were obtained from MB and miRNA hybridization in exosomes in a concentration-dependent manner. In addition, exosome miRNAs can be detected even in the presence of human urine, so this method can be applied directly using human urine to perform liquid biopsies for prostate cancer. Overall, the in situ detection of exosome miRNAs using molecular beacons can be developed as a simple, cost effective, and non-invasive liquid biopsy for diagnosing prostate cancer.
Collapse
Affiliation(s)
- Jinhee Lee
- a Division of Bioengineering , Incheon National University , Incheon , Republic of Korea
| | - Min Hee Kwon
- a Division of Bioengineering , Incheon National University , Incheon , Republic of Korea
| | - Jeong Ah Kim
- b Biomedical Omics Group , Korea Basic Science Institute , Cheongju , Republic of Korea
| | - Won Jong Rhee
- a Division of Bioengineering , Incheon National University , Incheon , Republic of Korea
| |
Collapse
|
|
39
|
Bellazzo A, Di Minin G, Valentino E, Sicari D, Torre D, Marchionni L, Serpi F, Stadler MB, Taverna D, Zuccolotto G, Montagner IM, Rosato A, Tonon F, Zennaro C, Agostinis C, Bulla R, Mano M, Del Sal G, Collavin L. Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells. Cell Death Differ 2018; 25:1224-1238. [PMID: 29568059 PMCID: PMC6030048 DOI: 10.1038/s41418-018-0088-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Revised: 01/11/2018] [Accepted: 02/13/2018] [Indexed: 01/03/2023] Open
Abstract
The tumor suppressor DAB2IP contributes to modulate the network of information established between cancer cells and tumor microenvironment. Epigenetic and post-transcriptional inactivation of this protein is commonly observed in multiple human malignancies, and can potentially favor progression of tumors driven by a variety of genetic mutations. Performing a high-throughput screening of a large collection of human microRNA mimics, we identified miR-149-3p as a negative post-transcriptional modulator of DAB2IP. By efficiently downregulating DAB2IP, this miRNA enhances cancer cell motility and invasiveness, facilitating activation of NF-kB signaling and promoting expression of pro-inflammatory and pro-angiogenic factors. In addition, we found that miR-149-3p secreted by prostate cancer cells induces DAB2IP downregulation in recipient vascular endothelial cells, stimulating their proliferation and motility, thus potentially remodeling the tumor microenvironment. Finally, we found that inhibition of endogenous miR-149-3p restores DAB2IP activity and efficiently reduces tumor growth and dissemination of malignant cells. These observations suggest that miR-149-3p can promote cancer progression via coordinated inhibition of DAB2IP in tumor cells and in stromal cells.
Collapse
Affiliation(s)
- Arianna Bellazzo
- National Laboratory CIB (LNCIB), AREA Science Park, 34149, Trieste, Italy
| | - Giulio Di Minin
- Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Hönggerberg, 8093, Zurich, Switzerland
| | - Elena Valentino
- National Laboratory CIB (LNCIB), AREA Science Park, 34149, Trieste, Italy
- Department of Life Sciences, University of Trieste, 34127, Trieste, Italy
| | - Daria Sicari
- National Laboratory CIB (LNCIB), AREA Science Park, 34149, Trieste, Italy
- Department of Life Sciences, University of Trieste, 34127, Trieste, Italy
| | - Denis Torre
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, BD2K-LINCS DCIC, Mount Sinai Center for Bioinformatics, New York, NY, 10029, USA
| | - Luigi Marchionni
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, 21205, USA
| | - Federica Serpi
- National Laboratory CIB (LNCIB), AREA Science Park, 34149, Trieste, Italy
| | - Michael B Stadler
- Friedrich Miescher Institute for Biomedical Research, Switzerland and Swiss Institute of Bioinformatics, 4058, Basel, Switzerland
| | - Daniela Taverna
- Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126, Torino, Italy
| | - Gaia Zuccolotto
- Department of Surgery Oncology and Gastroenterology, University of Padova, 35128, Padova, Italy
| | | | - Antonio Rosato
- Department of Surgery Oncology and Gastroenterology, University of Padova, 35128, Padova, Italy
- Istituto Oncologico Veneto IOV-IRCCS, 35128, Padova, Italy
| | - Federica Tonon
- Department of Medical Surgical and Health Sciences, University of Trieste, 34149, Trieste, Italy
| | - Cristina Zennaro
- Department of Medical Surgical and Health Sciences, University of Trieste, 34149, Trieste, Italy
| | - Chiara Agostinis
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, 34137, Trieste, Italy
| | - Roberta Bulla
- Department of Life Sciences, University of Trieste, 34127, Trieste, Italy
| | - Miguel Mano
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504, Coimbra, Portugal
- International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149, Trieste, Italy
| | - Giannino Del Sal
- National Laboratory CIB (LNCIB), AREA Science Park, 34149, Trieste, Italy.
- Department of Life Sciences, University of Trieste, 34127, Trieste, Italy.
| | - Licio Collavin
- National Laboratory CIB (LNCIB), AREA Science Park, 34149, Trieste, Italy.
- Department of Life Sciences, University of Trieste, 34127, Trieste, Italy.
| |
Collapse
|
|
40
|
Cai M, He H, Jia X, Chen S, Wang J, Shi Y, Liu B, Xiao W, Lai S. Genome-wide microRNA profiling of bovine milk-derived exosomes infected with Staphylococcus aureus. Cell Stress Chaperones 2018; 23:663-672. [PMID: 29383581 PMCID: PMC6045547 DOI: 10.1007/s12192-018-0876-3] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 01/16/2018] [Accepted: 01/16/2018] [Indexed: 12/31/2022] Open
Abstract
Bovine milk is rich in exosomes, which contain abundant miRNAs and play important roles in the regulation of neonatal growth and development of adaptive immunity. Here, we analyzed miRNA expression profiles of bovine milk exosomes from three healthy and three mastitic cows, and then six miRNA libraries were constructed. Interestingly, we detected no scRNAs and few snRNAs in milk exosomes; this result indicated a potential preference for RNA packaging in milk exosomes. A total of 492 known and 980 novel exosomal miRNAs were detected, and the 10 most expressed miRNAs in the six samples accounted for 80-90% of total miRNA-associated reads. Expression analyses identified 18 miRNAs with significantly different expression between healthy and infected animals; the predicted target genes of differentially expressed miRNAs were significantly enriched in immune system process, response to stimulus, growth, etc. Moreover, target genes were significantly enriched in several Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways including inflammatory, immune, and cancer pathways. Our survey provided comprehensive information about milk exosomes and exosomal miRNAs involved in mastitis. Moreover, the differentially expressed miRNAs, especially miR-223 and miR-142-5p, could be considered as potential candidates for mastitis.
Collapse
Affiliation(s)
- Mingcheng Cai
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, China
| | - Hongbing He
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, China
| | - Xianbo Jia
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, China
| | - Shiyi Chen
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, China
| | - Jie Wang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, China
| | - Yu Shi
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, China
| | - Buwei Liu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, China
| | - Wudian Xiao
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, China
| | - Songjia Lai
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, 611130, China.
| |
Collapse
|
|
41
|
Vlaeminck-Guillem V. Extracellular Vesicles in Prostate Cancer Carcinogenesis, Diagnosis, and Management. Front Oncol 2018; 8:222. [PMID: 29951375 PMCID: PMC6008571 DOI: 10.3389/fonc.2018.00222] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 05/29/2018] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs), especially exosomes, are now well recognized as major ways by which cancer cells interact with each other and stromal cells. The meaningful messages transmitted by the EVs are carried by all components of the EVs, i.e., the membrane lipids and the cargo (DNAs, RNAs, microRNAs, long non-coding RNAs, proteins). They are clearly part of the armed arsenal by which cancer cells obtain and share more and more advantages to grow and conquer new spaces. Identification of these messages offers a significant opportunity to better understand how a cancer occurs and then develops both locally and distantly. But it also provides a powerful means by which cancer progression can be detected and monitored. In the last few years, significant research efforts have been made to precisely identify how the EV trafficking is modified in cancer cells as compared to normal cells and how this trafficking is altered during cancer progression. Prostate cancer has not escaped this trend. The aim of this review is to describe the results obtained when assessing the meaningful content of prostate cancer- and stromal-derived EVs in terms of a better comprehension of the cellular and molecular mechanisms underlying prostate cancer occurrence and development. This review also deals with the use of EVs as powerful tools to diagnose non-indolent prostate cancer as early as possible and to accurately define, in a personalized approach, its present and potential aggressiveness, its response to treatment (androgen deprivation, chemotherapy, radiation, surgery), and the overall patients’ prognosis.
Collapse
Affiliation(s)
- Virginie Vlaeminck-Guillem
- Medical Unit of Molecular Oncology and Transfer, Department of Biochemistry and Molecular Biology, Centre Hospitalier Lyon-Sud, Hospices Civils of Lyon, Pierre-Bénite, France.,Cancer Research Centre of Lyon, U1052 INSERM, CNRS 5286, Claude Bernard University Lyon 1, Léon Bérard Centre, Lyon, France
| |
Collapse
|
|
42
|
Alfonsi R, Grassi L, Signore M, Bonci D. The Double Face of Exosome-Carried MicroRNAs in Cancer Immunomodulation. Int J Mol Sci 2018; 19:ijms19041183. [PMID: 29652798 PMCID: PMC5979514 DOI: 10.3390/ijms19041183] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 04/10/2018] [Accepted: 04/11/2018] [Indexed: 12/21/2022] Open
Abstract
In recent years many articles have underlined the key role of nanovesicles, i.e., exosomes, as information carriers among biological systems including cancer. Tumor-derived exosomes (TEXs) are key players in the dynamic crosstalk between cancer cells and the microenvironment while promote immune system control evasion. In fact, tumors are undoubtedly capable of silencing the immune response through multiple mechanisms, including the release of exosomes. TEXs have been shown to boost tumor growth and promote progression and metastatic spreading via suppression or stimulation of the immune response towards cancer cells. The advantage of immunotherapeutic treatment alone over combining immuno- and conventional therapy is currently debated. Understanding the role of tumor exosome-cargo is of crucial importance for our full comprehension of neoplastic immonosuppression and for the construction of novel therapies and vaccines based on (nano-) vesicles. Furthermore, to devise new anti-cancer approaches, diverse groups investigated the possibility of engineering TEXs by conditioning cancer cells’ own cargo. In this review, we summarize the state of art of TEX-based immunomodulation with a particular focus on the molecular function of non-coding family genes, microRNAs. Finally, we will report on recent efforts in the study of potential applications of engineered exosomes in cancer immunotherapy.
Collapse
Affiliation(s)
- Romina Alfonsi
- Institute of General Pathology, Università Cattolica and Policlinico Gemelli, 00168 Rome, Italy.
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
| | - Ludovica Grassi
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
- Department of Internal Medicine and Medical Specialties, "La Sapienza" University, 00161 Rome, Italy.
- Regina Elena National Cancer Institute, 00144 Rome, Italy.
| | - Michele Signore
- RPPA Unit, Proteomics Area, Core Facilties, Istituto Superiore di Sanità, 00162 Rome, Italy.
| | - Désirée Bonci
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
- Regina Elena National Cancer Institute, 00144 Rome, Italy.
| |
Collapse
|
|
43
|
Li S, Yao J, Xie M, Liu Y, Zheng M. Exosomal miRNAs in hepatocellular carcinoma development and clinical responses. J Hematol Oncol 2018; 11:54. [PMID: 29642941 PMCID: PMC5896112 DOI: 10.1186/s13045-018-0579-3] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 02/21/2018] [Indexed: 12/21/2022] Open
Abstract
Hepatocellular carcinoma remains the sixth most lethal malignancy in the world. While HCC is often diagnosed via current biomarkers at a late stage, early detection of HCC has proven to be very difficult. Recent studies have focused on using exosomal miRNAs in clinical diagnostics and therapeutics, because they have improved stability in exosomes than as free miRNAs themselves. Exosomal miRNAs act through novel mechanisms for inducing cellular responses in a variety of biological circumstances. Dysregulated expression of miRNAs in exosomes can also accelerate HCC progression, including cell proliferation and metastasis, via alteration of a network of genes. Growing evidence demonstrates that exosomal miRNAs can affect many aspects of physiological and pathological conditions in HCC and indicates that miRNAs in exosomes can not only serve as sensitive biomarkers for cancer diagnostics and recurrence but can also potentially be used as therapeutics to target HCC progression. In this review, we summarize the latest findings between exosomal miRNAs and HCC, in order to better comprehend the functions and applications in HCC. Moreover, we discuss critical issues to consider when developing anti-tumor exosomal miRNAs as a novel therapeutic strategy for treating HCC in the clinic.
Collapse
Affiliation(s)
- Shuangshuang Li
- Zhejiang University First Affiliated Hospital State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,Clinical research center for hepatobiliary and pancreatic diseases of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Jiping Yao
- Zhejiang University First Affiliated Hospital State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,Clinical research center for hepatobiliary and pancreatic diseases of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Mingjie Xie
- Zhejiang University First Affiliated Hospital State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,Clinical research center for hepatobiliary and pancreatic diseases of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Yanning Liu
- Zhejiang University First Affiliated Hospital State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,Clinical research center for hepatobiliary and pancreatic diseases of Zhejiang Province, Zhejiang University, Hangzhou, China
| | - Min Zheng
- Zhejiang University First Affiliated Hospital State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,Clinical research center for hepatobiliary and pancreatic diseases of Zhejiang Province, Zhejiang University, Hangzhou, China.
| |
Collapse
|
|
44
|
Li SP, Lin ZX, Jiang XY, Yu XY. Exosomal cargo-loading and synthetic exosome-mimics as potential therapeutic tools. Acta Pharmacol Sin 2018; 39:542-551. [PMID: 29417947 PMCID: PMC5888690 DOI: 10.1038/aps.2017.178] [Citation(s) in RCA: 277] [Impact Index Per Article: 39.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 12/08/2017] [Indexed: 02/07/2023]
Abstract
Exosomes are nano-sized vesicles that serve as mediators for intercellular communication through the delivery of cargo, including protein, lipids, nucleic acids or other cellular components, to neighboring or distant cells. Exosomal cargo may vary in response to different physiological or pathological conditions. The endosomal sorting complex required for transport (ESCRT) family has been widely accepted as a key mechanism in biogenesis and cargo sorting. On the other hand, accumulating evidence show that ESCRT-independent pathways exist. Due to the critical role of exosomes in intercellular communications in delivering cargo to recipient cells, exosomes have been investigated as a vector for the delivery of endogenous or exogenous cargo for therapeutic purposes. But the number of exosomes produced by cells is limited, which hampers their application. Synthetic exosome-mimics have been fabricated and investigated as a therapeutic tool for drug delivery. This review focuses on ESCRT-independent regulation of cargo loading into exosomes, including lipid raft and ceramide-mediated mechanisms, and reported exosomes or exosome-mimics with therapeutic effects.
Collapse
Affiliation(s)
- Song-pei Li
- Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutic Sciences & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Zhong-xiao Lin
- Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutic Sciences & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Xue-yan Jiang
- Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutic Sciences & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Xi-yong Yu
- Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutic Sciences & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| |
Collapse
|
|
45
|
Halvaei S, Daryani S, Eslami-S Z, Samadi T, Jafarbeik-Iravani N, Bakhshayesh TO, Majidzadeh-A K, Esmaeili R. Exosomes in Cancer Liquid Biopsy: A Focus on Breast Cancer. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 10:131-141. [PMID: 29499928 PMCID: PMC5862028 DOI: 10.1016/j.omtn.2017.11.014] [Citation(s) in RCA: 137] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 11/04/2017] [Accepted: 11/27/2017] [Indexed: 02/07/2023]
Abstract
The important challenge about cancer is diagnosis in primary stages and proper treatment. Although classical clinico-pathological features of the tumor have major prognostic value, the advances in diagnosis and treatment are indebted to discovery of molecular biomarkers and control of cancer in the pre-invasive state. Moreover, the efficiency of available therapeutic options is highly diminished, and chemotherapy is still the main treatment due to lack of enough specific targets. Accordingly, finding the new noninvasive biomarkers for cancer is still an important clinical challenge that is not achieved yet. There are current technologies to screen, diagnose, prognose, and treat cancer, but the limitations of these implements and procedures are undeniable. Liquid biopsy as a noninvasive method has a promising future in the field of cancer, and exosomes as one of the recent areas have drawn much attention. In this review, the potential capability of exosomes is summarized in cancer with the special focus on breast cancer as the second cause of cancer mortality in women all around the world. It discusses reasons to choose exosomes for liquid biopsy and the studies related to different potential biomarkers found in the exosomes. Moreover, exosome studies on milk as a specific biofluid are also discussed. At last, because choosing the method for exosome studies is very challenging, a summary of different techniques is provided.
Collapse
Affiliation(s)
- Sina Halvaei
- Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Shiva Daryani
- Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Zahra Eslami-S
- Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Tannaz Samadi
- Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Narges Jafarbeik-Iravani
- Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | | | - Keivan Majidzadeh-A
- Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Rezvan Esmaeili
- Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
| |
Collapse
|
|
46
|
Boriachek K, Islam MN, Möller A, Salomon C, Nguyen NT, Hossain MSA, Yamauchi Y, Shiddiky MJA. Biological Functions and Current Advances in Isolation and Detection Strategies for Exosome Nanovesicles. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2018; 14:1702153. [PMID: 29282861 DOI: 10.1002/smll.201702153] [Citation(s) in RCA: 324] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2017] [Revised: 09/26/2017] [Indexed: 05/20/2023]
Abstract
Exosomes are nanoscale (≈30-150 nm) extracellular vesicles of endocytic origin that are shed by most types of cells and circulate in bodily fluids. Exosomes carry a specific composition of proteins, lipids, RNA, and DNA and can work as cargo to transfer this information to recipient cells. Recent studies on exosomes have shown that they play an important role in various biological processes, such as intercellular signaling, coagulation, inflammation, and cellular homeostasis. These functional roles are attributed to their ability to transfer RNA, proteins, enzymes, and lipids, thereby affecting the physiological and pathological conditions in various diseases, including cancer and neurodegenerative, infectious, and autoimmune diseases (e.g., cancer initiation, progression, and metastasis). Due to these unique characteristics, exosomes are considered promising biomarkers for the diagnosis and prognosis of various diseases via noninvasive or minimally invasive procedures. Over the last decade, a plethora of methodologies have been developed for analyzing disease-specific exosomes using optical and nonoptical tools. Here, the major biological functions, significance, and potential role of exosomes as biomarkers and therapeutics are discussed. Furthermore, an overview of the most commonly used techniques for exosome analysis, highlighting the major technical challenges and limitations of existing techniques, is presented.
Collapse
Affiliation(s)
- Kseniia Boriachek
- School of Natural Sciences, Griffith University, Nathan Campus, QLD 4111, Australia
- Queensland Micro- and Nanotechnology Centre, Griffith University, Nathan Campus, QLD 4111, Australia
| | - Md Nazmul Islam
- School of Natural Sciences, Griffith University, Nathan Campus, QLD 4111, Australia
- Queensland Micro- and Nanotechnology Centre, Griffith University, Nathan Campus, QLD 4111, Australia
| | - Andreas Möller
- Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
| | - Carlos Salomon
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, QLD 4029, Australia
- Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción, Concepción, Chile
| | - Nam-Trung Nguyen
- Queensland Micro- and Nanotechnology Centre, Griffith University, Nathan Campus, QLD 4111, Australia
| | - Md Shahriar A Hossain
- Australian Institute for Innovative Materials (AIIM), University of Wollongong, Squires Way, Innovation Campus, North Wollongong, NSW, 2519, Australia
- International Center for Materials Nanoarchitectonics (MANA), National Institute for Materials Science (NIMS), Ibaraki, 305-0044, Japan
| | - Yusuke Yamauchi
- Australian Institute for Innovative Materials (AIIM), University of Wollongong, Squires Way, Innovation Campus, North Wollongong, NSW, 2519, Australia
- International Center for Materials Nanoarchitectonics (MANA), National Institute for Materials Science (NIMS), Ibaraki, 305-0044, Japan
| | - Muhammad J A Shiddiky
- School of Natural Sciences, Griffith University, Nathan Campus, QLD 4111, Australia
- Queensland Micro- and Nanotechnology Centre, Griffith University, Nathan Campus, QLD 4111, Australia
| |
Collapse
|
|
47
|
Armstrong D, Wildman DE. Extracellular Vesicles and the Promise of Continuous Liquid Biopsies. J Pathol Transl Med 2018; 52:1-8. [PMID: 29370511 PMCID: PMC5784223 DOI: 10.4132/jptm.2017.05.21] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Revised: 05/13/2017] [Accepted: 05/21/2017] [Indexed: 01/25/2023] Open
Abstract
The rapid and accurate diagnosis of patients with minimally invasive procedures was once only found in science fiction. However, the discovery of extracellular vesicles (EVs) and their near ubiquity in body fluids, coupled with the advent of inexpensive next generation sequencing techniques and EV purification protocols, promises to make science fiction a reality. Purifying and sequencing the RNA content of EV from routine blood draws and urine samples are likely to enable pathologists and physicians to diagnose and track the progress of diseases in many inaccessible tissues in the near future. Here we present the evolutionary background of EV, summarize the biology of EV formation and cargo selection, and discuss the current barriers to making continuous liquid biopsies through the use of EV a science reality.
Collapse
Affiliation(s)
- Don Armstrong
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Derek E Wildman
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.,Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| |
Collapse
|
|
48
|
Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci 2018; 75:193-208. [PMID: 28733901 PMCID: PMC5756260 DOI: 10.1007/s00018-017-2595-9] [Citation(s) in RCA: 1713] [Impact Index Per Article: 244.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 06/22/2017] [Accepted: 07/13/2017] [Indexed: 12/12/2022]
Abstract
Exosomes are nanosized membrane vesicles released by fusion of an organelle of the endocytic pathway, the multivesicular body, with the plasma membrane. This process was discovered more than 30 years ago, and during these years, exosomes have gone from being considered as cellular waste disposal to mediate a novel mechanism of cell-to-cell communication. The exponential interest in exosomes experienced during recent years is due to their important roles in health and disease and to their potential clinical application in therapy and diagnosis. However, important aspects of the biology of exosomes remain unknown. To explore the use of exosomes in the clinic, it is essential that the basic molecular mechanisms behind the transport and function of these vesicles are better understood. We have here summarized what is presently known about how exosomes are formed and released by cells. Moreover, other cellular processes related to exosome biogenesis and release, such as autophagy and lysosomal exocytosis are presented. Finally, methodological aspects related to exosome release studies are discussed.
Collapse
Affiliation(s)
- Nina Pettersen Hessvik
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, 0379, Oslo, Norway
- Centre for Cancer Biomedicine, University of Oslo, 0379, Oslo, Norway
| | - Alicia Llorente
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, 0379, Oslo, Norway.
- Centre for Cancer Biomedicine, University of Oslo, 0379, Oslo, Norway.
| |
Collapse
|
|
49
|
Detection of circulating miRNAs: comparative analysis of extracellular vesicle-incorporated miRNAs and cell-free miRNAs in whole plasma of prostate cancer patients. BMC Cancer 2017; 17:730. [PMID: 29121858 PMCID: PMC5679326 DOI: 10.1186/s12885-017-3737-z] [Citation(s) in RCA: 198] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Accepted: 10/30/2017] [Indexed: 12/11/2022] Open
Abstract
Background Circulating cell-free miRNAs have emerged as promising minimally-invasive biomarkers for early detection, prognosis and monitoring of cancer. They can exist in the bloodstream incorporated into extracellular vesicles (EVs) and ribonucleoprotein complexes. However, it is still debated if EVs contain biologically meaningful amounts of miRNAs and may provide a better source of miRNA biomarkers than whole plasma. The aim of this study was to systematically compare the diagnostic potential of prostate cancer-associated miRNAs in whole plasma and in plasma EVs. Methods RNA was isolated from whole plasma and plasma EV samples from a well characterised cohort of 50 patient with prostate cancer (PC) and 22 patients with benign prostatic hyperplasia (BPH). Nine miRNAs known to have a diagnostic potential for PC in cell-free blood were quantified by RT-qPCR and the relative quantities were compared between patients with PC and BPH and between PC patients with Gleason score ≥ 8 and ≤6. Results Only a small fraction of the total cell-free miRNA was recovered from the plasma EVs, however the EV-incorporated and whole plasma cell-free miRNA profiles were clearly different. Four of the miRNAs analysed showed a diagnostic potential in our patient cohort. MiR-375 could differentiate between PC and BPH patients when analysed in the whole plasma, while miR-200c-3p and miR-21-5p performed better when analysed in plasma EVs. EV-incorporated but not whole plasma Let-7a-5p level could distinguish PC patients with Gleason score ≥ 8 vs ≤6. Conclusions This study demonstrates that for some miRNA biomarkers EVs provide a more consistent source of RNA than whole plasma, while other miRNAs show better diagnostic performance when tested in the whole plasma.
Collapse
|
|
50
|
Kanwal R, Plaga AR, Liu X, Shukla GC, Gupta S. MicroRNAs in prostate cancer: Functional role as biomarkers. Cancer Lett 2017; 407:9-20. [DOI: 10.1016/j.canlet.2017.08.011] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 08/03/2017] [Accepted: 08/06/2017] [Indexed: 12/19/2022]
|