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Semeradtova A, Liegertova M, Herma R, Capkova M, Brignole C, Del Zotto G. Extracellular vesicles in cancer´s communication: messages we can read and how to answer. Mol Cancer 2025; 24:86. [PMID: 40108630 PMCID: PMC11921637 DOI: 10.1186/s12943-025-02282-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 02/24/2025] [Indexed: 03/22/2025] Open
Abstract
Extracellular vesicles (EVs) are emerging as critical mediators of intercellular communication in the tumor microenvironment (TME), profoundly influencing cancer progression. These nano-sized vesicles, released by both tumor and stromal cells, carry a diverse cargo of proteins, nucleic acids, and lipids, reflecting the dynamic cellular landscape and mediating intricate interactions between cells. This review provides a comprehensive overview of the biogenesis, composition, and functional roles of EVs in cancer, highlighting their significance in both basic research and clinical applications. We discuss how cancer cells manipulate EV biogenesis pathways to produce vesicles enriched with pro-tumorigenic molecules, explore the specific contributions of EVs to key hallmarks of cancer, such as angiogenesis, metastasis, and immune evasion, emphasizing their role in shaping TME and driving therapeutic resistance. Concurrently, we submit recent knowledge on how the cargo of EVs can serve as a valuable source of biomarkers for minimally invasive liquid biopsies, and its therapeutic potential, particularly as targeted drug delivery vehicles and immunomodulatory agents, showcasing their promise for enhancing the efficacy and safety of cancer treatments. By deciphering the intricate messages carried by EVs, we can gain a deeper understanding of cancer biology and develop more effective strategies for early detection, targeted therapy, and immunotherapy, paving the way for a new era of personalized and precise cancer medicine with the potential to significantly improve patient outcomes.
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Affiliation(s)
- Alena Semeradtova
- Institute of Photonics and Electronics of the CAS, Chaberská 1014/57, Prague, 182 51, Czech Republic.
| | - Michaela Liegertova
- Centre for Nanomaterials and Biotechnology, Faculty of Science, Jan Evangelista Purkyně University in Ústí Nad Labem, Pasteurova 3632/15, Ústí Nad Labem, 40096, Czech Republic
| | - Regina Herma
- Centre for Nanomaterials and Biotechnology, Faculty of Science, Jan Evangelista Purkyně University in Ústí Nad Labem, Pasteurova 3632/15, Ústí Nad Labem, 40096, Czech Republic
| | - Magdalena Capkova
- Institute of Photonics and Electronics of the CAS, Chaberská 1014/57, Prague, 182 51, Czech Republic
| | - Chiara Brignole
- Laboratory of Experimental Therapies in Oncology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147, Genoa, Italy.
| | - Genny Del Zotto
- Core Facilities, Department of Research and Diagnostics, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
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2
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Ghanam J, Lichá K, Chetty VK, Pour OA, Reinhardt D, Tamášová B, Hoyer P, Lötvall J, Thakur BK. Unravelling the Significance of Extracellular Vesicle-Associated DNA in Cancer Biology and Its Potential Clinical Applications. J Extracell Vesicles 2025; 14:e70047. [PMID: 40091452 PMCID: PMC11911540 DOI: 10.1002/jev2.70047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 01/30/2025] [Accepted: 02/04/2025] [Indexed: 03/19/2025] Open
Abstract
Extracellular vesicles (EVs) play a key role in cell-to-cell communication and have drawn significant attention due to their potential clinical applications. However, much remains to be understood about the biology of EV-associated DNA (EV-DNA). EV-DNA is actively released by both normal and malignant cells and consists of diverse fragments with varying structures. Because EV-DNA spans the entire genome of cells from which it originates, it continues to be attractive as a biomarker for cancer diagnosis and monitoring. Further, EV-DNA delivery can alter the function of recipient cells by interfering with cytoplasmic DNA sensor pathways. This review explores the biology and significance of EV-DNA, including its topology and fragmentomics features, modality of association with EVs, packaging mechanisms, and potential functions. It also emphasizes the specificity of vesicular DNA in identifying genetic and epigenetic changes in cancer. Additionally, it delves into the impact of EV-DNA on cellular behaviour and its potential use as a therapeutic target in cancer. The review discusses new insights into EV-DNA biology and provides perspectives and alternatives to address the challenges and concerns for future EV-DNA studies.
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Affiliation(s)
- Jamal Ghanam
- Department of Pediatrics IIIUniversity Hospital EssenEssenGermany
| | - Kristína Lichá
- Department of Pediatrics IIIUniversity Hospital EssenEssenGermany
- Institute of Molecular Biomedicine, Faculty of MedicineComenius UniversityBratislavaSlovakia
| | | | | | | | - Barbora Tamášová
- Institute of Molecular Biomedicine, Faculty of MedicineComenius UniversityBratislavaSlovakia
| | - Peter Hoyer
- Department of Pediatrics IIUniversity Hospital Essen, University of Duisburg‐EssenEssenGermany
| | - Jan Lötvall
- Krefting Research Centre, Institute of Medicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
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Rana R, Devi SN, Bhardwaj AK, Yashavarddhan MH, Bohra D, Ganguly NK. Exosomes as nature's nano carriers: Promising drug delivery tools and targeted therapy for glioma. Biomed Pharmacother 2025; 182:117754. [PMID: 39731936 DOI: 10.1016/j.biopha.2024.117754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/28/2024] [Accepted: 12/09/2024] [Indexed: 12/30/2024] Open
Abstract
Exosomes, minute vesicles originating from diverse cell types, exhibit considerable potential as carriers for drug delivery in glioma therapy. These naturally occurring nanocarriers facilitate the transfer of proteins, RNAs, and lipids between cells, offering advantages such as biocompatibility, efficient cellular absorption, and the capability to traverse the blood-brain barrier (BBB). In the realm of cancer, particularly gliomas, exosomes play pivotal roles in modulating tumor growth, regulating immunity, and combating drug resistance. Moreover, exosomes serve as valuable biomarkers for diagnosing diseases and assessing prognosis. This review aims to elucidate the therapeutic and diagnostic promise of exosomes in glioma treatment, highlighting the innovative advances in exosome engineering that enable precise drug loading and targeting. By circumventing challenges associated with current glioma treatments, exosome-mediated drug delivery strategies can enhance the efficacy of chemotherapy drugs like temozolomide and overcome drug resistance mechanisms. This review underscores the multifaceted roles of exosomes in glioma pathogenesis and therapy, underscoring their potential as natural nanocarriers for targeted therapy and heralding a new era of hope for glioma treatment.
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Affiliation(s)
- Rashmi Rana
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India.
| | | | - Amit Kumar Bhardwaj
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - M H Yashavarddhan
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Deepika Bohra
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Nirmal Kumar Ganguly
- Department of Biotechnology and Research, Sir Ganga Ram Hospital, New Delhi 110060, India
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4
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Tsering T, Nadeau A, Rak J, Burnier JV. Analyzing Extracellular Vesicle-associated DNA Using Transmission Electron Microscopy at the Single EV-level. Curr Protoc 2024; 4:e70047. [PMID: 39513551 PMCID: PMC11602948 DOI: 10.1002/cpz1.70047] [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] [Indexed: 11/15/2024]
Abstract
Extracellular vesicles (EVs) play an important role in cell-cell communication, carrying bioactive molecules including DNA. EV-associated DNA (EV-DNA) has created enormous interest in the field of biomarkers, particularly related to liquid biopsy. However, its analysis is challenging due to the nanoscale structure of EVs, the low abundance of EV-DNA, and surrounding biogenetic debate. Therefore, novel protocols to enhance the accurate detection of EV-DNA are essential to study its role in normal physiology and disease states. Here, we provide two protocols for confirming the presence of EV-DNA from biological samples. In the first protocol, ultrathin sectioning of EVs is combined with immunogold labeling to detect the presence of double-stranded (ds) DNA within the EV lumen using transmission electron microscopy (TEM). In the second protocol, whole-mount EV immunogold labeling allows detailed morphological analysis of EVs and their surface-associated DNA. Using TEM imaging, we have demonstrated that cancer-cell-derived individual EVs exhibit simultaneous positivity for dsDNA and the EV surface protein tetraspanin 9. We believe that this method can be used to label any proteins of interest inside as well as on the surface of EVs. This can aid in the characterization of single EVs and in the identification and verification of EV-associated biomarkers. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: EV isolation from cell-culture-conditioned medium, EV embedding, ultrathin sectioning, labeling, and imaging Basic Protocol 2: Whole-mount immunolabeling of EV-DNA.
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Affiliation(s)
- Thupten Tsering
- Research Institute of the McGill University Health CentreMontrealQuebecCanada
- Department of PathologyMcGill UniversityMontrealQuebecCanada
| | - Amélie Nadeau
- Research Institute of the McGill University Health CentreMontrealQuebecCanada
- Department of PathologyMcGill UniversityMontrealQuebecCanada
| | - Janusz Rak
- Research Institute of the McGill University Health CentreMontrealQuebecCanada
- Department of Medicine, Division of Experimental MedicineMcGill UniversityMontrealQuebecCanada
| | - Julia V. Burnier
- Research Institute of the McGill University Health CentreMontrealQuebecCanada
- Department of PathologyMcGill UniversityMontrealQuebecCanada
- Gerald Bronfman Department of OncologyMcGill UniversityMontrealQuebecCanada
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5
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Tsering T, Nadeau A, Wu T, Dickinson K, Burnier JV. Extracellular vesicle-associated DNA: ten years since its discovery in human blood. Cell Death Dis 2024; 15:668. [PMID: 39266560 PMCID: PMC11393322 DOI: 10.1038/s41419-024-07003-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 07/29/2024] [Accepted: 08/14/2024] [Indexed: 09/14/2024]
Abstract
Extracellular vesicles (EVs) have emerged as key players in intercellular communication, facilitating the transfer of crucial cargo between cells. Liquid biopsy, particularly through the isolation of EVs, has unveiled a rich source of potential biomarkers for health and disease, encompassing proteins and nucleic acids. A milestone in this exploration occurred a decade ago with the identification of extracellular vesicle-associated DNA (EV-DNA) in the bloodstream of a patient diagnosed with pancreatic cancer. Subsequent years have witnessed substantial advancements, deepening our insights into the molecular intricacies of EV-DNA emission, detection, and analysis. Understanding the complexities surrounding the release of EV-DNA and addressing the challenges inherent in EV-DNA research are pivotal steps toward enhancing liquid biopsy-based strategies. These strategies, crucial for the detection and monitoring of various pathological conditions, particularly cancer, rely on a comprehensive understanding of why and how EV-DNA is released. In our review, we aim to provide a thorough summary of a decade's worth of research on EV-DNA. We will delve into diverse mechanisms of EV-DNA emission, its potential as a biomarker, its functional capabilities, discordant findings in the field, and the hurdles hindering its clinical application. Looking ahead to the next decade, we envision that advancements in EV isolation and detection techniques, coupled with improved standardization and data sharing, will catalyze the development of novel strategies exploiting EV-DNA as both a source of biomarkers and therapeutic targets.
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Affiliation(s)
- Thupten Tsering
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Department of Pathology, McGill University, Montreal, QC, Canada
| | - Amélie Nadeau
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Department of Pathology, McGill University, Montreal, QC, Canada
| | - Tad Wu
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Department of Pathology, McGill University, Montreal, QC, Canada
| | - Kyle Dickinson
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Julia V Burnier
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
- Department of Pathology, McGill University, Montreal, QC, Canada.
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada.
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He D, Cui B, Lv H, Lu S, Zhu Y, Cheng Y, Dang L, Zhang H. Blood-Derived Extracellular Vesicles as a Promising Liquid Biopsy Diagnostic Tool for Early Cancer Detection. Biomolecules 2024; 14:847. [PMID: 39062561 PMCID: PMC11275243 DOI: 10.3390/biom14070847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 06/27/2024] [Accepted: 07/01/2024] [Indexed: 07/28/2024] Open
Abstract
Cancer poses a significant public health challenge worldwide, and timely screening has the potential to mitigate cancer progression and reduce mortality rates. Currently, early identification of most tumors relies on imaging techniques and tissue biopsies. However, the use of low-cost, highly sensitive, non-invasive detection methods for early cancer screening has become more attractive. Extracellular Vesicles (EVs) released by all living cells contain distinctive biological components, such as nucleic acids, proteins, and lipids. These vesicles play crucial roles in the tumor microenvironment and intercellular communication during tumor progression, rendering liquid biopsy a particularly suitable method for diagnosis. Nevertheless, challenges related to purification methods and validation of efficacy currently hinder its widespread clinical implementation. These limitations underscore the importance of refining isolation techniques and conducting comprehensive investigations on EVs. This study seeks to evaluate the potential of liquid biopsy utilizing blood-derived EVs as a practical, cost-effective, and secure approach for early cancer detection.
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Affiliation(s)
- Dan He
- Laboratory of Animal Center, Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang 712046, China; (D.H.); (S.L.); (Y.Z.)
| | - Bozhou Cui
- Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, China;
| | - Hongkai Lv
- Department of Clinical Medicine of Second Clinical Medical School, Shaanxi University of Chinese Medicine, Xianyang 712046, China; (H.L.); (Y.C.)
| | - Shuxian Lu
- Laboratory of Animal Center, Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang 712046, China; (D.H.); (S.L.); (Y.Z.)
| | - Yuan Zhu
- Laboratory of Animal Center, Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang 712046, China; (D.H.); (S.L.); (Y.Z.)
| | - Yuqiang Cheng
- Department of Clinical Medicine of Second Clinical Medical School, Shaanxi University of Chinese Medicine, Xianyang 712046, China; (H.L.); (Y.C.)
| | - Lin Dang
- Basic Medical Academy, Shaanxi University of Chinese Medicine, Xianyang 712046, China
| | - Hong Zhang
- Laboratory of Animal Center, Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang 712046, China; (D.H.); (S.L.); (Y.Z.)
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Leonov S, Dorfman A, Pershikova E, Inyang O, Alhaddad L, Wang Y, Pustovalova M, Merkher Y. Extracellular Vesicle- and Mitochondria-Based Targeting of Non-Small Cell Lung Cancer Response to Radiation: Challenges and Perspectives. Cancers (Basel) 2024; 16:2235. [PMID: 38927940 PMCID: PMC11201585 DOI: 10.3390/cancers16122235] [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: 03/11/2024] [Revised: 05/13/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024] Open
Abstract
During the cell life cycle, extracellular vesicles (EVs) transport different cargos, including organelles, proteins, RNAs, DNAs, metabolites, etc., that influence cell proliferation and apoptosis in recipient cells. EVs from metastatic cancer cells remodel the extracellular matrix and cells of the tumor microenvironment (TME), promoting tumor invasion and metastatic niche preparation. Although the process is not fully understood, evidence suggests that EVs facilitate genetic material transfer between cells. In the context of NSCLC, EVs can mediate intercellular mitochondrial (Mt) transfer, delivering mitochondria organelle (MtO), mitochondrial DNA (mtDNA), and/or mtRNA/proteinaceous cargo signatures (MtS) through different mechanisms. On the other hand, certain populations of cancer cells can hijack the MtO from TME cells mainly by using tunneling nanotubes (TNTs). This transfer aids in restoring mitochondrial function, benefiting benign cells with impaired metabolism and enabling restoration of their metabolic activity. However, the impact of transferring mitochondria versus transplanting intact mitochondrial organelles in cancer remains uncertain and the subject of debate. Some studies suggest that EV-mediated mitochondria delivery to cancer cells can impact how cancer responds to radiation. It might make the cancer more resistant or more sensitive to radiation. In our review, we aimed to point out the current controversy surrounding experimental data and to highlight new paradigm-shifting modalities in radiation therapy that could potentially overcome cancer resistance mechanisms in NSCLC.
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Affiliation(s)
- Sergey Leonov
- Department of Cell Technologies, Institute of Future Biophysics, 141700 Dolgoprudny, Russia
- Department of Cellular Mechanisms of Memory Pathology, Institute of Cell Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia
| | - Anna Dorfman
- Department of Cell Technologies, Institute of Future Biophysics, 141700 Dolgoprudny, Russia
| | - Elizaveta Pershikova
- Department of Cell Technologies, Institute of Future Biophysics, 141700 Dolgoprudny, Russia
| | - Olumide Inyang
- Department of Cell Technologies, Institute of Future Biophysics, 141700 Dolgoprudny, Russia
| | - Lina Alhaddad
- Department of Cell Technologies, Institute of Future Biophysics, 141700 Dolgoprudny, Russia
| | - Yuzhe Wang
- Department of Cell Technologies, Institute of Future Biophysics, 141700 Dolgoprudny, Russia
| | - Margarita Pustovalova
- Department of Cell Technologies, Institute of Future Biophysics, 141700 Dolgoprudny, Russia
| | - Yulia Merkher
- Department of Cell Technologies, Institute of Future Biophysics, 141700 Dolgoprudny, Russia
- Biomedical Engineering, Technion-Israel Institute of Technology, Haifa 3200003, Israel
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8
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Phillips D, Noble D. Reply from Daniel Phillips and Denis Noble. J Physiol 2024; 602:2669-2672. [PMID: 38305416 DOI: 10.1113/jp286224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024] Open
Affiliation(s)
- Daniel Phillips
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Denis Noble
- Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK
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Carreca AP, Tinnirello R, Miceli V, Galvano A, Gristina V, Incorvaia L, Pampalone M, Taverna S, Iannolo G. Extracellular Vesicles in Lung Cancer: Implementation in Diagnosis and Therapeutic Perspectives. Cancers (Basel) 2024; 16:1967. [PMID: 38893088 PMCID: PMC11171234 DOI: 10.3390/cancers16111967] [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: 04/10/2024] [Revised: 05/18/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024] Open
Abstract
Lung cancer represents the leading cause of cancer-related mortality worldwide, with around 1.8 million deaths in 2020. For this reason, there is an enormous interest in finding early diagnostic tools and novel therapeutic approaches, one of which is extracellular vesicles (EVs). EVs are nanoscale membranous particles that can carry proteins, lipids, and nucleic acids (DNA and RNA), mediating various biological processes, especially in cell-cell communication. As such, they represent an interesting biomarker for diagnostic analysis that can be performed easily by liquid biopsy. Moreover, their growing dataset shows promising results as drug delivery cargo. The aim of our work is to summarize the recent advances in and possible implications of EVs for early diagnosis and innovative therapies for lung cancer.
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Affiliation(s)
| | - Rosaria Tinnirello
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Via E. Tricomi 5, 90127 Palermo, Italy; (R.T.); (V.M.)
| | - Vitale Miceli
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Via E. Tricomi 5, 90127 Palermo, Italy; (R.T.); (V.M.)
| | - Antonio Galvano
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90133 Palermo, Italy; (A.G.); (V.G.); (L.I.)
| | - Valerio Gristina
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90133 Palermo, Italy; (A.G.); (V.G.); (L.I.)
| | - Lorena Incorvaia
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, 90133 Palermo, Italy; (A.G.); (V.G.); (L.I.)
| | | | - Simona Taverna
- Institute of Translational Pharmacology (IFT), National Research Council (CNR), 90146 Palermo, Italy;
| | - Gioacchin Iannolo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Via E. Tricomi 5, 90127 Palermo, Italy; (R.T.); (V.M.)
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10
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Anvari Y, Afrashteh A, Pourkaveh S, Salek SB, Al-Numan L, Khademnezhad S. Emerging role of mesenchymal stem cell-derived extracellular vesicles in periodontal regeneration. J Taibah Univ Med Sci 2024; 19:390-402. [PMID: 38380419 PMCID: PMC10876597 DOI: 10.1016/j.jtumed.2024.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/17/2023] [Accepted: 01/25/2024] [Indexed: 02/22/2024] Open
Abstract
Periodontitis is a prevalent oral ailment that harms both hard and soft tissues of the periodontium, leading to loosening and eventual removal of the teeth. Current clinical treatments have limitations in achieving complete periodontal tissue regeneration. Mesenchymal stem cells (MSCs) have garnered attention due to their unique characteristics and potential as a promising new therapy for periodontitis. Research suggests that the role of MSCs in regenerative medicine primarily occurs through the paracrine pathway, involving the emission of particles encased by lipids called extracellular vesicles (EVs) abundant in bioactive compounds. These EVs play a vital function in controlling the activities of periodontal tissues and immune system cells, and by influencing the immediate surrounding, thus fostering the healing of periodontal damage and renewal of tissues. EVs obtained from MSCs (MSC-EVs), in the form of a cell-free treatment, offer advantages in terms of stability, reduced immune rejection, and ethical considerations, elevating their potential as a hopeful choice for broad clinical applications. This concise overview highlights the mechanisms of MSC-EVs and the possibilities they hold in clinical application for periodontal regeneration.
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Affiliation(s)
- Yaldasadat Anvari
- Department of Dentistry, School of Dentistry, Near East University, Nicosia, Cyprus
| | - Ahmad Afrashteh
- Department of Periodontics, School of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sajjad Pourkaveh
- Department of Periodontics, School of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samira B. Salek
- Department of Periodontics, School of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Lelaw Al-Numan
- Department of Dentistry, School of Dentistry, Near East University, Nicosia, Cyprus
| | - Sahar Khademnezhad
- Department of Oral and Maxillofacial Medicine, School of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
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11
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Cui JZ, Chew ZH, Lim LHK. New insights into nucleic acid sensor AIM2: The potential benefit in targeted therapy for cancer. Pharmacol Res 2024; 200:107079. [PMID: 38272334 DOI: 10.1016/j.phrs.2024.107079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 01/17/2024] [Accepted: 01/19/2024] [Indexed: 01/27/2024]
Abstract
The AIM2 inflammasome represents a multifaceted oligomeric protein complex within the innate immune system, with the capacity to perceive double-stranded DNA (dsDNA) and engage in diverse physiological reactions and disease contexts, including cancer. While originally conceived as a discerning DNA sensor, AIM2 has demonstrated its capability to discern various nucleic acid variations, encompassing RNA and DNA-RNA hybrids. Through its interaction with nucleic acids, AIM2 orchestrates the assembly of a complex involving multiple proteins, aptly named the AIM2 inflammasome, which facilitates the enzymatic cleavage of proinflammatory cytokines, namely pro-IL-1β and pro-IL-18. This process, in turn, underpins its pivotal biological role. In this review, we provide a systematic summary and discussion of the latest advancements in AIM2 sensing various types of nucleic acids. Additionally, we discuss the modulation of AIM2 activation, which can cause cell death, including pyroptosis, apoptosis, and autophagic cell death. Finally, we fully illustrate the evidence for the dual role of AIM2 in different cancer types, including both anti-tumorigenic and pro-tumorigenic functions. Considering the above information, we uncover the therapeutic promise of modulating the AIM2 inflammasome in cancer treatment.
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Affiliation(s)
- Jian-Zhou Cui
- Translational Immunology Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Immunology Program, Life Sciences Institute, National University of Singapore, Singapore; NUS-Cambridge Immunophenotyping Centre, Life Science Institute, National University of Singapore, Singapore.
| | - Zhi Huan Chew
- Translational Immunology Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Immunology Program, Life Sciences Institute, National University of Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore; Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Lina H K Lim
- Translational Immunology Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Immunology Program, Life Sciences Institute, National University of Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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Welsh JA, Goberdhan DCI, O'Driscoll L, Buzas EI, Blenkiron C, Bussolati B, Cai H, Di Vizio D, Driedonks TAP, Erdbrügger U, Falcon‐Perez JM, Fu Q, Hill AF, Lenassi M, Lim SK, Mahoney MG, Mohanty S, Möller A, Nieuwland R, Ochiya T, Sahoo S, Torrecilhas AC, Zheng L, Zijlstra A, Abuelreich S, Bagabas R, Bergese P, Bridges EM, Brucale M, Burger D, Carney RP, Cocucci E, Colombo F, Crescitelli R, Hanser E, Harris AL, Haughey NJ, Hendrix A, Ivanov AR, Jovanovic‐Talisman T, Kruh‐Garcia NA, Ku'ulei‐Lyn Faustino V, Kyburz D, Lässer C, Lennon KM, Lötvall J, Maddox AL, Martens‐Uzunova ES, Mizenko RR, Newman LA, Ridolfi A, Rohde E, Rojalin T, Rowland A, Saftics A, Sandau US, Saugstad JA, Shekari F, Swift S, Ter‐Ovanesyan D, Tosar JP, Useckaite Z, Valle F, Varga Z, van der Pol E, van Herwijnen MJC, Wauben MHM, Wehman AM, Williams S, Zendrini A, Zimmerman AJ, MISEV Consortium, Théry C, Witwer KW. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. J Extracell Vesicles 2024; 13:e12404. [PMID: 38326288 PMCID: PMC10850029 DOI: 10.1002/jev2.12404] [Citation(s) in RCA: 1157] [Impact Index Per Article: 1157.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 12/15/2023] [Accepted: 12/19/2023] [Indexed: 02/09/2024] Open
Abstract
Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.
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Affiliation(s)
- Joshua A. Welsh
- Translational Nanobiology Section, Laboratory of PathologyNational Cancer Institute, National Institutes of HealthBethesdaMarylandUSA
| | - Deborah C. I. Goberdhan
- Nuffield Department of Women's and Reproductive HealthUniversity of Oxford, Women's Centre, John Radcliffe HospitalOxfordUK
| | - Lorraine O'Driscoll
- School of Pharmacy and Pharmaceutical SciencesTrinity College DublinDublinIreland
- Trinity Biomedical Sciences InstituteTrinity College DublinDublinIreland
- Trinity St. James's Cancer InstituteTrinity College DublinDublinIreland
| | - Edit I. Buzas
- Department of Genetics, Cell‐ and ImmunobiologySemmelweis UniversityBudapestHungary
- HCEMM‐SU Extracellular Vesicle Research GroupSemmelweis UniversityBudapestHungary
- HUN‐REN‐SU Translational Extracellular Vesicle Research GroupSemmelweis UniversityBudapestHungary
| | - Cherie Blenkiron
- Faculty of Medical and Health SciencesThe University of AucklandAucklandNew Zealand
| | - Benedetta Bussolati
- Department of Molecular Biotechnology and Health SciencesUniversity of TurinTurinItaly
| | | | - Dolores Di Vizio
- Department of Surgery, Division of Cancer Biology and TherapeuticsCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Tom A. P. Driedonks
- Department CDL ResearchUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Uta Erdbrügger
- University of Virginia Health SystemCharlottesvilleVirginiaUSA
| | - Juan M. Falcon‐Perez
- Exosomes Laboratory, Center for Cooperative Research in BiosciencesBasque Research and Technology AllianceDerioSpain
- Metabolomics Platform, Center for Cooperative Research in BiosciencesBasque Research and Technology AllianceDerioSpain
- IKERBASQUE, Basque Foundation for ScienceBilbaoSpain
| | - Qing‐Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Extracellular Vesicle Research and Clinical Translational CenterThe First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouChina
| | - Andrew F. Hill
- Institute for Health and SportVictoria UniversityMelbourneAustralia
| | - Metka Lenassi
- Faculty of MedicineUniversity of LjubljanaLjubljanaSlovenia
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology (IMCB)Agency for Science, Technology and Research (A*STAR)SingaporeSingapore
- Paracrine Therapeutics Pte. Ltd.SingaporeSingapore
- Department of Surgery, YLL School of MedicineNational University SingaporeSingaporeSingapore
| | - Mỹ G. Mahoney
- Thomas Jefferson UniversityPhiladelphiaPennsylvaniaUSA
| | - Sujata Mohanty
- Stem Cell FacilityAll India Institute of Medical SciencesNew DelhiIndia
| | - Andreas Möller
- Chinese University of Hong KongHong KongHong Kong S.A.R.
- QIMR Berghofer Medical Research InstituteBrisbaneAustralia
| | - Rienk Nieuwland
- Laboratory of Experimental Clinical Chemistry, Amsterdam University Medical Centers, Location AMCUniversity of AmsterdamAmsterdamThe Netherlands
- Amsterdam Vesicle Center, Amsterdam University Medical Centers, Location AMCUniversity of AmsterdamAmsterdamThe Netherlands
| | | | - Susmita Sahoo
- Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Ana C. Torrecilhas
- Laboratório de Imunologia Celular e Bioquímica de Fungos e Protozoários, Departamento de Ciências Farmacêuticas, Instituto de Ciências Ambientais, Químicas e FarmacêuticasUniversidade Federal de São Paulo (UNIFESP) Campus DiademaDiademaBrazil
| | - Lei Zheng
- Department of Laboratory Medicine, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Andries Zijlstra
- Department of PathologyVanderbilt University Medical CenterNashvilleTennesseeUSA
- GenentechSouth San FranciscoCaliforniaUSA
| | - Sarah Abuelreich
- Department of Molecular Medicine, Beckman Research InstituteCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Reem Bagabas
- Department of Molecular Medicine, Beckman Research InstituteCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Paolo Bergese
- Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
- Center for Colloid and Surface Science (CSGI)FlorenceItaly
- National Center for Gene Therapy and Drugs based on RNA TechnologyPaduaItaly
| | - Esther M. Bridges
- Weatherall Institute of Molecular MedicineUniversity of OxfordOxfordUK
| | - Marco Brucale
- Consiglio Nazionale delle Ricerche ‐ Istituto per lo Studio dei Materiali NanostrutturatiBolognaItaly
- Consorzio Interuniversitario per lo Sviluppo dei Sistemi a Grande InterfaseFlorenceItaly
| | - Dylan Burger
- Kidney Research CentreOttawa Hopsital Research InstituteOttawaCanada
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaCanada
- School of Pharmaceutical SciencesUniversity of OttawaOttawaCanada
| | - Randy P. Carney
- Department of Biomedical EngineeringUniversity of CaliforniaDavisCaliforniaUSA
| | - Emanuele Cocucci
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOhioUSA
- Comprehensive Cancer CenterThe Ohio State UniversityColumbusOhioUSA
| | - Federico Colombo
- Division of Pharmaceutics and Pharmacology, College of PharmacyThe Ohio State UniversityColumbusOhioUSA
| | - Rossella Crescitelli
- Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical SciencesSahlgrenska Academy, University of GothenburgGothenburgSweden
- Wallenberg Centre for Molecular and Translational Medicine, Institute of Clinical SciencesSahlgrenska Academy, University of GothenburgGothenburgSweden
| | - Edveena Hanser
- Department of BiomedicineUniversity Hospital BaselBaselSwitzerland
- Department of BiomedicineUniversity of BaselBaselSwitzerland
| | | | - Norman J. Haughey
- Departments of Neurology and PsychiatryJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - An Hendrix
- Laboratory of Experimental Cancer Research, Department of Human Structure and RepairGhent UniversityGhentBelgium
- Cancer Research Institute GhentGhentBelgium
| | - Alexander R. Ivanov
- Barnett Institute of Chemical and Biological Analysis, Department of Chemistry and Chemical BiologyNortheastern UniversityBostonMassachusettsUSA
| | - Tijana Jovanovic‐Talisman
- Department of Cancer Biology and Molecular Medicine, Beckman Research InstituteCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Nicole A. Kruh‐Garcia
- Bio‐pharmaceutical Manufacturing and Academic Resource Center (BioMARC)Infectious Disease Research Center, Colorado State UniversityFort CollinsColoradoUSA
| | - Vroniqa Ku'ulei‐Lyn Faustino
- Department of Molecular Medicine, Beckman Research InstituteCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Diego Kyburz
- Department of BiomedicineUniversity of BaselBaselSwitzerland
- Department of RheumatologyUniversity Hospital BaselBaselSwitzerland
| | - Cecilia Lässer
- Krefting Research Centre, Department of Internal Medicine and Clinical NutritionInstitute of Medicine at Sahlgrenska Academy, University of GothenburgGothenburgSweden
| | - Kathleen M. Lennon
- Department of Molecular Medicine, Beckman Research InstituteCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Jan Lötvall
- Krefting Research Centre, Institute of Medicine at Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Adam L. Maddox
- Department of Molecular Medicine, Beckman Research InstituteCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Elena S. Martens‐Uzunova
- Erasmus MC Cancer InstituteUniversity Medical Center Rotterdam, Department of UrologyRotterdamThe Netherlands
| | - Rachel R. Mizenko
- Department of Biomedical EngineeringUniversity of CaliforniaDavisCaliforniaUSA
| | - Lauren A. Newman
- College of Medicine and Public HealthFlinders UniversityAdelaideAustralia
| | - Andrea Ridolfi
- Department of Physics and Astronomy, and LaserLaB AmsterdamVrije Universiteit AmsterdamAmsterdamThe Netherlands
| | - Eva Rohde
- Department of Transfusion Medicine, University HospitalSalzburger Landeskliniken GmbH of Paracelsus Medical UniversitySalzburgAustria
- GMP Unit, Paracelsus Medical UniversitySalzburgAustria
- Transfer Centre for Extracellular Vesicle Theralytic Technologies, EV‐TTSalzburgAustria
| | - Tatu Rojalin
- Department of Biomedical EngineeringUniversity of CaliforniaDavisCaliforniaUSA
- Expansion Therapeutics, Structural Biology and BiophysicsJupiterFloridaUSA
| | - Andrew Rowland
- College of Medicine and Public HealthFlinders UniversityAdelaideAustralia
| | - Andras Saftics
- Department of Molecular Medicine, Beckman Research InstituteCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Ursula S. Sandau
- Department of Anesthesiology & Perioperative MedicineOregon Health & Science UniversityPortlandOregonUSA
| | - Julie A. Saugstad
- Department of Anesthesiology & Perioperative MedicineOregon Health & Science UniversityPortlandOregonUSA
| | - Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECRTehranIran
- Celer DiagnosticsTorontoCanada
| | - Simon Swift
- Waipapa Taumata Rau University of AucklandAucklandNew Zealand
| | - Dmitry Ter‐Ovanesyan
- Wyss Institute for Biologically Inspired EngineeringHarvard UniversityBostonMassachusettsUSA
| | - Juan P. Tosar
- Universidad de la RepúblicaMontevideoUruguay
- Institut Pasteur de MontevideoMontevideoUruguay
| | - Zivile Useckaite
- College of Medicine and Public HealthFlinders UniversityAdelaideAustralia
| | - Francesco Valle
- Consiglio Nazionale delle Ricerche ‐ Istituto per lo Studio dei Materiali NanostrutturatiBolognaItaly
- Consorzio Interuniversitario per lo Sviluppo dei Sistemi a Grande InterfaseFlorenceItaly
| | - Zoltan Varga
- Biological Nanochemistry Research GroupInstitute of Materials and Environmental Chemistry, Research Centre for Natural SciencesBudapestHungary
- Department of Biophysics and Radiation BiologySemmelweis UniversityBudapestHungary
| | - Edwin van der Pol
- Amsterdam Vesicle Center, Amsterdam University Medical Centers, Location AMCUniversity of AmsterdamAmsterdamThe Netherlands
- Biomedical Engineering and Physics, Amsterdam UMC, location AMCUniversity of AmsterdamAmsterdamThe Netherlands
- Laboratory of Experimental Clinical Chemistry, Amsterdam UMC, location AMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Martijn J. C. van Herwijnen
- Department of Biomolecular Health Sciences, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Marca H. M. Wauben
- Department of Biomolecular Health Sciences, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | | | | | - Andrea Zendrini
- Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
- Center for Colloid and Surface Science (CSGI)FlorenceItaly
| | - Alan J. Zimmerman
- Barnett Institute of Chemical and Biological Analysis, Department of Chemistry and Chemical BiologyNortheastern UniversityBostonMassachusettsUSA
| | | | - Clotilde Théry
- Institut Curie, INSERM U932PSL UniversityParisFrance
- CurieCoreTech Extracellular Vesicles, Institut CurieParisFrance
| | - Kenneth W. Witwer
- Department of Molecular and Comparative PathobiologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
- EV Core Facility “EXCEL”, Institute for Basic Biomedical SciencesJohns Hopkins University School of MedicineBaltimoreMarylandUSA
- The Richman Family Precision Medicine Center of Excellence in Alzheimer's DiseaseJohns Hopkins University School of MedicineBaltimoreMarylandUSA
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13
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Jiao Y, Gao L, Zhang T, He Z, Zheng SY, Liu W. Profiling DNA Cargos in Single Extracellular Vesicles via Hydrogel-Based Droplet Digital Multiple Displacement Amplification. Anal Chem 2024; 96:1293-1300. [PMID: 38189229 DOI: 10.1021/acs.analchem.3c04666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Due to the substantial heterogeneity among extracellular vesicle (EV) subpopulations, single-EV analysis has the potential to elucidate the mechanisms behind EV biogenesis and shed light on the myriad functions, leading to the development of novel diagnostics and therapeutics. While many studies have been devoted to reveal between-EV variations in surface proteins and RNAs, DNA cargos (EV-DNA) have received little attention. Here, we report a hydrogel-based droplet digital multiple displacement amplification approach for the comprehensive analysis of EV-DNA at the single-EV level. Single EVs are dispersed in thousands of hydrogel droplets and lysed for DNA amplification and identification. The droplet microfluidics strategy empowers the assay with single-molecule sensitivity and capability for absolute quantification of DNA-containing EVs. In particular, our findings indicate that 5-40% EVs are associated with DNA, depending on the cell of origin. Large EVs exhibit a higher proportion of DNA-containing EVs and a more substantial presence of intraluminal DNA, compared to small EVs. These DNA-containing EVs carry multiple DNA fragments on average. Furthermore, both double-stranded DNA and single-stranded DNA were able to be detected at the single-EV level. Utilizing this method, the abundance, distribution, and biophysical properties of EV-DNA in various EV populations are evaluated. The DNA level within EVs provides insight into the status of the originating cells and offers valuable information on the outcomes of anticancer treatments. The utilization of single-EV analysis for EV-DNA holds significant promise for early cancer detection and treatment response monitoring.
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Affiliation(s)
- Yufeng Jiao
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
| | - Liyang Gao
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
| | - Tao Zhang
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
| | - Ziyi He
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, Hubei, China
| | | | - Wu Liu
- School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
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14
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Witz A, Dardare J, Betz M, Gilson P, Merlin JL, Harlé A. Tumor-derived cell-free DNA and circulating tumor cells: partners or rivals in metastasis formation? Clin Exp Med 2024; 24:2. [PMID: 38231464 PMCID: PMC10794481 DOI: 10.1007/s10238-023-01278-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 11/20/2023] [Indexed: 01/18/2024]
Abstract
The origin of metastases is a topic that has sparked controversy. Despite recent advancements, metastatic disease continues to pose challenges. The first admitted model of how metastases develop revolves around cells breaking away from the primary tumor, known as circulating tumor cells (CTCs). These cells survive while circulating through the bloodstream and subsequently establish themselves in secondary organs, a process often referred to as the "metastatic cascade". This intricate and dynamic process involves various steps, but all the mechanisms behind metastatic dissemination are not yet comprehensively elucidated. The "seed and soil" theory has shed light on the phenomenon of metastatic organotropism and the existence of pre-metastatic niches. It is now established that these niches can be primed by factors secreted by the primary tumor before the arrival of CTCs. In particular, exosomes have been identified as important contributors to this priming. Another concept then emerged, i.e. the "genometastasis" theory, which challenged all other postulates. It emphasizes the intriguing but promising role of cell-free DNA (cfDNA) in metastasis formation through oncogenic formation of recipient cells. However, it cannot be ruled out that all these theories are intertwined. This review outlines the primary theories regarding the metastases formation that involve CTCs, and depicts cfDNA, a potential second player in the metastasis formation. We discuss the potential interrelationships between CTCs and cfDNA, and propose both in vitro and in vivo experimental strategies to explore all plausible theories.
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Affiliation(s)
- Andréa Witz
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France.
| | - Julie Dardare
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
| | - Margaux Betz
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
| | - Pauline Gilson
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
| | - Jean-Louis Merlin
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
| | - Alexandre Harlé
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
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15
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Adnani L, Rak J. Intercellular Molecular Transfer Mediated by Extracellular Vesicles in Cancer. Results Probl Cell Differ 2024; 73:327-352. [PMID: 39242385 DOI: 10.1007/978-3-031-62036-2_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/09/2024]
Abstract
Among multiple pathways of intercellular communication operative in multicellular organisms, the trafficking of extracellular vesicles (EVs) and particles (EP) represents a unique mode of cellular information exchange with emerging roles in health and disease, including cancer. A distinctive feature of EV/EP-mediated cell-cell communication is that it involves simultaneous short- or long-range transfer of numerous molecular constituents (cargo) from donor to recipient cells. EV/EP uptake by donor cells elicits signalling or metabolic responses, or else leads to EV-re-emission or degradation. EVs are heterogeneous membranous structures released from cells via increasingly defined mechanisms involving either formation of multivesicular endosomes (exosomes) or budding from the plasma membrane (ectosomes). EPs (exomeres, supermeres) are membraneless complex particles, smaller than EVs and of less defined biogenesis and function. EVs/EPs carry complex assemblies of proteins, lipids and nucleic acids (RNA, DNA), which they shuttle into intercellular milieu, body fluids and recipient cells, via surface contact, fusion and different forms of internalization (endocytosis, micropinocytosis). While the physiological functions of EVs/EPs communication pathways continue to be investigated, their roles in cancer are increasingly well-defined. For example, EVs are involved in the transmission of cancer-specific molecular cargo, including mutant, oncogenic, transforming, or regulatory macromolecules to indolent, or normal cells, sometimes triggering their quasi-transformation-like states, or phenotypic alterations. Conversely, a reciprocal and avid uptake of stromal EVs by cancer cells may be responsible for modulating their oncogenic repertoire, as exemplified by the angiocrine effects of endothelial EVs influencing cancer cell stemness. EV exchanges during cancer progression have also been implicated in the formation of tumour stroma, angiogenesis and non-angiogenic neovascularization processes, immunosuppression, colonization of metastatic organ sites (premetastatic niche), paraneoplastic and systemic pathologies (thrombosis, diabetes, hepatotoxicity). Thus, an EV/EP-mediated horizontal transfer of cellular content emerges as a new dimension in cancer pathogenesis with functional, diagnostic, and therapeutic implications.
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Affiliation(s)
- Lata Adnani
- The Research Institute of the McGill University Health Centre, McGill University, QC, Canada
| | - Janusz Rak
- The Research Institute of the McGill University Health Centre, McGill University, QC, Canada.
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16
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Gregory CD. Hijacking homeostasis: Regulation of the tumor microenvironment by apoptosis. Immunol Rev 2023; 319:100-127. [PMID: 37553811 PMCID: PMC10952466 DOI: 10.1111/imr.13259] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/18/2023] [Indexed: 08/10/2023]
Abstract
Cancers are genetically driven, rogue tissues which generate dysfunctional, obdurate organs by hijacking normal, homeostatic programs. Apoptosis is an evolutionarily conserved regulated cell death program and a profoundly important homeostatic mechanism that is common (alongside tumor cell proliferation) in actively growing cancers, as well as in tumors responding to cytotoxic anti-cancer therapies. Although well known for its cell-autonomous tumor-suppressive qualities, apoptosis harbors pro-oncogenic properties which are deployed through non-cell-autonomous mechanisms and which generally remain poorly defined. Here, the roles of apoptosis in tumor biology are reviewed, with particular focus on the secreted and fragmentation products of apoptotic tumor cells and their effects on tumor-associated macrophages, key supportive cells in the aberrant homeostasis of the tumor microenvironment. Historical aspects of cell loss in tumor growth kinetics are considered and the impact (and potential impact) on tumor growth of apoptotic-cell clearance (efferocytosis) as well as released soluble and extracellular vesicle-associated factors are discussed from the perspectives of inflammation, tissue repair, and regeneration programs. An "apoptosis-centric" view is proposed in which dying tumor cells provide an important platform for intricate intercellular communication networks in growing cancers. The perspective has implications for future research and for improving cancer diagnosis and therapy.
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Affiliation(s)
- Christopher D. Gregory
- Centre for Inflammation ResearchInstitute for Regeneration and Repair, University of Edinburgh, Edinburgh BioQuarterEdinburghUK
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17
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Kim O, Tran PT, Gal M, Lee SJ, Na SH, Hwangbo C, Lee JH. RAS‑stimulated release of exosomal miR‑494‑3p promotes the osteolytic bone metastasis of breast cancer cells. Int J Mol Med 2023; 52:84. [PMID: 37503759 PMCID: PMC10555479 DOI: 10.3892/ijmm.2023.5287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 07/11/2023] [Indexed: 07/29/2023] Open
Abstract
RAS activation is a key determinant of breast cancer progression and metastasis. However, the role of the interaction among exosomes, RAS and microRNAs (miRNAs/miRs) in the osteolytic bone metastasis of breast cancer remains unclear. Therefore, the present study aimed to examine the role of activated RAS (KRAS, HRAS and NRAS) in the release of exosome‑mediated osteoclastogenic miRNAs and to elucidate their functional role in bone microenvironment remodeling in vitro and in vivo. Exosomes derived from RAS‑activated breast cancer cells promoted RANKL‑induced osteoclastogenesis; however, RAS inhibition abolished this effect. miR‑494‑3p, miR‑4508 and miR‑6869‑5p were identified as osteoclastogenic miRNAs in the exosomes secreted by RAS‑activated breast cancer cells. The levels of these osteoclastogenic miRNAs in the sera of patients with human epidermal growth factor receptor 2‑positive luminal breast cancer were significantly higher than those in the sera of patients with triple‑negative breast cancer. miR‑494‑3p exhibited both osteoclastogenic and anti‑osteoblastogenic activity. Treatment with a miR‑494‑3p inhibitor abolished the exosome‑mediated increase in RANKL‑induced osteoclastogenesis. Treatment with a miR‑494‑3p mimic enhanced RANKL‑induced osteoclast formation; however, treatment with its inhibitor suppressed this effect by targeting leucine‑rich repeat‑containing G‑protein coupled receptor 4 in osteoclast precursors. Furthermore, miR‑494‑3p inhibited bone morphogenetic protein 2‑induced osteoblast formation by targeting semaphorin 3A. In a mouse model, exosomes derived from breast cancer cells promoted osteolytic bone lesions; however, treatment with a miR‑494‑3p inhibitor significantly suppressed this effect. On the whole, the present study provides a novel mechanism, demonstrating that the RAS activation of breast cancer cells induces osteolytic bone metastasis by stimulating the exosome‑mediated transfer of osteoclastogenic miRNAs, including miR‑494‑3p to bone cells.
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Affiliation(s)
- Okhwa Kim
- Department of Biochemistry, College of Natural Sciences, Kangwon National University
- Kangwon Institute of Inclusive Technology, Kangwon National University
| | - Phuong Thao Tran
- Department of Biochemistry, College of Natural Sciences, Kangwon National University
| | - Minju Gal
- Department of Biochemistry, College of Natural Sciences, Kangwon National University
| | - Se Jin Lee
- Department of Obstetrics and Gynecology, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon-Si, Gangwon-Do 24341
| | - Sung Hun Na
- Department of Obstetrics and Gynecology, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon-Si, Gangwon-Do 24341
| | - Cheol Hwangbo
- Division of Applied Life Science (BK21 Four), Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Gyeongsang 52828, Republic of Korea
| | - Jeong-Hyung Lee
- Department of Biochemistry, College of Natural Sciences, Kangwon National University
- Kangwon Institute of Inclusive Technology, Kangwon National University
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18
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Li C, Sun C, Lohcharoenkal W, Ali MM, Xing P, Zheng W, Görgens A, Gustafsson MO, El Andaloussi S, Sonkoly E, Pivarcsi A. Cutaneous squamous cell carcinoma-derived extracellular vesicles exert an oncogenic role by activating cancer-associated fibroblasts. Cell Death Discov 2023; 9:260. [PMID: 37495566 PMCID: PMC10372068 DOI: 10.1038/s41420-023-01555-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/04/2023] [Accepted: 07/12/2023] [Indexed: 07/28/2023] Open
Abstract
Cutaneous squamous cell carcinoma (cSCC) is a fast-increasing cancer with metastatic potential. Extracellular vesicles (EVs) are small membrane-bound vesicles that play important roles in intercellular communication, particularly in the tumor microenvironment (TME). Here we report that cSCC cells secrete an increased number of EVs relative to normal human epidermal keratinocytes (NHEKs) and that interfering with the capacity of cSCC to secrete EVs inhibits tumor growth in vivo in a xenograft model of human cSCC. Transcriptome analysis of tumor xenografts by RNA-sequencing enabling the simultaneous quantification of both the human and the mouse transcripts revealed that impaired EV-production of cSCC cells prominently altered the phenotype of stromal cells, in particular genes related to extracellular matrix (ECM)-formation and epithelial-mesenchymal transition (EMT). In line with these results, co-culturing of human dermal fibroblasts (HDFs) with cSCC cells, but not with normal keratinocytes in vitro resulted in acquisition of cancer-associated fibroblast (CAF) phenotype. Interestingly, EVs derived from metastatic cSCC cells, but not primary cSCCs or NHEKs, were efficient in converting HDFs to CAFs. Multiplex bead-based flow cytometry assay and mass-spectrometry (MS)-based proteomic analyses revealed the heterogenous cargo of cSCC-derived EVs and that especially EVs derived from metastatic cSCCs carry proteins associated with EV-biogenesis, EMT, and cell migration. Mechanistically, EVs from metastatic cSCC cells result in the activation of TGFβ signaling in HDFs. Altogether, our study suggests that cSCC-derived EVs mediate cancer-stroma communication, in particular the conversion of fibroblasts to CAFs, which eventually contribute to cSCC progression.
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Affiliation(s)
- Chen Li
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
- Dermatology and Venereology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Chengxi Sun
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
- Department of Clinical Laboratory, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China
| | - Warangkana Lohcharoenkal
- Unit of Dermatology and Venerology, Department of Medicine, Karolinska Institutet, Stockholm, SE, 17176, Sweden
| | - Mohamad Moustafa Ali
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Pengwei Xing
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Wenyi Zheng
- Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden
| | - André Görgens
- Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Manuela O Gustafsson
- Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden
| | - Samir El Andaloussi
- Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden
| | - Enikö Sonkoly
- Dermatology and Venereology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- Unit of Dermatology and Venerology, Department of Medicine, Karolinska Institutet, Stockholm, SE, 17176, Sweden
| | - Andor Pivarcsi
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
- Dermatology and Venereology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
- Unit of Dermatology and Venerology, Department of Medicine, Karolinska Institutet, Stockholm, SE, 17176, Sweden.
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19
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Filatova AA, Alekseeva LA, Savin IA, Sen'kova AV, Zenkova MA, Mironova NL. The Effect of Cell-Free DNA from Blood Serum of Mice with Metastatic Melanoma on Enhancement of Oncogenic Properties of Melanoma Cells. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:995-1007. [PMID: 37751869 DOI: 10.1134/s0006297923070118] [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: 03/13/2023] [Accepted: 03/13/2023] [Indexed: 09/28/2023]
Abstract
Currently, a significant increase in the levels of circulating cell-free DNA (cfDNA) in the blood of patients is considered as a generally recognized marker of the development of oncological diseases. Although the tumor-associated cfDNA has been well studied, its biological functions remain unclear. In this work, we investigated the effect of cfDNA isolated from the blood serum of the mice with B16-F10 metastatic melanoma on the properties of the B16-F10 melanoma cells in vitro. It was found that the profile of cfDNA isolated from the blood serum of mice with melanoma differs significantly from the cfDNA isolated from the blood serum of healthy mice, and is similar to the genomic DNA of B16 cells with regards to abundance of oncogenes and mobile genetic elements (MGE). It was shown that the cfDNA of mice with melanoma penetrated into B16 cells, resulting in the increase in abundance of oncogenes and MGE fragments, and caused 5-fold increase of the mRNA level of the secreted DNase Dnase1l3 and a slight increase of the mRNA level of the Jun, Fos, Ras, and Myc oncogenes. cfDNA of the healthy mice caused increase of the mRNA level of intracellular regulatory DNase EndoG and 4-fold increase of the mRNA level of Fos and Ras oncogenes, which are well-known triggers of a large number of signal cascades, from apoptosis inhibition to increased tumor cell proliferation. Thus, it is obvious that the circulating cfDNA of tumor origin is able to penetrate into the cells and, despite the fact that no changes were found in the level of viability and migration activity of the tumor cells, cfDNA, even with a single exposure, can cause changes at the cellular level that increase oncogenicity of the recipient cells.
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Affiliation(s)
- Alina A Filatova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.
- Novosibirsk State University, Novosibirsk, 630090, Russia
| | - Ludmila A Alekseeva
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.
| | - Innokenty A Savin
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.
| | - Aleksandra V Sen'kova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.
| | - Marina A Zenkova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.
| | - Nadezhda L Mironova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.
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20
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Arena GO, Forte S, Abdouh M, Vanier C, Corbeil D, Lorico A. Horizontal Transfer of Malignant Traits and the Involvement of Extracellular Vesicles in Metastasis. Cells 2023; 12:1566. [PMID: 37371036 PMCID: PMC10297028 DOI: 10.3390/cells12121566] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/31/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Metastases are responsible for the vast majority of cancer deaths, yet most therapeutic efforts have focused on targeting and interrupting tumor growth rather than impairing the metastatic process. Traditionally, cancer metastasis is attributed to the dissemination of neoplastic cells from the primary tumor to distant organs through blood and lymphatic circulation. A thorough understanding of the metastatic process is essential to develop new therapeutic strategies that improve cancer survival. Since Paget's original description of the "Seed and Soil" hypothesis over a hundred years ago, alternative theories and new players have been proposed. In particular, the role of extracellular vesicles (EVs) released by cancer cells and their uptake by neighboring cells or at distinct anatomical sites has been explored. Here, we will outline and discuss these alternative theories and emphasize the horizontal transfer of EV-associated biomolecules as a possibly major event leading to cell transformation and the induction of metastases. We will also highlight the recently discovered intracellular pathway used by EVs to deliver their cargoes into the nucleus of recipient cells, which is a potential target for novel anti-metastatic strategies.
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Affiliation(s)
- Goffredo O. Arena
- Department of Surgery, McGill University, Montréal, QC H3A 0G4, Canada;
- Fondazione Istituto G. Giglio, 90015 Cefalù, Italy
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy;
| | - Stefano Forte
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy;
| | - Mohamed Abdouh
- Cancer Research Program, Research Institute, McGill University Health Centre, Montréal, QC H3A 0G4, Canada;
| | - Cheryl Vanier
- Touro University Nevada College of Medicine, Henderson, NV 89014, USA;
| | - Denis Corbeil
- Biotechnology Center (BIOTEC) and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, 01307 Dresden, Germany;
| | - Aurelio Lorico
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy;
- Touro University Nevada College of Medicine, Henderson, NV 89014, USA;
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21
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Ferlizza E, Romaniello D, Borrelli F, Pagano F, Girone C, Gelfo V, Kuhre RS, Morselli A, Mazzeschi M, Sgarzi M, Filippini DM, D'Uva G, Lauriola M. Extracellular Vesicles and Epidermal Growth Factor Receptor Activation: Interplay of Drivers in Cancer Progression. Cancers (Basel) 2023; 15:cancers15112970. [PMID: 37296932 DOI: 10.3390/cancers15112970] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/12/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Extracellular vesicles (EVs) are of great interest to study the cellular mechanisms of cancer development and to diagnose and monitor cancer progression. EVs are a highly heterogeneous population of cell derived particles, which include microvesicles (MVs) and exosomes (EXOs). EVs deliver intercellular messages transferring proteins, lipids, nucleic acids, and metabolites with implications for tumour progression, invasiveness, and metastasis. Epidermal Growth Factor Receptor (EGFR) is a major driver of cancer. Tumour cells with activated EGFR could produce EVs disseminating EGFR itself or its ligands. This review provides an overview of EVs (mainly EXOs and MVs) and their cargo, with a subsequent focus on their production and effects related to EGFR activation. In particular, in vitro studies performed in EGFR-dependent solid tumours and/or cell cultures will be explored, thus shedding light on the interplay between EGFR and EVs production in promoting cancer progression, metastases, and resistance to therapies. Finally, an overview of liquid biopsy approaches involving EGFR and EVs in the blood/plasma of EGFR-dependent tumour patients will also be discussed to evaluate their possible application as candidate biomarkers.
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Affiliation(s)
- Enea Ferlizza
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Donatella Romaniello
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Francesco Borrelli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Federica Pagano
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Cinzia Girone
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Valerio Gelfo
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Rikke Sofie Kuhre
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Alessandra Morselli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Martina Mazzeschi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Michela Sgarzi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Daria Maria Filippini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Gabriele D'Uva
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Mattia Lauriola
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
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22
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Kalluri R, McAndrews KM. The role of extracellular vesicles in cancer. Cell 2023; 186:1610-1626. [PMID: 37059067 PMCID: PMC10484374 DOI: 10.1016/j.cell.2023.03.010] [Citation(s) in RCA: 262] [Impact Index Per Article: 131.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/17/2023] [Accepted: 03/07/2023] [Indexed: 04/16/2023]
Abstract
Intercellular communication is a key feature of cancer progression and metastasis. Extracellular vesicles (EVs) are generated by all cells, including cancer cells, and recent studies have identified EVs as key mediators of cell-cell communication via packaging and transfer of bioactive constituents to impact the biology and function of cancer cells and cells of the tumor microenvironment. Here, we review recent advances in understanding the functional contribution of EVs to cancer progression and metastasis, as cancer biomarkers, and the development of cancer therapeutics.
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Affiliation(s)
- Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
| | - Kathleen M McAndrews
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
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23
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Robado de Lope L, Sánchez‐Herrero E, Serna‐Blasco R, Provencio M, Romero A. Cancer as an infective disease: the role of EVs in tumorigenesis. Mol Oncol 2023; 17:390-406. [PMID: 36168102 PMCID: PMC9980310 DOI: 10.1002/1878-0261.13316] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 08/19/2022] [Accepted: 09/26/2022] [Indexed: 11/09/2022] Open
Abstract
Cancer is conventionally considered an evolutionary disease where tumor cells adapt to the environment and evolve eventually leading to the formation of metastasis through the seeding and growth of metastasis-initiating cells in distant organs. Tumor cell and tumor-stroma communication via soluble factors and extracellular vesicles (EVs) are essential for the success of the metastatic process. As the field of EVs advances, growing data support the role of tumor-derived EVs not only in modifying the microenvironment to facilitate tumor progression but also in inducing changes in cells outside the primary tumor that may lead to a malignant transformation. Thus, an alternative hypothesis has emerged suggesting the conceptualization of cancer as an 'infective' disease. Still, tackling EVs as a possible cancer treatment has not been widely explored. A major understanding is needed to unveil possible additional contributions of EVs in progression and metastasis, which may be essential for the development of novel approaches to treat cancer patients. Here, we review the contribution of EVs to cancer progression and the possible implication of these factors in the oncogenic transformation of indolent cells.
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Affiliation(s)
- Lucia Robado de Lope
- Liquid Biopsy LaboratoryBiomedical Sciences Research Institute Puerta de Hierro‐MajadahondaSpain
| | - Estela Sánchez‐Herrero
- Liquid Biopsy LaboratoryBiomedical Sciences Research Institute Puerta de Hierro‐MajadahondaSpain
- Atrys HealthBarcelonaSpain
| | - Roberto Serna‐Blasco
- Liquid Biopsy LaboratoryBiomedical Sciences Research Institute Puerta de Hierro‐MajadahondaSpain
| | - Mariano Provencio
- Liquid Biopsy LaboratoryBiomedical Sciences Research Institute Puerta de Hierro‐MajadahondaSpain
- Medical Oncology DepartmentHospital Universitario Puerta de Hierro‐MajadahondaSpain
| | - Atocha Romero
- Liquid Biopsy LaboratoryBiomedical Sciences Research Institute Puerta de Hierro‐MajadahondaSpain
- Medical Oncology DepartmentHospital Universitario Puerta de Hierro‐MajadahondaSpain
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24
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Tatischeff I. Extracellular Vesicle-DNA: The Next Liquid Biopsy Biomarker for Early Cancer Diagnosis? Cancers (Basel) 2023; 15:cancers15051456. [PMID: 36900248 PMCID: PMC10000627 DOI: 10.3390/cancers15051456] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/17/2023] [Accepted: 02/17/2023] [Indexed: 03/03/2023] Open
Abstract
After a short introduction about the history of liquid biopsy, aimed to noninvasively replace the common tissue biopsy as a help for cancer diagnosis, this review is focused on extracellular vesicles (EVs), as the main third component, which is now coming into the light of liquid biopsy. Cell-derived EV release is a recently discovered general cellular property, and EVs harbor many cellular components reflecting their cell of origin. This is also the case for tumoral cells, and their cargoes might therefore be a "treasure chest" for cancer biomarkers. This has been extensively explored for a decade, but the EV-DNA content escaped this worldwide query until recently. The aim of this review is to gather the pilot studies focused on the DNA content of circulating cell-derived EVs, and the following five years of studies about the circulating tumor EV-DNA. The recent preclinical studies about the circulating tEV-derived gDNA as a potential cancer biomarker developed into a puzzling controversy about the presence of DNA into exosomes, coupled with an increased unexpected non vesicular complexity of the extracellular environment. This is discussed in the present review, together with the challenges that need to be solved before any efficient clinical transfer of EV-DNA as a quite promising cancer diagnosis biomarker.
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Affiliation(s)
- Irène Tatischeff
- Honorary CNRS and UPMC Research Director, Founder of RevInterCell, a Scientific Consulting Service, 91400 Orsay, France
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25
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Mechanisms and clinical application potential of mesenchymal stem cells-derived extracellular vesicles in periodontal regeneration. Stem Cell Res Ther 2023; 14:26. [PMID: 36782259 PMCID: PMC9925224 DOI: 10.1186/s13287-023-03242-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 01/17/2023] [Indexed: 02/15/2023] Open
Abstract
Periodontitis is a high prevalence oral disease which damages both the hard and soft tissue of the periodontium, resulting in tooth mobility and even loss. Existing clinical treatment methods cannot fully achieve periodontal tissue regeneration; thus, due to the unique characteristics of mesenchymal stem cells (MSCs), they have become the focus of attention and may be the most promising new therapy for periodontitis. Accumulating evidence supports the view that the role of MSCs in regenerative medicine is mainly achieved by the paracrine pathway rather than direct proliferation and differentiation at the injured site. Various cells release lipid-enclosed particles known as extracellular vesicles (EVs), which are rich in bioactive substances. In periodontitis, EVs play a pivotal role in regulating the biological functions of both periodontal tissue cells and immune cells, as well as the local microenvironment, thereby promoting periodontal injury repair and tissue regeneration. As a cell-free therapy, MSCs-derived extracellular vesicles (MSC-EVs) have some preponderance on stability, immune rejection, ethical supervision, and other problems; therefore, they may have a broad clinical application prospect. Herein, we gave a brief introduction to MSC-EVs and focused on their mechanisms and clinical application in periodontal regeneration.
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26
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Heterogeneity of Extracellular Vesicles and Particles: Molecular Voxels in the Blood Borne "Hologram" of Organ Function, Disfunction and Cancer. Arch Immunol Ther Exp (Warsz) 2023; 71:5. [PMID: 36729313 DOI: 10.1007/s00005-023-00671-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 12/17/2022] [Indexed: 02/03/2023]
Abstract
Extracellular vesicles (EVs) and particles (EPs) serve as unique carriers of complex molecular information with increasingly recognized roles in health and disease. Individual EVs/EPs collectively contribute to the molecular fingerprint of their producing cell, reflecting its identity, state, function and phenotype. This property is of particular interest in cancer where enormous heterogeneity of cancer cells is compounded by the presence of altered stromal, vascular and immune cell populations, which is further complicated by systemic responses elicited by the disease in individual patients. These diverse and interacting cellular compartments are dynamically represented by myriads of EVs/EPs released into the circulating biofluids (blood) during cancer progression and treatment. Current approaches of liquid biopsy seek to follow specific elements of the EV/EP cargo that may have diagnostic utility (as biomarkers), such as cancer cell-derived mutant oncoproteins or nucleic acids. However, with emerging technologies enabling high-throughput EV/EP analysis at a single particle level, a more holistic approach may be on the horizon. Indeed, each EV/EP carries multidimensional information (molecular "voxel") that could be integrated across thousands of particles into a larger and unbiased landscape (EV/EP "hologram") reflecting the true cellular complexity of the disease, along with cellular interactions, systemic responses and effects of treatment. Thus, the longitudinal molecular mapping of EV/EP populations may add a new dimension to crucial aspects of cancer biology, personalized diagnostics, and therapy.
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27
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Intravesicular Genomic DNA Enriched by Size Exclusion Chromatography Can Enhance Lung Cancer Oncogene Mutation Detection Sensitivity. Int J Mol Sci 2022; 23:ijms232416052. [PMID: 36555692 PMCID: PMC9785009 DOI: 10.3390/ijms232416052] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 12/11/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Extracellular vesicles (EVs) are cell-derived structures surrounded by a lipid bilayer that carry RNA and DNA as potential templates for molecular diagnostics, e.g., in cancer genotyping. While it has been established that DNA templates appear on the outside of EVs, no consensus exists on which nucleic acid species inside small EVs (<200 nm, sEVs) are sufficiently abundant and accessible for developing genotyping protocols. We investigated this by extracting total intravesicular nucleic acid content from sEVs isolated from the conditioned cell medium of the human NCI-H1975 cell line containing the epidermal growth factor (EGFR) gene mutation T790M as a model system for non-small cell lung cancer. We observed that mainly short genomic DNA (<35−100 bp) present in the sEVs served as a template. Using qEV size exclusion chromatography (SEC), significantly lower yield and higher purity of isolated sEV fractions were obtained as compared to exoEasy membrane affinity purification and ultracentrifugation. Nevertheless, we detected the EGFR T790M mutation in the sEVs’ lumen with similar sensitivity using digital PCR. When applying SEC-based sEV separation prior to cell-free DNA extraction on spiked human plasma samples, we found significantly higher mutant allele frequencies as compared to standard cell-free DNA extraction, which in part was due to co-purification of circulating tumor DNA. We conclude that intravesicular genomic DNA can be exploited next to ctDNA to enhance EGFR T790M mutation detection sensitivity by adding a fast and easy-to-use sEV separation method, such as SEC, upstream of standard clinical cell-free DNA workflows.
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28
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Kuhn M, Zhang Y, Favate J, Morita M, Blucher A, Das S, Liang S, Preet R, Parham LR, Williams KN, Molugu S, Armstrong RJ, Zhang W, Yang J, Hamilton KE, Dixon DA, Mills G, Morgan TK, Shah P, Andres SF. IMP1/IGF2BP1 in human colorectal cancer extracellular vesicles. Am J Physiol Gastrointest Liver Physiol 2022; 323:G571-G585. [PMID: 36194131 PMCID: PMC9678429 DOI: 10.1152/ajpgi.00121.2022] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 09/22/2022] [Accepted: 09/27/2022] [Indexed: 01/31/2023]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related death. There is an urgent need for new methods of early CRC detection and monitoring to improve patient outcomes. Extracellular vesicles (EVs) are secreted, lipid-bilayer bound, nanoparticles that carry biological cargo throughout the body and in turn exhibit cancer-related biomarker potential. RNA binding proteins (RBPs) are posttranscriptional regulators of gene expression that may provide a link between host cell gene expression and EV phenotypes. Insulin-like growth factor 2 RNA binding protein 1 (IGF2BP1/IMP1) is an RBP that is highly expressed in CRC with higher levels of expression correlating with poor prognosis. IMP1 binds and potently regulates tumor-associated transcripts that may impact CRC EV phenotypes. Our objective was to test whether IMP1 expression levels impact EV secretion and/or cargo. We used RNA sequencing, in vitro CRC cell lines, ex vivo colonoid models, and xenograft mice to test the hypothesis that IMP1 influences EV secretion and/or cargo in human CRC. Our data demonstrate that IMP1 modulates the RNA expression of transcripts associated with extracellular vesicle pathway regulation, but it has no effect on EV secretion levels in vitro or in vivo. Rather, IMP1 appears to affect EV regulation by directly entering EVs in a transformation-dependent manner. These findings suggest that IMP1 has the ability to shape EV cargo in human CRC, which could serve as a diagnostic/prognostic circulating tumor biomarker.NEW & NOTEWORTHY This work demonstrates that the RNA binding protein IGF2BP1/IMP1 alters the transcript profile of colorectal cancer cell (CRC) mRNAs from extracellular vesicle (EV) pathways. IMP1 does not alter EV production or secretion in vitro or in vivo, but rather enters CRC cells where it may further impact EV cargo. Our work shows that IMP1 has the ability to shape EV cargo in human CRC, which could serve as a diagnostic/prognostic circulating tumor biomarker.
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Affiliation(s)
- Madeline Kuhn
- Pediatric Gastroenterology Division, Department of Pediatrics, School of Medicine, Oregon Health and Science University, Portland, Oregon
| | - Yang Zhang
- Pediatric Gastroenterology Division, Department of Pediatrics, School of Medicine, Oregon Health and Science University, Portland, Oregon
| | - John Favate
- Department of Genetics, Rutgers University, Piscataway, New Jersey
| | - Mayu Morita
- Department of Pathology, Oregon Health and Science University, Portland, Oregon
| | - Aurora Blucher
- Division of Oncological Sciences, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon
| | - Sukanya Das
- Department of Genetics, Rutgers University, Piscataway, New Jersey
| | - Shun Liang
- Department of Genetics, Rutgers University, Piscataway, New Jersey
| | - Ranjan Preet
- Department of Molecular Biosciences, University of Kansas Cancer Center, University of Kansas, Lawrence, Kansas
| | - Louis R Parham
- Division of Gastroenterology Hepatology and Nutrition, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Kathy N Williams
- Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Sudheer Molugu
- Electron Microscopy Resource Lab, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Randall J Armstrong
- Division of Oncological Sciences, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon
- Cancer Early Detection Advanced Research, Oregon Health and Science University, Portland, Oregon
| | - Wei Zhang
- Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jiegang Yang
- Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kathryn E Hamilton
- Division of Gastroenterology Hepatology and Nutrition, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Dan A Dixon
- Department of Molecular Biosciences, University of Kansas Cancer Center, University of Kansas, Lawrence, Kansas
| | - Gordon Mills
- Division of Oncological Sciences, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon
| | - Terry K Morgan
- Department of Pathology, Oregon Health and Science University, Portland, Oregon
- Cancer Early Detection Advanced Research, Oregon Health and Science University, Portland, Oregon
| | - Premal Shah
- Department of Genetics, Rutgers University, Piscataway, New Jersey
| | - Sarah F Andres
- Pediatric Gastroenterology Division, Department of Pediatrics, School of Medicine, Oregon Health and Science University, Portland, Oregon
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Adnani L, Spinelli C, Tawil N, Rak J. Role of extracellular vesicles in cancer-specific interactions between tumour cells and the vasculature. Semin Cancer Biol 2022; 87:196-213. [PMID: 36371024 DOI: 10.1016/j.semcancer.2022.11.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/25/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022]
Abstract
Cancer progression impacts and exploits the vascular system in several highly consequential ways. Among different types of vascular cells, blood cells and mediators that are engaged in these processes, endothelial cells are at the centre of the underlying circuitry, as crucial constituents of angiogenesis, angiocrine stimulation, non-angiogenic vascular growth, interactions with the coagulation system and other responses. Tumour-vascular interactions involve soluble factors, extracellular matrix molecules, cell-cell contacts, as well as extracellular vesicles (EVs) carrying assemblies of molecular effectors. Oncogenic mutations and transforming changes in the cancer cell genome, epigenome and signalling circuitry exert important and often cancer-specific influences upon pathways of tumour-vascular interactions, including the biogenesis, content, and biological activity of EVs and responses of cancer cells to them. Notably, EVs may carry and transfer bioactive, oncogenic macromolecules (oncoproteins, RNA, DNA) between tumour and vascular cells and thereby elicit unique functional changes and forms of vascular growth and remodeling. Cancer EVs influence the state of the vasculature both locally and systemically, as exemplified by cancer-associated thrombosis. EV-mediated communication pathways represent attractive targets for therapies aiming at modulation of the tumour-vascular interface (beyond angiogenesis) and could also be exploited for diagnostic purposes in cancer.
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Affiliation(s)
- Lata Adnani
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Cristiana Spinelli
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Nadim Tawil
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Janusz Rak
- McGill University and Research Institute of the McGill University Health Centre, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
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30
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Műzes G, Bohusné Barta B, Szabó O, Horgas V, Sipos F. Cell-Free DNA in the Pathogenesis and Therapy of Non-Infectious Inflammations and Tumors. Biomedicines 2022; 10:2853. [PMID: 36359370 PMCID: PMC9687442 DOI: 10.3390/biomedicines10112853] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 10/31/2022] [Accepted: 11/07/2022] [Indexed: 11/09/2022] Open
Abstract
The basic function of the immune system is the protection of the host against infections, along with the preservation of the individual antigenic identity. The process of self-tolerance covers the discrimination between self and foreign antigens, including proteins, nucleic acids, and larger molecules. Consequently, a broken immunological self-tolerance results in the development of autoimmune or autoinflammatory disorders. Immunocompetent cells express pattern-recognition receptors on their cell membrane and cytoplasm. The majority of endogenous DNA is located intracellularly within nuclei and mitochondria. However, extracellular, cell-free DNA (cfDNA) can also be detected in a variety of diseases, such as autoimmune disorders and malignancies, which has sparked interest in using cfDNA as a possible biomarker. In recent years, the widespread use of liquid biopsies and the increasing demand for screening, as well as monitoring disease activity and therapy response, have enabled the revival of cfDNA research. The majority of studies have mainly focused on the function of cfDNA as a biomarker. However, research regarding the immunological consequences of cfDNA, such as its potential immunomodulatory or therapeutic benefits, is still in its infancy. This article discusses the involvement of various DNA-sensing receptors (e.g., absent in melanoma-2; Toll-like receptor 9; cyclic GMP-AMP synthase/activator of interferon genes) in identifying host cfDNA as a potent danger-associated molecular pattern. Furthermore, we aim to summarize the results of the experimental studies that we recently performed and highlight the immunomodulatory capacity of cfDNA, and thus, the potential for possible therapeutic consideration.
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Affiliation(s)
| | | | | | | | - Ferenc Sipos
- Department of Internal Medicine and Hematology, Semmelweis University, Szentkirályi Street 46, 1088 Budapest, Hungary
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31
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Tsering T, Li M, Chen Y, Nadeau A, Laskaris A, Abdouh M, Bustamante P, Burnier JV. EV-ADD, a database for EV-associated DNA in human liquid biopsy samples. J Extracell Vesicles 2022; 11:e12270. [PMID: 36271888 PMCID: PMC9587709 DOI: 10.1002/jev2.12270] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 08/20/2022] [Accepted: 09/06/2022] [Indexed: 11/06/2022] Open
Abstract
Extracellular vesicles (EVs) play a key role in cellular communication both in physiological conditions and in pathologies such as cancer. Emerging evidence has shown that EVs are active carriers of molecular cargo (e.g. protein and nucleic acids) and a powerful source of biomarkers and targets. While recent studies on EV‐associated DNA (EV‐DNA) in human biofluids have generated a large amount of data, there is currently no database that catalogues information on EV‐DNA. To fill this gap, we have manually curated a database of EV‐DNA data derived from human biofluids (liquid biopsy) and in‐vitro studies, called the Extracellular Vesicle‐Associated DNA Database (EV‐ADD). This database contains validated experimental details and data extracted from peer‐reviewed published literature. It can be easily queried to search for EV isolation methods and characterization, EV‐DNA isolation techniques, quality validation, DNA fragment size, volume of starting material, gene names and disease context. Currently, our database contains samples representing 23 diseases, with 13 different types of EV isolation techniques applied on eight different human biofluids (e.g. blood, saliva). In addition, EV‐ADD encompasses EV‐DNA data both representing the whole genome and specifically including oncogenes, such as KRAS, EGFR, BRAF, MYC, and mitochondrial DNA (mtDNA). An EV‐ADD data metric system was also integrated to assign a compliancy score to the MISEV guidelines based on experimental parameters reported in each study. While currently available databases document the presence of proteins, lipids, RNA and metabolites in EVs (e.g. Vesiclepedia, ExoCarta, ExoBCD, EVpedia, and EV‐TRACK), to the best of our knowledge, EV‐ADD is the first of its kind to compile all available EV‐DNA datasets derived from human biofluid samples. We believe that this database provides an important reference resource on EV‐DNA‐based liquid biopsy research, serving as a learning tool and to showcase the latest developments in the EV‐DNA field. EV‐ADD will be updated yearly as newly published EV‐DNA data becomes available and it is freely available at www.evdnadatabase.com.
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Affiliation(s)
- Thupten Tsering
- Cancer Research ProgramResearch Institute of the McGill University Health CentreMontrealQuebecCanada
| | - Mingyang Li
- Cancer Research ProgramResearch Institute of the McGill University Health CentreMontrealQuebecCanada
| | - Yunxi Chen
- Cancer Research ProgramResearch Institute of the McGill University Health CentreMontrealQuebecCanada
| | - Amélie Nadeau
- Cancer Research ProgramResearch Institute of the McGill University Health CentreMontrealQuebecCanada
| | - Alexander Laskaris
- Cancer Research ProgramResearch Institute of the McGill University Health CentreMontrealQuebecCanada
| | - Mohamed Abdouh
- Cancer Research ProgramResearch Institute of the McGill University Health CentreMontrealQuebecCanada
| | - Prisca Bustamante
- Cancer Research ProgramResearch Institute of the McGill University Health CentreMontrealQuebecCanada
| | - Julia V. Burnier
- Cancer Research ProgramResearch Institute of the McGill University Health CentreMontrealQuebecCanada
- Gerald Bronfman Department of OncologyMcGill UniversityMontrealQuebecCanada
- Experimental Pathology UnitDepartment of PathologyMcGill UniversityMontrealQuebecCanada
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32
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Lucotti S, Kenific CM, Zhang H, Lyden D. Extracellular vesicles and particles impact the systemic landscape of cancer. EMBO J 2022; 41:e109288. [PMID: 36052513 PMCID: PMC9475536 DOI: 10.15252/embj.2021109288] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 02/16/2022] [Accepted: 03/23/2022] [Indexed: 11/09/2022] Open
Abstract
Intercellular cross talk between cancer cells and stromal and immune cells is essential for tumor progression and metastasis. Extracellular vesicles and particles (EVPs) are a heterogeneous class of secreted messengers that carry bioactive molecules and that have been shown to be crucial for this cell-cell communication. Here, we highlight the multifaceted roles of EVPs in cancer. Functionally, transfer of EVP cargo between cells influences tumor cell growth and invasion, alters immune cell composition and function, and contributes to stromal cell activation. These EVP-mediated changes impact local tumor progression, foster cultivation of pre-metastatic niches at distant organ-specific sites, and mediate systemic effects of cancer. Furthermore, we discuss how exploiting the highly selective enrichment of molecules within EVPs has profound implications for advancing diagnostic and prognostic biomarker development and for improving therapy delivery in cancer patients. Altogether, these investigations into the role of EVPs in cancer have led to discoveries that hold great promise for improving cancer patient care and outcome.
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Affiliation(s)
- Serena Lucotti
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Candia M Kenific
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Haiying Zhang
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - David Lyden
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
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33
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Bronkhorst AJ, Ungerer V, Oberhofer A, Gabriel S, Polatoglou E, Randeu H, Uhlig C, Pfister H, Mayer Z, Holdenrieder S. New Perspectives on the Importance of Cell-Free DNA Biology. Diagnostics (Basel) 2022; 12:2147. [PMID: 36140548 PMCID: PMC9497998 DOI: 10.3390/diagnostics12092147] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 08/24/2022] [Accepted: 08/31/2022] [Indexed: 11/28/2022] Open
Abstract
Body fluids are constantly replenished with a population of genetically diverse cell-free DNA (cfDNA) fragments, representing a vast reservoir of information reflecting real-time changes in the host and metagenome. As many body fluids can be collected non-invasively in a one-off and serial fashion, this reservoir can be tapped to develop assays for the diagnosis, prognosis, and monitoring of wide-ranging pathologies, such as solid tumors, fetal genetic abnormalities, rejected organ transplants, infections, and potentially many others. The translation of cfDNA research into useful clinical tests is gaining momentum, with recent progress being driven by rapidly evolving preanalytical and analytical procedures, integrated bioinformatics, and machine learning algorithms. Yet, despite these spectacular advances, cfDNA remains a very challenging analyte due to its immense heterogeneity and fluctuation in vivo. It is increasingly recognized that high-fidelity reconstruction of the information stored in cfDNA, and in turn the development of tests that are fit for clinical roll-out, requires a much deeper understanding of both the physico-chemical features of cfDNA and the biological, physiological, lifestyle, and environmental factors that modulate it. This is a daunting task, but with significant upsides. In this review we showed how expanded knowledge on cfDNA biology and faithful reverse-engineering of cfDNA samples promises to (i) augment the sensitivity and specificity of existing cfDNA assays; (ii) expand the repertoire of disease-specific cfDNA markers, thereby leading to the development of increasingly powerful assays; (iii) reshape personal molecular medicine; and (iv) have an unprecedented impact on genetics research.
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Affiliation(s)
- Abel J. Bronkhorst
- Munich Biomarker Research Center, Institute for Laboratory Medicine, German Heart Centre, Technical University Munich, Lazarettstraße 36, D-80636 Munich, Germany
| | | | | | | | | | | | | | | | | | - Stefan Holdenrieder
- Munich Biomarker Research Center, Institute for Laboratory Medicine, German Heart Centre, Technical University Munich, Lazarettstraße 36, D-80636 Munich, Germany
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34
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Valcz G, Újvári B, Buzás EI, Krenács T, Spisák S, Kittel Á, Tulassay Z, Igaz P, Takács I, Molnár B. Small extracellular vesicle DNA-mediated horizontal gene transfer as a driving force for tumor evolution: Facts and riddles. Front Oncol 2022; 12:945376. [PMID: 36003770 PMCID: PMC9393732 DOI: 10.3389/fonc.2022.945376] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/06/2022] [Indexed: 11/13/2022] Open
Abstract
The basis of the conventional gene-centric view on tumor evolution is that vertically inherited mutations largely define the properties of tumor cells. In recent years, however, accumulating evidence shows that both the tumor cells and their microenvironment may acquire external, non-vertically inherited genetic properties via horizontal gene transfer (HGT), particularly through small extracellular vesicles (sEVs). Many phases of sEV-mediated HGT have been described, such as DNA packaging into small vesicles, their release, uptake by recipient cells, and incorporation of sEV-DNA into the recipient genome to modify the phenotype and properties of cells. Recent techniques in sEV separation, genome sequencing and editing, as well as the identification of new secretion mechanisms, shed light on a number of additional details of this phenomenon. Here, we discuss the key features of this form of gene transfer and make an attempt to draw relevant conclusions on the contribution of HGT to tumor evolution.
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Affiliation(s)
- Gábor Valcz
- MTA-SE Molecular Medicine Research Group, Eötvös Loránd Research Network, Budapest, Hungary
| | - Beáta Újvári
- School of Life and Environmental Sciences, Centre for Integrative Ecology, Deakin University, Waurn Ponds, VIC, Australia
| | - Edit I. Buzás
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
- ELKH-SE Immune-Proteogenomics Extracellular Vesicle Research Group, Semmelweis University, Budapest, Hungary
- HCEMM-SU Extracellular Vesicle Research Group, Semmelweis University, Budapest, Hungary
| | - Tibor Krenács
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Sándor Spisák
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
| | - Ágnes Kittel
- Institute of Experimental Medicine, Eötvös Loránd Research Network, Budapest, Hungary
| | - Zsolt Tulassay
- MTA-SE Molecular Medicine Research Group, Eötvös Loránd Research Network, Budapest, Hungary
| | - Péter Igaz
- MTA-SE Molecular Medicine Research Group, Eötvös Loránd Research Network, Budapest, Hungary
- Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
- Department of Endocrinology, Semmelweis University, Budapest, Hungary
| | - István Takács
- Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - Béla Molnár
- MTA-SE Molecular Medicine Research Group, Eötvös Loránd Research Network, Budapest, Hungary
- Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
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35
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Zhao L, Corvigno S, Ma S, Celestino J, Fleming ND, Hajek RA, Lankenau Ahumada A, Jennings NB, Thompson EJ, Tang H, Westin SN, Jazaeri AA, Zhang J, Futreal PA, Sood AK, Lee S. Molecular Profiles of Serum-Derived Extracellular Vesicles in High-Grade Serous Ovarian Cancer. Cancers (Basel) 2022; 14:cancers14153589. [PMID: 35892848 PMCID: PMC9330879 DOI: 10.3390/cancers14153589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/18/2022] [Accepted: 07/20/2022] [Indexed: 02/04/2023] Open
Abstract
Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (R0) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have a response enabling interval cytoreductive surgery. Clinically useful biomarkers for predicting these outcomes are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. In this study, we performed extensive molecular characterization of serum-derived EVs and correlated the findings with therapeutic outcomes in patients with HGSC. Using EV-DNA whole-genome sequencing and EV-RNA sequencing, we identified distinct somatic EV-DNA alterations in cancer-hallmark genes and in ovarian cancer genes, as well as significantly altered oncogenic pathways between the R0 group and NACT groups. We also found significantly altered EV-RNA transcriptomic variations and enriched pathways between the groups. Taken together, our data suggest that the molecular characteristics of EVs could enable prediction of patients with HGSC who could undergo R0 surgery or respond to chemotherapy.
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Affiliation(s)
- Li Zhao
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (L.Z.); (J.Z.); (P.A.F.)
| | - Sara Corvigno
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Shaolin Ma
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Joseph Celestino
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Nicole D. Fleming
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Richard A. Hajek
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Adrian Lankenau Ahumada
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Nicholas B. Jennings
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Erika J. Thompson
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (E.J.T.); (H.T.)
| | - Hongli Tang
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (E.J.T.); (H.T.)
| | - Shannon N. Westin
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Amir A. Jazaeri
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Jianhua Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (L.Z.); (J.Z.); (P.A.F.)
| | - P. Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (L.Z.); (J.Z.); (P.A.F.)
| | - Anil K. Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
- Correspondence: (A.K.S.); (S.L.)
| | - Sanghoon Lee
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
- Correspondence: (A.K.S.); (S.L.)
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Elzanowska J, Berrocal L, García-Peláez B, Vives-Usano M, Sebo BP, Maia J, Batista S, Teppo J, Varjosalo M, Moraes MCS, Molina-Vila MÁ, Costa-Silva B. Defining Optimal Conditions for Tumor Extracellular Vesicle DNA Extraction for Mutation Profiling. Cancers (Basel) 2022; 14:cancers14133258. [PMID: 35805031 PMCID: PMC9265681 DOI: 10.3390/cancers14133258] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/23/2022] [Accepted: 07/01/2022] [Indexed: 12/12/2022] Open
Abstract
(1) Background: Extracellular vesicles (EVs) have emerged as crucial players in the communication between cells in both physiological and pathological scenarios. The functions of EVs are strongly determined by their molecular content, which includes all bioactive molecules, such as proteins, lipids, RNA, and, as more recently described, double-stranded DNA. It has been shown that in oncological settings DNA associated with EVs (EV-DNA) is representative of the genome of parental cells and that it reflects the mutational status of the tumor, gaining much attention as a promising source of biomarker mutant DNA. However, one of the challenges in studies of EV-DNA is the lack of standardization of protocols for the DNA extraction from EVs, as well as ways to assess quality control, which hinders its future implementation in clinics. (2) Methods: We performed a comprehensive comparison of commonly used approaches for EV-DNA extraction by assessing DNA quantity, quality, and suitability for downstream analyses. (3) Results: We here established strategic points to consider for EV-DNA preparation for mutational analyses, including qPCR and NGS. (4) Conclusions: We put in place a workflow that can be applied for the detection of clinically relevant mutations in the EV-DNA of cancer patients.
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Affiliation(s)
- Julia Elzanowska
- Champalimaud Physiology and Cancer Programme, Champalimaud Foundation, 1400-038 Lisbon, Portugal; (J.E.); (B.P.S.); (J.M.); (S.B.); (M.C.S.M.)
| | - Laura Berrocal
- Laboratorio de Oncología/Pangaea Oncology, Hospital Universitario Quirón-Dexeus, 08028 Barcelona, Spain; (L.B.); (B.G.-P.); (M.V.-U.)
| | - Beatriz García-Peláez
- Laboratorio de Oncología/Pangaea Oncology, Hospital Universitario Quirón-Dexeus, 08028 Barcelona, Spain; (L.B.); (B.G.-P.); (M.V.-U.)
| | - Marta Vives-Usano
- Laboratorio de Oncología/Pangaea Oncology, Hospital Universitario Quirón-Dexeus, 08028 Barcelona, Spain; (L.B.); (B.G.-P.); (M.V.-U.)
| | - Beatriz Passos Sebo
- Champalimaud Physiology and Cancer Programme, Champalimaud Foundation, 1400-038 Lisbon, Portugal; (J.E.); (B.P.S.); (J.M.); (S.B.); (M.C.S.M.)
| | - Joana Maia
- Champalimaud Physiology and Cancer Programme, Champalimaud Foundation, 1400-038 Lisbon, Portugal; (J.E.); (B.P.S.); (J.M.); (S.B.); (M.C.S.M.)
| | - Silvia Batista
- Champalimaud Physiology and Cancer Programme, Champalimaud Foundation, 1400-038 Lisbon, Portugal; (J.E.); (B.P.S.); (J.M.); (S.B.); (M.C.S.M.)
| | - Jaakko Teppo
- Drug Research Program, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland;
- Molecular Systems Biology Research Group and Proteomics Unit, Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland;
| | - Markku Varjosalo
- Molecular Systems Biology Research Group and Proteomics Unit, Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland;
| | - Maria Carolina Strano Moraes
- Champalimaud Physiology and Cancer Programme, Champalimaud Foundation, 1400-038 Lisbon, Portugal; (J.E.); (B.P.S.); (J.M.); (S.B.); (M.C.S.M.)
| | - Miguel Ángel Molina-Vila
- Laboratorio de Oncología/Pangaea Oncology, Hospital Universitario Quirón-Dexeus, 08028 Barcelona, Spain; (L.B.); (B.G.-P.); (M.V.-U.)
- Correspondence: (M.Á.M.-V.); (B.C.-S.)
| | - Bruno Costa-Silva
- Champalimaud Physiology and Cancer Programme, Champalimaud Foundation, 1400-038 Lisbon, Portugal; (J.E.); (B.P.S.); (J.M.); (S.B.); (M.C.S.M.)
- Correspondence: (M.Á.M.-V.); (B.C.-S.)
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37
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Li X, Wang Q, Wang R. Roles of Exosome Genomic DNA in Colorectal Cancer. Front Pharmacol 2022; 13:923232. [PMID: 35721181 PMCID: PMC9198365 DOI: 10.3389/fphar.2022.923232] [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: 04/19/2022] [Accepted: 05/18/2022] [Indexed: 12/03/2022] Open
Abstract
Exosomes are extracellular vesicles that mediate cell-to-cell communication. Bioactive substances such as DNA, RNA, lipids, and proteins are present in it, and they play an essential role in the pathogenesis of colorectal cancer (CRC). The role of RNA and protein in exosomes has been extensively studied. Exosome DNA has recently attracted the attention of a great deal of scientists. According to studies, exosome DNA mainly contains genomic DNA (gDNA) and mitochondrial DNA (mtDNA), of which exosome gDNA is widely used in liquid biopsy of CRC. It includes a variety of clinically relevant tumor-specific mutation genes. In addition to liquid biopsy, researchers find that exosome gDNA regulates immune and metabolic functions in CRC, making it an important research object. However, the primary research on exosome gDNA is still limited. Here, we describe the occurrence and composition of exosomes. Summarize the essential characteristics and mode of action of exosome gDNA. Remarkably, this paper constitutes a comprehensive summary on the role of exosome gDNA on CRC with the intent of providing a theoretical basis and reference for early diagnosis and clinical treatment of cancer.
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Affiliation(s)
- Xiaoshuai Li
- Department of Blood Transfusion, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qiushi Wang
- Department of Blood Transfusion, Shengjing Hospital of China Medical University, Shenyang, China
| | - Rui Wang
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, China
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Ashique S, Upadhyay A, Garg A, Mishra N, Hussain A, Negi P, Hing GB, Bhatt S, Ali MK, Gowthamarajan K, Singh SK, Gupta G, Chellappan DK, Dua K. Impact of ecDNA: A mechanism that directs tumorigenesis in cancer drug Resistance-A review. Chem Biol Interact 2022; 363:110000. [DOI: 10.1016/j.cbi.2022.110000] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/22/2022] [Accepted: 05/28/2022] [Indexed: 12/16/2022]
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Clancy JW, Sheehan CS, Boomgarden AC, D'Souza-Schorey C. Recruitment of DNA to tumor-derived microvesicles. Cell Rep 2022; 38:110443. [PMID: 35235806 DOI: 10.1016/j.celrep.2022.110443] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 12/16/2021] [Accepted: 02/04/2022] [Indexed: 02/08/2023] Open
Abstract
The shedding of extracellular vesicles (EVs) represents an important but understudied means of cell-cell communication in cancer. Among the currently described classes of EVs, tumor-derived microvesicles (TMVs) comprise a class of vesicles released directly from the cell surface. TMVs contain abundant cargo, including functional proteins and miRNA, which can be transferred to and alter the behavior of recipient cells. Here, we document that a fraction of extracellular double-stranded DNA (dsDNA) is enclosed within TMVs and protected from nuclease degradation. dsDNA inclusion in TMVs is regulated by ARF6 cycling and occurs with the cytosolic DNA sensor, cGAS, but independent of amphisome or micronuclei components. Our studies suggest that dsDNA is trafficked to TMVs via a mechanism distinct from the multivesicular body-dependent secretion reported for the extracellular release of cytosolic DNA. Furthermore, TMV dsDNA can be transferred to recipient cells with consequences to recipient cell behavior, reinforcing its relevance in mediating cell-cell communication.
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Affiliation(s)
- James W Clancy
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Colin S Sheehan
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Alex C Boomgarden
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA
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Exosomes and Other Extracellular Vesicles with High Therapeutic Potential: Their Applications in Oncology, Neurology, and Dermatology. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27041303. [PMID: 35209095 PMCID: PMC8879284 DOI: 10.3390/molecules27041303] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/28/2022] [Accepted: 02/08/2022] [Indexed: 02/06/2023]
Abstract
Until thirty years ago, it was believed that extracellular vesicles (EVs) were used to remove unnecessary compounds from the cell. Today, we know about their enormous potential in diagnosing and treating various diseases. EVs are essential mediators of intercellular communication, enabling the functional transfer of bioactive molecules from one cell to another. Compared to laboratory-created drug nanocarriers, they are stable in physiological conditions. Furthermore, they are less immunogenic and cytotoxic compared to polymerized vectors. Finally, EVs can transfer cargo to particular cells due to their membrane proteins and lipids, which can implement them to specific receptors in the target cells. Recently, new strategies to produce ad hoc exosomes have been devised. Cells delivering exosomes have been genetically engineered to overexpress particular macromolecules, or transformed to release exosomes with appropriate targeting molecules. In this way, we can say tailor-made therapeutic EVs are created. Nevertheless, there are significant difficulties to solve during the application of EVs as drug-delivery agents in the clinic. This review explores the diversity of EVs and the potential therapeutic options for exosomes as natural drug-delivery vehicles in oncology, neurology, and dermatology. It also reflects future challenges in clinical translation.
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Syntenin-1-mediated small extracellular vesicles promotes cell growth, migration, and angiogenesis by increasing onco-miRNAs secretion in lung cancer cells. Cell Death Dis 2022; 13:122. [PMID: 35136055 PMCID: PMC8826407 DOI: 10.1038/s41419-022-04594-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 01/17/2022] [Accepted: 01/27/2022] [Indexed: 12/13/2022]
Abstract
Small extracellular vesicles (sEVs) play a pivotal role in tumor progression by mediating intercellular communication in the tumor microenvironment (TME). Syntenin-1 induces malignant tumor progression in various types of human cancers, including human lung cancer and regulates biogenesis of sEVs. However, the function of syntenin-1-regulated sEVs and miRNAs in sEVs remains to be elucidated. In the present study, we aimed to demonstrate the role of oncogenic Ras/syntenin-1 axis in the release of sEVs and elucidate the function of syntenin-1-mediated miRNAs in sEVs in lung cancer progression. The results revealed that oncogenic Ras promoted the release of sEVs by inducing syntenin-1 expression; disruption of syntenin-1 expression impaired the release of sEVs as well as sEV-mediated cancer cell migration and angiogenesis. Moreover, we identified three miRNAs, namely miR-181a, miR-425-5p, and miR-494-3p, as onco-miRNAs loaded into syntenin-1-dependent sEVs. Remarkably, miR-494-3p was highly abundant in sEVs and its release was triggered by syntenin-1 expression and oncogenic Ras. Ectopic expression of the miR-494-3p mimic enhanced the migration and proliferation of lung cancer cells as well as tube formation in endothelial cells; however, the miR-494-3p inhibitor blocked sEV-mediated effects by targeting tyrosine-protein phosphatase nonreceptor type 12 (PTPN12), a tumor suppressor. sEVs promoted tumor growth and angiogenesis by downregulating PTPN12 expression; however, the miR-494-3p inhibitor significantly suppressed these effects in vivo, confirming that miR-494-3p acts as a major onco-miRNA loaded into lung cancer cell-derived sEVs. Eventually, the oncogenic Ras/syntenin-1 axis may induce cancer progression by increasing miR-494-3p loading into sEVs in lung cancer cells in the TME.
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Kim HJ, Kim G, Lee J, Lee Y, Kim JH. Secretome of Stem Cells: Roles of Extracellular Vesicles in Diseases, Stemness, Differentiation, and Reprogramming. Tissue Eng Regen Med 2022; 19:19-33. [PMID: 34817808 PMCID: PMC8782975 DOI: 10.1007/s13770-021-00406-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/05/2021] [Accepted: 10/13/2021] [Indexed: 12/16/2022] Open
Abstract
Increasing evidence suggests that stem cells or stem cell-derived cells may contribute to tissue repair, not only by replacing lost tissue but also by delivering complex sets of secretory molecules, called secretomes, into host injured tissues. In recent years, extracellular vesicles (EVs) have gained much attention for their diverse and important roles in a wide range of pathophysiological processes. EVs are released from most types of cells and mediates cell-cell communication by activating receptors on target cells or by being taken up by recipient cells. EVs, including microvesicles and exosomes, encapsulate and carry proteins, nucleic acids, and lipids in the lumen and on the cell surface. Thus, EV-mediated intercellular communication has been extensively studied across various biological processes. While a number of investigations has been conducted in different tissues and body fluids, the field lacks a systematic review on stem cell-derived EVs, especially regarding their roles in stemness and differentiation. Here, we provide an overview of the pathophysiological roles of EVs and summarize recent findings focusing on EVs released from various types of stem cells. We also highlight emerging evidence for the potential implication of EVs in self-renewal, differentiation, and reprograming and discuss the benefits and limitations in translational approaches.
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Affiliation(s)
- Hyo Jin Kim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 145, Anam-ro, Seongbuk-gu, West building of Life Sciences, Seoul, 02841, South Korea
| | - Gyeongmin Kim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 145, Anam-ro, Seongbuk-gu, West building of Life Sciences, Seoul, 02841, South Korea
| | - Jihun Lee
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 145, Anam-ro, Seongbuk-gu, West building of Life Sciences, Seoul, 02841, South Korea
| | - Youngseok Lee
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 145, Anam-ro, Seongbuk-gu, West building of Life Sciences, Seoul, 02841, South Korea
| | - Jong-Hoon Kim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 145, Anam-ro, Seongbuk-gu, West building of Life Sciences, Seoul, 02841, South Korea.
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Pink RC, Beaman EM, Samuel P, Brooks SA, Carter DRF. Utilising extracellular vesicles for early cancer diagnostics: benefits, challenges and recommendations for the future. Br J Cancer 2022; 126:323-330. [PMID: 35013578 PMCID: PMC8810954 DOI: 10.1038/s41416-021-01668-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 11/26/2021] [Accepted: 12/03/2021] [Indexed: 01/12/2023] Open
Abstract
To increase cancer patient survival and wellbeing, diagnostic assays need to be able to detect cases earlier, be applied more frequently, and preferably before symptoms develop. The expansion of blood biopsy technologies such as detection of circulating tumour cells and cell-free DNA has shown clinical promise for this. Extracellular vesicles released into the blood from tumour cells may offer a snapshot of the whole of the tumour. They represent a stable and multifaceted complex of a number of different types of molecules including DNA, RNA and protein. These represent biomarker targets that can be collected and analysed from blood samples, offering great potential for early diagnosis. In this review we discuss the benefits and challenges of the use of extracellular vesicles in this context and provide recommendations on where this developing field should focus their efforts to bring future success.
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Affiliation(s)
- Ryan Charles Pink
- Department of Biological and Medical Sciences, Faculty of Health & Life Sciences, Oxford Brookes University, Oxford, UK.
| | - Ellie-May Beaman
- grid.7628.b0000 0001 0726 8331Department of Biological and Medical Sciences, Faculty of Health & Life Sciences, Oxford Brookes University, Oxford, UK
| | - Priya Samuel
- grid.7628.b0000 0001 0726 8331Department of Biological and Medical Sciences, Faculty of Health & Life Sciences, Oxford Brookes University, Oxford, UK
| | - Susan Ann Brooks
- grid.7628.b0000 0001 0726 8331Department of Biological and Medical Sciences, Faculty of Health & Life Sciences, Oxford Brookes University, Oxford, UK
| | - David Raul Francisco Carter
- grid.7628.b0000 0001 0726 8331Department of Biological and Medical Sciences, Faculty of Health & Life Sciences, Oxford Brookes University, Oxford, UK ,Therapeutics Limited Oxford Science Park Medawar Centre 2nd Floor East Building Robert Robinson Avenue, Oxford, OX4 4HG UK
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Glennon KI, Maralani M, Abdian N, Paccard A, Montermini L, Nam AJ, Arseneault M, Staffa A, Jandaghi P, Meehan B, Brimo F, Tanguay S, Rak J, Riazalhosseini Y. Rational Development of Liquid Biopsy Analysis in Renal Cell Carcinoma. Cancers (Basel) 2021; 13:cancers13225825. [PMID: 34830979 PMCID: PMC8616270 DOI: 10.3390/cancers13225825] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 11/15/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Among patients affected by renal cell carcinoma (RCC), the most common type of kidney cancer, it remains difficult to identify those who are at high risk for relapse or metastasis. This is in part due to the absence of reliable clinical biomarkers and robust methods to capture them. The aim of our study was to develop an improved assay to capture prognostic genomic biomarkers in circulating tumor DNA (ctDNA) in RCC. For this purpose, we first established a next generation sequencing (NGS) assay, targeting genes that are tailored for RCC and that are largely excluded from commercially available assays. Next, we showed the reliable performance of this assay to detect prognostic gene mutations in tumor DNA isolated from plasma, and from extracellular vesicles. Thus, our study provides a resource to facilitate ctDNA analysis for precision medicine in RCC. Abstract Renal cell carcinoma (RCC) is known for its variable clinical behavior and outcome, including heterogeneity in developing relapse or metastasis. Recent data highlighted the potential of somatic mutations as promising biomarkers for risk stratification in RCC. Likewise, the analysis of circulating tumor DNA (ctDNA) for such informative somatic mutations (liquid biopsy) is considered an important advance for precision oncology in RCC, allowing to monitor molecular disease evolution in real time. However, our knowledge about the utility of ctDNA analysis in RCC is limited, in part due to the lack of RCC-appropriate assays for ctDNA analysis. Here, by interrogating different blood compartments in xenograft models, we identified plasma cell-free (cf) DNA and extracellular vesicles (ev) DNA enriched for RCC-associated ctDNA. Additionally, we developed sensitive targeted sequencing and bioinformatics workflows capable of detecting somatic mutations in RCC-relevant genes with allele frequencies ≥ 0.5%. Applying this assay to patient-matched tumor and liquid biopsies, we captured tumor mutations in cf- and ev-DNA fractions isolated from the blood, highlighting the potentials of both fractions for ctDNA analysis. Overall, our study presents an RCC-appropriate sequencing assay and workflow for ctDNA analysis and provides a proof of principle as to the feasibility of detecting tumor-specific mutations in liquid biopsy in RCC patients.
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Affiliation(s)
- Kate I. Glennon
- McGill Genome Centre, McGill University, 740 Doctor Penfield Avenue, Montreal, QC H3A 0G1, Canada; (K.I.G.); (M.M.); (A.P.); (A.J.N.); (M.A.); (A.S.); (P.J.)
- Department of Human Genetics, McGill University, 1205 Doctor Penfield Avenue, Montreal, QC H3A 1B1, Canada
| | - Mahafarin Maralani
- McGill Genome Centre, McGill University, 740 Doctor Penfield Avenue, Montreal, QC H3A 0G1, Canada; (K.I.G.); (M.M.); (A.P.); (A.J.N.); (M.A.); (A.S.); (P.J.)
- Department of Human Genetics, McGill University, 1205 Doctor Penfield Avenue, Montreal, QC H3A 1B1, Canada
- The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (N.A.); (L.M.); (B.M.); (J.R.)
| | - Narges Abdian
- The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (N.A.); (L.M.); (B.M.); (J.R.)
| | - Antoine Paccard
- McGill Genome Centre, McGill University, 740 Doctor Penfield Avenue, Montreal, QC H3A 0G1, Canada; (K.I.G.); (M.M.); (A.P.); (A.J.N.); (M.A.); (A.S.); (P.J.)
| | - Laura Montermini
- The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (N.A.); (L.M.); (B.M.); (J.R.)
| | - Alice Jisoo Nam
- McGill Genome Centre, McGill University, 740 Doctor Penfield Avenue, Montreal, QC H3A 0G1, Canada; (K.I.G.); (M.M.); (A.P.); (A.J.N.); (M.A.); (A.S.); (P.J.)
| | - Madeleine Arseneault
- McGill Genome Centre, McGill University, 740 Doctor Penfield Avenue, Montreal, QC H3A 0G1, Canada; (K.I.G.); (M.M.); (A.P.); (A.J.N.); (M.A.); (A.S.); (P.J.)
| | - Alfredo Staffa
- McGill Genome Centre, McGill University, 740 Doctor Penfield Avenue, Montreal, QC H3A 0G1, Canada; (K.I.G.); (M.M.); (A.P.); (A.J.N.); (M.A.); (A.S.); (P.J.)
| | - Pouria Jandaghi
- McGill Genome Centre, McGill University, 740 Doctor Penfield Avenue, Montreal, QC H3A 0G1, Canada; (K.I.G.); (M.M.); (A.P.); (A.J.N.); (M.A.); (A.S.); (P.J.)
- Department of Human Genetics, McGill University, 1205 Doctor Penfield Avenue, Montreal, QC H3A 1B1, Canada
| | - Brian Meehan
- The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (N.A.); (L.M.); (B.M.); (J.R.)
| | - Fadi Brimo
- Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada;
| | - Simon Tanguay
- Division of Urology, McGill University, Montreal, QC H4A 3J1, Canada;
| | - Janusz Rak
- The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (N.A.); (L.M.); (B.M.); (J.R.)
| | - Yasser Riazalhosseini
- McGill Genome Centre, McGill University, 740 Doctor Penfield Avenue, Montreal, QC H3A 0G1, Canada; (K.I.G.); (M.M.); (A.P.); (A.J.N.); (M.A.); (A.S.); (P.J.)
- Department of Human Genetics, McGill University, 1205 Doctor Penfield Avenue, Montreal, QC H3A 1B1, Canada
- Correspondence:
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Role of Extracellular Vesicle-Based Cell-to-Cell Communication in Multiple Myeloma Progression. Cells 2021; 10:cells10113185. [PMID: 34831408 PMCID: PMC8625088 DOI: 10.3390/cells10113185] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/04/2021] [Accepted: 11/12/2021] [Indexed: 02/07/2023] Open
Abstract
Multiple myeloma (MM) progression closely depends on the bidirectional crosstalk between tumor cells and the surrounding microenvironment, which leads to the creation of a tumor supportive niche. Extracellular vesicles (EVs) have emerged as key players in the pathological interplay between the malignant clone and near/distal bone marrow (BM) cells through their biologically active cargo. Here, we describe the role of EVs derived from MM and BM cells in reprogramming the tumor microenvironment and in fostering bone disease, angiogenesis, immunosuppression, drug resistance, and, ultimately, tumor progression. We also examine the emerging role of EVs as new therapeutic agents for the treatment of MM, and their potential use as clinical biomarkers for early diagnosis, disease classification, and therapy monitoring.
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Alekseeva L, Mironova N. Role of Cell-Free DNA and Deoxyribonucleases in Tumor Progression. Int J Mol Sci 2021; 22:12246. [PMID: 34830126 PMCID: PMC8625144 DOI: 10.3390/ijms222212246] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 12/30/2022] Open
Abstract
Many studies have reported an increase in the level of circulating cell-free DNA (cfDNA) in the blood of patients with cancer. cfDNA mainly comes from tumor cells and, therefore, carries features of its genomic profile. Moreover, tumor-derived cfDNA can act like oncoviruses, entering the cells of vulnerable organs, transforming them and forming metastatic nodes. Another source of cfDNA is immune cells, including neutrophils that generate neutrophil extracellular traps (NETs). Despite the potential eliminative effect of NETs on tumors, in some cases, their excessive generation provokes tumor growth as well as invasion. Considering both possible pathological contributions of cfDNA, as an agent of oncotransformation and the main component of NETs, the study of deoxyribonucleases (DNases) as anticancer and antimetastatic agents is important and promising. This review considers the pathological role of cfDNA in cancer development and the role of DNases as agents to prevent and/or prohibit tumor progression and the development of metastases.
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Affiliation(s)
| | - Nadezhda Mironova
- Institute of Chemical Biology and Fundamental Medicine, SB RAS, Lavrentiev Ave., 8, 630090 Novosibirsk, Russia;
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Abhange K, Makler A, Wen Y, Ramnauth N, Mao W, Asghar W, Wan Y. Small extracellular vesicles in cancer. Bioact Mater 2021; 6:3705-3743. [PMID: 33898874 PMCID: PMC8056276 DOI: 10.1016/j.bioactmat.2021.03.015] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/03/2021] [Accepted: 03/04/2021] [Indexed: 02/07/2023] Open
Abstract
Extracellular vesicles (EV) are lipid-bilayer enclosed vesicles in submicron size that are released from cells. A variety of molecules, including proteins, DNA fragments, RNAs, lipids, and metabolites can be selectively encapsulated into EVs and delivered to nearby and distant recipient cells. In tumors, through such intercellular communication, EVs can regulate initiation, growth, metastasis and invasion of tumors. Recent studies have found that EVs exhibit specific expression patterns which mimic the parental cell, providing a fingerprint for early cancer diagnosis and prognosis as well as monitoring responses to treatment. Accordingly, various EV isolation and detection technologies have been developed for research and diagnostic purposes. Moreover, natural and engineered EVs have also been used as drug delivery nanocarriers, cancer vaccines, cell surface modulators, therapeutic agents and therapeutic targets. Overall, EVs are under intense investigation as they hold promise for pathophysiological and translational discoveries. This comprehensive review examines the latest EV research trends over the last five years, encompassing their roles in cancer pathophysiology, diagnostics and therapeutics. This review aims to examine the full spectrum of tumor-EV studies and provide a comprehensive foundation to enhance the field. The topics which are discussed and scrutinized in this review encompass isolation techniques and how these issues need to be overcome for EV-based diagnostics, EVs and their roles in cancer biology, biomarkers for diagnosis and monitoring, EVs as vaccines, therapeutic targets, and EVs as drug delivery systems. We will also examine the challenges involved in EV research and promote a framework for catalyzing scientific discovery and innovation for tumor-EV-focused research.
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Affiliation(s)
- Komal Abhange
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University-SUNY, Binghamton, NY 13902, USA
| | - Amy Makler
- Micro and Nanotechnology in Medicine, Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Yi Wen
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University-SUNY, Binghamton, NY 13902, USA
| | - Natasha Ramnauth
- Micro and Nanotechnology in Medicine, Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Wenjun Mao
- Department of Cardiothoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu 214023, China
| | - Waseem Asghar
- Micro and Nanotechnology in Medicine, Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Yuan Wan
- The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University-SUNY, Binghamton, NY 13902, USA
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Pancreatic Cancer Small Extracellular Vesicles (Exosomes): A Tale of Short- and Long-Distance Communication. Cancers (Basel) 2021; 13:cancers13194844. [PMID: 34638330 PMCID: PMC8508300 DOI: 10.3390/cancers13194844] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/21/2021] [Accepted: 09/24/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Even today, pancreatic cancer still has a dismal prognosis. It is characterized by a lack of early symptoms and thus late diagnosis as well as early metastasis. The majority of patients suffer from pancreatic ductal adenocarcinoma (PDAC). PDACs communicate extensively with cellular components of their microenvironment, but also with distant metastatic niches to facilitate tumor progression and dissemination. This crosstalk is substantially enabled by small extracellular vesicles (sEVs, exosomes) with a size of 30–150 nm that are released from the tumor cells. sEVs carry bioactive cargos that reprogram target cells to promote tumor growth, migration, metastasis, immune evasion, or chemotherapy resistance. Interestingly, sEVs also carry novel diagnostic, prognostic and potentially also predictive biomarkers. Moreover, engineered sEVs may be utilized as therapeutic agents, improving treatment options. The role of sEVs for PDAC development, progression, diagnosis, prognosis, and treatment is the focus of this review. Abstract Even with all recent advances in cancer therapy, pancreatic cancer still has a dismal 5-year survival rate of less than 7%. The most prevalent tumor subtype is pancreatic ductal adenocarcinoma (PDAC). PDACs display an extensive crosstalk with their tumor microenvironment (TME), e.g., pancreatic stellate cells, but also immune cells to regulate tumor growth, immune evasion, and metastasis. In addition to crosstalk in the local TME, PDACs were shown to induce the formation of pre-metastatic niches in different organs. Recent advances have attributed many of these interactions to intercellular communication by small extracellular vesicles (sEVs, exosomes). These nanovesicles are derived of endo-lysosomal structures (multivesicular bodies) with a size range of 30–150 nm. sEVs carry various bioactive cargos, such as proteins, lipids, DNA, mRNA, or miRNAs and act in an autocrine or paracrine fashion to educate recipient cells. In addition to tumor formation, progression, and metastasis, sEVs were described as potent biomarker platforms for diagnosis and prognosis of PDAC. Advances in sEV engineering have further indicated that sEVs might once be used as effective drug carriers. Thus, extensive sEV-based communication and applications as platform for biomarker analysis or vehicles for treatment suggest a major impact of sEVs in future PDAC research.
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Fathi M, Joseph R, Adolacion JRT, Martinez-Paniagua M, An X, Gabrusiewicz K, Mani SA, Varadarajan N. Single-Cell Cloning of Breast Cancer Cells Secreting Specific Subsets of Extracellular Vesicles. Cancers (Basel) 2021; 13:cancers13174397. [PMID: 34503207 PMCID: PMC8430892 DOI: 10.3390/cancers13174397] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/24/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Extracellular vesicles (EVs) are a pivotal mechanism for long-distance intercellular communication and facilitate the stable transport of biological information. Conventional methods for profiling EVs are focused on the biological cargo obtained from large populations of cells and cannot map the secretion of specific subsets of EVs onto their cell of origin. We developed a high-throughput single-cell cloning method that can identify the kinetics of secretion of specific subsets of EVs. With the aid of this methodology, we illustrate that secretion of specific subsets of EVs can be an inheritable property of cancer cells. Our single-cell methodology enables the direct integration of EV secretion with multiple cellular functions and can enable new insights into cell and disease biology. Abstract Extracellular vesicles (EVs) mediate communication in health and disease. Conventional assays are limited in profiling EVs secreted from large populations of cells and cannot map EV secretion onto individual cells and their functional profiles. We developed a high-throughput single-cell technique that enabled the mapping of dynamics of EV secretion. By utilizing breast cancer cell lines, we established that EV secretion is heterogeneous at the single-cell level and that non-metastatic cancer cells can secrete specific subsets of EVs. Single-cell RNA sequencing confirmed that pathways related to EV secretion were enriched in the non-metastatic cells compared with metastatic cells. We established isogenic clonal cell lines from non-metastatic cells with differing propensities for CD81+CD63+EV secretion and showed for the first time that specificity in EV secretion is an inheritable property preserved during cell division. Combined in vitro and animal studies with these cell lines suggested that CD81+CD63+EV secretion can impede tumor formation. In human non-metastatic breast tumors, tumors enriched in signatures of CD81+CD63+EV have a better prognosis, higher immune cytolytic activity, and enrichment of pro-inflammatory macrophages compared with tumors with low CD81+CD63+EVs signatures. Our single-cell methodology enables the direct integration of EV secretion with multiple cellular functions and enables new insights into cell/disease biology.
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Affiliation(s)
- Mohsen Fathi
- Chemical and Biomolecular Engineering Department, University of Houston, 4726 Calhoun Rd, Houston, TX 77204, USA; (M.F.); (J.T.A.); (M.M.-P.); (X.A.)
| | - Robiya Joseph
- Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, 2130 W Holcombe Blvd, Houston, TX 77030, USA; (R.J.); (S.A.M.)
| | - Jay R T. Adolacion
- Chemical and Biomolecular Engineering Department, University of Houston, 4726 Calhoun Rd, Houston, TX 77204, USA; (M.F.); (J.T.A.); (M.M.-P.); (X.A.)
- Department of Chemical Engineering, College of Engineering, University of the Philippines Diliman, Quezon City 1101, Philippines
| | - Melisa Martinez-Paniagua
- Chemical and Biomolecular Engineering Department, University of Houston, 4726 Calhoun Rd, Houston, TX 77204, USA; (M.F.); (J.T.A.); (M.M.-P.); (X.A.)
| | - Xingyue An
- Chemical and Biomolecular Engineering Department, University of Houston, 4726 Calhoun Rd, Houston, TX 77204, USA; (M.F.); (J.T.A.); (M.M.-P.); (X.A.)
| | - Konrad Gabrusiewicz
- Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, 1400 Holcombe Blvd, Houston, TX 77030, USA;
| | - Sendurai A. Mani
- Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, 2130 W Holcombe Blvd, Houston, TX 77030, USA; (R.J.); (S.A.M.)
| | - Navin Varadarajan
- Chemical and Biomolecular Engineering Department, University of Houston, 4726 Calhoun Rd, Houston, TX 77204, USA; (M.F.); (J.T.A.); (M.M.-P.); (X.A.)
- Correspondence: ; Tel.: +1-713-743-1691
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Seibold T, Waldenmaier M, Seufferlein T, Eiseler T. Small Extracellular Vesicles and Metastasis-Blame the Messenger. Cancers (Basel) 2021; 13:cancers13174380. [PMID: 34503190 PMCID: PMC8431296 DOI: 10.3390/cancers13174380] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/23/2021] [Accepted: 08/26/2021] [Indexed: 01/18/2023] Open
Abstract
Simple Summary Due to their systemic nature, metastatic lesions are a major problem for curative cancer treatment. According to a common model for metastasis, tumor cells disseminate by local invasion, survival in the blood stream and extravasation into suitable tissue environments. At secondary sites, metastatic cells adapt, proliferate and foster vascularization to satisfy nutrient and oxygen demand. In recent years, tumors were shown to extensively communicate with cells in the local microenvironment and future metastatic sites by secreting small extracellular vesicles (sEVs, exosomes). sEVs deliver bioactive cargos, e.g., proteins, and in particular, several nucleic acid classes to reprogram target cells, which in turn facilitate tumor growth, cell motility, angiogenesis, immune evasion and establishment of pre-metastatic niches. sEV-cargos also act as biomarkers for diagnosis and prognosis. This review discusses how tumor cells utilize sEVs with nucleic acid cargos to progress through metastasis, and how sEVs may be employed for prognosis and treatment. Abstract Cancer is a complex disease, driven by genetic defects and environmental cues. Systemic dissemination of cancer cells by metastasis is generally associated with poor prognosis and is responsible for more than 90% of cancer deaths. Metastasis is thought to follow a sequence of events, starting with loss of epithelial features, detachment of tumor cells, basement membrane breakdown, migration, intravasation and survival in the circulation. At suitable distant niches, tumor cells reattach, extravasate and establish themselves by proliferating and attracting vascularization to fuel metastatic growth. These processes are facilitated by extensive cross-communication of tumor cells with cells in the primary tumor microenvironment (TME) as well as at distant pre-metastatic niches. A vital part of this communication network are small extracellular vesicles (sEVs, exosomes) with a size of 30–150 nm. Tumor-derived sEVs educate recipient cells with bioactive cargos, such as proteins, and in particular, major nucleic acid classes, to drive tumor growth, cell motility, angiogenesis, immune evasion and formation of pre-metastatic niches. Circulating sEVs are also utilized as biomarker platforms for diagnosis and prognosis. This review discusses how tumor cells facilitate progression through the metastatic cascade by employing sEV-based communication and evaluates their role as biomarkers and vehicles for drug delivery.
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