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Yu Z, Fu J, Mantareva V, Blažević I, Wu Y, Wen D, Battulga T, Wang Y, Zhang J. The role of tumor-derived exosomal LncRNA in tumor metastasis. Cancer Gene Ther 2025; 32:273-285. [PMID: 40011710 DOI: 10.1038/s41417-024-00852-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 10/22/2024] [Accepted: 11/05/2024] [Indexed: 02/28/2025]
Abstract
Tumor metastasis regulated by multiple complicated pathways is closely related to variations in the tumor microenvironment. Exosomes can regulate the tumor microenvironment through various mechanisms. Exosomes derived from tumor cells carry a variety of substances, including long non-coding RNAs (lncRNAs), play important roles in intercellular communication and act as critical determinants influencing tumor metastasis. In this review, we elaborate on several pivotal processes through which lncRNAs regulate tumor metastasis, including the regulation of epithelial‒mesenchymal transition, promotion of angiogenesis and lymphangiogenesis, enhancement of the stemness of tumor cells, and evasion of immune clearance. Additionally, we comprehensively summarized a diverse array of potential tumor-derived exosomal lncRNA biomarkers to facilitate accurate diagnosis and prognosis in a clinical setting.
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Affiliation(s)
- Zhile Yu
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China
| | - Jiali Fu
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China
| | - Vanya Mantareva
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Bld. 9, 1113, Sofia, Bulgaria
| | - Ivica Blažević
- Department of Organic Chemistry, Faculty of Chemistry and Technology, University of Split, Ruđera Boškovića 35, 21000, Split, Croatia
| | - Yusong Wu
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China
| | - Dianchang Wen
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China
| | - Tungalag Battulga
- School of Pharmacy, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia.
| | - Yuqing Wang
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China.
- The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, 510140, PR China.
| | - Jianye Zhang
- The Fifth Affiliated Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510700, PR China.
- The Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, 511518, PR China.
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2
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He GD, Sun S, Huang YQ. Association of Circulating, Inflammatory Response Exosomal Long RNAs with Ischemic Stroke. FRONT BIOSCI-LANDMRK 2025; 30:25355. [PMID: 40018923 DOI: 10.31083/fbl25355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 09/07/2024] [Accepted: 09/19/2024] [Indexed: 03/01/2025]
Abstract
BACKGROUND The expression profiles and function of exosomal long RNAs (exoLRs) in ischemic stroke remain unknown. This study aimed to investigate the pathophysiologic responses reflected by exoLRs. METHODS The expression profile of exosomal messenger RNA, long non-coding RNA and circular RNA in 9 patients with ischemic stroke and 12 healthy individuals were analyzed by sequencing. We assessed the immune cell landscape to reveal the pathophysiologic responses reflected by exoLRs and performed biological process and pathway enrichment analyses. Competing endogenous RNA networks were constructed to explore the molecular functions of exoLRs. RESULTS A total of 321 up- and 187 down-regulated messenger RNAs, 31 up- and 9 down-regulated long non-coding RNAs, and 67 up- and 48 down-regulated circular RNAs were identified. The immune cell landscape analysis identified that the proportions of exhausted and gamma delta T cells were statistically higher in patients with ischemic stroke. Bioinformatics analyses, including enrichment and competing endogenous RNA network analyses, also indicated that exoLRs were associated with T- cell-mediated inflammatory responses. CONCLUSIONS The expression patterns of exoLRs highlighted the association between ischemic stroke and inflammatory responses mediated by T cells.
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Affiliation(s)
- Guo-Dong He
- Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080 Guangzhou, Guangdong, China
- Institute of Medical Research, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080 Guangzhou, Guangdong, China
| | - Shuo Sun
- Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080 Guangzhou, Guangdong, China
| | - Yu-Qing Huang
- Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080 Guangzhou, Guangdong, China
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3
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Mohamed AH, Abaza T, Youssef YA, Rady M, Fahmy SA, Kamel R, Hamdi N, Efthimiado E, Braoudaki M, Youness RA. Extracellular vesicles: from intracellular trafficking molecules to fully fortified delivery vehicles for cancer therapeutics. NANOSCALE ADVANCES 2025; 7:934-962. [PMID: 39823046 PMCID: PMC11733735 DOI: 10.1039/d4na00393d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 12/22/2024] [Indexed: 01/19/2025]
Abstract
Extracellular vesicles (EVs) are emerging as viable tools in cancer treatment due to their ability to carry a wide range of theranostic activities. This review summarizes different forms of EVs such as exosomes, microvesicles, apoptotic bodies, and oncosomes. It also sheds the light onto isolation methodologies, characterization techniques and therapeutic applications of all discussed EVs. Evidence indicates that EVs are particularly effective in delivering chemotherapeutic medications, and immunomodulatory agents. However, the advancement of EV-based therapies into clinical practice is hindered by challenges including EVs heterogeneity, cargo loading efficiency, and in vivo stability. Overall, EVs have the potential to change cancer therapeutic paradigms. Continued research and development activities are critical for improving EV-based medications and increasing their therapeutic impact.
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Affiliation(s)
- Adham H Mohamed
- Department of Chemistry, Faculty of Science, Cairo University 12613 Giza Egypt
| | - Tasneem Abaza
- Biotechnology and Biomolecular Chemistry Program, Faculty of Science, Cairo University 12613 Giza Egypt
- Université Paris-Saclay, Université d'Evry Val D'Essonne 91000 Évry-Courcouronnes Île-de-France France
| | - Yomna A Youssef
- Department of Physiology, Faculty of Physical Therapy, German International University (GIU) 11835 Cairo Egypt
- Molecular Biology and Biochemistry Department, Faculty of Biotechnology, German International University (GIU) 11835 Cairo Egypt
| | - Mona Rady
- Microbiology, Immunology and Biotechnology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC) 11835 Cairo Egypt
- Faculty of Biotechnology, German International University New Administrative Capital 11835 Cairo Egypt
| | - Sherif Ashraf Fahmy
- Department of Pharmaceutics and Biopharmaceutics, University of Marburg Robert-Koch-Str. 4 35037 Marburg Germany
| | - Rabab Kamel
- Pharmaceutical Technology Department, National Research Centre 12622 Cairo Egypt
| | - Nabila Hamdi
- Pharmacology and Toxicology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC) 11835 Cairo Egypt
| | - Eleni Efthimiado
- Inorganic Chemistry Laboratory, Chemistry Department, National and Kapodistrian University of Athens Athens Greece
| | - Maria Braoudaki
- Department of Clinical, Pharmaceutical, and Biological Science, School of Life and Medical Sciences, University of Hertfordshire Hatfield AL10 9AB UK
| | - Rana A Youness
- Molecular Biology and Biochemistry Department, Faculty of Biotechnology, German International University (GIU) 11835 Cairo Egypt
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4
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Ghahramani Almanghadim H, Karimi B, Valizadeh S, Ghaedi K. Biological functions and affected signaling pathways by Long Non-Coding RNAs in the immune system. Noncoding RNA Res 2025; 10:70-90. [PMID: 39315339 PMCID: PMC11417496 DOI: 10.1016/j.ncrna.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 08/14/2024] [Accepted: 09/01/2024] [Indexed: 09/25/2024] Open
Abstract
Recently, the various regulative functions of long non-coding RNAs (LncRNAs) have been well determined. Recently, the vital role of LncRNAs as gene regulators has been identified in the immune system, especially in the inflammatory response. All cells of the immune system are governed by a complex and ever-changing gene expression program that is regulated through both transcriptional and post-transcriptional processes. LncRNAs regulate gene expression within the cell nucleus by influencing transcription or through post-transcriptional processes that affect the splicing, stability, or translation of messenger RNAs (mRNAs). Recent studies in immunology have revealed substantial alterations in the expression of lncRNAs during the activation of the innate immune system as well as the development, differentiation, and activation of T cells. These lncRNAs regulate key aspects of immune function, including the manufacturing of inflammatory molecules, cellular distinction, and cell movement. They do this by modulating protein-protein interactions or through base pairing with RNA and DNA. Here we review the current understanding of the mechanism of action of lncRNAs as novel immune-related regulators and their impact on physiological and pathological processes related to the immune system, including autoimmune diseases. We also highlight the emerging pattern of gene expression control in important research areas at the intersection between immunology and lncRNA biology.
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Affiliation(s)
| | - Bahareh Karimi
- Department of Cellular and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Sepehr Valizadeh
- Department of Internal Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
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Nie X, Chen L, Wang B, Wang S, Li Y. FOXO3 induces TUG1-mediated miR-375/GATA3 signaling axis to promote the survival of melanocytes in vitiligo. FASEB J 2024; 38:e70145. [PMID: 39520296 DOI: 10.1096/fj.202400676rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 10/15/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024]
Abstract
Vitiligo is characterized by the depletion of melanocytes due to the activation of CD8+ T cells. Taurine-upregulated gene 1 (TUG1), a long noncoding RNA, is involved in melanogenesis. This study aimed to explore the role and mechanism of TUG1 in vitiligo. RT-qPCR and western blot analyses demonstrated decreased TUG1 levels and increased miR-375 levels in patients with vitiligo. MTT and transwell assays indicated that TUG1 upregulation facilitated melanocyte survival and inhibited CD8+ T cell migration. Dual luciferase reporter and chromatin immunoprecipitation assays verified that Forkhead box O3 (FOXO3) directly interacted with the TUG1 promoter, leading to the positive regulation of TUG1 expression. In addition, FOXO3 promoted melanocyte survival by enhancing the transcription of TUG1. Luciferase reporter assay and RNA immunoprecipitation assay confirmed that TUG1 upregulated GATA binding protein 3 (GATA3) expression by targeting miR-375. TUG1 facilitated melanocyte survival by regulating the miR-375/GATA3 axis. In vitiligo, melanocyte survival is promoted by the induction of the TUG1-mediated miR-375/GATA3 axis by FOXO3, which offers new therapeutic targets for vitiligo treatment.
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Affiliation(s)
- Xiaojuan Nie
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Lamei Chen
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Baihe Wang
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Shengnan Wang
- Department of Dermatology, Shenxian People's Hospital of Shandong Province, Liaocheng, Shandong Province, China
| | - Yuanyuan Li
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
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Sharma S, Artner T, Preissner KT, Lang IM. Nucleic acid liquid biopsies in cardiovascular disease: Cell-free RNA liquid biopsies in cardiovascular disease. Atherosclerosis 2024; 398:118584. [PMID: 39306538 DOI: 10.1016/j.atherosclerosis.2024.118584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 08/15/2024] [Accepted: 08/29/2024] [Indexed: 11/17/2024]
Abstract
Cardiovascular diseases (CVD) and their complications continue to be the leading cause of mortality globally. With recent advancements in molecular analytics, individualized treatments are gradually applied to the diagnosis and treatment of CVD. In the field of diagnostics, liquid biopsy combined with modern analytical technologies is the most popular natural source to identify disease biomarkers, as has been successfully demonstrated in the cancer field. While it is not easy to obtain any diseased tissue for different types of CVD such as atherosclerosis, deep vein thrombosis or stroke, liquid biopsies provide a simple and non-invasive alternative to surgical tissue specimens to obtain dynamic molecular information reflecting disease states. The release of cell-free ribonucleic acids (cfRNA) from stressed/damaged/dying and/or necrotic cells is a common physiological phenomenon. CfRNAs are a heterogeneous population of various types of extracellular RNA found in body fluids (blood, urine, saliva, cerebrospinal fluid) or in association with vascular/atherosclerotic tissue, offering insights into disease pathology on a diagnostic front. In particular, cf-ribosomal RNA has been shown to act as a damaging molecule in several cardio-vascular disease conditions. Moreover, such pathophysiological functions of cfRNA in CVD have been successfully antagonized by the administration of RNases. In this review, we discuss the origin, structure, types, and potential utilization of cfRNA in the diagnosis of CVD. Together with the analysis of established CVD biomarkers, the profiling of cfRNA in body fluids may thereby provide a promising approach for early disease detection and monitoring.
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Affiliation(s)
- Smriti Sharma
- Department of Internal Medicine II, Cardiology, Medical University of Vienna, Vienna, Austria
| | - Tyler Artner
- Department of Internal Medicine II, Cardiology, Medical University of Vienna, Vienna, Austria
| | - Klaus T Preissner
- Kerckhoff-Heart Research Institute, Department Cardiology, Justus-Liebig-University, Giessen, Germany
| | - Irene M Lang
- Department of Internal Medicine II, Cardiology, Medical University of Vienna, Vienna, Austria.
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7
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Zabeti Touchaei A, Norollahi SE, Najafizadeh A, Babaei K, Bakhshalipour E, Vahidi S, Samadani AA. Therapeutic combinations of exosomes alongside cancer stem cells (CSCs) and of CSC-derived exosomes (CSCEXs) in cancer therapy. Cancer Cell Int 2024; 24:334. [PMID: 39369258 PMCID: PMC11453077 DOI: 10.1186/s12935-024-03514-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 09/22/2024] [Indexed: 10/07/2024] Open
Abstract
Exosomes which are membrane vesicles released by cells have gained significant interest in the field of cancer therapy as a novel means of intercellular communication. Their role in immune activation and their pathophysiological functions in cancer therapy have been recognized. Exosomes carry diverse bioactive components including proteins, mRNA, microRNAs, and bioactive lipids. These molecules have therapeutic potential in promoting tissue regeneration, supporting stem cell activity, preventing cell death, modulating immune responses, and promoting the growth of new blood vessels. However, the precise roles of exosomes derived from mesenchymal stem cells (MSCs) in the treatment of various cancers are still not fully understood. Consequently, cancer stem cells (CSCs) can self-renew and differentiate into various cell types. Understanding the mechanisms that sustain their persistence is crucial for developing effective therapies. Exosomes have recently gained interest as vehicles for intercellular communication between CSCs and non-CSCs, influencing cancer progression and the microenvironment. Research is ongoing on the utilization of exosomes derived from cancer stem cells (CSC-Exosome) for cancer treatment. The composition of extracellular vesicles is influenced by the specific type and condition of the cells from which they are secreted. Circulating exosomes contain stable RNA molecules such as mRNAs, microRNAs, and long non-coding RNAs (lncRNAs). In this review, we will explore the significance of exosomes and their diverse cellular combinations in the context of cancer therapy.
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Affiliation(s)
| | - Seyedeh Elham Norollahi
- Cancer Research Center and Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Najafizadeh
- School of Paramedicine Sciences, Guilan University of Medical Sciences, Langarud, Iran
| | - Kosar Babaei
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Elahe Bakhshalipour
- School of Paramedicine Sciences, Guilan University of Medical Sciences, Langarud, Iran
| | - Sogand Vahidi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Ali Akbar Samadani
- Neuroscience Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran.
- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran.
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8
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Lin Y, Zhao W, Pu R, Lv Z, Xie H, Li Y, Zhang Z. Long non‑coding RNAs as diagnostic and prognostic biomarkers for colorectal cancer (Review). Oncol Lett 2024; 28:486. [PMID: 39185489 PMCID: PMC11342420 DOI: 10.3892/ol.2024.14619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 07/29/2024] [Indexed: 08/27/2024] Open
Abstract
Colorectal cancer (CRC) ranks as the 3rd most common cancer globally and is the 2nd leading cause of cancer-related death. Owing to the lack of specific early symptoms and the limitations of existing early diagnostic methods, most patients with CRC are diagnosed at advanced stages. To overcome these challenges, researchers have increasingly focused on molecular biomarkers, with particular interest in long non-coding RNAs (lncRNAs). These non-protein-coding RNAs, which exceed 200 nucleotides in length, play critical roles in the development and progression of CRC. The stability and detectability of lncRNAs in the circulatory system make them promising candidate biomarkers. The analysis of circulating lncRNAs in peripheral blood represents a potential option for minimally invasive diagnostic tests based on liquid biopsy samples. The present review aimed to evaluate the efficacy of lncRNAs with altered expression levels in peripheral blood as diagnostic markers for CRC. Additionally, the clinical significance of lncRNAs as prognostic markers for this disease were summarized.
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Affiliation(s)
- Yuning Lin
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
| | - Wenzhen Zhao
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
| | - Ruonan Pu
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
| | - Zhenyi Lv
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
| | - Hongyan Xie
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
| | - Ying Li
- Department of Ultrasonography, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Zhongying Zhang
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361009, P.R. China
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9
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Rizk NI, Kassem DH, Abulsoud AI, AbdelHalim S, Yasser MB, Kamal MM, Hamdy NM. Revealing the role of serum exosomal novel long non-coding RNA NAMPT-AS as a promising diagnostic/prognostic biomarker in colorectal cancer patients. Life Sci 2024; 352:122850. [PMID: 38901687 DOI: 10.1016/j.lfs.2024.122850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 06/08/2024] [Accepted: 06/14/2024] [Indexed: 06/22/2024]
Abstract
AIMS Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Nicotinamide phosphoribosyl-transferase (NAMPT) was found to be over-expressed in several cancers including CRC. NAMPT-Antisense (NAMPT-AS) is a novel long non-coding RNA (lncRNA) recently reported to be associated with triple negative breast cancer. However, its role in CRC has not been investigated. This study was designed to explore the role of lncRNA NAMPT-AS in CRC, and to investigate its circulating serum exosomal levels in subjects with/without CRC. MAIN METHODS We analyzed CRC patients' data in The Cancer Genome Atlas (TCGA). LncRNA NAMPT-AS and NAMPT mRNA levels were measured in serum exosomes isolated from CRC patients and healthy control subjects and were also measured in CRC-tissues using qRT-PCR. Serum NAMPT protein levels were measured by ELISA, and immunohistochemical analyses were done for NAMPT and Ki67 in CRC tissues. KEY FINDINGS Serum exosomal NAMPT-AS levels were found to be significantly higher in CRC patients compared to control subjects and significantly positively correlated with serum exosomal NAMPT mRNA and circulating NAMPT protein. Tissue NAMPT-AS was found to be significantly positively associated with tissue and serum exosomal NAMPT levels. Higher serum exosomal NAMPT-AS levels were found to be associated with higher susceptibility for CRC. Gene-ontology results and survival analysis of TCGA-data showed a potential classification of CRC samples based on NAMPT-AS levels and association of NAMPT-AS upregulation with poor CRC prognosis and survival. SIGNIFICANCE These results portray NAMPT-AS as a novel potential diagnostic/prognostic biomarker and key molecular mediator in CRC.
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Affiliation(s)
- Nehal I Rizk
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt
| | - Dina H Kassem
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Ahmed I Abulsoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt; Department of Biochemistry, Faculty of Pharmacy (Boys Branch), Al-Azhar University, Nasr City, Cairo, Egypt
| | - Sherif AbdelHalim
- Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Montaser Bellah Yasser
- Bioinformatics Group, Center for Informatics Sciences (CIS), School of Information Technology and Computer Science (ITCS), Nile University, Giza, Egypt
| | - Mohamed M Kamal
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; Pharmacology and Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Health Research Centre of Excellence, Drug Research and Development Group, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt.
| | - Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
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Wei C, Zhang C, Zhou Y, Wang J, Jin Y. Progress of Exosomal LncRNAs in Pancreatic Cancer. Int J Mol Sci 2024; 25:8665. [PMID: 39201351 PMCID: PMC11354448 DOI: 10.3390/ijms25168665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/27/2024] [Accepted: 07/28/2024] [Indexed: 09/02/2024] Open
Abstract
Pancreatic cancer is a prevalent malignant tumor with rising medication resistance and mortality. Due to a dearth of specific and trustworthy biomarkers and therapeutic targets, pancreatic cancer early detection and treatment are still not at their best. Exosomal LncRNAs have been found to be plentiful and persistent within exosomes, and they are capable of functioning whether the exosomes are traveling to close or distant cells. Furthermore, increasing evidence suggests that exosomal LncRNA, identified as an oncogene or tumor suppressor-control the growth, metastasis, and susceptibility of pancreatic cancer to chemotherapy and radiation therapy. Promising prospects for both antitumor targets and diagnostic biomarkers are exosomal LncRNAs. The primary features of exosomal LncRNAs, their biological roles in the onset and progression of pancreatic cancer, and their potential as therapeutic targets and diagnostic molecular markers are outlined in this review.
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Affiliation(s)
| | | | | | | | - Yong Jin
- School of Pharmacy, Anhui Medical University, Hefei 230032, China
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11
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Li G, Zhang S, Zou Y, Ai H, Zheng X, Qian K, Lei C, Fu W. The therapeutic potential of exosomes in immunotherapy. Front Immunol 2024; 15:1424081. [PMID: 39040108 PMCID: PMC11260647 DOI: 10.3389/fimmu.2024.1424081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 06/24/2024] [Indexed: 07/24/2024] Open
Abstract
Exosomes are found in various tissues of the body and carry abundant contents including nucleic acids, proteins, and metabolites, which continuously flow between cells of various tissues and mediate important intercellular communication. In addition, exosomes from different cellular sources possess different physiopathological immunomodulatory effects, which are closely related to the immune regeneration of normal or abnormal organs and tissues. Here, we focus on the mechanistic interactions between exosomes and the human immune system, introduce the immuno-regenerative therapeutic potential of exosomes in common clinical immune-related diseases, such as infectious diseases, autoimmune diseases, and tumors, and reveal the safety and efficacy of exosomes as a novel cell-free immune regenerative therapy.
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Affiliation(s)
- Guangyao Li
- Department of Biophysics, College of Basic Medical Sciences, Naval Medical University (Second Military Medical University), Shanghai, China
- Department of Biomedical Engineering, College of Basic Medical Sciences, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Shuyi Zhang
- Department of Biophysics, College of Basic Medical Sciences, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Yitan Zou
- Department of Biomedical Engineering, College of Basic Medical Sciences, Naval Medical University (Second Military Medical University), Shanghai, China
- Department of Respiratory and Critical Care Medicine, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Hongru Ai
- Department of Biomedical Engineering, College of Basic Medical Sciences, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Xinya Zheng
- Department of Biomedical Engineering, College of Basic Medical Sciences, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Kewen Qian
- Department of Biomedical Engineering, College of Basic Medical Sciences, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Changhai Lei
- Department of Biophysics, College of Basic Medical Sciences, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Wenyan Fu
- Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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12
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Lin Y, Zhao W, Lv Z, Xie H, Li Y, Zhang Z. The functions and mechanisms of long non-coding RNA in colorectal cancer. Front Oncol 2024; 14:1419972. [PMID: 39026978 PMCID: PMC11254705 DOI: 10.3389/fonc.2024.1419972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 06/18/2024] [Indexed: 07/20/2024] Open
Abstract
CRC poses a significant challenge in the global health domain, with a high number of deaths attributed to this disease annually. If CRC is detected only in its advanced stages, the difficulty of treatment increases significantly. Therefore, biomarkers for the early detection of CRC play a crucial role in improving patient outcomes and increasing survival rates. The development of a reliable biomarker for early detection of CRC is particularly important for timely diagnosis and treatment. However, current methods for CRC detection, such as endoscopic examination, blood, and stool tests, have certain limitations and often only detect cases in the late stages. To overcome these constraints, researchers have turned their attention to molecular biomarkers, which are considered a promising approach to improving CRC detection. Non-invasive methods using biomarkers such as mRNA, circulating cell-free DNA, microRNA, LncRNA, and proteins can provide more reliable diagnostic information. These biomarkers can be found in blood, tissue, stool, and volatile organic compounds. Identifying molecular biomarkers with high sensitivity and specificity for the early and safe, economic, and easily measurable detection of CRC remains a significant challenge for researchers.
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Affiliation(s)
- Yuning Lin
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, China
| | - Wenzhen Zhao
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, China
| | - Zhenyi Lv
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, China
| | - Hongyan Xie
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, China
| | - Ying Li
- Ultrasonography Department, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Zhongying Zhang
- Medical Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, China
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13
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Shyu KG, Wang BW, Pan CM, Fang WJ, Lin CM. Exosomal MALAT1 from macrophages treated with high levels of glucose upregulates LC3B expression via miR-204-5p downregulation. J Chin Med Assoc 2024; 87:581-589. [PMID: 38651895 DOI: 10.1097/jcma.0000000000001098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Metastasis-associated lung adenocarcinoma transcript 1 ( MALAT1 ) plays a critical role in the pathophysiology of diabetes-related complications. However, whether macrophage-derived MALAT1 affects autophagic activity under hyperglycemic conditions is unclear. Therefore, we investigated the molecular regulatory mechanisms of macrophage-derived MALAT1 and autophagy under hyperglycemic conditions. METHODS Hyperglycemia was induced by culturing macrophages in 25 mM glucose for 1 hour. Exosomes were extracted from the culture media. A rat model of carotid artery balloon injury was established to assess the effect of MALAT1 on vascular injury. Reverse transcription, real-time quantitative polymerase chain reaction, western blotting, immunohistochemical staining, and luciferase activity assays were performed. RESULTS Stimulation with high levels of glucose significantly enhanced MALAT1 expression in macrophage-derived exosomes. MALAT1 inhibited miR-204-5p expression in macrophage-derived exosomes under hyperglycemic conditions. siRNA-induced silencing of MALAT1 significantly reversed macrophage-derived exosome-induced miR-204-5p expression. Hyperglycemic treatment caused a significant, exosome-induced increase in the expression of the autophagy marker LC3B in macrophages. Silencing MALAT1 and overexpression of miR-204-5p significantly decreased LC3B expression induced by macrophage-derived exosomes. Overexpression of miR-204-5p significantly reduced LC3B luciferase activity induced by macrophage-derived exosomes. Balloon injury to the carotid artery in rats significantly enhanced MALAT1 and LC3B expression, and significantly reduced miR-204-5p expression in carotid artery tissue. Silencing MALAT1 significantly reversed miR-204-5p expression in carotid artery tissue after balloon injury. MALAT1 silencing or miR-204-5p overexpression significantly reduced LC3B expression after balloon injury. CONCLUSION This study demonstrated that hyperglycemia upregulates MALAT1 . MALAT1 suppresses miR-204-5p expression and counteracts the inhibitory effect of miR-204-5p on LC3B expression in macrophages to promote vascular disease.
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Affiliation(s)
- Kou-Gi Shyu
- Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC
| | - Bao-Wei Wang
- Department of Research, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC
| | - Chun-Ming Pan
- Department of Research, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC
| | - Wei-Jen Fang
- Department of Research, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC
| | - Chiu-Mei Lin
- Department of Emergency Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC
- School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan, ROC
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14
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Shi X, Zhao X, Xue J, Jia E. Extracellular vesicle biomarkers in circulation for colorectal cancer detection: a systematic review and meta-analysis. BMC Cancer 2024; 24:623. [PMID: 38778252 PMCID: PMC11110411 DOI: 10.1186/s12885-024-12312-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 04/25/2024] [Indexed: 05/25/2024] Open
Abstract
We provided an overview which evaluated the diagnostic performance of circulation EV biomarkers for CRC from PubMed, Medline, and Web of Science until 21 August 2022.Weidentified 48 studies that involved 7727 participants and evaluated 162 plasma/serum individual EV biomarkers including 117 RNAs and 45 proteins, as well as 45 EV biomarker panels for CRC detection. 12 studies evaluated the diagnostic performance of EV biomarkers for early CRC. The summarized sensitivity, specificity, and AUC value of individual EV RNAs and EV RNA panels were 76%, 75%, 0.87 and 82%, 79% and 0.90, respectively. Meanwhile, those of individual EV proteins and EV protein panels were 85%, 84%, 0.92 and 87%, 83%, 0.92, respectively. These results indicated that EV biomarker panels revealed superior diagnostic performance than the corresponding individual biomarkers. In early CRC, EV biomarkers showed available diagnostic value with the sensitivity, specificity, and AUC value of 80%, 75%, and 0.89.In subgroup analyses, EV miRNAs and LncRNAs held similar diagnostic value with the sensitivity, specificity and AUC value of 75%, 78%, 0.90 and 79%, 72%, 0.83, which was highly consistent with the whole EV RNAs. Significantly, the diagnostic values of EV miRNAs in plasma were marginally higher than those based on serum. In detail, the sensitivity, specificity, and AUC values were 79%, 81%, and 0.92 in plasma, as well as 74%, 77%, and 0.88 in serum, respectively. Therefore, circulation EV biomarkers could be considered as a promising biomarker for the early detection of CRC.
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Affiliation(s)
- Xianquan Shi
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xinyu Zhao
- Clinical Epidemiology & EBM Unit, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Jinru Xue
- Department of Thoracic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
| | - Erna Jia
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, China.
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15
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Cao X, Liu Z, Qin X, Gu Y, Huang Y, Qian Y, Wang Z, Li H, Zhu Q, Wei W. LoC-SERS platform for rapid and sensitive detection of colorectal cancer protein biomarkers. Talanta 2024; 270:125563. [PMID: 38134815 DOI: 10.1016/j.talanta.2023.125563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 12/13/2023] [Accepted: 12/16/2023] [Indexed: 12/24/2023]
Abstract
Colorectal cancer (CRC) remains a significant contributor to the global mortality rate, and a single biomarker cannot meet the specificity required for CRC screening. To this end, we developed a multiplexed, pump-free surface-enhanced Raman scattering (SERS) microfluidic chip (LoC-SERS) using a one-step recognition release mechanism; the aptamer-functionalized novel Au nanocrown array (AuNCA) was used as the detection element embedded in the detection zone of the platform for rapid and specific detection of protein markers in multiple samples simultaneously. Here, the corresponding aptamer specifically captured the protein marker, causing the complementary strand of the aptamer carrying the Raman signal molecule to be shed, reducing the SERS signal. Based on this platform, sensitive and specific detection of the target can be accomplished within 15 min with detection limits of 0.031 pg/mL (hnRNP A1) and 0.057 pg/mL (S100P). Meanwhile, the platform was consistent with ELISA results when used to test clinical. By substituting different aptamers, this platform can provide a new solution for the rapid and sensitive detection of protein markers, which has promising applications in future disease detection.
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Affiliation(s)
- Xiaowei Cao
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China
| | - Zhengqing Liu
- Department of Endocrinology, Suzhou Ninth People's Hospital, Suzhou, China
| | - Xiaogang Qin
- Department of Gastroenterology, Traditional Chinese Medicine Hospital of Tongzhou District, Nantong, Jiangsu, China
| | - Yuexing Gu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China
| | - Yong Huang
- Department of General Surgery, Jiangdu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Yayun Qian
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China
| | - Zhenguang Wang
- Department of General Surgery, Jiangdu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Hongbo Li
- Department of General Surgery, Jiangdu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Qunshan Zhu
- Department of General Surgery, Jiangdu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Wei Wei
- Department of General Surgery, Jiangdu People's Hospital Affiliated to Yangzhou University, Yangzhou, China.
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16
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Ren Y, Manoharan T, Liu B, Cheng CZM, En Siew B, Cheong WK, Lee KY, Tan IJW, Lieske B, Tan KK, Chia G. Circular RNA as a source of neoantigens for cancer vaccines. J Immunother Cancer 2024; 12:e008402. [PMID: 38508656 PMCID: PMC10952939 DOI: 10.1136/jitc-2023-008402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/03/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND The effectiveness of somatic neoantigen-based immunotherapy is often hindered by the limited number of mutations in tumors with low to moderate mutation burden. Focusing on microsatellite-stable colorectal cancer (CRC), this study investigates the potential of tumor-associated circular RNAs (circRNAs) as an alternative source of neoepitopes in CRC. METHODS Tumor-associated circRNAs in CRC were identified using the MiOncoCirc database and ribo-depletion RNA sequencing of paired clinical normal and tumor samples. Candidate circRNA expression was validated by quantitative real-time PCR (RT-qPCR) using divergent primers. TransCirc database was used for translation prediction. Human leukocyte antigen binding affinity of open reading frames from potentially translatable circRNA was predicted using pVACtools. Strong binders from messenger RNA-encoded proteins were excluded using BlastP. The immunogenicity of the candidate antigens was functionally validated through stimulation of naïve CD8+ T cells against the predicted neoepitopes and subsequent analysis of the T cells through enzyme-linked immunospot (ELISpot) assay, intracellular cytokine staining (ICS) and granzyme B (GZMB) reporter. The cytotoxicity of T cells trained with antigen peptides was further tested using patient-derived organoids. RESULTS We identified a neoepitope from circRAPGEF5 that is upregulated in CRC tumor samples from MiOncoCirc database, and two neoepitopes from circMYH9, which is upregulated across various tumor samples from our matched clinical samples. The translation potential of candidate peptides was supported by Clinical Proteomic Tumor Analysis Consortium database using PepQuery. The candidate peptides elicited antigen-specific T cells response and expansion, evidenced by various assays including ELISpot, ICS and GZMB reporter. Furthermore, T cells trained with circMYH9 peptides were able to specifically target and eliminate tumor-derived organoids but not match normal organoids. This observation underscores the potential of circRNAs as a source of immunogenic neoantigens. Lastly, circMYH9 was enriched in the liquid biopsies of patients with CRC, thus enabling a detection-to-vaccination treatment strategy for patients with CRC. CONCLUSIONS Our findings underscore the feasibility of tumor-associated circRNAs as an alternative source of neoantigens for cancer vaccines targeting tumors with moderate mutation levels.
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Affiliation(s)
- Yi Ren
- Department of Pharmacy, National University of Singapore, Singapore
- NUS iHealthtech, Singapore
| | - Thamizhanban Manoharan
- Department of Pharmacy, National University of Singapore, Singapore
- NUS iHealthtech, Singapore
| | - Beijia Liu
- Department of Pharmacy, National University of Singapore, Singapore
| | - Cyrus Zai Ming Cheng
- Department of Pharmacy, National University of Singapore, Singapore
- NUS iHealthtech, Singapore
| | - Bei En Siew
- Department of Surgery, National University of Singapore, Singapore
- Department of Surgery, National University Hospital, Singapore
| | - Wai-Kit Cheong
- Department of Surgery, National University Hospital, Singapore
| | - Kai Yin Lee
- Department of Surgery, National University Hospital, Singapore
| | - Ian Jse-Wei Tan
- Department of Surgery, National University Hospital, Singapore
| | - Bettina Lieske
- Department of Surgery, National University Hospital, Singapore
| | - Ker-Kan Tan
- Department of Surgery, National University of Singapore, Singapore
- Department of Surgery, National University Hospital, Singapore
| | - Gloryn Chia
- Department of Pharmacy, National University of Singapore, Singapore
- NUS iHealthtech, Singapore
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17
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Khoushab S, Aghmiuni MH, Esfandiari N, Sarvandani MRR, Rashidi M, Taheriazam A, Entezari M, Hashemi M. Unlocking the potential of exosomes in cancer research: A paradigm shift in diagnosis, treatment, and prevention. Pathol Res Pract 2024; 255:155214. [PMID: 38430814 DOI: 10.1016/j.prp.2024.155214] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 02/11/2024] [Accepted: 02/15/2024] [Indexed: 03/05/2024]
Abstract
Exosomes, which are tiny particles released by cells, have the ability to transport various molecules, including proteins, lipids, and genetic material containing non-coding RNAs (ncRNAs). They are associated with processes like cancer metastasis, immunity, and tissue repair. Clinical trials have shown exosomes to be effective in treating cancer, inflammation, and chronic diseases. Mesenchymal stem cells (MSCs) and dendritic cells (DCs) are common sources of exosome production. Exosomes have therapeutic potential due to their ability to deliver cargo, modulate the immune system, and promote tissue regeneration. Bioengineered exosomes could revolutionize disease treatment. However, more research is needed to understand exosomes in tumor growth and develop new therapies. This paper provides an overview of exosome research, focusing on cancer and exosome-based therapies including chemotherapy, radiotherapy, and vaccines. It explores exosomes as a drug delivery system for cancer therapy, highlighting their advantages. The article discusses using exosomes for various therapeutic agents, including drugs, antigens, and RNAs. It also examines challenges with engineered exosomes. Analyzing exosomes for clinical purposes faces limitations in sensitivity, specificity, and purification. On the other hand, Nanotechnology offers solutions to overcome these challenges and unlock exosome potential in healthcare. Overall, the article emphasizes the potential of exosomes for personalized and targeted cancer therapy, while acknowledging the need for further research.
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Affiliation(s)
- Saloomeh Khoushab
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mina Hobabi Aghmiuni
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Negin Esfandiari
- Department of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | | | - Mohsen Rashidi
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran; Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Department of Orthopedics, Faculty of Medicine, Tehran medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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18
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Anitha K, Posinasetty B, Naveen Kumari K, Chenchula S, Padmavathi R, Prakash S, Radhika C. Liquid biopsy for precision diagnostics and therapeutics. Clin Chim Acta 2024; 554:117746. [PMID: 38151071 DOI: 10.1016/j.cca.2023.117746] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/22/2023] [Accepted: 12/23/2023] [Indexed: 12/29/2023]
Abstract
Liquid biopsy (LB) has emerged as a highly promising and non-invasive diagnostic approach, particularly in the field of oncology, and has garnered interest in various medical disciplines. This technique involves the examination of biomolecules released into physiological fluids, such as urine samples, blood, and cerebrospinal fluid (CSF). The analysed biomolecules included circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), cell-free DNA (cfDNA), exosomes, and other cell-free components. In contrast to conventional tissue biopsies, LB provides minimally invasive diagnostics, offering invaluable insights into tumor characteristics, treatment response, and early disease detection. This Review explores the contemporary landscape of technologies and clinical applications in the realm of LB, with a particular emphasis on the isolation and analysis of ctDNA and/or cfDNA. Various methodologies have been employed, including droplet digital polymerase chain reaction (DDP), BEAMing (beads, emulsion, amplification, and magnetics), TAm-Seq (tagged-amplicon deep sequencing), CAPP-Seq (cancer personalized profiling by deep sequencing), WGBS-Seq (whole genome bisulfite sequencing), WES (whole exome sequencing), and WGS (whole-genome sequencing). Additionally, CTCs have been successfully isolated through biomarker-based cell capture, employing both positive and negative enrichment strategies based on diverse biophysical and other inherent properties. This approach also addresses challenges and limitations associated with liquid biopsy techniques, such as sensitivity, specificity, standardization and interpretability of findings. This review seeks to identify the current technologies used in liquid biopsy samples, emphasizing their significance in identifying tumor markers for cancer detection, prognosis, and treatment outcome monitoring.
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Affiliation(s)
- Kuttiappan Anitha
- Department of Pharmacology, School of Pharmacy and Technology Management (SPTM), SVKM's Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-University, Shirpur 425405, India
| | | | - K Naveen Kumari
- Sri Krishna Teja Pharmacy College, Tirupati, Andhra Pradesh 517502, India
| | | | - R Padmavathi
- SVS Medical College, Hyderabad, Telangana, India
| | - Satya Prakash
- All India Institute of Medical Sciences, Bhopal 462020, India
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19
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Schneider N, Hermann PC, Eiseler T, Seufferlein T. Emerging Roles of Small Extracellular Vesicles in Gastrointestinal Cancer Research and Therapy. Cancers (Basel) 2024; 16:567. [PMID: 38339318 PMCID: PMC10854789 DOI: 10.3390/cancers16030567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/22/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
Discovered in the late eighties, sEVs are small extracellular nanovesicles (30-150 nm diameter) that gained increasing attention due to their profound roles in cancer, immunology, and therapeutic approaches. They were initially described as cellular waste bins; however, in recent years, sEVs have become known as important mediators of intercellular communication. They are secreted from cells in substantial amounts and exert their influence on recipient cells by signaling through cell surface receptors or transferring cargos, such as proteins, RNAs, miRNAs, or lipids. A key role of sEVs in cancer is immune modulation, as well as pro-invasive signaling and formation of pre-metastatic niches. sEVs are ideal biomarker platforms, and can be engineered as drug carriers or anti-cancer vaccines. Thus, sEVs further provide novel avenues for cancer diagnosis and treatment. This review will focus on the role of sEVs in GI-oncology and delineate their functions in cancer progression, diagnosis, and therapeutic use.
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Affiliation(s)
- Nora Schneider
- Department for Internal Medicine 1, University Clinic Ulm, 89081 Ulm, Germany; (P.C.H.); (T.S.)
| | | | - Tim Eiseler
- Correspondence: (N.S.); (T.E.); Tel.: +49-731-500-44678 (N.S.); +49-731-500-44523 (T.E.)
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20
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Najafi S, Majidpoor J, Mortezaee K. Liquid biopsy in colorectal cancer. Clin Chim Acta 2024; 553:117674. [PMID: 38007059 DOI: 10.1016/j.cca.2023.117674] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 11/16/2023] [Accepted: 11/20/2023] [Indexed: 11/27/2023]
Abstract
Liquid biopsy refers to a set of pathological samples retrieved from non-solid sources, such as blood, cerebrospinal fluid, urine, and saliva through non-invasive or minimally invasive approaches. In the recent decades, an increasing number of studies have focused on clinical applications and improving technological investigation of liquid biopsy biosources for diagnostic goals particularly in cancer. Materials extracted from these sources and used for medical evaluations include cells like circulating tumor cells (CTCs), tumor-educated platelets (TEPs), cell-free nucleic acids released by cells, such as circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), cell-free RNA (cfRNA), and exosomes. Playing significant roles in the pathogenesis of human malignancies, analysis of these sources can provide easier access to genetic and transcriptomic information of the cancer tissue even better than the conventional tissue biopsy. Notably, they can represent the inter- and intra-tumoral heterogeneity and accordingly, liquid biopsies demonstrate strengths for improving diagnosis in early detection and screening, monitoring and follow-up after therapies, and personalization of therapeutical strategies in various types of human malignancies. In this review, we aim to discuss the roles, functions, and analysis approaches of liquid biopsy sources and their clinical implications in human malignancies with a focus on colorectal cancer.
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Affiliation(s)
- Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jamal Majidpoor
- Department of Anatomy, School of Medicine, Infectious Diseases Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
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Santiago JV, Natu A, Ramelow CC, Rayaprolu S, Xiao H, Kumar V, Kumar P, Seyfried NT, Rangaraju S. Identification of State-Specific Proteomic and Transcriptomic Signatures of Microglia-Derived Extracellular Vesicles. Mol Cell Proteomics 2023; 22:100678. [PMID: 37952696 PMCID: PMC10755493 DOI: 10.1016/j.mcpro.2023.100678] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 10/26/2023] [Accepted: 11/08/2023] [Indexed: 11/14/2023] Open
Abstract
Microglia are resident immune cells of the brain that play important roles in mediating inflammatory responses in several neurological diseases via direct and indirect mechanisms. One indirect mechanism may involve extracellular vesicle (EV) release, so that the molecular cargo transported by microglia-derived EVs can have functional effects by facilitating intercellular communication. The molecular composition of microglia-derived EVs, and how microglial activation states impact EV composition and EV-mediated effects in neuroinflammation, remain poorly understood. We hypothesize that microglia-derived EVs have unique molecular profiles that are determined by microglial activation state. Using size-exclusion chromatography to purify EVs from BV2 microglia, combined with proteomic (label-free quantitative mass spectrometry or LFQ-MS) and transcriptomic (mRNA and noncoding RNA seq) methods, we obtained comprehensive molecular profiles of microglia-derived EVs. LFQ-MS identified several classic EV proteins (tetraspanins, ESCRT machinery, and heat shock proteins), in addition to over 200 proteins not previously reported in the literature. Unique mRNA and microRNA signatures of microglia-derived EVs were also identified. After treating BV2 microglia with lipopolysaccharide (LPS), interleukin-10, or transforming growth factor beta, to mimic pro-inflammatory, anti-inflammatory, or homeostatic states, respectively, LFQ-MS and RNA seq revealed novel state-specific proteomic and transcriptomic signatures of microglia-derived EVs. Particularly, LPS treatment had the most profound impact on proteomic and transcriptomic compositions of microglia-derived EVs. Furthermore, we found that EVs derived from LPS-activated microglia were able to induce pro-inflammatory transcriptomic changes in resting responder microglia, confirming the ability of microglia-derived EVs to relay functionally relevant inflammatory signals. These comprehensive microglia-EV molecular datasets represent important resources for the neuroscience and omics communities and provide novel insights into the role of microglia-derived EVs in neuroinflammation.
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Affiliation(s)
- Juliet V Santiago
- Department of Neurology, Emory University, Atlanta, Georgia, USA; Center for Neurodegenerative Diseases, Emory University, Atlanta, Georgia, USA
| | - Aditya Natu
- Department of Neurology, Emory University, Atlanta, Georgia, USA; Center for Neurodegenerative Diseases, Emory University, Atlanta, Georgia, USA
| | - Christina C Ramelow
- Department of Neurology, Emory University, Atlanta, Georgia, USA; Center for Neurodegenerative Diseases, Emory University, Atlanta, Georgia, USA
| | - Sruti Rayaprolu
- Department of Neurology, Emory University, Atlanta, Georgia, USA; Center for Neurodegenerative Diseases, Emory University, Atlanta, Georgia, USA
| | - Hailian Xiao
- Department of Neurology, Emory University, Atlanta, Georgia, USA; Center for Neurodegenerative Diseases, Emory University, Atlanta, Georgia, USA
| | - Vishnu Kumar
- Department of Neurology, Emory University, Atlanta, Georgia, USA; Center for Neurodegenerative Diseases, Emory University, Atlanta, Georgia, USA
| | - Prateek Kumar
- Department of Neurology, Emory University, Atlanta, Georgia, USA; Center for Neurodegenerative Diseases, Emory University, Atlanta, Georgia, USA
| | - Nicholas T Seyfried
- Department of Neurology, Emory University, Atlanta, Georgia, USA; Center for Neurodegenerative Diseases, Emory University, Atlanta, Georgia, USA; Department of Biochemistry, Emory University, Atlanta, Georgia, USA
| | - Srikant Rangaraju
- Department of Neurology, Emory University, Atlanta, Georgia, USA; Center for Neurodegenerative Diseases, Emory University, Atlanta, Georgia, USA.
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22
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Marassi V, Giordani S, Placci A, Punzo A, Caliceti C, Zattoni A, Reschiglian P, Roda B, Roda A. Emerging Microfluidic Tools for Simultaneous Exosomes and Cargo Biosensing in Liquid Biopsy: New Integrated Miniaturized FFF-Assisted Approach for Colon Cancer Diagnosis. SENSORS (BASEL, SWITZERLAND) 2023; 23:9432. [PMID: 38067805 PMCID: PMC10708636 DOI: 10.3390/s23239432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 11/18/2023] [Accepted: 11/21/2023] [Indexed: 12/18/2023]
Abstract
The early-stage diagnosis of cancer is a crucial clinical need. The inadequacies of surgery tissue biopsy have prompted a transition to a less invasive profiling of molecular biomarkers from biofluids, known as liquid biopsy. Exosomes are phospholipid bilayer vesicles present in many biofluids with a biologically active cargo, being responsible for cell-to-cell communication in biological systems. An increase in their excretion and changes in their cargo are potential diagnostic biomarkers for an array of diseases, including cancer, and they constitute a promising analyte for liquid biopsy. The number of exosomes released, the morphological properties, the membrane composition, and their content are highly related to the physiological and pathological states. The main analytical challenge to establishing liquid biopsy in clinical practice is the development of biosensors able to detect intact exosomes concentration and simultaneously analyze specific membrane biomarkers and those contained in their cargo. Before analysis, exosomes also need to be isolated from biological fluids. Microfluidic systems can address several issues present in conventional methods (i.e., ultracentrifugation, size-exclusion chromatography, ultrafiltration, and immunoaffinity capture), which are time-consuming and require a relatively high amount of sample; in addition, they can be easily integrated with biosensing systems. A critical review of emerging microfluidic-based devices for integrated biosensing approaches and following the major analytical need for accurate diagnostics is presented here. The design of a new miniaturized biosensing system is also reported. A device based on hollow-fiber flow field-flow fractionation followed by luminescence-based immunoassay is applied to isolate intact exosomes and characterize their cargo as a proof of concept for colon cancer diagnosis.
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Affiliation(s)
- Valentina Marassi
- Department of Chemistry “G. Ciamician”, University of Bologna, 40126 Bologna, Italy; (V.M.); (S.G.); (A.P.); (A.Z.); (P.R.)
- National Institute of Biostructure and Biosystems (INBB), 00136 Rome, Italy; (A.P.); (C.C.)
- byFlow srl, 40129 Bologna, Italy
| | - Stefano Giordani
- Department of Chemistry “G. Ciamician”, University of Bologna, 40126 Bologna, Italy; (V.M.); (S.G.); (A.P.); (A.Z.); (P.R.)
| | - Anna Placci
- Department of Chemistry “G. Ciamician”, University of Bologna, 40126 Bologna, Italy; (V.M.); (S.G.); (A.P.); (A.Z.); (P.R.)
| | - Angela Punzo
- National Institute of Biostructure and Biosystems (INBB), 00136 Rome, Italy; (A.P.); (C.C.)
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40138 Bologna, Italy
| | - Cristiana Caliceti
- National Institute of Biostructure and Biosystems (INBB), 00136 Rome, Italy; (A.P.); (C.C.)
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40138 Bologna, Italy
- Interdepartmental Centre for Renewable Sources, Environment, Sea and Energy—CIRI FRAME, University of Bologna, 40131 Bologna, Italy
- Interdepartmental Centre for Industrial Agrofood Research—CIRI Agrofood, University of Bologna, 47521 Cesena, Italy
| | - Andrea Zattoni
- Department of Chemistry “G. Ciamician”, University of Bologna, 40126 Bologna, Italy; (V.M.); (S.G.); (A.P.); (A.Z.); (P.R.)
- National Institute of Biostructure and Biosystems (INBB), 00136 Rome, Italy; (A.P.); (C.C.)
- byFlow srl, 40129 Bologna, Italy
| | - Pierluigi Reschiglian
- Department of Chemistry “G. Ciamician”, University of Bologna, 40126 Bologna, Italy; (V.M.); (S.G.); (A.P.); (A.Z.); (P.R.)
- National Institute of Biostructure and Biosystems (INBB), 00136 Rome, Italy; (A.P.); (C.C.)
- byFlow srl, 40129 Bologna, Italy
| | - Barbara Roda
- Department of Chemistry “G. Ciamician”, University of Bologna, 40126 Bologna, Italy; (V.M.); (S.G.); (A.P.); (A.Z.); (P.R.)
- National Institute of Biostructure and Biosystems (INBB), 00136 Rome, Italy; (A.P.); (C.C.)
- byFlow srl, 40129 Bologna, Italy
| | - Aldo Roda
- Department of Chemistry “G. Ciamician”, University of Bologna, 40126 Bologna, Italy; (V.M.); (S.G.); (A.P.); (A.Z.); (P.R.)
- National Institute of Biostructure and Biosystems (INBB), 00136 Rome, Italy; (A.P.); (C.C.)
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23
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Zhang X, Sun S, Ren G, Liu W, Chen H. Advances in Intercellular Communication Mediated by Exosomal ncRNAs in Cardiovascular Disease. Int J Mol Sci 2023; 24:16197. [PMID: 38003385 PMCID: PMC10671547 DOI: 10.3390/ijms242216197] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 09/28/2023] [Accepted: 09/29/2023] [Indexed: 11/26/2023] Open
Abstract
Cardiovascular diseases are a leading cause of worldwide mortality, and exosomes have recently gained attention as key mediators of intercellular communication in these diseases. Exosomes are double-layered lipid vesicles that can carry biomolecules such as miRNAs, lncRNAs, and circRNAs, and the content of exosomes is dependent on the cell they originated from. They can be involved in the pathophysiological processes of cardiovascular diseases and hold potential as diagnostic and monitoring tools. Exosomes mediate intercellular communication, stimulate or inhibit the activity of target cells, and affect myocardial hypertrophy, injury and infarction, ventricular remodeling, angiogenesis, and atherosclerosis. Exosomes can be released from various types of cells, including endothelial cells, smooth muscle cells, cardiomyocytes, fibroblasts, platelets, adipocytes, immune cells, and stem cells. In this review, we highlight the communication between different cell-derived exosomes and cardiovascular cells, with a focus on the roles of RNAs. This provides new insights for further exploring targeted therapies in the clinical management of cardiovascular diseases.
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Affiliation(s)
- Xiaoyan Zhang
- College of Animal Science, Xinjiang Agricultural University, Urumqi 830052, China;
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China; (S.S.); (G.R.)
| | - Shengjie Sun
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China; (S.S.); (G.R.)
| | - Gang Ren
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Xianyang 712100, China; (S.S.); (G.R.)
| | - Wujun Liu
- College of Animal Science, Xinjiang Agricultural University, Urumqi 830052, China;
| | - Hong Chen
- College of Animal Science, Xinjiang Agricultural University, Urumqi 830052, China;
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24
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Alemi F, Sadeghsoltani F, Fattah K, Hassanpour P, Malakoti F, Kardeh S, Izadpanah M, de Campos Zuccari DAP, Yousefi B, Majidinia M. Applications of engineered exosomes in drugging noncoding RNAs for cancer therapy. Chem Biol Drug Des 2023; 102:1257-1275. [PMID: 37496299 DOI: 10.1111/cbdd.14300] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 05/31/2023] [Accepted: 07/17/2023] [Indexed: 07/28/2023]
Abstract
Noncoding RNAs (ncRNAs) are engaged in key cell biological and pathological events, and their expression alteration is connected to cancer progression both directly and indirectly. A huge number of studies have mentioned the significant role of ncRNAs in cancer prevention and therapy that make them an interesting subject for cancer therapy. However, there are several limitations, including delivery, uptake, and short half-life, in the application of ncRNAs in cancer treatment. Exosomes are introduced as promising options for the delivery of ncRNAs to the target cells. In this review, we will briefly discuss the application and barriers of ncRNAs. After that we will focus on exosome-based ncRNAs delivery and their advantages as well as the latest achievements in drugging ncRNAs with exosomes.
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Affiliation(s)
- Forough Alemi
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Sadeghsoltani
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khashayar Fattah
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parisa Hassanpour
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faezeh Malakoti
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sina Kardeh
- Central Clinical School, Monash University, Melbourne, Australia
| | - Melika Izadpanah
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Bahman Yousefi
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
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25
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Jankowski M, Farzaneh M, Ghaedrahmati F, Shirvaliloo M, Moalemnia A, Kulus M, Ziemak H, Chwarzyński M, Dzięgiel P, Zabel M, Piotrowska-Kempisty H, Bukowska D, Antosik P, Mozdziak P, Kempisty B. Unveiling Mesenchymal Stem Cells' Regenerative Potential in Clinical Applications: Insights in miRNA and lncRNA Implications. Cells 2023; 12:2559. [PMID: 37947637 PMCID: PMC10649218 DOI: 10.3390/cells12212559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/20/2023] [Accepted: 10/28/2023] [Indexed: 11/12/2023] Open
Abstract
It is now widely recognized that mesenchymal stem cells (MSCs) possess the capacity to differentiate into a wide array of cell types. Numerous studies have identified the role of lncRNA in the regulation of MSC differentiation. It is important to elucidate the role and interplay of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the regulation of signalling pathways that govern MSC function. Furthermore, miRNAs and lncRNAs are important clinical for innovative strategies aimed at addressing a wide spectrum of existing and emerging disease. Hence it is important to consider their impact on MSC function and differentiation. Examining the data available in public databases, we have collected the literature containing the latest discoveries pertaining to human stem cells and their potential in both fundamental research and clinical applications. Furthermore, we have compiled completed clinical studies that revolve around the application of MSCs, shedding light on the opportunities presented by harnessing the regulatory potential of miRNAs and lncRNAs. This exploration of the therapeutic possibilities offered by miRNAs and lncRNAs within MSCs unveils exciting prospects for the development of precision therapies and personalized treatment approaches. Ultimately, these advancements promise to augment the efficacy of regenerative strategies and produce positive outcomes for patients. As research in this field continues to evolve, it is imperative to explore and exploit the vast potential of miRNAs and lncRNAs as therapeutic agents. The findings provide a solid basis for ongoing investigations, fuelling the quest to fully unlock the regenerative potential of MSCs.
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Affiliation(s)
- Maurycy Jankowski
- Department of Computer Science and Statistics, Poznan University of Medical Sciences, 60-812 Poznan, Poland;
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Farhoodeh Ghaedrahmati
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Milad Shirvaliloo
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Future Science Group, Unitec House, 2 Albert Place, London N3 1QB, UK
| | - Arash Moalemnia
- Faculty of Medicine, Dezful University of Medical Sciences, Dezful, Iran
| | - Magdalena Kulus
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Hanna Ziemak
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Mikołaj Chwarzyński
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Piotr Dzięgiel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Department of Physiotherapy, Wroclaw University School of Physical Education, 50-038 Wroclaw, Poland
| | - Maciej Zabel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Division of Anatomy and Histology, University of Zielona Góra, 65-046 Zielona Góra, Poland
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Dorota Bukowska
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Paweł Antosik
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Paul Mozdziak
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27607, USA
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27613, USA
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27613, USA
- Division of Anatomy, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Department of Obstetrics and Gynecology, University Hospital and Masaryk University, 602 00 Brno, Czech Republic
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26
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Cha BS, Jang YJ, Lee ES, Kim DY, Woo JS, Son J, Kim S, Shin J, Han J, Kim S, Park KS. Development of a Novel DNA Aptamer Targeting Colorectal Cancer Cell-Derived Small Extracellular Vesicles as a Potential Diagnostic and Therapeutic Agent. Adv Healthc Mater 2023; 12:e2300854. [PMID: 37129521 DOI: 10.1002/adhm.202300854] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/20/2023] [Indexed: 05/03/2023]
Abstract
Colorectal cancer (CRC) as the second leading cause of global cancer deaths poses critical challenges in clinical settings. Cancer-derived small extracellular vesicles (sEVs), which are secreted by cancer cells, have been shown to mediate tumor development, invasion, and even metastasis, and have thus received increasing attention for the development of cancer diagnostic or therapeutic platforms. In the present study, the sEV-targeted systematic evolution of ligands by exponential enrichment (E-SELEX) is developed to generate a high-quality aptamer (CCE-10F) that recognizes and binds to CRC-derived sEVs. Via an in-depth investigation, it is confirmed that this novel aptamer possesses high affinity (Kd = 3.41 nm) for CRC-derived sEVs and exhibits a wide linear range (2.0 × 104 -1.0 × 106 particles µL-1 ) with a limit of detection (LOD) of 1.0 × 103 particles µL-1 . Furthermore, the aptamer discriminates CRC cell-derived sEVs from those derived from normal colon cell, human serum, and other cancer cells, showing high specificity for CRC cell-derived sEVs and significantly suppresses the critical processes of metastasis, including cellular migration, invasion, and angiogenesis, which are originally induced by sEVs themselves. These findings are highly encouraging for the potential use of the aptamer in sEV-based diagnostic and therapeutic applications.
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Affiliation(s)
- Byung Seok Cha
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Young Jun Jang
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Eun Sung Lee
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Do Yeon Kim
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Ji Su Woo
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Jinseo Son
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Seokjoon Kim
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Jiye Shin
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Jinjoo Han
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Seokhwan Kim
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Ki Soo Park
- Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea
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27
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Mahdi Khanifar M, Zafari Z, Sheykhhasan M. Crosstalk between long non-coding RNAs and p53 signaling pathway in colorectal cancer: A review study. Pathol Res Pract 2023; 249:154756. [PMID: 37611430 DOI: 10.1016/j.prp.2023.154756] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/08/2023] [Accepted: 08/08/2023] [Indexed: 08/25/2023]
Abstract
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide and the third leading cause of cancer-related fatalities. Long non-coding RNAs (lncRNAs) are key regulators of diverse physiological processes and are dysregulated in a wide range of pathophysiological circumstances such as CRC. Studies revealed that aberrant expressions of lncRNAs clearly modulate the expression level of p53 gene in CRC, thereby transactivating multiple downstream pathways. P53 is regarded as a crucial tumor suppressor gene which promotes cell-cycle arrest, DNA repair, senescence or apoptosis in response to cellular stresses. P53 is also mutated in CRC as well as various types of human malignancies. Therefore, lncRNAs interact with the p53 signaling pathway in numerus ways and significantly influence CRC-related processes. The current findings in the investigation of the crosstalk between lncRNAs and the P53 pathway in controlling CRC carcinogenesis, tumor progression, and therapeutic resistance are summarized in the this review. A deeper knowledge of CRC carcinogenesis may also have implications in CRC prevention and treatment through more research.
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Affiliation(s)
- Mohammad Mahdi Khanifar
- School of Molecular Science, University of Western Australia, Perth, Western Australia, Australia; Department of Biology, Shahed University, Tehran, Iran
| | - Zahra Zafari
- Department of Biology, Shahed University, Tehran, Iran.
| | - Mohsen Sheykhhasan
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research, Qom, Iran.
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28
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Ponomaryova AA, Rykova EY, Solovyova AI, Tarasova AS, Kostromitsky DN, Dobrodeev AY, Afanasiev SA, Cherdyntseva NV. Genomic and Transcriptomic Research in the Discovery and Application of Colorectal Cancer Circulating Markers. Int J Mol Sci 2023; 24:12407. [PMID: 37569782 PMCID: PMC10419249 DOI: 10.3390/ijms241512407] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/24/2023] [Accepted: 08/02/2023] [Indexed: 08/13/2023] Open
Abstract
Colorectal cancer (CRC) is the most frequently occurring malignancy in the world. However, the mortality from CRC can be reduced through early diagnostics, selection of the most effective treatment, observation of the therapy success, and the earliest possible diagnosis of recurrences. A comprehensive analysis of genetic and epigenetic factors contributing to the CRC development is needed to refine diagnostic, therapeutic, and preventive strategies and to ensure appropriate decision making in managing specific CRC cases. The liquid biopsy approach utilizing circulating markers has demonstrated its good performance as a tool to detect the changes in the molecular pathways associated with various cancers. In this review, we attempted to brief the main tendencies in the development of circulating DNA and RNA-based markers in CRC such as cancer-associated DNA mutations, DNA methylation changes, and non-coding RNA expression shifts. Attention is devoted to the existing circulating nucleic acid-based CRC markers, the possibility of their application in clinical practice today, and their future improvement. Approaches to the discovery and verification of new markers are described, and the existing problems and potential solutions for them are highlighted.
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Affiliation(s)
- Anastasia A. Ponomaryova
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634009 Tomsk, Russia
| | - Elena Yu. Rykova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
- Department of Engineering Problems of Ecology, Novosibirsk State Technical University, 630087 Novosibirsk, Russia
| | - Anastasia I. Solovyova
- Department of Biochemistry, Medico-Biological Faculty, Siberian State Medical University, 634050 Tomsk, Russia
| | - Anna S. Tarasova
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634009 Tomsk, Russia
| | - Dmitry N. Kostromitsky
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634009 Tomsk, Russia
| | - Alexey Yu. Dobrodeev
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634009 Tomsk, Russia
| | - Sergey A. Afanasiev
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634009 Tomsk, Russia
| | - Nadezhda V. Cherdyntseva
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634009 Tomsk, Russia
- Faculty of Chemistry, National Research Tomsk State University, 634050 Tomsk, Russia
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29
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Mishra S, Kumarasamy M. Microfluidics engineering towards personalized oncology-a review. IN VITRO MODELS 2023; 2:69-81. [PMID: 39871996 PMCID: PMC11756504 DOI: 10.1007/s44164-023-00054-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 06/16/2023] [Accepted: 06/19/2023] [Indexed: 01/29/2025]
Abstract
Identifying and monitoring the presence of cancer metastasis and highlighting inter-and intratumoral heterogeneity is a central tenet of targeted precision oncology medicine (POM). This process of relocation of cancer cells is often referred to as the missing link between a tumor and metastasis. In recent years, microfluidic technologies have been developed to isolate a plethora of different biomarkers, such as circulating tumor cells (CTCs), tumor-derived vesicles (exosomes), or cell/free nucleic acids and proteins directly from patients' blood samples. With the advent of microfluidic developments, minimally invasive and quantitative assessment of different tumors is becoming a reality. This short review article will touch briefly on how microfluidics at early-stage achievements can be combined or developed with the active vs passive microfluidic technologies, depending on whether they utilize external fields and forces (active) or just microchannel geometry and inherent fluid forces (passive) from the market to precision oncology research and our future prospectives in terms of the emergence of ultralow cost and rapid prototyping of microfluidics in precision oncology.
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Affiliation(s)
- Sushmita Mishra
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Hajipur (NIPERHajipur) Export Promotion Industrial Park (EPIP), Industrial Area, Vaishali, 844102 Bihar India
| | - Murali Kumarasamy
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Hajipur (NIPERHajipur) Export Promotion Industrial Park (EPIP), Industrial Area, Vaishali, 844102 Bihar India
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30
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Santiago JV, Natu A, Ramelow CC, Rayaprolu S, Xiao H, Kumar V, Seyfried NT, Rangaraju S. Identification of state-specific proteomic and transcriptomic signatures of microglia-derived extracellular vesicles. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.28.551012. [PMID: 37546899 PMCID: PMC10402142 DOI: 10.1101/2023.07.28.551012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
Microglia are resident immune cells of the brain that play important roles in mediating inflammatory responses in several neurological diseases via direct and indirect mechanisms. One indirect mechanism may involve extracellular vesicle (EV) release, so that the molecular cargo transported by microglia-derived EVs can have functional effects by facilitating intercellular communication. The molecular composition of microglia-derived EVs, and how microglial activation states impacts EV composition and EV-mediated effects in neuroinflammation, remain poorly understood. We hypothesize that microglia-derived EVs have unique molecular profiles that are determined by microglial activation state. Using size-exclusion chromatography to purify EVs from BV2 microglia, combined with proteomic (label-free quantitative mass spectrometry or LFQ-MS) and transcriptomic (mRNA and non-coding RNA seq) methods, we obtained comprehensive molecular profiles of microglia-derived EVs. LFQ-MS identified several classic EV proteins (tetraspanins, ESCRT machinery, and heat shock proteins), in addition to over 200 proteins not previously reported in the literature. Unique mRNA and microRNA signatures of microglia-derived EVs were also identified. After treating BV2 microglia with lipopolysaccharide (LPS), interleukin-10, or transforming growth factor beta, to mimic pro-inflammatory, anti-inflammatory, or homeostatic states, respectively, LFQ-MS and RNA seq revealed novel state-specific proteomic and transcriptomic signatures of microglia-derived EVs. Particularly, LPS treatment had the most profound impact on proteomic and transcriptomic compositions of microglia-derived EVs. Furthermore, we found that EVs derived from LPS-activated microglia were able to induce pro-inflammatory transcriptomic changes in resting responder microglia, confirming the ability of microglia-derived EVs to relay functionally-relevant inflammatory signals. These comprehensive microglia-EV molecular datasets represent important resources for the neuroscience and glial communities, and provide novel insights into the role of microglia-derived EVs in neuroinflammation.
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Affiliation(s)
- Juliet V. Santiago
- Department of Neurology, Emory University, 201 Dowman Drive Atlanta, Georgia, 30322, United States of America
- Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA
| | - Aditya Natu
- Department of Neurology, Emory University, 201 Dowman Drive Atlanta, Georgia, 30322, United States of America
- Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA
| | - Christina C. Ramelow
- Department of Neurology, Emory University, 201 Dowman Drive Atlanta, Georgia, 30322, United States of America
- Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA
| | - Sruti Rayaprolu
- Department of Neurology, Emory University, 201 Dowman Drive Atlanta, Georgia, 30322, United States of America
- Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA
| | - Hailian Xiao
- Department of Neurology, Emory University, 201 Dowman Drive Atlanta, Georgia, 30322, United States of America
- Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA
| | - Vishnu Kumar
- Department of Neurology, Emory University, 201 Dowman Drive Atlanta, Georgia, 30322, United States of America
- Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA
| | - Nicholas T. Seyfried
- Department of Neurology, Emory University, 201 Dowman Drive Atlanta, Georgia, 30322, United States of America
- Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA
- Department of Biochemistry, Emory University, Atlanta, GA 30322, USA
| | - Srikant Rangaraju
- Department of Neurology, Emory University, 201 Dowman Drive Atlanta, Georgia, 30322, United States of America
- Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA
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Ferlizza E, Romaniello D, Borrelli F, Pagano F, Girone C, Gelfo V, Kuhre RS, Morselli A, Mazzeschi M, Sgarzi M, Filippini DM, D'Uva G, Lauriola M. Extracellular Vesicles and Epidermal Growth Factor Receptor Activation: Interplay of Drivers in Cancer Progression. Cancers (Basel) 2023; 15:cancers15112970. [PMID: 37296932 DOI: 10.3390/cancers15112970] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/12/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Extracellular vesicles (EVs) are of great interest to study the cellular mechanisms of cancer development and to diagnose and monitor cancer progression. EVs are a highly heterogeneous population of cell derived particles, which include microvesicles (MVs) and exosomes (EXOs). EVs deliver intercellular messages transferring proteins, lipids, nucleic acids, and metabolites with implications for tumour progression, invasiveness, and metastasis. Epidermal Growth Factor Receptor (EGFR) is a major driver of cancer. Tumour cells with activated EGFR could produce EVs disseminating EGFR itself or its ligands. This review provides an overview of EVs (mainly EXOs and MVs) and their cargo, with a subsequent focus on their production and effects related to EGFR activation. In particular, in vitro studies performed in EGFR-dependent solid tumours and/or cell cultures will be explored, thus shedding light on the interplay between EGFR and EVs production in promoting cancer progression, metastases, and resistance to therapies. Finally, an overview of liquid biopsy approaches involving EGFR and EVs in the blood/plasma of EGFR-dependent tumour patients will also be discussed to evaluate their possible application as candidate biomarkers.
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Affiliation(s)
- Enea Ferlizza
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Donatella Romaniello
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Francesco Borrelli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Federica Pagano
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Cinzia Girone
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Valerio Gelfo
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Rikke Sofie Kuhre
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Alessandra Morselli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Martina Mazzeschi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Michela Sgarzi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Daria Maria Filippini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Gabriele D'Uva
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Mattia Lauriola
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
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Ahmadzada T, Vijayan A, Vafaee F, Azimi A, Reid G, Clarke S, Kao S, Grau GE, Hosseini-Beheshti E. Small and Large Extracellular Vesicles Derived from Pleural Mesothelioma Cell Lines Offer Biomarker Potential. Cancers (Basel) 2023; 15:cancers15082364. [PMID: 37190292 DOI: 10.3390/cancers15082364] [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: 02/02/2023] [Revised: 03/21/2023] [Accepted: 03/27/2023] [Indexed: 05/17/2023] Open
Abstract
Pleural mesothelioma, previously known as malignant pleural mesothelioma, is an aggressive and fatal cancer of the pleura, with one of the poorest survival rates. Pleural mesothelioma is in urgent clinical need for biomarkers to aid early diagnosis, improve prognostication, and stratify patients for treatment. Extracellular vesicles (EVs) have great potential as biomarkers; however, there are limited studies to date on their role in pleural mesothelioma. We conducted a comprehensive proteomic analysis on different EV populations derived from five pleural mesothelioma cell lines and an immortalized control cell line. We characterized three subtypes of EVs (10 K, 18 K, and 100 K), and identified a total of 4054 unique proteins. Major differences were found in the cargo between the three EV subtypes. We show that 10 K EVs were enriched in mitochondrial components and metabolic processes, while 18 K and 100 K EVs were enriched in endoplasmic reticulum stress. We found 46 new cancer-associated proteins for pleural mesothelioma, and the presence of mesothelin and PD-L1/PD-L2 enriched in 100 K and 10 K EV, respectively. We demonstrate that different EV populations derived from pleural mesothelioma cells have unique cancer-specific proteomes and carry oncogenic cargo, which could offer a novel means to extract biomarkers of interest for pleural mesothelioma from liquid biopsies.
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Affiliation(s)
- Tamkin Ahmadzada
- School of Medical Sciences, The University of Sydney, Camperdown, NSW 2006, Australia
| | - Abhishek Vijayan
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia
| | - Fatemeh Vafaee
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia
- UNSW Data Science Hub, University of New South Wales, Sydney, NSW 2052, Australia
| | - Ali Azimi
- Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia
- Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia
- Department of Dermatology, Westmead Hospital, Westmead, NSW 2145, Australia
| | - Glen Reid
- Department of Pathology, University of Otago, Dunedin 9016, New Zealand
| | - Stephen Clarke
- School of Medical Sciences, The University of Sydney, Camperdown, NSW 2006, Australia
- Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW 2065, Australia
| | - Steven Kao
- School of Medical Sciences, The University of Sydney, Camperdown, NSW 2006, Australia
- Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW 2050, Australia
- Asbestos Diseases Research Institute, Sydney, NSW 2139, Australia
| | - Georges E Grau
- School of Medical Sciences, The University of Sydney, Camperdown, NSW 2006, Australia
- The Sydney Nano Institute, The University of Sydney, Camperdown, NSW 2006, Australia
| | - Elham Hosseini-Beheshti
- School of Medical Sciences, The University of Sydney, Camperdown, NSW 2006, Australia
- The Sydney Nano Institute, The University of Sydney, Camperdown, NSW 2006, Australia
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Pan Y, Liu Y, Wei W, Yang X, Wang Z, Xin W. Extracellular Vesicles as Delivery Shippers for Noncoding RNA-Based Modulation of Angiogenesis: Insights from Ischemic Stroke and Cancer. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2205739. [PMID: 36592424 DOI: 10.1002/smll.202205739] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 12/02/2022] [Indexed: 06/17/2023]
Abstract
Ischemic stroke and systemic cancer are two of the leading causes of mortality. Hypoxia is a central pathophysiological component in ischemic stroke and cancer, representing a joint medical function. This function includes angiogenesis regulation. Vascular remodeling coupled with axonal outgrowth following cerebral ischemia is critical in improving poststroke neurological functional recovery. Antiangiogenic strategies can inhibit cancer vascularization and play a vital role in impeding cancer growth, invasion, and metastasis. Although there are significant differences in the cause of angiogenesis across both pathophysiological conditions, emerging evidence states that common signaling structures, such as extracellular vesicles (EVs) and noncoding RNAs (ncRNAs), are involved in this context. EVs, heterogeneous membrane vesicles encapsulating proteomic genetic information from parental cells, act as multifunctional regulators of intercellular communication. Among the multifaceted roles in modulating biological responses, exhaustive evidence shows that ncRNAs are selectively sorted into EVs, modulating common specific aspects of cancer development and stroke prognosis, namely, angiogenesis. This review will discuss recent advancements in the EV-facilitated/inhibited progression of specific elements of angiogenesis with a particular concern about ncRNAs within these vesicles. The review is concluded by underlining the clinical opportunities of EV-derived ncRNAs as diagnostic, prognostic, and therapeutic agents.
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Affiliation(s)
- Yongli Pan
- Department of Neurology, University Medical Center of Göttingen, Georg-August-University of Göttingen, 37075, Göttingen, Lower Saxony, Germany
- Department of Neurology, Weifang Medical University, Weifang, Shandong, 261053, China
| | - Yuheng Liu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Tianjin Neurological Institute, Tianjin, 300052, China
| | - Wei Wei
- Department of Neurology, University Medical Center of Göttingen, Georg-August-University of Göttingen, 37075, Göttingen, Lower Saxony, Germany
- Department of Neurology, Mianyang Central Hospital, Mianyang, Sichuan, 621000, China
| | - Xinyu Yang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Tianjin Neurological Institute, Tianjin, 300052, China
| | - Zengguang Wang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Tianjin Neurological Institute, Tianjin, 300052, China
| | - Wenqiang Xin
- Department of Neurology, University Medical Center of Göttingen, Georg-August-University of Göttingen, 37075, Göttingen, Lower Saxony, Germany
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China
- Tianjin Neurological Institute, Tianjin, 300052, China
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Park W, Maeng SW, Mok JW, Choi M, Cha HJ, Joo CK, Hahn SK. Hydrogel Microneedles Extracting Exosomes for Early Detection of Colorectal Cancer. Biomacromolecules 2023; 24:1445-1452. [PMID: 36908257 DOI: 10.1021/acs.biomac.2c01449] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
Abstract
There are several methods for early diagnosis of tumors, such as detecting circulating tumor DNAs, detecting circulating tumor cells, or imaging with tumor-targeting contrast agents. However, these assays are time-consuming and may cause patient discomfort during the biopsy collecting process. Here, we develop a facile method for early diagnosis of tumors by extracting exosomes from interstitial fluid (ISF) using hydrogel microneedles (MNs). The hydrogel MNs expand in the skin to absorb the ISF, and the tumor exosomes contained in the ISF bind with the glypican-1 antibodies inside the hydrogel of MNs. After removing the hydrogel on the MNs, exosomes are separately purified from the ISF to analyze tumor-related biomarkers. Finally, colorectal cancer can be diagnosed by ELISA for the colorectal cancer-induced model mice. This noninvasive hydrogel MN system to obtain the exosome samples would play an important role in early cancer diagnosis.
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Affiliation(s)
- Wonchan Park
- Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk 37673, Republic of Korea
| | - Seong-Woo Maeng
- Department of Chemical Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk 37673, Republic of Korea
| | - Jee Won Mok
- CK St. Mary's Eye Center, CK Building, 559, Gangnam-daero, Seocho-gu, Seoul 06531, Republic of Korea
| | - Minji Choi
- Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk 37673, Republic of Korea
| | - Hyung Joon Cha
- Department of Chemical Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk 37673, Republic of Korea
| | - Choun-Ki Joo
- CK St. Mary's Eye Center, CK Building, 559, Gangnam-daero, Seocho-gu, Seoul 06531, Republic of Korea
| | - Sei Kwang Hahn
- Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk 37673, Republic of Korea
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35
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Rashid G, Khan NA, Elsori D, Rehman A, Tanzeelah, Ahmad H, Maryam H, Rais A, Usmani MS, Babker AM, Kamal MA, Hafez W. Non-steroidal anti-inflammatory drugs and biomarkers: A new paradigm in colorectal cancer. Front Med (Lausanne) 2023; 10:1130710. [PMID: 36950511 PMCID: PMC10025514 DOI: 10.3389/fmed.2023.1130710] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 02/08/2023] [Indexed: 03/08/2023] Open
Abstract
Colorectal cancer is a sporadic, hereditary, or familial based disease in its origin, caused due to diverse set of mutations in large intestinal epithelial cells. Colorectal cancer (CRC) is a common and deadly disease that accounts for the 4th worldwide highly variable malignancy. For the early detection of CRC, the most common predictive biomarker found endogenously are KRAS and ctDNA/cfDNA along with SEPT9 methylated DNA. Early detection and screening for CRC are necessary and multiple methods can be employed to screen and perform early diagnosis of CRC. Colonoscopy, an invasive method is most prevalent for diagnosing CRC or confirming the positive result as compared to other screening methods whereas several non-invasive techniques such as molecular analysis of breath, urine, blood, and stool can also be performed for early detection. Interestingly, widely used medicines known as non-steroidal anti-inflammatory drugs (NSAIDs) to reduce pain and inflammation have reported chemopreventive impact on gastrointestinal malignancies, especially CRC in several epidemiological and preclinical types of research. NSAID acts by inhibiting two cyclooxygenase enzymes, thereby preventing the synthesis of prostaglandins (PGs) and causing NSAID-induced apoptosis and growth inhibition in CRC cells. This review paper majorly focuses on the diversity of natural and synthetic biomarkers and various techniques for the early detection of CRC. An approach toward current advancement in CRC detection techniques and the role of NSAIDs in CRC chemoprevention has been explored systematically. Several prominent governing mechanisms of the anti-cancer effects of NSAIDs and their synergistic effect with statins for an effective chemopreventive measure have also been discussed in this review paper.
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Affiliation(s)
- Gowhar Rashid
- Department of Amity Medical School, Amity University, Gurugram, India
| | - Nihad Ashraf Khan
- Department of Biosciences, Jamia Millia Islamia, Central University, New Delhi, India
| | - Deena Elsori
- Faculty of Resillience, Deans Office Rabdan Academy, Abu Dhabi, United Arab Emirates
| | - Andleeb Rehman
- Department of Biotechnology, Shri Mata Vaishno Devi University, Katra, India
| | - Tanzeelah
- Department of Biochemistry, University of Kashmir, Srinagar, India
| | - Haleema Ahmad
- Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, India
| | - Humaira Maryam
- Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, India
| | - Amaan Rais
- Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, India
| | - Mohd Salik Usmani
- The Department of Surgery, Faculty of Medicine, JNMCH, AMU, Uttar Pradesh, India
| | - Asaad Ma Babker
- Department of Medical Laboratory Sciences, Gulf Medical University, Ajman, United Arab Emirates
| | - Mohammad Azhar Kamal
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Wael Hafez
- Department of Internal Medicine, NMC Royal Hospital, Abu Dhabi, United Arab Emirates
- The Medical Research Division, Department of Internal Medicine, The National Research Center, Ad Doqi, Egypt
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Armakolas A, Kotsari M, Koskinas J. Liquid Biopsies, Novel Approaches and Future Directions. Cancers (Basel) 2023; 15:1579. [PMID: 36900369 PMCID: PMC10000663 DOI: 10.3390/cancers15051579] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/22/2023] [Accepted: 03/01/2023] [Indexed: 03/06/2023] Open
Abstract
Cancer is among the leading causes of death worldwide. Early diagnosis and prognosis are vital to improve patients' outcomes. The gold standard of tumor characterization leading to tumor diagnosis and prognosis is tissue biopsy. Amongst the constraints of tissue biopsy collection is the sampling frequency and the incomplete representation of the entire tumor bulk. Liquid biopsy approaches, including the analysis of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating miRNAs, and tumor-derived extracellular vesicles (EVs), as well as certain protein signatures that are released in the circulation from primary tumors and their metastatic sites, present a promising and more potent candidate for patient diagnosis and follow up monitoring. The minimally invasive nature of liquid biopsies, allowing frequent collection, can be used in the monitoring of therapy response in real time, allowing the development of novel approaches in the therapeutic management of cancer patients. In this review we will describe recent advances in the field of liquid biopsy markers focusing on their advantages and disadvantages.
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Affiliation(s)
- Athanasios Armakolas
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece
- B' Department of Medicine, Hippokration Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece
| | - Maria Kotsari
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece
| | - John Koskinas
- B' Department of Medicine, Hippokration Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece
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He J, Wu W. A glimpse of research cores and frontiers on the relationship between long noncoding RNAs (lncRNAs) and colorectal cancer (CRC) using the VOSviewer tool. Scand J Gastroenterol 2023; 58:254-263. [PMID: 36121831 DOI: 10.1080/00365521.2022.2124537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/01/2022] [Accepted: 09/09/2022] [Indexed: 02/04/2023]
Abstract
As lncRNAs are essential participants in colorectal carcinogenesis. This study aimed to use the VOSviewer tool to access the research cores and frontiers on the relationship between lncRNAs and CRC. Our findings showed that the mechanism of lncRNA in the occurrence and development of CRC was the core theme of the field. (1) Immunotherapy and immune microenvironment of CRC and lncRNAs, (2) CRC and lncRNAs in exosomes and (3) CRC and lncRNA-targeted therapy might represent three research frontiers. A comprehensive understanding of their existing mechanisms and the search for new regulatory paradigms are the core topics of future research. This knowledge will also help us select appropriate targeting methods and select appropriate preclinical models to promote clinical translation and ultimately achieve precise treatment of CRC.
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Affiliation(s)
- Jia He
- Faculty Affairs and Human Resources Management Department, Southwest Medical University, Luzhou, PR China
| | - Wenhan Wu
- Department of General Surgery (Gastrointestinal Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, PR China
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Yu J, Ostowari A, Gonda A, Mashayekhi K, Dayyani F, Hughes CCW, Senthil M. Exosomes as a Source of Biomarkers for Gastrointestinal Cancers. Cancers (Basel) 2023; 15:cancers15041263. [PMID: 36831603 PMCID: PMC9954462 DOI: 10.3390/cancers15041263] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/18/2023] Open
Abstract
Exosomes are small, lipid-bilayer bound extracellular vesicles of 40-160 nanometers in size that carry important information for intercellular communication. Exosomes are produced more by tumor cells than normal cells and carry tumor-specific content, such as DNA, RNA, and proteins, which have been implicated in tumorigenesis, tumor progression, and treatment response. Due to the critical role of exosomes in cancer development and progression, they can be exploited to develop specific biomarkers and therapeutic targets. Since exosomes are present in various biofluids, such as blood, saliva, urine, and peritoneal fluid, they are ideally suited to be developed as liquid biopsy tools for early diagnosis, molecular profiling, disease surveillance, and treatment response monitoring. In the past decade, numerous studies have been published about the functional significance of exosomes in a wide variety of cancers, with a particular focus on exosome-derived RNAs and proteins as biomarkers. In this review, utilizing human studies on exosomes, we highlight their potential as diagnostic, prognostic, and predictive biomarkers in gastrointestinal cancers.
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Affiliation(s)
- Jingjing Yu
- Department of Surgery, University of California, Irvine Medical Center, Orange, CA 92868, USA
| | - Arsha Ostowari
- Department of Surgery, University of California, Irvine Medical Center, Orange, CA 92868, USA
| | - Amber Gonda
- Department of Surgery, University of California, Irvine Medical Center, Orange, CA 92868, USA
| | - Kiarash Mashayekhi
- Department of Surgery, University of California, Irvine Medical Center, Orange, CA 92868, USA
| | - Farshid Dayyani
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine Medical Center, Orange, CA 92868, USA
| | - Christopher C. W. Hughes
- Department of Molecular Biology & Biochemistry and Department of Biomedical Engineering, University of California, Irvine, CA 92697, USA
| | - Maheswari Senthil
- Department of Surgery, University of California, Irvine Medical Center, Orange, CA 92868, USA
- Correspondence:
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Application value of circulating LncRNA in diagnosis, treatment, and prognosis of breast cancer. Funct Integr Genomics 2023; 23:61. [PMID: 36792760 DOI: 10.1007/s10142-023-00983-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/17/2023]
Abstract
Breast cancer is the malignant tumor with the highest incidence in women worldwide. It is highly heterogeneous, has a high incidence of drug resistance, recurrence, and metastasis, and is one of the malignant tumors with the highest mortality rate. The early diagnosis, treatment monitoring, and prognosis assessment of breast cancer are the key factors affecting the survival of patients. However, due to the lack of specific biomarkers, breast cancer is still an essential factor affecting women's quality of life and physical and mental health. Long non-coding RNA can regulate various genes and different signaling pathways and plays an essential role in the occurrence and development of tumors. Recent studies have found that the abnormal expression of circulating long non-coding RNA in serum, saliva, and other biological body fluids plays a significant role in early diagnosis, pathological classification, stage, therapeutic effect monitoring, and prognosis evaluation of breast cancer. This article will review the potential application value of circulating lncRNA in breast cancer.
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40
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Exosomal LncRNAs in Gastrointestinal Cancer: Biological Functions and Emerging Clinical Applications. Cancers (Basel) 2023; 15:cancers15030959. [PMID: 36765913 PMCID: PMC9913195 DOI: 10.3390/cancers15030959] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/28/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
Due to the lack of specific and effective biomarkers and therapeutic targets, the early diagnosis and treatment of gastrointestinal cancer remain unsatisfactory. As a type of nanosized vesicles derived from living cells, exosomes mediate cell-to-cell communication by transporting bioactive molecules, thus participating in the regulation of many pathophysiological processes. Recent evidence has revealed that several long non-coding RNAs (lncRNAs) are enriched in exosomes. Exosomes-mediated lncRNAs delivery is critically involved in various aspects of gastrointestinal cancer progression, such as tumor proliferation, metastasis, angiogenesis, stemness, immune microenvironment, and drug resistance. Exosomal lncRNAs represent promising candidates to act as the diagnosis biomarkers and anti-tumor targets. This review introduces the major characteristics of exosomes and lncRNAs and describes the biological functions of exosomal lncRNAs in gastrointestinal cancer development. The preclinical studies on using exosomal lncRNAs to monitor and treat gastrointestinal cancer are also discussed, and the opportunities and challenges for translating them into clinical practice are evaluated.
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Vosough P, Khatami SH, Hashemloo A, Tajbakhsh A, Karimi-Fard F, Taghvimi S, Taheri-Anganeh M, Soltani Fard E, Savardashtaki A, Movahedpour A. Exosomal lncRNAs in gastrointestinal cancer. Clin Chim Acta 2023; 540:117216. [PMID: 36592922 DOI: 10.1016/j.cca.2022.117216] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 12/24/2022] [Accepted: 12/29/2022] [Indexed: 01/01/2023]
Abstract
Gastrointestinal cancer (GIC) remains a leading cause of morbidity and mortality worldwide. Unfortunately, these cancers are diagnosed in advanced metastatic stages due to lack of reliable biomarkers that are sufficiently specific and sensitive in early disease. There has been growing evidence that circulating exosomes can be used to diagnose cancer non-invasively with limited risks and side effects. Furthermore, exosomal long non-coding RNAs (lncRNAs) are emerging as a new class of promising biomarkers in cancer. This review provides an overview of the extraction and detection of exosomal lncRNAs with a focus on their potential role in GIC.
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Affiliation(s)
- Parisa Vosough
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyyed Hossein Khatami
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Amir Tajbakhsh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Sina Taghvimi
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mortaza Taheri-Anganeh
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Elahe Soltani Fard
- Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran; Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Stejskal P, Goodarzi H, Srovnal J, Hajdúch M, van ’t Veer LJ, Magbanua MJM. Circulating tumor nucleic acids: biology, release mechanisms, and clinical relevance. Mol Cancer 2023; 22:15. [PMID: 36681803 PMCID: PMC9862574 DOI: 10.1186/s12943-022-01710-w] [Citation(s) in RCA: 103] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 12/29/2022] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Despite advances in early detection and therapies, cancer is still one of the most common causes of death worldwide. Since each tumor is unique, there is a need to implement personalized care and develop robust tools for monitoring treatment response to assess drug efficacy and prevent disease relapse. MAIN BODY Recent developments in liquid biopsies have enabled real-time noninvasive monitoring of tumor burden through the detection of molecules shed by tumors in the blood. These molecules include circulating tumor nucleic acids (ctNAs), comprising cell-free DNA or RNA molecules passively and/or actively released from tumor cells. Often highlighted for their diagnostic, predictive, and prognostic potential, these biomarkers possess valuable information about tumor characteristics and evolution. While circulating tumor DNA (ctDNA) has been in the spotlight for the last decade, less is known about circulating tumor RNA (ctRNA). There are unanswered questions about why some tumors shed high amounts of ctNAs while others have undetectable levels. Also, there are gaps in our understanding of associations between tumor evolution and ctNA characteristics and shedding kinetics. In this review, we summarize current knowledge about ctNA biology and release mechanisms and put this information into the context of tumor evolution and clinical utility. CONCLUSIONS A deeper understanding of the biology of ctDNA and ctRNA may inform the use of liquid biopsies in personalized medicine to improve cancer patient outcomes.
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Affiliation(s)
- Pavel Stejskal
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University and University Hospital in Olomouc, Olomouc, 779 00 Czech Republic
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158 USA
| | - Hani Goodarzi
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158 USA
- Department of Urology, University of California San Francisco, San Francisco, CA 94158 USA
| | - Josef Srovnal
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University and University Hospital in Olomouc, Olomouc, 779 00 Czech Republic
| | - Marián Hajdúch
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University and University Hospital in Olomouc, Olomouc, 779 00 Czech Republic
| | - Laura J. van ’t Veer
- Department of Laboratory Medicine, University of California San Francisco, 2340 Sutter Street, San Francisco, CA USA
| | - Mark Jesus M. Magbanua
- Department of Laboratory Medicine, University of California San Francisco, 2340 Sutter Street, San Francisco, CA USA
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Copy Number Variations as Determinants of Colorectal Tumor Progression in Liquid Biopsies. Int J Mol Sci 2023; 24:ijms24021738. [PMID: 36675253 PMCID: PMC9866722 DOI: 10.3390/ijms24021738] [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: 12/01/2022] [Revised: 01/09/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
Over the years, increasing evidence has shown that copy number variations (CNVs) play an important role in the pathogenesis and prognosis of Colorectal Cancer (CRC). Colorectal adenomas are highly prevalent lesions, but only 5% of these adenomas ever progress to carcinoma. This review summarizes the different CNVs associated with adenoma-carcinoma CRC progression and with CRC staging. Characterization of CNVs in circulating free-RNA and in blood-derived exosomes augers well with the potential of using such assays for patient management and early detection of metastasis. To overcome the limitations related to tissue biopsies and tumor heterogeneity, using CNVs to characterize tumor-derived materials in biofluids provides less invasive sampling methods and a sample that collectively represents multiple tumor sites in heterogeneous samples. Liquid biopsies provide a source of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), tumor-derived exosomes (TDE), circulating free RNA, and non-coding RNA. This review provides an overview of the current diagnostic and predictive models from liquid biopsies.
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Mirza S, Bhadresha K, Mughal MJ, McCabe M, Shahbazi R, Ruff P, Penny C. Liquid biopsy approaches and immunotherapy in colorectal cancer for precision medicine: Are we there yet? Front Oncol 2023; 12:1023565. [PMID: 36686736 PMCID: PMC9853908 DOI: 10.3389/fonc.2022.1023565] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 12/08/2022] [Indexed: 01/07/2023] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths globally, with nearly half of patients detected in the advanced stages. This is due to the fact that symptoms associated with CRC often do not appear until the cancer has reached an advanced stage. This suggests that CRC is a cancer with a slow progression, making it curable and preventive if detected in its early stage. Therefore, there is an urgent clinical need to improve CRC early detection and personalize therapy for patients with this cancer. Recently, liquid biopsy as a non-invasive or nominally invasive approach has attracted considerable interest for its real-time disease monitoring capability through repeated sample analysis. Several studies in CRC have revealed the potential for liquid biopsy application in a real clinical setting using circulating RNA/miRNA, circulating tumor cells (CTCs), exosomes, etc. However, Liquid biopsy still remains a challenge since there are currently no promising results with high specificity and specificity that might be employed as optimal circulatory biomarkers. Therefore, in this review, we conferred the plausible role of less explored liquid biopsy components like mitochondrial DNA (mtDNA), organoid model of CTCs, and circulating cancer-associated fibroblasts (cCAFs); which may allow researchers to develop improved strategies to unravel unfulfilled clinical requirements in CRC patients. Moreover, we have also discussed immunotherapy approaches to improve the prognosis of MSI (Microsatellite Instability) CRC patients using neoantigens and immune cells in the tumor microenvironment (TME) as a liquid biopsy approach in detail.
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Affiliation(s)
- Sheefa Mirza
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa,Department of Internal Medicine, Common Epithelial Cancer Research Centre, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Kinjal Bhadresha
- Hematology/Oncology Division, School of Medicine, Indiana University, Indianapolis, IN, United States
| | - Muhammed Jameel Mughal
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Science, The George Washington University, Washington, DC, United States
| | - Michelle McCabe
- Department of Anatomical Pathology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg, South Africa
| | - Reza Shahbazi
- Hematology/Oncology Division, School of Medicine, Indiana University, Indianapolis, IN, United States
| | - Paul Ruff
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa,Department of Internal Medicine, Common Epithelial Cancer Research Centre, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Clement Penny
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa,Department of Internal Medicine, Common Epithelial Cancer Research Centre, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa,*Correspondence: Clement Penny,
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Protein-Coding Region Derived Small RNA in Exosomes from Influenza A Virus-Infected Cells. Int J Mol Sci 2023; 24:ijms24010867. [PMID: 36614310 PMCID: PMC9820831 DOI: 10.3390/ijms24010867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/28/2022] [Accepted: 12/30/2022] [Indexed: 01/05/2023] Open
Abstract
Exosomes may function as multifactorial mediators of cell-to-cell communication, playing crucial roles in both physiological and pathological processes. Exosomes released from virus-infected cells may contain RNA and proteins facilitating infection spread. The purpose of our study was to analyze how the small RNA content of exosomes is affected by infection with the influenza A virus (IAV). Exosomes were isolated by ultracentrifugation after hemadsorption of virions and their small RNA content was identified using high-throughput sequencing. As compared to mock-infected controls, 856 RNA transcripts were significantly differentially expressed in exosomes from IAV-infected cells, including fragments of 458 protein-coding (pcRNA), 336 small, 28 long intergenic non-coding RNA transcripts, and 33 pseudogene transcripts. Upregulated pcRNA species corresponded mainly to proteins associated with translation and antiviral response, and the most upregulated among them were RSAD2, CCDC141 and IFIT2. Downregulated pcRNA species corresponded to proteins associated with the cell cycle and DNA packaging. Analysis of differentially expressed pseudogenes showed that in most cases, an increase in the transcription level of pseudogenes was correlated with an increase in their parental genes. Although the role of exosome RNA in IAV infection remains undefined, the biological processes identified based on the corresponding proteins may indicate the roles of some of its parts in IAV replication.
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Datta B, Dutta N, Ashish A, Mandal M, Shukla J, Suresh R, Choudhury P, Chaudhury K, Dutta G. Electrochemical Detection of Cancer Fingerprint: A Systematic Review on Recent Progress in Extracellular Vesicle Research from Lab to Market. NEXT-GENERATION NANOBIOSENSOR DEVICES FOR POINT-OF-CARE DIAGNOSTICS 2023:47-77. [DOI: 10.1007/978-981-19-7130-3_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/19/2023]
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Dash S, Wu CC, Wu CC, Chiang SF, Lu YT, Yeh CY, You JF, Chu LJ, Yeh TS, Yu JS. Extracellular Vesicle Membrane Protein Profiling and Targeted Mass Spectrometry Unveil CD59 and Tetraspanin 9 as Novel Plasma Biomarkers for Detection of Colorectal Cancer. Cancers (Basel) 2022; 15:cancers15010177. [PMID: 36612172 PMCID: PMC9818822 DOI: 10.3390/cancers15010177] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/23/2022] [Accepted: 12/26/2022] [Indexed: 12/29/2022] Open
Abstract
Extracellular vesicles (EVs) are valuable sources for the discovery of useful cancer biomarkers. This study explores the potential usefulness of tumor cell-derived EV membrane proteins as plasma biomarkers for early detection of colorectal cancer (CRC). EVs were isolated from the culture supernatants of four CRC cell lines by ultracentrifugation, and their protein profiles were analyzed by LC-MS/MS. Bioinformatics analysis of identified proteins revealed 518 EV membrane proteins in common among at least three CRC cell lines. We next used accurate inclusion mass screening (AIMS) in parallel with iTRAQ-based quantitative proteomic analysis to highlight candidate proteins and validated their presence in pooled plasma-generated EVs from 30 healthy controls and 30 CRC patients. From these, we chose 14 potential EV-derived targets for further quantification by targeted MS assay in a separate individual cohort comprising of 73 CRC and 80 healthy subjects. Quantitative analyses revealed significant increases in ADAM10, CD59 and TSPAN9 levels (2.19- to 5.26-fold, p < 0.0001) in plasma EVs from CRC patients, with AUC values of 0.83, 0.95 and 0.87, respectively. Higher EV CD59 levels were significantly correlated with distant metastasis (p = 0.0475), and higher EV TSPAN9 levels were significantly associated with lymph node metastasis (p = 0.0011), distant metastasis at diagnosis (p = 0.0104) and higher TNM stage (p = 0.0065). A two-marker panel consisting of CD59 and TSPAN9 outperformed the conventional marker CEA in discriminating CRC and stage I/II CRC patients from healthy controls, with AUC values of 0.98 and 0.99, respectively. Our results identify EV membrane proteins in common among CRC cell lines and altered plasma EV protein profiles in CRC patients and suggest plasma EV CD59 and TSPAN9 as a novel biomarker panel for detecting early-stage CRC.
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Affiliation(s)
- Srinivas Dash
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Chia-Chun Wu
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan
| | - Chih-Ching Wu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, New Taipei City 33305, Taiwan
| | - Sum-Fu Chiang
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, New Taipei City 33305, Taiwan
- School of Traditional Chinese Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yu-Ting Lu
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan
| | - Chien-Yuh Yeh
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, New Taipei City 33305, Taiwan
| | - Jeng-Fu You
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, New Taipei City 33305, Taiwan
| | - Lichieh Julie Chu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan
- Liver Research Center, Chang Gung Memorial Hospital, New Taipei City 33305, Taiwan
| | - Ta-Sen Yeh
- Department of Surgery, Chang Gung Memorial Hospital, Linkou & Chang Gung University, New Taipei City 33305, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Jau-Song Yu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, New Taipei City 33305, Taiwan
- Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33302, Taiwan
- Correspondence: ; Tel.: +886-3-2118800 (ext. 5171); Fax: +886-3-2118891
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48
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The Convergence of FTIR and EVs: Emergence Strategy for Non-Invasive Cancer Markers Discovery. Diagnostics (Basel) 2022; 13:diagnostics13010022. [PMID: 36611313 PMCID: PMC9818376 DOI: 10.3390/diagnostics13010022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/01/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
In conjunction with imaging analysis, pathology-based assessments of biopsied tissue are the gold standard for diagnosing solid tumors. However, the disadvantages of tissue biopsies, such as being invasive, time-consuming, and labor-intensive, have urged the development of an alternate method, liquid biopsy, that involves sampling and clinical assessment of various bodily fluids for cancer diagnosis. Meanwhile, extracellular vesicles (EVs) are circulating biomarkers that carry molecular profiles of their cell or tissue origins and have emerged as one of the most promising biomarkers for cancer. Owing to the biological information that can be obtained through EVs' membrane surface markers and their cargo loaded with biomolecules such as nucleic acids, proteins, and lipids, EVs have become useful in cancer diagnosis and therapeutic applications. Fourier-transform infrared spectroscopy (FTIR) allows rapid, non-destructive, label-free molecular profiling of EVs with minimal sample preparation. Since the heterogeneity of EV subpopulations may result in complicated FTIR spectra that are highly diverse, computational-assisted FTIR spectroscopy is employed in many studies to provide fingerprint spectra of malignant and non-malignant samples, allowing classification with high accuracy, specificity, and sensitivity. In view of this, FTIR-EV approach carries a great potential in cancer detection. The progression of FTIR-based biomarker identification in EV research, the rationale of the integration of a computationally assisted approach, along with the challenges of clinical translation are the focus of this review.
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Symeonidis A, Chatzilygeroudi T, Chondrou V, Sgourou A. Contingent Synergistic Interactions between Non-Coding RNAs and DNA-Modifying Enzymes in Myelodysplastic Syndromes. Int J Mol Sci 2022; 23:16069. [PMID: 36555712 PMCID: PMC9785516 DOI: 10.3390/ijms232416069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders with maturation and differentiation defects exhibiting morphological dysplasia in one or more hematopoietic cell lineages. They are associated with peripheral blood cytopenias and by increased risk for progression into acute myelogenous leukemia. Among their multifactorial pathogenesis, age-related epigenetic instability and the error-rate DNA methylation maintenance have been recognized as critical factors for both the initial steps of their pathogenesis and for disease progression. Although lower-risk MDS is associated with an inflammatory bone marrow microenvironment, higher-risk disease is delineated by immunosuppression and clonal expansion. "Epigenetics" is a multidimensional level of gene regulation that determines the specific gene networks expressed in tissues under physiological conditions and guides appropriate chromatin rearrangements upon influence of environmental stimulation. Regulation of this level consists of biochemical modifications in amino acid residues of the histone proteins' N-terminal tails and their concomitant effects on chromatin structure, DNA methylation patterns in CpG dinucleotides and the tissue-specific non-coding RNAs repertoire, which are directed against various gene targets. The role of epigenetic modifications is widely recognized as pivotal both in gene expression control and differential molecular response to drug therapies in humans. Insights to the potential of synergistic cooperations of epigenetic mechanisms provide new avenues for treatment development to comfort human diseases with a known epigenetic shift, such as MDS. Hypomethylating agents (HMAs), such as epigenetic modulating drugs, have been widely used in the past years as first line treatment for elderly higher-risk MDS patients; however, just half of them respond to therapy and are benefited. Rational outcome predictors following epigenetic therapy in MDS and biomarkers associated with disease relapse are of high importance to improve our efforts in developing patient-tailored clinical approaches.
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Affiliation(s)
- Argiris Symeonidis
- Hematology Division & Stem Cell Transplantation Unit, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece
- Medical School University of Patras, University Campus, 26500 Patras, Greece
| | - Theodora Chatzilygeroudi
- Hematology Division & Stem Cell Transplantation Unit, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece
| | - Vasiliki Chondrou
- Biology Laboratory, School of Science and Technology, Hellenic Open University, 26335 Patras, Greece
| | - Argyro Sgourou
- Biology Laboratory, School of Science and Technology, Hellenic Open University, 26335 Patras, Greece
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50
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Huang X, Hürlimann D, Spanke HT, Wu D, Skowicki M, Dinu IA, Dufresne ER, Palivan CG. Cell-Derived Vesicles with Increased Stability and On-Demand Functionality by Equipping Their Membrane with a Cross-Linkable Copolymer. Adv Healthc Mater 2022; 11:e2202100. [PMID: 36208079 PMCID: PMC11469159 DOI: 10.1002/adhm.202202100] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Indexed: 01/28/2023]
Abstract
Cell-derived vesicles retain the cytoplasm and much of the native cell membrane composition. Therefore, they are attractive for investigations of membrane biophysics, drug delivery systems, and complex molecular factories. However, their fragility and aggregation limit their applications. Here, the mechanical properties and stability of giant plasma membrane vesicles (GPMVs) are enhanced by decorating them with a specifically designed diblock copolymer, cholesteryl-poly[2-aminoethyl methacrylate-b-poly(ethylene glycol) methyl ether acrylate]. When cross-linked, this polymer brush enhances the stability of the GPMVs. Furthermore, the pH-responsiveness of the copolymer layer allows for a controlled cargo loading/release, which may enable various bioapplications. Importantly, the cross-linked-copolymer GPMVs are not cytotoxic and preserve in vitro membrane integrity and functionality. This effective strategy to equip the cell-derived vesicles with stimuli-responsive cross-linkable copolymers is expected to open a new route to the stabilization of natural membrane systems and overcome barriers to biomedical applications.
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Affiliation(s)
- Xinan Huang
- Department of ChemistryUniversity of BaselBPR1096, Mattenstrasse 24aBasel4058Switzerland
| | - Dimitri Hürlimann
- Department of ChemistryUniversity of BaselBPR1096, Mattenstrasse 24aBasel4058Switzerland
- NCCR‐Molecular Systems EngineeringBPR1095, Mattenstrasse 24aBasel4058Switzerland
| | - Hendrik T. Spanke
- Laboratory for Soft and Living MaterialsDepartment of MaterialsETH ZurichVladimir‐Prelog‐Weg 5Zurich8093Switzerland
| | - Dalin Wu
- Department of ChemistryUniversity of BaselBPR1096, Mattenstrasse 24aBasel4058Switzerland
| | - Michal Skowicki
- Department of ChemistryUniversity of BaselBPR1096, Mattenstrasse 24aBasel4058Switzerland
- NCCR‐Molecular Systems EngineeringBPR1095, Mattenstrasse 24aBasel4058Switzerland
| | - Ionel Adrian Dinu
- Department of ChemistryUniversity of BaselBPR1096, Mattenstrasse 24aBasel4058Switzerland
- NCCR‐Molecular Systems EngineeringBPR1095, Mattenstrasse 24aBasel4058Switzerland
| | - Eric R. Dufresne
- Laboratory for Soft and Living MaterialsDepartment of MaterialsETH ZurichVladimir‐Prelog‐Weg 5Zurich8093Switzerland
| | - Cornelia G. Palivan
- Department of ChemistryUniversity of BaselBPR1096, Mattenstrasse 24aBasel4058Switzerland
- NCCR‐Molecular Systems EngineeringBPR1095, Mattenstrasse 24aBasel4058Switzerland
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