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Díaz Méndez AB, Di Giuliani M, Sacconi A, Tremante E, Lulli V, Di Martile M, Vari G, De Bacco F, Boccaccio C, Regazzo G, Rizzo MG. Androgen receptor inhibition sensitizes glioblastoma stem cells to temozolomide by the miR-1/miR-26a-1/miR-487b signature mediated WT1 and FOXA1 silencing. Cell Death Discov 2025; 11:248. [PMID: 40399259 PMCID: PMC12095541 DOI: 10.1038/s41420-025-02517-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/24/2025] [Accepted: 04/29/2025] [Indexed: 05/23/2025] Open
Abstract
Glioblastomas (GBMs) are aggressive brain tumors and challenging cancers for diagnosis and treatment. Therapeutic options include surgery followed by chemotherapy with the DNA alkylator temozolomide (TMZ) and radiotherapy. However, the patient's prognosis remains poor due to tumor heterogeneity, cell infiltration and intrinsic or acquired resistance to therapy. Understanding the resistance mechanisms together with identifying new biomarkers are crucial for developing novel therapeutic strategies. MiRNAs play an important role in the biology of gliomas, they modulate tumorigenesis and therapy response. We recently identified the diagnostic/prognostic miR-1-3p, miR-26a-1-3p and miR-487b-3p signature that displays an oncosuppressive role on several glioma biological functions. In this study, we investigated the effects of the therapeutic potential of this three-miRNA signature as a regulator of response to TMZ. We found that ectopic expression of the miRNA signature in patient-derived GBM neurospheres treated with TMZ impaired cell proliferation and viability by necroptosis induction. Moreover, we identified WT1 and FOXA1, two transcription factors specifically involved in TMZ resistance, as novel direct targets of the miRNA signature. Of note, the repression of WT1 and FOXA1, elicited by the signature, caused a downregulation of the Androgen Receptor (AR) expression, an impairment of tumor-spheroid formation and reversed cancer cell stemness. These results were recapitulated using the AR inhibitor enzalutamide, confirming the involvement of the AR pathway. Our data indicate that the miR-1-3p/miR-26a-1-3p/miR-487b-3p signature, which has an impact on treatment response and cell stemness, may pave the way for miRNA-based complementary therapies in GBM patients.
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Affiliation(s)
- Ana Belén Díaz Méndez
- Department of Research, Advanced Diagnostics and Technological Innovation, Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Marta Di Giuliani
- Department of Research, Advanced Diagnostics and Technological Innovation, Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Andrea Sacconi
- Clinical Trial Center, Biostatistics and Bioinformatics Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Elisa Tremante
- Department of Research, Advanced Diagnostics and Technological Innovation, Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Valentina Lulli
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Marta Di Martile
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Giulia Vari
- Department of Research, Advanced Diagnostics and Technological Innovation, Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
- PhD Program in Molecular Medicine, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Francesca De Bacco
- Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
- Department of Oncology, University of Torino, Turin, Italy
| | - Carla Boccaccio
- Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
- Department of Oncology, University of Torino, Turin, Italy
| | - Giulia Regazzo
- Department of Research, Advanced Diagnostics and Technological Innovation, Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
| | - Maria Giulia Rizzo
- Department of Research, Advanced Diagnostics and Technological Innovation, Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
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2
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Mohak S, Fabian Z. Extracellular Vesicles as Precision Delivery Systems for Biopharmaceuticals: Innovations, Challenges, and Therapeutic Potential. Pharmaceutics 2025; 17:641. [PMID: 40430932 PMCID: PMC12115175 DOI: 10.3390/pharmaceutics17050641] [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: 04/10/2025] [Revised: 05/06/2025] [Accepted: 05/07/2025] [Indexed: 05/29/2025] Open
Abstract
Unlike traditional small-molecule agents, biopharmaceuticals, like synthetic RNAs, enzymes, and monoclonal antibodies, are highly vulnerable to environmental conditions. Preservation of their functional integrity necessitates advanced delivery methods. Being biocompatible, extracellular vesicles (EVs) gained attention as a promising system for delivering biopharmaceuticals, addressing challenges related to the stability and efficacy of sensitive therapeutic molecules. Indeed, EVs can cross biological barriers like the blood-brain barrier, delivering therapeutic cargo to tissues that are traditionally difficult to reach. Recent innovations in surface modification technologies, including ligand and antibody attachment, have further enhanced EVs' targeting capabilities, making them particularly effective in personalized medicine. Here, we review the versatile suitability of EVs for being next-generation delivery vehicles of biopharmaceuticals, including current standings, practical challenges, and possible future directions of the technology.
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Affiliation(s)
- Sidhesh Mohak
- Department of Medicine, South Texas Health System, McAllen, TX 78503, USA;
- Department of Clinical Sciences, Saint James School of Medicine, Arnos Vale VC0280, Saint Vincent and the Grenadines
| | - Zsolt Fabian
- School of Medicine and Dentistry, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Fylde Rd, Preston PR1 2HE, UK
- Translocon Biotechnologies PLC, Akadémia u. 6, 1054 Budapest, Hungary
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3
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Ramezani A, Rahnama M, Mahmoudian F, Shirazi F, Ganji M, Bakhshi S, Khalesi B, Hashemi ZS, Khalili S. Current Understanding of the Exosomes and Their Associated Biomolecules in the Glioblastoma Biology, Clinical Treatment, and Diagnosis. J Neuroimmune Pharmacol 2025; 20:48. [PMID: 40299204 DOI: 10.1007/s11481-025-10204-7] [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: 07/23/2024] [Accepted: 04/08/2025] [Indexed: 04/30/2025]
Abstract
Glioblastoma is the most common and aggressive brain tumor with a low survival rate. Due to its heterogeneous composition, high invasiveness, and frequent recurrence after surgery, treatment success has been limited. In addition, due to the brain's unique immune status and the suppressor tumor microenvironment (TME), glioblastoma treatment has faced more challenges. Exosomes play a critical role in cancer metastasis by regulating cell-cell interactions that promote tumor growth, angiogenesis, metastasis, treatment resistance, and immunological regulation in the tumor microenvironment. This review explores the pivotal role of exosomes in the development of glioblastoma, with a focus on their potential as non-invasive biomarkers for prognosis, early detection and real-time monitoring of disease progression. Notably, exosome-based drug delivery methods hold promise for overcoming the blood-brain barrier (BBB) and developing targeted therapies for glioblastoma. Despite challenges in clinical translation, the potential for personalized exosome = -054321`therapies and the capacity to enhance therapeutic responses in glioblastoma, present intriguing opportunities for improving patient outcomes. It seems that getting a good and current grasp of the role of exosomes in the fight against glioblastoma would properly serve the scientific community to further their understanding of the related potentials of these biological moieties.
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Affiliation(s)
- Aghdas Ramezani
- Department of Molecular Imaging, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Maryam Rahnama
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Mahmoudian
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Shirazi
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Sciences and Technologies, University of Isfahan, Isfahan, Iran
| | - Mahmoud Ganji
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Shohreh Bakhshi
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahman Khalesi
- Department of Research and Production of Poultry Viral Vaccine, Education and Extension Organization, Razi Vaccine and Serum Research Institute, Agricultural Research, Karaj, 3197619751, Iran
| | - Zahra Sadat Hashemi
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
| | - Saeed Khalili
- Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran.
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4
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Hao Z, Guan W, Wei W, Li M, Xiao Z, Sun Q, Pan Y, Xin W. Unlocking the therapeutic potential of tumor-derived EVs in ischemia-reperfusion: a breakthrough perspective from glioma and stroke. J Neuroinflammation 2025; 22:84. [PMID: 40089793 PMCID: PMC11909855 DOI: 10.1186/s12974-025-03405-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Accepted: 03/04/2025] [Indexed: 03/17/2025] Open
Abstract
Clinical studies have revealed a bidirectional relationship between glioma and ischemic stroke, with evidence of spatial overlap between the two conditions. This connection arises from significant similarities in their pathological processes, including the regulation of cellular metabolism, inflammation, coagulation, hypoxia, angiogenesis, and neural repair, all of which involve common biological factors. A significant shared feature of both diseases is the crucial role of extracellular vesicles (EVs) in mediating intercellular communication. Extracellular vesicles, with their characteristic bilayer structure, encapsulate proteins, lipids, and nucleic acids, shielding them from enzymatic degradation by ribonucleases, deoxyribonucleases, and proteases. This structural protection facilitates long-distance intercellular communication in multicellular organisms. In gliomas, EVs are pivotal in intracranial signaling and shaping the tumor microenvironment. Importantly, the cargos carried by glioma-derived EVs closely align with the biological factors involved in ischemic stroke, underscoring the substantial impact of glioma on stroke pathology, particularly through the crucial roles of EVs as key mediators in this interaction. This review explores the pathological interplay between glioma and ischemic stroke, addressing clinical manifestations and pathophysiological processes across the stages of hypoxia, stroke onset, progression, and recovery, with a particular focus on the crucial role of EVs and their cargos in these interactions.
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Affiliation(s)
- Zhongnan Hao
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, P. R. China
- Jiangxi Key Laboratory of Neurological Diseases, Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
- Department of Neurology, The Affiliated Hospital of Qingdao University, Medical School of Qingdao University, Qingdao, 266100, Shandong Province, China
| | - Wenxin Guan
- Queen Mary School, Nanchang University, Xuefu Avenue, Nanchang, Jiangxi, China
| | - Wei Wei
- Department of Neurology, the Affiliated Hospital of Southwest Jiaotong University & The Third People's Hospital of Chengdu, Chengdu, 610031, Sichuan, PR China
| | - Meihua Li
- Jiangxi Key Laboratory of Neurological Diseases, Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Zhipeng Xiao
- Jiangxi Key Laboratory of Neurological Diseases, Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Qinjian Sun
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, P. R. China
| | - Yongli Pan
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, P. R. China.
| | - Wenqiang Xin
- Jiangxi Key Laboratory of Neurological Diseases, Department of Neurosurgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
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Wang J, Liu L, Gao X, Liu X, Dai Y, Mao Z, Huang S, Li J, Wang D, Qi Y, Han Y, Xu Y, Chua CYX, Grattoni A, Xie W, Yang H, Huang G. A novel pathway for stemness propagation and chemoresistance in non-small cell lung cancer via phosphorylated PKM2-loaded small extracellular vesicles. Theranostics 2025; 15:3439-3461. [PMID: 40093893 PMCID: PMC11905138 DOI: 10.7150/thno.103722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 02/11/2025] [Indexed: 03/19/2025] Open
Abstract
Rationale: Non-small cell lung cancer (NSCLC) is a predominant cause of cancer-related mortality, with its progression and treatment resistance significantly influenced by cancer stem cells (CSCs) and their complex intercellular communication mechanisms. Small extracellular vesicles (sEVs) have emerged as pivotal mediators of intercellular signaling, affecting tumor microenvironment modulation and therapeutic resistance. This study investigates the role of CSC-derived sEVs in transmitting stemness traits through the selective sorting of pyruvate kinase M2 phosphorylated at the Y105 site (pY105-PKM2), mediated by the adaptor protein IQGAP1, which supports CSC maintenance and drug resistance in NSCLC. Methods: In vitro and in vivo experiments, including proteomic and transcriptomic analyses, were conducted to identify key regulators of sEV-mediated signaling. Immunoprecipitation, proximity ligation assays, and immunofluorescence were used to examine the role of IQGAP1 in the sorting of pY105-PKM2 into sEVs. Functional assays, including sphere formation, chemoresistance tests, metabolic assessments, and cell cycle analysis, were conducted to evaluate the effects of sEV-mediated delivery of pY105-PKM2 on recipient cells. Additionally, immunohistochemistry and survival analysis were performed on tumor samples from NSCLC patients to establish clinical correlations. Results: We unveiled a novel mechanism by which CSC-derived sEVs transmit stemness traits to replenish the CSC pool in NSCLC. CSC-derived sEVs were enriched with pY105-PKM2, correlating with enhanced stemness, chemoresistance, and poor clinical outcomes. Mechanistically, IQGAP1 was identified as an adaptor facilitating the selective sorting of pY105-PKM2 into sEVs through interactions with the ESCRT component TSG101. Recipient cells treated with CSC-derived sEVs exhibited metabolic reprogramming, slower cell cycle progression, and enhanced chemoresistance. The synergistic role of IQGAP1 and pY105-PKM2 was confirmed, highlighting their critical contributions to CSC maintenance and malignant progression. Conclusion: This study highlights the critical role of CSC-derived sEVs in NSCLC progression and therapy resistance through the IQGAP1-mediated selective sorting of pY105-PKM2. By uncovering this novel pathway, our findings provide valuable insights into CSC pool replenishment and therapeutic resistance mechanisms in NSCLC, identifying IQGAP1 and pY105-PKM2 as promising therapeutic targets for mitigating CSC-driven malignancy and enhancing treatment efficacy.
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Affiliation(s)
- Jingyi Wang
- Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Liu Liu
- Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xinyu Gao
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Xiyu Liu
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Yitian Dai
- Laboratory of Stem Cell Biology and Engineering, New York Blood Center, New York, NY 10065, USA
| | - Zijun Mao
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Shengzhe Huang
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Junjian Li
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Dongliang Wang
- Department of Nuclear Medicine, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Yu Qi
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Yingwen Han
- Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yunjing Xu
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Corrine Ying Xuan Chua
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Alessandro Grattoni
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA
- Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Wenhui Xie
- Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hao Yang
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Gang Huang
- Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
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Mastantuono S, Manini I, Di Loreto C, Beltrami AP, Vindigni M, Cesselli D. Glioma-Derived Exosomes and Their Application as Drug Nanoparticles. Int J Mol Sci 2024; 25:12524. [PMID: 39684236 DOI: 10.3390/ijms252312524] [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: 11/04/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
Glioblastoma Multiforme (GBM) is the most aggressive primary tumor of the Central Nervous System (CNS) with a low survival rate. The malignancy of GBM is sustained by a bidirectional crosstalk between tumor cells and the Tumor Microenvironment (TME). This mechanism of intercellular communication is mediated, at least in part, by the release of exosomes. Glioma-Derived Exosomes (GDEs) work, indeed, as potent signaling particles promoting the progression of brain tumors by inducing tumor proliferation, invasion, migration, angiogenesis and resistance to chemotherapy or radiation. Given their nanoscale size, exosomes can cross the blood-brain barrier (BBB), thus becoming not only a promising biomarker to predict diagnosis and prognosis but also a therapeutic target to treat GBM. In this review, we describe the structural and functional characteristics of exosomes and their involvement in GBM development, diagnosis, prognosis and treatment. In addition, we discuss how exosomes can be modified to be used as a therapeutic target/drug delivery system for clinical applications.
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Affiliation(s)
- Serena Mastantuono
- Department of Medicine, University of Udine, Piazzale S. Maria della Misericordia 15, 33100 Udine, Italy
| | - Ivana Manini
- Department of Pathological Anatomy, University Hospital of Udine, Piazzale S. Maria della Misericordia 15, 33100 Udine, Italy
| | - Carla Di Loreto
- Department of Pathological Anatomy, University Hospital of Udine, Piazzale S. Maria della Misericordia 15, 33100 Udine, Italy
| | - Antonio Paolo Beltrami
- Department of Medicine, University of Udine, Piazzale S. Maria della Misericordia 15, 33100 Udine, Italy
- Institute of Clinical Pathology, University Hospital of Udine, Piazzale S. Maria della Misericordia 15, 33100 Udine, Italy
| | - Marco Vindigni
- Department of Neurosurgery, University Hospital of Udine, Piazzale S. Maria della Misericordia 15, 33100 Udine, Italy
| | - Daniela Cesselli
- Department of Medicine, University of Udine, Piazzale S. Maria della Misericordia 15, 33100 Udine, Italy
- Department of Pathological Anatomy, University Hospital of Udine, Piazzale S. Maria della Misericordia 15, 33100 Udine, Italy
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Yang L, Niu Z, Ma Z, Wu X, Vong CT, Li G, Feng Y. Exploring the clinical implications and applications of exosomal miRNAs in gliomas: a comprehensive study. Cancer Cell Int 2024; 24:323. [PMID: 39334350 PMCID: PMC11437892 DOI: 10.1186/s12935-024-03507-x] [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: 05/11/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Gliomas are aggressive brain tumors associated with poor prognosis and limited treatment options due to their invasive nature and resistance to current therapeutic modalities. Research suggests that exosomal microRNAs have emerged as key players in intercellular communication within the tumor microenvironment, influencing tumor progression and therapeutic responses. Exosomal microRNAs (miRNAs), small non-coding RNAs, are crucial in glioma development, invasion, metastasis, angiogenesis, and immune evasion by binding to target genes. This comprehensive review examines the clinical relevance and implications of exosomal miRNAs in gliomas, highlighting their potential as diagnostic biomarkers, therapeutic targets and prognosis biomarker. Additionally, we also discuss the limitations of current exsomal miRNA treatments and address challenges and propose future directions for leveraging exosomal miRNAs in precision oncology for glioma management.
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Affiliation(s)
- Liang Yang
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Zhen Niu
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Zhixuan Ma
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Xiaojie Wu
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
| | - Chi Teng Vong
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
- Macau Centre for Research and Development in Chinese Medicine, University of Macau, Macau, China
| | - Ge Li
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510100, China.
| | - Ying Feng
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.
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Tataranu LG, Turliuc S, Kamel A, Rizea RE, Dricu A, Staicu GA, Baloi SC, Rodriguez SMB, Manole AIM. Glioblastoma Tumor Microenvironment: An Important Modulator for Tumoral Progression and Therapy Resistance. Curr Issues Mol Biol 2024; 46:9881-9894. [PMID: 39329940 PMCID: PMC11430601 DOI: 10.3390/cimb46090588] [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: 08/01/2024] [Revised: 08/23/2024] [Accepted: 09/04/2024] [Indexed: 09/28/2024] Open
Abstract
The race to find an effective treatment for glioblastoma (GBM) remains a critical topic, because of its high aggressivity and impact on survival and the quality of life. Currently, due to GBM's high heterogeneity, the conventional treatment success rate and response to therapy are relatively low, with a median survival rate of less than 20 months. A new point of view can be provided by the comprehension of the tumor microenvironment (TME) in pursuance of the development of new therapeutic strategies to aim for a longer survival rate with an improved quality of life and longer disease-free interval (DFI). The main components of the GBM TME are represented by the extracellular matrix (ECM), glioma cells and glioma stem cells (GSCs), immune cells (microglia, macrophages, neutrophils, lymphocytes), neuronal cells, all of them having dynamic interactions and being able to influence the tumoral growth, progression, and drug resistance thus being a potential therapeutic target. This paper will review the latest research on the GBM TME and the potential therapeutic targets to form an up-to-date strategy.
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Affiliation(s)
- Ligia Gabriela Tataranu
- Neurosurgical Department, University of Medicine and Pharmacy "Carol Davila", 020022 Bucharest, Romania
- Neurosurgical Department, Clinical Emergency Hospital "Bagdasar-Arseni", 041915 Bucharest, Romania
| | - Serban Turliuc
- Medical Department, University of Medicine and Pharmacy "G. T. Popa", 700115 Iasi, Romania
| | - Amira Kamel
- Neurosurgical Department, Clinical Emergency Hospital "Bagdasar-Arseni", 041915 Bucharest, Romania
| | - Radu Eugen Rizea
- Neurosurgical Department, University of Medicine and Pharmacy "Carol Davila", 020022 Bucharest, Romania
- Neurosurgical Department, Clinical Emergency Hospital "Bagdasar-Arseni", 041915 Bucharest, Romania
| | - Anica Dricu
- Biochemistry Department, University of Medicine and Pharmacy, 200349 Craiova, Romania
| | | | - Stefania Carina Baloi
- Biochemistry Department, University of Medicine and Pharmacy, 200349 Craiova, Romania
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9
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Di Francesco V, Chua AJ, Huang D, D'Souza A, Yang A, Bleier BS, Amiji MM. RNA therapies for CNS diseases. Adv Drug Deliv Rev 2024; 208:115283. [PMID: 38494152 DOI: 10.1016/j.addr.2024.115283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 03/06/2024] [Accepted: 03/09/2024] [Indexed: 03/19/2024]
Abstract
Neurological disorders are a diverse group of conditions that pose an increasing health burden worldwide. There is a general lack of effective therapies due to multiple reasons, of which a key obstacle is the presence of the blood-brain barrier, which limits drug delivery to the central nervous system, and generally restricts the pool of candidate drugs to small, lipophilic molecules. However, in many cases, these are unable to target key pathways in the pathogenesis of neurological disorders. As a group, RNA therapies have shown tremendous promise in treating various conditions because they offer unique opportunities for specific targeting by leveraging Watson-Crick base pairing systems, opening up possibilities to modulate pathological mechanisms that previously could not be addressed by small molecules or antibody-protein interactions. This potential paradigm shift in disease management has been enabled by recent advances in synthesizing, purifying, and delivering RNA. This review explores the use of RNA-based therapies specifically for central nervous system disorders, where we highlight the inherent limitations of RNA therapy and present strategies to augment the effectiveness of RNA therapeutics, including physical, chemical, and biological methods. We then describe translational challenges to the widespread use of RNA therapies and close with a consideration of future prospects in this field.
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Affiliation(s)
- Valentina Di Francesco
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, 140 The Fenway Building, Boston, MA 02115, USA; Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA
| | - Andy J Chua
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, 140 The Fenway Building, Boston, MA 02115, USA; Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA; Department of Otorhinolaryngology - Head and Neck Surgery, Sengkang General Hospital, 110 Sengkang E Way, 544886, Singapore
| | - Di Huang
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, 140 The Fenway Building, Boston, MA 02115, USA; Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA
| | - Anisha D'Souza
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, 140 The Fenway Building, Boston, MA 02115, USA; Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA
| | - Alicia Yang
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Benjamin S Bleier
- Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA
| | - Mansoor M Amiji
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, 140 The Fenway Building, Boston, MA 02115, USA; Department of Chemical Engineering, College of Engineering, Northeastern University, 360 Huntington Avenue, 140 The Fenway Building, Boston, MA 02115, USA.
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10
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Kiel K, Król SK, Bronisz A, Godlewski J. MiR-128-3p - a gray eminence of the human central nervous system. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102141. [PMID: 38419943 PMCID: PMC10899074 DOI: 10.1016/j.omtn.2024.102141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/02/2024]
Abstract
MicroRNA-128-3p (miR-128-3p) is a versatile molecule with multiple functions in the physiopathology of the human central nervous system. Perturbations of miR-128-3p, which is enriched in the brain, contribute to a plethora of neurodegenerative disorders, brain injuries, and malignancies, as this miRNA is a crucial regulator of gene expression in the brain, playing an essential role in the maintenance and function of cells stemming from neuronal lineage. However, the differential expression of miR-128-3p in pathologies underscores the importance of the balance between its high and low levels. Significantly, numerous reports pointed to miR-128-3p as one of the most depleted in glioblastoma, implying it is a critical player in the disease's pathogenesis and thus may serve as a therapeutic agent for this most aggressive form of brain tumor. In this review, we summarize the current knowledge of the diverse roles of miR-128-3p. We focus on its involvement in the neurogenesis and pathophysiology of malignant and neurodegenerative diseases. We also highlight the promising potential of miR-128-3p as an antitumor agent for the future therapy of human cancers, including glioblastoma, and as the linchpin of brain development and function, potentially leading to the development of new therapies for neurological conditions.
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Affiliation(s)
- Klaudia Kiel
- Tumor Microenvironment Laboratory, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego Street, Warsaw, Poland
| | - Sylwia Katarzyna Król
- Department of Neurooncology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego Street, Warsaw, Poland
| | - Agnieszka Bronisz
- Tumor Microenvironment Laboratory, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego Street, Warsaw, Poland
| | - Jakub Godlewski
- Department of Neurooncology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego Street, Warsaw, Poland
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11
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Al-Hawary SIS, Alhajlah S, Olegovich BD, Hjazi A, Rajput P, Ali SHJ, Abosoda M, Ihsan A, Oudah SK, Mustafa YF. Effective extracellular vesicles in glioma: Focusing on effective ncRNA exosomes and immunotherapy methods for treatment. Cell Biochem Funct 2024; 42:e3921. [PMID: 38269511 DOI: 10.1002/cbf.3921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 12/26/2023] [Accepted: 12/27/2023] [Indexed: 01/26/2024]
Abstract
This comprehensive article explores the complex field of glioma treatment, with a focus on the important roles of non-coding RNAsRNAs (ncRNAs) and exosomes, as well as the potential synergies of immunotherapy. The investigation begins by examining the various functions of ncRNAs and their involvement in glioma pathogenesis, progression, and as potential diagnostic biomarkers. Special attention is given to exosomes as carriers of ncRNAs and their intricate dynamics within the tumor microenvironment. The exploration extends to immunotherapy methods, analyzing their mechanisms and clinical implications in the treatment of glioma. By synthesizing these components, the article aims to provide a comprehensive understanding of how ncRNAs, exosomes, and immunotherapy interact, offering valuable insights into the evolving landscape of glioma research and therapeutic strategies.
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Affiliation(s)
| | - Sharif Alhajlah
- Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqraa, Saudi Arabia
| | - Bokov Dmitry Olegovich
- Institute of Pharmacy, Sechenov First Moscow State Medical University, Moscow, Russian Federation
- Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, Moscow, Russian Federation
| | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Pranchal Rajput
- School of Applied and Life Sciences, Uttaranchal University, Dehradun, India
| | - Saad Hayif Jasim Ali
- Department of Medical Laboratory, College of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq
| | - Munther Abosoda
- College of Pharmacy, The Islamic University, Najaf, Iraq
- College of Pharmacy, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Pharmacy, The Islamic University of Babylon, Babylon, Iraq
| | - Ali Ihsan
- Department of Medical Laboratories Techniques, Imam Ja'afar Al-Sadiq University, Iraq
| | - Shamam Kareem Oudah
- College of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
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12
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Song YX, Li X, Nie SD, Hu ZX, Zhou D, Sun DY, Zhou GY, Wang Y, Liu JJ, Song T, Wang S. Extracellular vesicles released by glioma cells are decorated by Annexin A2 allowing for cellular uptake via heparan sulfate. Cancer Gene Ther 2023; 30:1156-1166. [PMID: 37231059 DOI: 10.1038/s41417-023-00627-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 04/20/2023] [Accepted: 05/12/2023] [Indexed: 05/27/2023]
Abstract
Extracellular vesicles (EVs) play a crucial role in regulating cell behavior by delivering their cargo to target cells. However, the mechanisms underlying EV-cell interactions are not well understood. Previous studies have shown that heparan sulfate (HS) on target cell surfaces can act as receptors for exosomes uptake, but the ligand for HS on EVs has not been identified. In this study, we isolated EVs from glioma cell lines and glioma patients and identified Annexin A2 (AnxA2) on EVs as a key HS-binding ligand and mediator of EV-cell interactions. Our findings suggest that HS plays a dual role in EV-cell interactions, where HS on EVs captures AnxA2, and on target cells, it acts as a receptor for AnxA2. Removal of HS from the EV surface inhibits EV-target cell interaction by releasing AnxA2. Furthermore, we found that AnxA2-mediated binding of EVs to vascular endothelial cells promotes angiogenesis, and that antibody against AnxA2 inhibited the ability of glioma-derived EVs to stimulate angiogenesis by reducing the uptake of EVs. Our study also suggests that the AnxA2-HS interaction may accelerate the glioma-derived EVs-mediated angiogenesis and that combining AnxA2 on glioma cells with HS on endothelial cells may effectively improve the prognosis evaluation of glioma patients.
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Affiliation(s)
- Yu-Xi Song
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, China
- Department of Neurosurgery, Xiang-Ya Hospital, Central South University, Changsha, China
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Xin Li
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, China.
- Department of Neurosurgery, Xiang-Ya Hospital, Central South University, Changsha, China.
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China.
| | - Sheng-Dan Nie
- Institute of Clinical Medicine, Hunan provincial people's hospital, the first affiliated hospital of Hunan Normal University, Changsha, China
| | - Zhong-Xu Hu
- Department of Neurosurgery, Xiang-Ya Hospital, Central South University, Changsha, China
| | - Di Zhou
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Ding-Ya Sun
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Gao-Ya Zhou
- Department of Neurology, Brain hospital of Hunan Province, Changsha, China
| | - Ying Wang
- Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China
| | - Jia-Jia Liu
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Tao Song
- Department of Neurosurgery, Xiang-Ya Hospital, Central South University, Changsha, China.
| | - Shan Wang
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China.
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13
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Ponomarev AS, Gilazieva ZE, Solovyova VV, Rizvanov AA. Molecular Mechanisms of Tumor Cell Stemness Modulation during Formation of Spheroids. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:979-994. [PMID: 37751868 DOI: 10.1134/s0006297923070106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 05/30/2023] [Accepted: 06/07/2023] [Indexed: 09/28/2023]
Abstract
Cancer stem cells (CSCs), their properties and interaction with microenvironment are of interest in modern medicine and biology. There are many studies on the emergence of CSCs and their involvement in tumor pathogenesis. The most important property inherent to CSCs is their stemness. Stemness combines ability of the cell to maintain its pluripotency, give rise to differentiated cells, and interact with environment to maintain a balance between dormancy, proliferation, and regeneration. While adult stem cells exhibit these properties by participating in tissue homeostasis, CSCs behave as their malignant equivalents. High tumor resistance to therapy, ability to differentiate, activate angiogenesis and metastasis arise precisely due to the stemness of CSCs. These cells can be used as a target for therapy of different types of cancer. Laboratory models are needed to study cancer biology and find new therapeutic strategies. A promising direction is three-dimensional tumor models or spheroids. Such models exhibit properties resembling stemness in a natural tumor. By modifying spheroids, it becomes possible to investigate the effect of therapy on CSCs, thus contributing to the development of anti-tumor drug test systems. The review examines the niche of CSCs, the possibility of their study using three-dimensional spheroids, and existing markers for assessing stemness of CSCs.
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Affiliation(s)
- Aleksei S Ponomarev
- Kazan (Volga Region) Federal University, Kazan, Republic of Tatarstan, 420008, Russia
| | - Zarema E Gilazieva
- Kazan (Volga Region) Federal University, Kazan, Republic of Tatarstan, 420008, Russia
| | - Valeriya V Solovyova
- Kazan (Volga Region) Federal University, Kazan, Republic of Tatarstan, 420008, Russia
| | - Albert A Rizvanov
- Kazan (Volga Region) Federal University, Kazan, Republic of Tatarstan, 420008, Russia.
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14
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Skouras P, Gargalionis AN, Piperi C. Exosomes as Novel Diagnostic Biomarkers and Therapeutic Tools in Gliomas. Int J Mol Sci 2023; 24:10162. [PMID: 37373314 DOI: 10.3390/ijms241210162] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Exosomes constitute small extracellular vesicles that contain lipids, proteins, nucleic acids, and glycoconjugates from the secreted cells and are capable of transmitting signals between cells and coordinating cellular communication. By this means, they are ultimately involved in physiology and disease, including development, homeostasis, and immune system regulation, as well as contributing to tumor progression and neurodegenerative diseases pathology. Recent studies have shown that gliomas secrete a panel of exosomes which have been associated with cell invasion and migration, tumor immune tolerance, potential for malignant transformation, neovascularization, and resistance to treatment. Exosomes have therefore emerged as intercellular communicators, which mediate the tumor-microenvironment interactions and exosome-regulated glioma cell stemness and angiogenesis. They may induce tumor proliferation and malignancy in normal cells by carrying pro-migratory modulators from cancer cells as well as many different molecular cancer modifiers, such as oncogenic transcripts, miRNAs, mutant oncoproteins, etc., which promote the communication of cancer cells with the surrounding stromal cells and provide valuable information on the molecular profile of the existing tumor. Moreover, engineered exosomes can provide an alternative system for drug delivery and enable efficient treatment. In the present review, we discuss the latest findings regarding the role of exosomes in glioma pathogenesis, their utility in non-invasive diagnosis, and potential applications to treatment.
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Affiliation(s)
- Panagiotis Skouras
- Department of Neurosurgery, 'Evangelismos' Hospital, Medical School, National and Kapodistrian University of Athens, 10676 Athens, Greece
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Antonios N Gargalionis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Department of Biopathology, 'Eginition' Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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15
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Avgoulas DI, Tasioulis KS, Papi RM, Pantazaki AA. Therapeutic and Diagnostic Potential of Exosomes as Drug Delivery Systems in Brain Cancer. Pharmaceutics 2023; 15:pharmaceutics15051439. [PMID: 37242681 DOI: 10.3390/pharmaceutics15051439] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/26/2023] [Accepted: 05/03/2023] [Indexed: 05/28/2023] Open
Abstract
Cancer is designated as one of the principal causes of mortality universally. Among different types of cancer, brain cancer remains the most challenging one due to its aggressiveness, the ineffective permeation ability of drugs through the blood-brain barrier (BBB), and drug resistance. To overcome the aforementioned issues in fighting brain cancer, there is an imperative need for designing novel therapeutic approaches. Exosomes have been proposed as prospective "Trojan horse" nanocarriers of anticancer theranostics owing to their biocompatibility, increased stability, permeability, negligible immunogenicity, prolonged circulation time, and high loading capacity. This review provides a comprehensive discussion on the biological properties, physicochemical characteristics, isolation methods, biogenesis and internalization of exosomes, while it emphasizes their therapeutic and diagnostic potential as drug vehicle systems in brain cancer, highlighting recent advances in the research field. A comparison of the biological activity and therapeutic effectiveness of several exosome-encapsulated cargo including drugs and biomacromolecules underlines their great supremacy over the non-exosomal encapsulated cargo in the delivery, accumulation, and biological potency. Various studies on cell lines and animals give prominence to exosome-based nanoparticles (NPs) as a promising and alternative approach in the management of brain cancer.
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Affiliation(s)
- Dimitrios I Avgoulas
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Konstantinos S Tasioulis
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Rigini M Papi
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Anastasia A Pantazaki
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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16
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Galardi A, De Bethlen A, Di Paolo V, Lampis S, Mastronuzzi A, Di Giannatale A. Recent Advancements on the Use of Exosomes as Drug Carriers for the Treatment of Glioblastoma. Life (Basel) 2023; 13:life13040964. [PMID: 37109493 PMCID: PMC10142357 DOI: 10.3390/life13040964] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/29/2023] [Accepted: 04/05/2023] [Indexed: 04/29/2023] Open
Abstract
Glioblastoma (GBM) is the most common and aggressive cancer of the brain. Presently, GBM patients have a poor prognosis, and therapy primarily aims to extend the life expectancy of affected patients. The current treatment of GBM in adult cases and high-grade gliomas in the pediatric population involves a multimodal approach that includes surgical resection followed by simultaneous chemo/radiotherapy. Exosomes are nanoparticles that transport proteins and nucleic acids and play a crucial role in mediating intercellular communication. Recent evidence suggests that these microvesicles may be used as biological carriers and offer significant advantages in targeted therapy. Due to their inherent cell-targeting properties, circulation stability, and biocompatibility, exosomes are emerging as promising new carriers for drugs and biotherapeutics. Furthermore, these nanovesicles are a repository of potential diagnostic and prognostic markers. In this review, we focus on the therapeutic potentials of exosomes in nano-delivery and describe the latest evidence of their use as a therapeutic tool in GBM.
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Affiliation(s)
- Angela Galardi
- Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS, Bambino Gesù Children's Hospital, 00165 Rome, Italy
| | - Alexander De Bethlen
- Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS, Bambino Gesù Children's Hospital, 00165 Rome, Italy
| | - Virginia Di Paolo
- Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS, Bambino Gesù Children's Hospital, 00165 Rome, Italy
| | - Silvia Lampis
- Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS, Bambino Gesù Children's Hospital, 00165 Rome, Italy
| | - Angela Mastronuzzi
- Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS, Bambino Gesù Children's Hospital, 00165 Rome, Italy
| | - Angela Di Giannatale
- Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, IRCCS, Bambino Gesù Children's Hospital, 00165 Rome, Italy
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17
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Díaz Méndez AB, Sacconi A, Tremante E, Lulli V, Caprara V, Rosanò L, Goeman F, Carosi M, Di Giuliani M, Vari G, Silvani A, Pollo B, Garufi C, Ramponi S, Simonetti G, Ciusani E, Mandoj C, Scalera S, Villani V, Po A, Ferretti E, Regazzo G, Rizzo MG. A diagnostic circulating miRNA signature as orchestrator of cell invasion via TKS4/TKS5/EFHD2 modulation in human gliomas. J Exp Clin Cancer Res 2023; 42:66. [PMID: 36932446 PMCID: PMC10022260 DOI: 10.1186/s13046-023-02639-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/06/2023] [Indexed: 03/19/2023] Open
Abstract
BACKGROUND Altered microRNA profiles have been observed not only in tumour tissues but also in biofluids, where they circulate in a stable form thus representing interesting biomarker candidates. This study aimed to identify a microRNA signature as a non-invasive biomarker and to investigate its impact on glioma biology. METHODS MicroRNAs were selected using a global expression profile in preoperative serum samples from 37 glioma patients. Comparison between serum samples from age and gender-matched controls was performed by using the droplet digital PCR. The ROC curve and Kaplan-Meier survival analyses were used to evaluate the diagnostic/prognostic values. The functional role of the identified signature was assessed by gain/loss of function strategies in glioma cells. RESULTS A three-microRNA signature (miR-1-3p/-26a-1-3p/-487b-3p) was differentially expressed in the serum of patients according to the isocitrate dehydrogenase (IDH) genes mutation status and correlated with both patient Overall and Progression Free Survival. The identified signature was also downregulated in the serum of patients compared to controls. Consistent with these results, the signature expression and release in the conditioned medium of glioma cells was lower in IDH-wild type cells compared to the mutated counterpart. Furthermore, in silico analysis of glioma datasets showed a consistent deregulation of the signature according to the IDH mutation status in glioma tumour tissues. Ectopic expression of the signature negatively affects several glioma functions. Notably, it impacts the glioma invasive phenotype by directly targeting the invadopodia-related proteins TKS4, TKS5 and EFHD2. CONCLUSIONS We identified a three microRNA signature as a promising complementary or even an independent non-invasive diagnostic/prognostic biomarker. The signature displays oncosuppressive functions in glioma cells and impacts on proteins crucial for migration and invasion, providing potential targets for therapeutic intervention.
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Affiliation(s)
- Ana Belén Díaz Méndez
- grid.417520.50000 0004 1760 5276Department of Research, Advanced Diagnostics and Technological Innovation, Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
| | - Andrea Sacconi
- grid.417520.50000 0004 1760 5276Biostatistics and Bioinformatics Unit, Clinical Trial Center, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Elisa Tremante
- grid.417520.50000 0004 1760 5276Department of Research, Advanced Diagnostics and Technological Innovation, Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
| | - Valentina Lulli
- grid.416651.10000 0000 9120 6856Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Valentina Caprara
- grid.417520.50000 0004 1760 5276Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Laura Rosanò
- grid.417520.50000 0004 1760 5276Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
- grid.5326.20000 0001 1940 4177Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR), Rome, Italy
| | - Frauke Goeman
- grid.417520.50000 0004 1760 5276SAFU Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Mariantonia Carosi
- grid.417520.50000 0004 1760 5276Pathology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Marta Di Giuliani
- grid.417520.50000 0004 1760 5276Department of Research, Advanced Diagnostics and Technological Innovation, Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
| | - Giulia Vari
- grid.417520.50000 0004 1760 5276Department of Research, Advanced Diagnostics and Technological Innovation, Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
- grid.7841.aPhD Program in Molecular Medicine, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Antonio Silvani
- grid.417894.70000 0001 0707 5492Neuro-Oncology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Bianca Pollo
- grid.417894.70000 0001 0707 5492Neuro-Oncology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Carlo Garufi
- grid.416308.80000 0004 1805 3485Medical-Oncology Unit, San Camillo Forlanini Hospital, Rome, Italy
| | - Sara Ramponi
- grid.416308.80000 0004 1805 3485Medical-Oncology Unit, San Camillo Forlanini Hospital, Rome, Italy
| | - Giorgia Simonetti
- grid.417894.70000 0001 0707 5492Neuro-Oncology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Emilio Ciusani
- grid.417894.70000 0001 0707 5492Neuro-Oncology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Chiara Mandoj
- grid.417520.50000 0004 1760 5276Clinical Pathology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Stefano Scalera
- grid.417520.50000 0004 1760 5276SAFU Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
- grid.6530.00000 0001 2300 0941PhD Program in Cellular and Molecular Biology, Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
| | - Veronica Villani
- grid.417520.50000 0004 1760 5276Neuro-Oncology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Agnese Po
- grid.7841.aDepartment of Experimental Medicine, Sapienza University, Rome, Italy
| | - Elisabetta Ferretti
- grid.7841.aDepartment of Experimental Medicine, Sapienza University, Rome, Italy
| | - Giulia Regazzo
- grid.417520.50000 0004 1760 5276Department of Research, Advanced Diagnostics and Technological Innovation, Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
| | - Maria Giulia Rizzo
- grid.417520.50000 0004 1760 5276Department of Research, Advanced Diagnostics and Technological Innovation, Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
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18
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Khan P, Siddiqui JA, Kshirsagar PG, Venkata RC, Maurya SK, Mirzapoiazova T, Perumal N, Chaudhary S, Kanchan RK, Fatima M, Khan MA, Rehman AU, Lakshmanan I, Mahapatra S, Talmon GA, Kulkarni P, Ganti AK, Jain M, Salgia R, Batra SK, Nasser MW. MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis. Mol Cancer 2023; 22:1. [PMID: 36597126 PMCID: PMC9811802 DOI: 10.1186/s12943-022-01695-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 12/06/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood. METHODS To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions. RESULTS A consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4/FOXM1/RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC. CONCLUSIONS Our findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4/FOXM1/RRM2 axis and has a high potential for the development of novel SCLC therapies. MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis.
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Affiliation(s)
- Parvez Khan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Jawed Akhtar Siddiqui
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Prakash G Kshirsagar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | | | - Shailendra Kumar Maurya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Tamara Mirzapoiazova
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, 91010, USA
| | - Naveenkumar Perumal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Sanjib Chaudhary
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ranjana Kumari Kanchan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Mahek Fatima
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Md Arafat Khan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Asad Ur Rehman
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Imayavaramban Lakshmanan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Sidharth Mahapatra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Geoffrey A Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Prakash Kulkarni
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, 91010, USA
| | - Apar K Ganti
- Division of Oncology-Hematology, Department of Internal Medicine, VA-Nebraska Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ravi Salgia
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, 91010, USA
| | - Surinder Kumar Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Mohd Wasim Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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19
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Musatova OE, Rubtsov YP. Effects of glioblastoma-derived extracellular vesicles on the functions of immune cells. Front Cell Dev Biol 2023; 11:1060000. [PMID: 36960410 PMCID: PMC10028257 DOI: 10.3389/fcell.2023.1060000] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 02/22/2023] [Indexed: 03/09/2023] Open
Abstract
Glioblastoma is the most aggressive variant of glioma, the tumor of glial origin which accounts for 80% of brain tumors. Glioblastoma is characterized by astoundingly poor prognosis for patients; a combination of surgery, chemo- and radiotherapy used for clinical treatment of glioblastoma almost inevitably results in rapid relapse and development of more aggressive and therapy resistant tumor. Recently, it was demonstrated that extracellular vesicles produced by glioblastoma (GBM-EVs) during apoptotic cell death can bind to surrounding cells and change their phenotype to more aggressive. GBM-EVs participate also in establishment of immune suppressive microenvironment that protects glioblastoma from antigen-specific recognition and killing by T cells. In this review, we collected present data concerning characterization of GBM-EVs and study of their effects on different populations of the immune cells (T cells, macrophages, dendritic cells, myeloid-derived suppressor cells). We aimed at critical analysis of experimental evidence in order to conclude whether glioblastoma-derived extracellular vesicles are a major factor in immune evasion of this deadly tumor. We summarized data concerning potential use of GBM-EVs for non-invasive diagnostics of glioblastoma. Finally, the applicability of approaches aimed at blocking of GBM-EVs production or their fusion with target cells for treatment of glioblastoma was analyzed.
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Affiliation(s)
- Oxana E. Musatova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, RAS, Moscow, Russia
| | - Yury P. Rubtsov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, RAS, Moscow, Russia
- N.N.Blokhin Russian Cancer Research Center, Ministry of Health of the Russian Federation, Moscow, Russia
- *Correspondence: Yury P. Rubtsov,
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20
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Khan SU, Khan MI, Khan MU, Khan NM, Bungau S, Hassan SSU. Applications of Extracellular Vesicles in Nervous System Disorders: An Overview of Recent Advances. Bioengineering (Basel) 2022; 10:51. [PMID: 36671622 PMCID: PMC9854809 DOI: 10.3390/bioengineering10010051] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/19/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Diseases affecting the brain and spinal cord fall under the umbrella term "central nervous system disease". Most medications used to treat or prevent chronic diseases of the central nervous system cannot cross the blood-brain barrier (BBB) and hence cannot reach their intended target. Exosomes facilitate cellular material movement and signal transmission. Exosomes can pass the blood-brain barrier because of their tiny size, high delivery efficiency, minimal immunogenicity, and good biocompatibility. They enter brain endothelial cells via normal endocytosis and reverse endocytosis. Exosome bioengineering may be a method to produce consistent and repeatable isolation for clinical usage. Because of their tiny size, stable composition, non-immunogenicity, non-toxicity, and capacity to carry a wide range of substances, exosomes are indispensable transporters for targeted drug administration. Bioengineering has the potential to improve these aspects of exosomes significantly. Future research into exosome vectors must focus on redesigning the membrane to produce vesicles with targeting abilities to increase exosome targeting. To better understand exosomes and their potential as therapeutic vectors for central nervous system diseases, this article explores their basic biological properties, engineering modifications, and promising applications.
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Affiliation(s)
- Safir Ullah Khan
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Muhammad Imran Khan
- School of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Munir Ullah Khan
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, International Research Center for X Polymers, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
| | | | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
| | - Syed Shams ul Hassan
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
- Department of Natural Product Chemistry, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
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21
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Lei Q, Yang Y, Zhou W, Liu W, Li Y, Qi N, Li Q, Wen Z, Ding L, Huang X, Li Y, Wu J. MicroRNA-based therapy for glioblastoma: Opportunities and challenges. Eur J Pharmacol 2022; 938:175388. [PMID: 36403686 DOI: 10.1016/j.ejphar.2022.175388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 10/26/2022] [Accepted: 11/10/2022] [Indexed: 11/18/2022]
Abstract
Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor and is characterized by high mortality and morbidity rates and unpredictable clinical behavior. The disappointing prognosis for patients with GBM even after surgery and postoperative radiation and chemotherapy has fueled the search for specific targets to provide new insights into the development of modern therapies. MicroRNAs (miRNAs/miRs) act as oncomirs and tumor suppressors to posttranscriptionally regulate the expression of various genes and silence many target genes involved in cell proliferation, the cell cycle, apoptosis, invasion, stem cell behavior, angiogenesis, the microenvironment and chemo- and radiotherapy resistance, which makes them attractive candidates as prognostic biomarkers and therapeutic targets or agents to advance GBM therapeutics. However, one of the major challenges of successful miRNA-based therapy is the need for an effective and safe system to deliver therapeutic compounds to specific tumor cells or tissues in vivo, particularly systems that can cross the blood-brain barrier (BBB). This challenge has shifted gradually as progress has been achieved in identifying novel tumor-related miRNAs and their targets, as well as the development of nanoparticles (NPs) as new carriers to deliver therapeutic compounds. Here, we provide an up-to-date summary (in recent 5 years) of the current knowledge of GBM-related oncomirs, tumor suppressors and microenvironmental miRNAs, with a focus on their potential applications as prognostic biomarkers and therapeutic targets, as well as recent advances in the development of carriers for nontoxic miRNA-based therapy delivery systems and how they can be adapted for therapy.
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Affiliation(s)
- Qingchun Lei
- Department of Neurosurgery, Pu'er People's Hospital, Pu'er, 665000, Yunnan, PR China
| | - Yongmin Yang
- School of Life Sciences, Yunnan University, Kunming, 650091, Yunnan, PR China
| | - Wenhui Zhou
- School of Life Sciences, Yunnan University, Kunming, 650091, Yunnan, PR China
| | - Wenwen Liu
- School of Life Sciences, Yunnan University, Kunming, 650091, Yunnan, PR China; School of Medicine, Yunnan University, Kunming, 650091, Yunnan, PR China
| | - Yixin Li
- School of Life Sciences, Yunnan University, Kunming, 650091, Yunnan, PR China
| | - Nanchang Qi
- Clinical Laboratory, The First People's Hospital of Kunming, Kunming, 650021, Yunnan, PR China
| | - Qiangfeng Li
- Department of Neurosurgery, Pu'er People's Hospital, Pu'er, 665000, Yunnan, PR China
| | - Zhonghui Wen
- Department of Neurosurgery, Pu'er People's Hospital, Pu'er, 665000, Yunnan, PR China
| | - Lei Ding
- School of Life Sciences, Yunnan University, Kunming, 650091, Yunnan, PR China
| | - Xiaobin Huang
- Department of Neurosurgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650000, Yunnan, PR China
| | - Yu Li
- Yunnan Provincial Key Lab of Agricultural Biotechnology, Biotechnology and Germplasm Resources Institute, Yunnan Academy of Agricultural Sciences, Kunming, Yunnan, 650223, PR China.
| | - Jin Wu
- Department of Neurosurgery, Pu'er People's Hospital, Pu'er, 665000, Yunnan, PR China.
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22
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André-Grégoire G, Maghe C, Douanne T, Rosińska S, Spinelli F, Thys A, Trillet K, Jacobs KA, Ballu C, Dupont A, Lyne AM, Cavalli FM, Busnelli I, Hyenne V, Goetz JG, Bidère N, Gavard J. Inhibition of the pseudokinase MLKL alters extracellular vesicle release and reduces tumor growth in glioblastoma. iScience 2022; 25:105118. [PMID: 36185361 PMCID: PMC9519628 DOI: 10.1016/j.isci.2022.105118] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 08/04/2022] [Accepted: 09/08/2022] [Indexed: 11/25/2022] Open
Abstract
Extracellular vesicles (EVs) are lipid-based nanosized particles that convey biological material from donor to recipient cells. EVs play key roles in glioblastoma progression because glioblastoma stem-like cells (GSCs) release pro-oncogenic, pro-angiogenic, and pro-inflammatory EVs. However, the molecular basis of EV release remains poorly understood. Here, we report the identification of the pseudokinase MLKL, a crucial effector of cell death by necroptosis, as a regulator of the constitutive secretion of EVs in GSCs. We find that genetic, protein, and pharmacological targeting of MLKL alters intracellular trafficking and EV release, and reduces GSC expansion. Nevertheless, this function ascribed to MLKL appears independent of its role during necroptosis. In vivo, pharmacological inhibition of MLKL reduces the tumor burden and the level of plasmatic EVs. This work highlights the necroptosis-independent role of MLKL in vesicle release and suggests that interfering with EVs is a promising therapeutic option to sensitize glioblastoma cells.
The pseudokinase MLKL governs extracellular vesicle release in glioblastoma cells Blocking MLKL is deleterious to glioblastoma cell expansion in vitro and in vivo MLKL action in glioblastoma patient cells does not involve necroptosis death MLKL inhibition potentiates TMZ-induced cell death in glioblastoma patient cells
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23
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Verdugo E, Puerto I, Medina MÁ. An update on the molecular biology of glioblastoma, with clinical implications and progress in its treatment. CANCER COMMUNICATIONS (LONDON, ENGLAND) 2022; 42:1083-1111. [PMID: 36129048 DOI: 10.1002/cac2.12361] [Citation(s) in RCA: 102] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 08/07/2022] [Accepted: 09/05/2022] [Indexed: 11/08/2022]
Abstract
Glioblastoma multiforme (GBM) is the most aggressive and common malignant primary brain tumor. Patients with GBM often have poor prognoses, with a median survival of ∼15 months. Enhanced understanding of the molecular biology of central nervous system tumors has led to modifications in their classifications, the most recent of which classified these tumors into new categories and made some changes in their nomenclature and grading system. This review aims to give a panoramic view of the last 3 years' findings in glioblastoma characterization, its heterogeneity, and current advances in its treatment. Several molecular parameters have been used to achieve an accurate and personalized characterization of glioblastoma in patients, including epigenetic, genetic, transcriptomic and metabolic features, as well as age- and sex-related patterns and the involvement of several noncoding RNAs in glioblastoma progression. Astrocyte-like neural stem cells and outer radial glial-like cells from the subventricular zone have been proposed as agents involved in GBM of IDH-wildtype origin, but this remains controversial. Glioblastoma metabolism is characterized by upregulation of the PI3K/Akt/mTOR signaling pathway, promotion of the glycolytic flux, maintenance of lipid storage, and other features. This metabolism also contributes to glioblastoma's resistance to conventional therapies. Tumor heterogeneity, a hallmark of GBM, has been shown to affect the genetic expression, modulation of metabolic pathways, and immune system evasion. GBM's aggressive invasion potential is modulated by cell-to-cell crosstalk within the tumor microenvironment and altered expressions of specific genes, such as ANXA2, GBP2, FN1, PHIP, and GLUT3. Nevertheless, the rising number of active clinical trials illustrates the efforts to identify new targets and drugs to treat this malignancy. Immunotherapy is still relevant for research purposes, given the amount of ongoing clinical trials based on this strategy to treat GBM, and neoantigen and nucleic acid-based vaccines are gaining importance due to their antitumoral activity by inducing the immune response. Furthermore, there are clinical trials focused on the PI3K/Akt/mTOR axis, angiogenesis, and tumor heterogeneity for developing molecular-targeted therapies against GBM. Other strategies, such as nanodelivery and computational models, may improve the drug pharmacokinetics and the prognosis of patients with GBM.
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Affiliation(s)
- Elena Verdugo
- Department of Molecular Biology and Biochemistry, University of Málaga, Málaga, Málaga, E-29071, Spain
| | - Iker Puerto
- Department of Molecular Biology and Biochemistry, University of Málaga, Málaga, Málaga, E-29071, Spain
| | - Miguel Ángel Medina
- Department of Molecular Biology and Biochemistry, University of Málaga, Málaga, Málaga, E-29071, Spain.,Biomedical Research Institute of Málaga (IBIMA-Plataforma Bionand), Málaga, Málaga, E-29071, Spain.,Spanish Biomedical Research Network Center for Rare Diseases (CIBERER), Spanish Health Institute Carlos III (ISCIII), Málaga, Málaga, E-29071, Spain
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24
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Mumtaz I, Ayaz MO, Khan MS, Manzoor U, Ganayee MA, Bhat AQ, Dar GH, Alghamdi BS, Hashem AM, Dar MJ, Ashraf GM, Maqbool T. Clinical relevance of biomarkers, new therapeutic approaches, and role of post-translational modifications in the pathogenesis of Alzheimer's disease. Front Aging Neurosci 2022; 14:977411. [PMID: 36158539 PMCID: PMC9490081 DOI: 10.3389/fnagi.2022.977411] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/18/2022] [Indexed: 12/14/2022] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive loss of cognitive functions like thinking, memory, reasoning, behavioral abilities, and social skills thus affecting the ability of a person to perform normal daily functions independently. There is no definitive cure for this disease, and treatment options available for the management of the disease are not very effective as well. Based on histopathology, AD is characterized by the accumulation of insoluble deposits of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs). Although several molecular events contribute to the formation of these insoluble deposits, the aberrant post-translational modifications (PTMs) of AD-related proteins (like APP, Aβ, tau, and BACE1) are also known to be involved in the onset and progression of this disease. However, early diagnosis of the disease as well as the development of effective therapeutic approaches is impeded by lack of proper clinical biomarkers. In this review, we summarized the current status and clinical relevance of biomarkers from cerebrospinal fluid (CSF), blood and extracellular vesicles involved in onset and progression of AD. Moreover, we highlight the effects of several PTMs on the AD-related proteins, and provide an insight how these modifications impact the structure and function of proteins leading to AD pathology. Finally, for disease-modifying therapeutics, novel approaches, and targets are discussed for the successful treatment and management of AD.
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Affiliation(s)
- Ibtisam Mumtaz
- Laboratory of Nanotherapeutics and Regenerative Medicine, Department of Nanotechnology, University of Kashmir, Srinagar, India
| | - Mir Owais Ayaz
- Laboratory of Cell and Molecular Biology, Department of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, India
- Centre for Scientific and Innovative Research, Ghaziabad, Utter Pradesh, India
| | - Mohamad Sultan Khan
- Neurobiology and Molecular Chronobiology Laboratory, Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Umar Manzoor
- Laboratory of Immune and Inflammatory Disease, Jeju Research Institute of Pharmaceutical Sciences, Jeju National University, Jeju, South Korea
| | - Mohd Azhardin Ganayee
- Laboratory of Nanotherapeutics and Regenerative Medicine, Department of Nanotechnology, University of Kashmir, Srinagar, India
- Department of Chemistry, Indian Institute of Technology Madras, Chennai, India
| | - Aadil Qadir Bhat
- Laboratory of Cell and Molecular Biology, Department of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, India
- Centre for Scientific and Innovative Research, Ghaziabad, Utter Pradesh, India
| | - Ghulam Hassan Dar
- Sri Pratap College, Cluster University Srinagar, Jammu and Kashmir, India
| | - Badrah S. Alghamdi
- Department of Physiology, Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Pre-clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Anwar M. Hashem
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohd Jamal Dar
- Laboratory of Cell and Molecular Biology, Department of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, India
- Centre for Scientific and Innovative Research, Ghaziabad, Utter Pradesh, India
| | - Gulam Md. Ashraf
- Pre-clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Tariq Maqbool
- Laboratory of Nanotherapeutics and Regenerative Medicine, Department of Nanotechnology, University of Kashmir, Srinagar, India
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25
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Iglesia RP, Prado MB, Alves RN, Escobar MIM, Fernandes CFDL, Fortes ACDS, Souza MCDS, Boccacino JM, Cangiano G, Soares SR, de Araújo JPA, Tiek DM, Goenka A, Song X, Keady JR, Hu B, Cheng SY, Lopes MH. Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression. Front Cell Dev Biol 2022; 10:907423. [PMID: 35784465 PMCID: PMC9242006 DOI: 10.3389/fcell.2022.907423] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/26/2022] [Indexed: 11/28/2022] Open
Abstract
Non-canonical secretion pathways, collectively known as unconventional protein secretion (UPS), are alternative secretory mechanisms usually associated with stress-inducing conditions. UPS allows proteins that lack a signal peptide to be secreted, avoiding the conventional endoplasmic reticulum-Golgi complex secretory pathway. Molecules that generally rely on the canonical pathway to be secreted may also use the Golgi bypass, one of the unconventional routes, to reach the extracellular space. UPS studies have been increasingly growing in the literature, including its implication in the biology of several diseases. Intercellular communication between brain tumor cells and the tumor microenvironment is orchestrated by various molecules, including canonical and non-canonical secreted proteins that modulate tumor growth, proliferation, and invasion. Adult brain tumors such as gliomas, which are aggressive and fatal cancers with a dismal prognosis, could exploit UPS mechanisms to communicate with their microenvironment. Herein, we provide functional insights into the UPS machinery in the context of tumor biology, with a particular focus on the secreted proteins by alternative routes as key regulators in the maintenance of brain tumors.
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Affiliation(s)
- Rebeca Piatniczka Iglesia
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil,The Robert H. Lurie Comprehensive Cancer Center, The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Mariana Brandão Prado
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Rodrigo Nunes Alves
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Maria Isabel Melo Escobar
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Camila Felix de Lima Fernandes
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Ailine Cibele dos Santos Fortes
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Maria Clara da Silva Souza
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Jacqueline Marcia Boccacino
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Giovanni Cangiano
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Samuel Ribeiro Soares
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - João Pedro Alves de Araújo
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Deanna Marie Tiek
- The Robert H. Lurie Comprehensive Cancer Center, The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Anshika Goenka
- The Robert H. Lurie Comprehensive Cancer Center, The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Xiao Song
- The Robert H. Lurie Comprehensive Cancer Center, The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Jack Ryan Keady
- The Robert H. Lurie Comprehensive Cancer Center, The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Bo Hu
- The Robert H. Lurie Comprehensive Cancer Center, The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Shi Yuan Cheng
- The Robert H. Lurie Comprehensive Cancer Center, The Ken and Ruth Davee Department of Neurology, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Marilene Hohmuth Lopes
- Laboratory of Neurobiology and Stem Cells, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil,*Correspondence: Marilene Hohmuth Lopes,
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26
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Sivanantham A, Jin Y. Impact of Storage Conditions on EV Integrity/Surface Markers and Cargos. Life (Basel) 2022; 12:life12050697. [PMID: 35629364 PMCID: PMC9146501 DOI: 10.3390/life12050697] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/05/2022] [Accepted: 05/06/2022] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) are small biological particles released into biofluids by every cell. Based on their size, they are classified into small EVs (<100 nm or <200 nm) and medium or large EVs (>200 nm). In recent years, EVs have garnered interest for their potential medical applications, including disease diagnosis, cell-based biotherapies, targeted drug delivery systems, and others. Currently, the long-term and short-term storage temperatures for biofluids and EVs are −80 °C and 4 °C, respectively. The storage capacity of EVs can depend on their number, size, function, temperature, duration, and freeze−thaw cycles. While these parameters are increasingly studied, the effects of preservation and storage conditions of EVs on their integrity remain to be understood. Knowledge gaps in these areas may ultimately impede the widespread applicability of EVs. Therefore, this review summarizes the current knowledge on the effect of storage conditions on EVs and their stability and critically explores prospective ways for improving long-term storage conditions to ensure EV stability.
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Affiliation(s)
| | - Yang Jin
- Correspondence: ; Tel.: +1-617-358-1356
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27
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Recent advances in the therapeutic strategies of glioblastoma multiforme. Neuroscience 2022; 491:240-270. [PMID: 35395355 DOI: 10.1016/j.neuroscience.2022.03.030] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 03/21/2022] [Accepted: 03/24/2022] [Indexed: 02/07/2023]
Abstract
Glioblastoma multiforme (GBM) is one of the most common, most formidable, and deadliest malignant types of primary astrocytoma with a poor prognosis. At present, the standard of care includes surgical tumor resection, followed by radiation therapy concomitant with chemotherapy and temozolomide. New developments and significant advances in the treatment of GBM have been achieved in recent decades. However, despite the advances, recurrence is often inevitable, and the survival of patients remains low. Various factors contribute to the difficulty in identifying an effective therapeutic option, among which are tumor complexity, the presence of the blood-brain barrier (BBB), and the presence of GBM cancer stem cells, prompting the need for improving existing treatment approaches and investigating new treatment alternatives for ameliorating the treatment strategies of GBM. In this review, we outline some of the most recent literature on the various available treatment options such as surgery, radiotherapy, cytotoxic chemotherapy, gene therapy, immunotherapy, phototherapy, nanotherapy, and tumor treating fields in the treatment of GBM, and we list some of the potential future directions of GBM. The reviewed studies confirm that GBM is a sophisticated disease with several challenges for scientists to address. Hence, more studies and a multimodal therapeutic approach are crucial to yield an effective cure and prolong the survival of GBM patients.
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28
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Bouzari B, Mohammadi S, Bokov DO, Krasnyuk II, Hosseini-Fard SR, Hajibaba M, Mirzaei R, Karampoor S. Angioregulatory role of miRNAs and exosomal miRNAs in glioblastoma pathogenesis. Biomed Pharmacother 2022; 148:112760. [PMID: 35228062 DOI: 10.1016/j.biopha.2022.112760] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 02/23/2022] [Accepted: 02/23/2022] [Indexed: 11/19/2022] Open
Abstract
Glioblastoma (GB) is a highly aggressive cancer of the central nervous system, occurring in the brain or spinal cord. Many factors such as angiogenesis are associated with GB development. Angiogenesis is a procedure by which the pre-existing blood vessels create new vessels that play an essential role in health and disease, including tumors. Also, angiogenesis is one of the significant factors thought to be responsible for treatment resistance in many tumors, including GB. Hence, an improved understanding of the molecular processes underlying GB angiogenesis will pave the way for developing potential new treatments. Recently, it has been found that microRNAs (miRNAs) and exosomal miRNAs have a crucial role in inducing or inhibiting the angiogenesis process in GB development. A better knowledge of the miRNA's regulation pathway in the angiogenesis process in cancer offers unique mechanistic insight into the mechanism of tumor-associated neovascularization. Because of advancements in miRNA characterization and delivery methods, miRNAs can also be employed in clinical settings as potential biomarkers for anti-angiogenic treatment response as well as therapies targeting tumor angiogenesis. The recent finding and insights about miRNAs' angioregulatory role and exosomal miRNAs in GB are provided throughout the review. Also, we discuss the new concept of miRNAs-based therapies for GB in the future.
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Affiliation(s)
- Behnaz Bouzari
- Department of Pathology, Firouzgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Shabahang Mohammadi
- ENT and Head and Neck Research Center and Department, Firoozgar General Hospital, The Five Senses Health Institute, Iran
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow 119991, Russian Federation; Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, 2/14 Ustyinsky pr., Moscow 109240, Russian Federation
| | - Ivan Ivanovich Krasnyuk
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow 119991, Russian Federation
| | - Seyed Reza Hosseini-Fard
- Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Marzieh Hajibaba
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
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29
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Fang Z, Zhang X, Huang H, Wu J. Exosome based miRNA delivery strategy for disease treatment. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2021.11.050] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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30
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Salarpour S, Barani M, Pardakhty A, Khatami M, Pal Singh Chauhan N. The application of exosomes and Exosome-nanoparticle in treating brain disorders. J Mol Liq 2022. [DOI: 10.1016/j.molliq.2022.118549] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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31
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Glioblastoma Microenvironment and Cellular Interactions. Cancers (Basel) 2022; 14:cancers14041092. [PMID: 35205842 PMCID: PMC8870579 DOI: 10.3390/cancers14041092] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/31/2022] [Accepted: 02/16/2022] [Indexed: 12/11/2022] Open
Abstract
Simple Summary This paper summarizes the crosstalk between tumor/non-tumor cells and other elements of the glioblastoma (GB) microenvironment. In tumor pathology, glial cells result in the highest number of cancers, and GB is considered the most lethal tumor of the central nervous system (CNS). The tumor microenvironment (TME) is a complex peritumoral hallo composed of tumor cells and several non-tumor cells (e.g., nervous cells, stem cells, fibroblasts, vascular and immune cells), which might be a key factor for the ineffective treatment since the microenvironment modulates the biologic status of the tumor with the increase in its evasion capacity. A deeper understanding of cell–cell interactions in the TME and with the tumor cells could be the basis for a more efficient therapy. Abstract The central nervous system (CNS) represents a complex network of different cells, such as neurons, glial cells, and blood vessels. In tumor pathology, glial cells result in the highest number of cancers, and glioblastoma (GB) is considered the most lethal tumor in this region. The development of GB leads to the infiltration of healthy tissue through the interaction between all the elements of the brain network. This results in a GB microenvironment, a complex peritumoral hallo composed of tumor cells and several non-tumor cells (e.g., nervous cells, stem cells, fibroblasts, vascular and immune cells), which might be the principal factor for the ineffective treatment due to the fact that the microenvironment modulates the biologic status of the tumor with the increase in its evasion capacity. Crosstalk between glioma cells and the brain microenvironment finally inhibits the beneficial action of molecular pathways, favoring the development and invasion of the tumor and its increasing resistance to treatment. A deeper understanding of cell–cell interactions in the tumor microenvironment (TME) and with the tumor cells could be the basis for a more efficient therapy.
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32
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Ponomarev A, Gilazieva Z, Solovyeva V, Allegrucci C, Rizvanov A. Intrinsic and Extrinsic Factors Impacting Cancer Stemness and Tumor Progression. Cancers (Basel) 2022; 14:970. [PMID: 35205716 PMCID: PMC8869813 DOI: 10.3390/cancers14040970] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/03/2022] [Accepted: 02/08/2022] [Indexed: 02/06/2023] Open
Abstract
Tumor heterogeneity represents an important limitation to the development of effective cancer therapies. The presence of cancer stem cells (CSCs) and their differentiation hierarchies contribute to cancer complexity and confer tumors the ability to grow, resist treatment, survive unfavorable conditions, and invade neighboring and distant tissues. A large body of research is currently focusing on understanding the properties of CSCs, including their cellular and molecular origin, as well as their biological behavior in different tumor types. In turn, this knowledge informs strategies for targeting these tumor initiating cells and related cancer stemness. Cancer stemness is modulated by the tumor microenvironment, which influences CSC function and survival. Several advanced in vitro models are currently being developed to study cancer stemness in order to advance new knowledge of the key molecular pathways involved in CSC self-renewal and dormancy, as well as to mimic the complexity of patients' tumors in pre-clinical drug testing. In this review, we discuss CSCs and the modulation of cancer stemness by the tumor microenvironment, stemness factors and signaling pathways. In addition, we introduce current models that allow the study of CSCs for the development of new targeted therapies.
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Affiliation(s)
- Alexey Ponomarev
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
| | - Zarema Gilazieva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
| | - Valeriya Solovyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
| | - Cinzia Allegrucci
- School of Veterinary Medicine and Science (SVMS) and Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK;
| | - Albert Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
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33
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Zhang Z, Huang Q, Yu L, Zhu D, Li Y, Xue Z, Hua Z, Luo X, Song Z, Lu C, Zhao T, Liu Y. The Role of miRNA in Tumor Immune Escape and miRNA-Based Therapeutic Strategies. Front Immunol 2022; 12:807895. [PMID: 35116035 PMCID: PMC8803638 DOI: 10.3389/fimmu.2021.807895] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/22/2021] [Indexed: 12/19/2022] Open
Abstract
Tumor immune escape is a critical step in the malignant progression of tumors and one of the major barriers to immunotherapy, making immunotherapy the most promising therapeutic approach against tumors today. Tumor cells evade immune surveillance by altering the structure of their own, or by causing abnormal gene and protein expression, allowing for unrestricted development and invasion. These genetic or epigenetic changes have been linked to microRNAs (miRNAs), which are important determinants of post-transcriptional regulation. Tumor cells perform tumor immune escape by abnormally expressing related miRNAs, which reduce the killing effect of immune cells, disrupt the immune response, and disrupt apoptotic pathways. Consequently, there is a strong trend toward thoroughly investigating the role of miRNAs in tumor immune escape and utilizing them in tumor treatment. However, because of the properties of miRNAs, there is an urgent need for a safe, targeted and easily crossed biofilm vehicle to protect and deliver them in vivo, and exosomes, with their excellent biological properties, have successfully beaten traditional vehicles to provide strong support for miRNA therapy. This review summarizes the multiple roles of miRNAs in tumor immune escape and discusses their potential applications as an anti-tumor therapy. Also, this work proposes exosomes as a new opportunity for miRNA therapy, to provide novel ideas for the development of more effective tumor-fighting therapeutic approaches based on miRNAs.
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Affiliation(s)
- Zhengjia Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Qingcai Huang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Liuchunyang Yu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Dongjie Zhu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yang Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zeyu Xue
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhenglai Hua
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xinyi Luo
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhiqian Song
- Institute of Basic Theory, China Academy of Chinese Medical Sciences, Beijing, China
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Yuanyan Liu, ; Cheng Lu, ; Ting Zhao,
| | - Ting Zhao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Yuanyan Liu, ; Cheng Lu, ; Ting Zhao,
| | - Yuanyan Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Yuanyan Liu, ; Cheng Lu, ; Ting Zhao,
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34
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Peng J, Liang Q, Xu Z, Cai Y, Peng B, Li J, Zhang W, Kang F, Hong Q, Yan Y, Zhang M. Current Understanding of Exosomal MicroRNAs in Glioma Immune Regulation and Therapeutic Responses. Front Immunol 2022; 12:813747. [PMID: 35095909 PMCID: PMC8796999 DOI: 10.3389/fimmu.2021.813747] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/27/2021] [Indexed: 02/05/2023] Open
Abstract
Exosomes, the small extracellular vesicles, are released by multiple cell types, including tumor cells, and represent a novel avenue for intercellular communication via transferring diverse biomolecules. Recently, microRNAs (miRNAs) were demonstrated to be enclosed in exosomes and therefore was protected from degradation. Such exosomal miRNAs can be transmitted to recipient cells where they could regulate multiple cancer-associated biological processes. Accumulative evidence suggests that exosomal miRNAs serve essential roles in modifying the glioma immune microenvironment and potentially affecting the malignant behaviors and therapeutic responses. As exosomal miRNAs are detectable in almost all kinds of biofluids and correlated with clinicopathological characteristics of glioma, they might be served as promising biomarkers for gliomas. We reviewed the novel findings regarding the biological functions of exosomal miRNAs during glioma pathogenesis and immune regulation. Furthermore, we elaborated on their potential clinical applications as biomarkers in glioma diagnosis, prognosis and treatment response prediction. Finally, we summarized the accessible databases that can be employed for exosome-associated miRNAs identification and functional exploration of cancers, including glioma.
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Affiliation(s)
- Jinwu Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- Department of Pathology, Xiangya Changde Hospital, Changde, China
| | - Qiuju Liang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
| | - Zhijie Xu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- Department of Pathology, Xiangya Changde Hospital, Changde, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yuan Cai
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Bi Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Jianbo Li
- Department of Pathology, Xiangya Changde Hospital, Changde, China
| | - Wenqin Zhang
- Department of Pathology, Xiangya Changde Hospital, Changde, China
| | - Fanhua Kang
- Department of Pathology, Xiangya Changde Hospital, Changde, China
| | - Qianhui Hong
- Department of Pathology, Xiangya Changde Hospital, Changde, China
| | - Yuanliang Yan
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Mingyu Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
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35
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The von Willebrand factor stamps plasmatic extracellular vesicles from glioblastoma patients. Sci Rep 2021; 11:22792. [PMID: 34815502 PMCID: PMC8611030 DOI: 10.1038/s41598-021-02254-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 11/11/2021] [Indexed: 01/08/2023] Open
Abstract
Glioblastoma is a devastating tumor of the central nervous system characterized by a poor survival and an extremely dark prognosis, making its diagnosis, treatment and monitoring highly challenging. Numerous studies have highlighted extracellular vesicles (EVs) as key players of tumor growth, invasiveness and resistance, as they carry and disseminate oncogenic material in the local tumor microenvironment and at distance. However, whether their quality and quantity reflect individual health status and changes in homeostasis is still not fully elucidated. Here, we separated EVs from plasma collected at different time points alongside with the clinical management of GBM patients. Our findings confirm that plasmatic EVs could be separated and characterized with standardized protocols, thereby ensuring the reliability of measuring vesiclemia, i.e. extracellular vesicle concentration in plasma. This unveils that vesiclemia is a dynamic parameter, which could be reflecting tumor burden and/or response to treatments. Further label-free liquid chromatography tandem mass spectrometry unmasks the von Willebrand Factor (VWF) as a selective protein hallmark for GBM-patient EVs. Our data thus support the notion that EVs from GBM patients showed differential protein cargos that can be further surveyed in circulating EVs, together with vesiclemia.
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36
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Gao L, Nie X, Gou R, Hu Y, Dong H, Li X, Lin B. Exosomal ANXA2 derived from ovarian cancer cells regulates epithelial-mesenchymal plasticity of human peritoneal mesothelial cells. J Cell Mol Med 2021; 25:10916-10929. [PMID: 34725902 PMCID: PMC8642686 DOI: 10.1111/jcmm.16983] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 09/14/2021] [Accepted: 09/23/2021] [Indexed: 01/15/2023] Open
Abstract
Ovarian cancer, one of the malignant gynaecological tumours with the highest mortality rate among female reproductive system, is prone to metastasis, recurrence and chemotherapy resistance, causing a poor prognosis. Exosomes can regulate the epithelial‐mesenchymal plasticity of tumour cells, remodel surrounding tumour microenvironment, and affect tumour cell proliferation, invasion and metastasis. However, the function and mechanism of exosomes in the intraperitoneal implantation of ovarian cancer remain unclear. In this study, exosomal annexin A2 (ANXA2) derived from ovarian cancer cells was co‐cultured with human peritoneal mesothelial (HMrSV5) cells; functional experiments were conducted to explore the effects of exosomal ANXA2 on the biological behaviour of HMrSV5 and the related mechanisms. This study showed that ANXA2 in ovarian cancer cells can be transferred to HMrSV5 cells through exosomes, exosomal ANXA2 can not only promote the migration, invasion and apoptosis of HMrSV5 cells, but also regulates morphological changes and fibrosis of HMrSV5 cells. Furthermore, ANXA2 promotes the mesothelial‐mesenchymal transition (MMT) and degradation of the extracellular matrix of HMrSV5 cells through PI3K/AKT/mTOR pathway, finally affects pre‐metastasis microenvironment of ovarian cancer, which provides a new theoretical basis for the mechanism of intraperitoneal implantation and metastasis of ovarian cancer.
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Affiliation(s)
- Lingling Gao
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China
| | - Xin Nie
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China
| | - Rui Gou
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China
| | - Yuexin Hu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China
| | - Hui Dong
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China
| | - Xiao Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China
| | - Bei Lin
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China
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Barthel L, Hadamitzky M, Dammann P, Schedlowski M, Sure U, Thakur BK, Hetze S. Glioma: molecular signature and crossroads with tumor microenvironment. Cancer Metastasis Rev 2021; 41:53-75. [PMID: 34687436 PMCID: PMC8924130 DOI: 10.1007/s10555-021-09997-9] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/06/2021] [Indexed: 11/29/2022]
Abstract
In patients with glioblastoma, the average survival time with current treatments is short, mainly due to recurrences and resistance to therapy. This insufficient treatment success is, in large parts, due to the tremendous molecular heterogeneity of gliomas, which affects the overall prognosis and response to therapies and plays a vital role in gliomas’ grading. In addition, the tumor microenvironment is a major player for glioma development and resistance to therapy. Active communication between glioma cells and local or neighboring healthy cells and the immune environment promotes the cancerogenic processes and contributes to establishing glioma stem cells, which drives therapy resistance. Besides genetic alterations in the primary tumor, tumor-released factors, cytokines, proteins, extracellular vesicles, and environmental influences like hypoxia provide tumor cells the ability to evade host tumor surveillance machinery and promote disease progression. Moreover, there is increasing evidence that these players affect the molecular biological properties of gliomas and enable inter-cell communication that supports pro-cancerogenic cell properties. Identifying and characterizing these complex mechanisms are inevitably necessary to adapt therapeutic strategies and to develop novel measures. Here we provide an update about these junctions where constant traffic of biomolecules adds complexity in the management of glioblastoma.
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Affiliation(s)
- Lennart Barthel
- Department of Neurosurgery and Spine Surgery, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Hufelandstraße 55, 45147, Essen, Germany. .,Institute of Medical Psychology and Behavioral Immunobiology Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany.
| | - Martin Hadamitzky
- Institute of Medical Psychology and Behavioral Immunobiology Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany
| | - Philipp Dammann
- Department of Neurosurgery and Spine Surgery, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Hufelandstraße 55, 45147, Essen, Germany
| | - Manfred Schedlowski
- Institute of Medical Psychology and Behavioral Immunobiology Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany.,Department of Clinical Neuroscience, Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ulrich Sure
- Department of Neurosurgery and Spine Surgery, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Hufelandstraße 55, 45147, Essen, Germany
| | - Basant Kumar Thakur
- Cancer Exosome Research Lab, Department of Pediatric Hematology and Oncology, University Hospital Essen, 45147, Essen, Germany
| | - Susann Hetze
- Department of Neurosurgery and Spine Surgery, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Hufelandstraße 55, 45147, Essen, Germany.,Institute of Medical Psychology and Behavioral Immunobiology Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, 45147, Essen, Germany
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38
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Aili Y, Maimaitiming N, Mahemuti Y, Qin H, Wang Y, Wang Z. The Role of Exosomal miRNAs in Glioma: Biological Function and Clinical Application. Front Oncol 2021; 11:686369. [PMID: 34540663 PMCID: PMC8442992 DOI: 10.3389/fonc.2021.686369] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 08/10/2021] [Indexed: 12/16/2022] Open
Abstract
Gliomas are complex and heterogeneous central nervous system tumors with poor prognosis. Despite the increasing development of aggressive combination therapies, the prognosis of glioma is generally unsatisfactory. Exosomal microRNA (miRNA) has been successfully used in other diseases as a reliable biomarker and even therapeutic target. Recent studies show that exosomal miRNA plays an important role in glioma occurrence, development, invasion, metastasis, and treatment resistance. However, the association of exosomal miRNA between glioma has not been systemically characterized. This will provide a theoretical basis for us to further explore the relationship between exosomal miRNAs and glioma and also has a positive clinical significance in the innovative diagnosis and treatment of glioma.
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Affiliation(s)
- Yirizhati Aili
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | | | - Yusufu Mahemuti
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Hu Qin
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Yongxin Wang
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Zengliang Wang
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
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39
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Wei J, Gilboa E, Calin GA, Heimberger AB. Immune Modulatory Short Noncoding RNAs Targeting the Glioblastoma Microenvironment. Front Oncol 2021; 11:682129. [PMID: 34532286 PMCID: PMC8438301 DOI: 10.3389/fonc.2021.682129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 08/11/2021] [Indexed: 12/22/2022] Open
Abstract
Glioblastomas are heterogeneous and have a poor prognosis. Glioblastoma cells interact with their neighbors to form a tumor-permissive and immunosuppressive microenvironment. Short noncoding RNAs are relevant mediators of the dynamic crosstalk among cancer, stromal, and immune cells in establishing the glioblastoma microenvironment. In addition to the ease of combinatorial strategies that are capable of multimodal modulation for both reversing immune suppression and enhancing antitumor immunity, their small size provides an opportunity to overcome the limitations of blood-brain-barrier (BBB) permeability. To enhance glioblastoma delivery, these RNAs have been conjugated with various molecules or packed within delivery vehicles for enhanced tissue-specific delivery and increased payload. Here, we focus on the role of RNA therapeutics by appraising which types of nucleotides are most effective in immune modulation, lead therapeutic candidates, and clarify how to optimize delivery of the therapeutic RNAs and their conjugates specifically to the glioblastoma microenvironment.
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Affiliation(s)
- Jun Wei
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Eli Gilboa
- Department of Microbiology & Immunology, Dodson Interdisciplinary Immunotherapy Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States
| | - George A Calin
- Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Amy B Heimberger
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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40
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Exosomes as cell-derivative carriers in the diagnosis and treatment of central nervous system diseases. Drug Deliv Transl Res 2021; 12:1047-1079. [PMID: 34365576 PMCID: PMC8942947 DOI: 10.1007/s13346-021-01026-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2021] [Indexed: 02/08/2023]
Abstract
Exosomes are extracellular vesicles with the diameter ranging from 50 to 100 nm and are found in different body fluids such as blood, cerebrospinal fluid (CSF), urine and saliva. Like in case of various diseases, based on the parent cells, the content of exosomes (protein, mRNA, miRNA, DNA, lipids and metabolites) varies and thus can be utilized as potential biomarker for diagnosis and prognosis of the brain diseases. Furthermore, utilizing the natural potential exosomes to cross the blood–brain barrier and by specifically decorating it with the ligand as per the desired brain sites therapeutics can be delivered to brain parenchyma. This review article conveys the importance of exosomes and their use in the treatment and diagnosis of brain/central nervous system diseases.
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41
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Luo X, Jean-Toussaint R, Sacan A, Ajit SK. Differential RNA packaging into small extracellular vesicles by neurons and astrocytes. Cell Commun Signal 2021; 19:75. [PMID: 34246289 PMCID: PMC8272329 DOI: 10.1186/s12964-021-00757-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 06/03/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Small extracellular vesicles (sEVs) mediate intercellular communication by transferring RNA, proteins, and lipids to recipient cells. These cargo molecules are selectively loaded into sEVs and mirror the physiological state of the donor cells. Given that sEVs can cross the blood-brain barrier and their composition can change in neurological disorders, the molecular signatures of sEVs in circulation can be potential disease biomarkers. Characterizing the molecular composition of sEVs from different cell types is an important first step in determining which donor cells contribute to the circulating sEVs. METHODS Cell culture supernatants from primary mouse cortical neurons and astrocytes were used to purify sEVs by differential ultracentrifugation and sEVs were characterized using nanoparticle tracking analysis, transmission electron microscopy and western blot. RNA sequencing was used to determine differential expression and loading patterns of miRNAs in sEVs released by primary neurons and astrocytes. Motif analysis was conducted on enriched miRNAs in sEVs and their respective donor cells. RESULTS Sequencing total cellular RNA, and miRNAs from sEVs isolated from culture media of postnatal mouse cortical neurons and astrocytes revealed a distinct profile between sEVs and their corresponding cells. Though the total number of detected miRNAs in astrocytes was greater than neurons, neurons expressed more sEV-associated miRNAs than astrocytes. Only 20.7% of astrocytic miRNAs were loaded into sEVs, while 41.0% of neuronal miRNAs were loaded into sEVs, suggesting differences in the cellular sorting mechanisms. We identified short RNA sequence motifs, or EXOmotifs, on the miRNAs that were differentially loaded or excluded from sEVs. A sequence motif GUAC was enriched in astrocytic sEVs. miRNAs preferably retained in neurons or astrocytes had a similar RNA motif CACACA, suggesting a cell-type-independent mechanism to maintain cellular miRNAs. mRNAs of five RNA-binding proteins associated with passive or active RNA sorting into sEVs were differentially expressed between neurons and astrocytes, one of which, major vault protein was higher in astrocytes than in neurons and detected in astrocytic sEVs. CONCLUSIONS Our studies suggest differences in RNA sorting into sEVs. These differences in miRNA signatures can be used for determining the cellular sources of sEVs altered in neurological disorders. Video abstract.
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Affiliation(s)
- Xuan Luo
- Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102 USA
| | - Renée Jean-Toussaint
- Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102 USA
| | - Ahmet Sacan
- School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104 USA
| | - Seena K. Ajit
- Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102 USA
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Mahjoum S, Rufino-Ramos D, Pereira de Almeida L, Broekman MLD, Breakefield XO, van Solinge TS. Living Proof of Activity of Extracellular Vesicles in the Central Nervous System. Int J Mol Sci 2021; 22:ijms22147294. [PMID: 34298912 PMCID: PMC8303915 DOI: 10.3390/ijms22147294] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/01/2021] [Accepted: 07/03/2021] [Indexed: 12/27/2022] Open
Abstract
The central nervous system (CNS) consists of a heterogeneous population of cells with highly specialized functions. For optimal functioning of the CNS, in disease and in health, intricate communication between these cells is vital. One important mechanism of cellular communication is the release and uptake of extracellular vesicles (EVs). EVs are membrane enclosed particles actively released by cells, containing a wide array of proteins, lipids, RNA, and DNA. These EVs can be taken up by neighboring or distant cells, and influence a wide range of processes. Due to the complexity and relative inaccessibility of the CNS, our current understanding of the role of EVs is mainly derived in vitro work. However, recently new methods and techniques have opened the ability to study the role of EVs in the CNS in vivo. In this review, we discuss the current developments in our understanding of the role of EVs in the CNS in vivo.
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Affiliation(s)
- Shadi Mahjoum
- Program in Neuroscience, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02119, USA; (S.M.); (M.L.D.B.); (X.O.B.)
| | - David Rufino-Ramos
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal; (D.R.-R.); (L.P.d.A.)
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, Polo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
| | - Luís Pereira de Almeida
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal; (D.R.-R.); (L.P.d.A.)
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, Polo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
| | - Marike L. D. Broekman
- Program in Neuroscience, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02119, USA; (S.M.); (M.L.D.B.); (X.O.B.)
- Department of Neurosurgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
- Department of Neurosurgery, Haaglanden Medical Center, 2512 VA The Hague, The Netherlands
| | - Xandra O. Breakefield
- Program in Neuroscience, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02119, USA; (S.M.); (M.L.D.B.); (X.O.B.)
| | - Thomas S. van Solinge
- Program in Neuroscience, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02119, USA; (S.M.); (M.L.D.B.); (X.O.B.)
- Department of Neurosurgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
- Correspondence:
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Simionescu N, Zonda R, Petrovici AR, Georgescu A. The Multifaceted Role of Extracellular Vesicles in Glioblastoma: microRNA Nanocarriers for Disease Progression and Gene Therapy. Pharmaceutics 2021; 13:988. [PMID: 34210109 PMCID: PMC8309075 DOI: 10.3390/pharmaceutics13070988] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 06/25/2021] [Accepted: 06/27/2021] [Indexed: 12/16/2022] Open
Abstract
Glioblastoma (GB) is the most aggressive form of brain cancer in adults, characterized by poor survival rates and lack of effective therapies. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression post-transcriptionally through specific pairing with target messenger RNAs (mRNAs). Extracellular vesicles (EVs), a heterogeneous group of cell-derived vesicles, transport miRNAs, mRNAs and intracellular proteins, and have been shown to promote horizontal malignancy into adjacent tissue, as well as resistance to conventional therapies. Furthermore, GB-derived EVs have distinct miRNA contents and are able to penetrate the blood-brain barrier. Numerous studies have attempted to identify EV-associated miRNA biomarkers in serum/plasma and cerebrospinal fluid, but their collective findings fail to identify reliable biomarkers that can be applied in clinical settings. However, EVs carrying specific miRNAs or miRNA inhibitors have great potential as therapeutic nanotools in GB, and several studies have investigated this possibility on in vitro and in vivo models. In this review, we discuss the role of EVs and their miRNA content in GB progression and resistance to therapy, with emphasis on their potential as diagnostic, prognostic and disease monitoring biomarkers and as nanocarriers for gene therapy.
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Affiliation(s)
- Natalia Simionescu
- Center of Advanced Research in Bionanoconjugates and Biopolymers, “Petru Poni” Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania; (N.S.); (R.Z.); (A.R.P.)
- “Prof. Dr. Nicolae Oblu” Emergency Clinical Hospital, 2 Ateneului Street, 700309 Iasi, Romania
| | - Radu Zonda
- Center of Advanced Research in Bionanoconjugates and Biopolymers, “Petru Poni” Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania; (N.S.); (R.Z.); (A.R.P.)
| | - Anca Roxana Petrovici
- Center of Advanced Research in Bionanoconjugates and Biopolymers, “Petru Poni” Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania; (N.S.); (R.Z.); (A.R.P.)
| | - Adriana Georgescu
- Department of Pathophysiology and Pharmacology, Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 8 B.P. Hasdeu Street, 050568 Bucharest, Romania
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Jafari SH, Rabiei N, Taghizadieh M, Mirazimi SMA, Kowsari H, Farzin MA, Razaghi Bahabadi Z, Rezaei S, Mohammadi AH, Alirezaei Z, Dashti F, Nejati M. Joint application of biochemical markers and imaging techniques in the accurate and early detection of glioblastoma. Pathol Res Pract 2021; 224:153528. [PMID: 34171601 DOI: 10.1016/j.prp.2021.153528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 06/09/2021] [Accepted: 06/14/2021] [Indexed: 11/28/2022]
Abstract
Glioblastoma is a primary brain tumor with the most metastatic effect in adults. Despite the wide range of multidimensional treatments, tumor heterogeneity is one of the main causes of tumor spread and gives great complexity to diagnostic and therapeutic methods. Therefore, featuring noble noninvasive prognostic methods that are focused on glioblastoma heterogeneity is perceived as an urgent need. Imaging neuro-oncological biomarkers including MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation status, tumor grade along with other tumor characteristics and demographic features (e.g., age) are commonly referred to during diagnostic, therapeutic and prognostic processes. Therefore, the use of new noninvasive prognostic methods focused on glioblastoma heterogeneity is considered an urgent need. Some neuronal biomarkers, including the promoter methylation status of the promoter MGMT, the characteristics and grade of the tumor, along with the patient's demographics (such as age and sex) are involved in diagnosis, treatment, and prognosis. Among the wide array of imaging techniques, magnetic resonance imaging combined with the more physiologically detailed technique of H-magnetic resonance spectroscopy can be useful in diagnosing neurological cancer patients. In addition, intracranial tumor qualitative analysis and sometimes tumor biopsies help in accurate diagnosis. This review summarizes the evidence for biochemical biomarkers being a reliable biomarker in the early detection and disease management in GBM. Moreover, we highlight the correlation between Imaging techniques and biochemical biomarkers and ask whether they can be combined.
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Affiliation(s)
- Seyed Hamed Jafari
- Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women's Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sayad Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Kowsari
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Amin Farzin
- Department of Laboratory Medicine, School of Allied Medical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Zahra Razaghi Bahabadi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Samaneh Rezaei
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Hossein Mohammadi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Zahra Alirezaei
- Department of Medical Physics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Paramedical School, Bushehr University of Medical Sciences, Bushehr, Iran.
| | - Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran.
| | - Majid Nejati
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Rosińska S, Gavard J. Tumor Vessels Fuel the Fire in Glioblastoma. Int J Mol Sci 2021; 22:6514. [PMID: 34204510 PMCID: PMC8235363 DOI: 10.3390/ijms22126514] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma, a subset of aggressive brain tumors, deploy several means to increase blood vessel supply dedicated to the tumor mass. This includes typical program borrowed from embryonic development, such as vasculogenesis and sprouting angiogenesis, as well as unconventional processes, including co-option, vascular mimicry, and transdifferentiation, in which tumor cells are pro-actively engaged. However, these neo-generated vascular networks are morphologically and functionally abnormal, suggesting that the vascularization processes are rather inefficient in the tumor ecosystem. In this review, we reiterate the specificities of each neovascularization modality in glioblastoma, and, how they can be hampered mechanistically in the perspective of anti-cancer therapies.
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Affiliation(s)
- Sara Rosińska
- CRCINA, Inserm, CNRS, Université de Nantes, 44000 Nantes, France;
| | - Julie Gavard
- CRCINA, Inserm, CNRS, Université de Nantes, 44000 Nantes, France;
- Integrated Center for Oncology, ICO, 44800 St. Herblain, France
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The Acidic Brain-Glycolytic Switch in the Microenvironment of Malignant Glioma. Int J Mol Sci 2021; 22:ijms22115518. [PMID: 34073734 PMCID: PMC8197239 DOI: 10.3390/ijms22115518] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/16/2021] [Accepted: 05/19/2021] [Indexed: 12/15/2022] Open
Abstract
Malignant glioma represents a fatal disease with a poor prognosis and development of resistance mechanisms against conventional therapeutic approaches. The distinct tumor zones of this heterogeneous neoplasm develop their own microenvironment, in which subpopulations of cancer cells communicate. Adaptation to hypoxia in the center of the expanding tumor mass leads to the glycolytic and angiogenic switch, accompanied by upregulation of different glycolytic enzymes, transporters, and other metabolites. These processes render the tumor microenvironment more acidic, remodel the extracellular matrix, and create energy gradients for the metabolic communication between different cancer cells in distinct tumor zones. Escape mechanisms from hypoxia-induced cell death and energy deprivation are the result. The functional consequences are more aggressive and malignant behavior with enhanced proliferation and survival, migration and invasiveness, and the induction of angiogenesis. In this review, we go from the biochemical principles of aerobic and anaerobic glycolysis over the glycolytic switch, regulated by the key transcription factor hypoxia-inducible factor (HIF)-1α, to other important metabolic players like the monocarboxylate transporters (MCTs)1 and 4. We discuss the metabolic symbiosis model via lactate shuttling in the acidic tumor microenvironment and highlight the functional consequences of the glycolytic switch on glioma malignancy. Furthermore, we illustrate regulation by micro ribonucleic acids (miRNAs) and the connection between isocitrate dehydrogenase (IDH) mutation status and glycolytic metabolism. Finally, we give an outlook about the diagnostic and therapeutic implications of the glycolytic switch and the relation to tumor immunity in malignant glioma.
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Khan P, Ebenezer NS, Siddiqui JA, Maurya SK, Lakshmanan I, Salgia R, Batra SK, Nasser MW. MicroRNA-1: Diverse role of a small player in multiple cancers. Semin Cell Dev Biol 2021; 124:114-126. [PMID: 34034986 DOI: 10.1016/j.semcdb.2021.05.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 05/07/2021] [Accepted: 05/16/2021] [Indexed: 12/12/2022]
Abstract
The process of cancer initiation and development is a dynamic and complex mechanism involving multiple genetic and non-genetic variations. With the development of high throughput techniques like next-generation sequencing, the field of cancer biology extended beyond the protein-coding genes. It brought the functional role of noncoding RNAs into cancer-associated pathways. MicroRNAs (miRNAs) are one such class of noncoding RNAs regulating different cancer development aspects, including progression and metastasis. MicroRNA-1 (miR-1) is a highly conserved miRNA with a functional role in developing skeletal muscle precursor cells and cardiomyocytes and acts as a consistent tumor suppressor gene. In humans, two discrete genes, MIR-1-1 located on 20q13.333 and MIR-1-2 located on 18q11.2 loci encode for a single mature miR-1. Downregulation of miR-1 has been demonstrated in multiple cancers, including lung, breast, liver, prostate, colorectal, pancreatic, medulloblastoma, and gastric cancer. A vast number of studies have shown that miR-1 affects the hallmarks of cancer like proliferation, invasion and metastasis, apoptosis, angiogenesis, chemosensitization, and immune modulation. The potential therapeutic applications of miR-1 in multiple cancer pathways provide a novel platform for developing anticancer therapies. This review focuses on the different antitumorigenic and therapeutic aspects of miR-1, including how it regulates tumor development and associated immunomodulatory functions.
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Affiliation(s)
- Parvez Khan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Nivetha Sarah Ebenezer
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Jawed Akhtar Siddiqui
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Shailendra Kumar Maurya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Imayavaramban Lakshmanan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Ravi Salgia
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA 91010, USA
| | - Surinder Kumar Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Mohd Wasim Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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Visualizing Extracellular Vesicles and Their Function in 3D Tumor Microenvironment Models. Int J Mol Sci 2021; 22:ijms22094784. [PMID: 33946403 PMCID: PMC8125158 DOI: 10.3390/ijms22094784] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) are cell-derived nanostructures that mediate intercellular communication by delivering complex signals in normal tissues and cancer. The cellular coordination required for tumor development and maintenance is mediated, in part, through EV transport of molecular cargo to resident and distant cells. Most studies on EV-mediated signaling have been performed in two-dimensional (2D) monolayer cell cultures, largely because of their simplicity and high-throughput screening capacity. Three-dimensional (3D) cell cultures can be used to study cell-to-cell and cell-to-matrix interactions, enabling the study of EV-mediated cellular communication. 3D cultures may best model the role of EVs in formation of the tumor microenvironment (TME) and cancer cell-stromal interactions that sustain tumor growth. In this review, we discuss EV biology in 3D culture correlates of the TME. This includes EV communication between cell types of the TME, differences in EV biogenesis and signaling associated with differing scaffold choices and in scaffold-free 3D cultures and cultivation of the premetastatic niche. An understanding of EV biogenesis and signaling within a 3D TME will improve culture correlates of oncogenesis, enable molecular control of the TME and aid development of drug delivery tools based on EV-mediated signaling.
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Zhou X, Hu S, Zhang Y, Du G, Li Y. The mechanism by which noncoding RNAs regulate muscle wasting in cancer cachexia. PRECISION CLINICAL MEDICINE 2021; 4:136-147. [PMID: 35694153 DOI: 10.1093/pcmedi/pbab008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/10/2021] [Accepted: 04/13/2021] [Indexed: 02/05/2023] Open
Abstract
Abstract
Cancer cachexia (CC) is a complex metabolic syndrome that accelerates muscle wasting and affects up to 80% of patients with cancer; however, timely diagnostic methods and effective cures are lacking. Although a considerable number of studies have focused on the mechanism of CC-induced muscle atrophy, few novel therapies have been applied in the last decade. In recent years, noncoding RNAs (ncRNAs) have attracted great attention as many differentially expressed ncRNAs in cancer cachectic muscles have been reported to participate in the inhibition of myogenesis and activation of proteolysis. In addition, extracellular vesicles (EVs), which function as ncRNA carriers in intercellular communication, are closely involved in changing ncRNA expression profiles in muscle and promoting the development of muscle wasting; thus, EV-related ncRNAs may represent potential therapeutic targets. This review comprehensively describes the process of ncRNA transmission through EVs and summarizes the pathways and targets of ncRNAs that lead to CC-induced muscle atrophy.
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Affiliation(s)
- Xueer Zhou
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Shoushan Hu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yunan Zhang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Guannan Du
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yi Li
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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50
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Xiao L, Hareendran S, Loh YP. Function of exosomes in neurological disorders and brain tumors. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2021; 2:55-79. [PMID: 34368812 PMCID: PMC8341051 DOI: 10.20517/evcna.2021.04] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/15/2021] [Accepted: 03/19/2021] [Indexed: 12/11/2022]
Abstract
Exosomes are a subtype of extracellular vesicles released from different cell types including those in the nervous system, and are enriched in a variety of bioactive molecules such as RNAs, proteins and lipids. Numerous studies have indicated that exosomes play a critical role in many physiological and pathological activities by facilitating intercellular communication and modulating cells' responses to external environments. Particularly in the central nervous system, exosomes have been implicated to play a role in many neurological disorders such as abnormal neuronal development, neurodegenerative diseases, epilepsy, mental disorders, stroke, brain injury and brain cancer. Since exosomes recapitulate the characteristics of the parental cells and have the capacity to cross the blood-brain barrier, their cargo can serve as potential biomarkers for early diagnosis and clinical assessment of disease treatment. In this review, we describe the latest findings and current knowledge of the roles exosomes play in various neurological disorders and brain cancer, as well as their application as promising biomarkers. The potential use of exosomes to deliver therapeutic molecules to treat diseases of the central nervous system is also discussed.
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Affiliation(s)
| | | | - Y. Peng Loh
- Section on Cellular Neurobiology, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
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