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Jin Z, Zhang C, Shen L, Cao Y. Harnessing Exosomes: From Tumor Immune Escape to Therapeutic Innovation in Gastric Cancer Immunotherapy. Cancer Lett 2025:217792. [PMID: 40409451 DOI: 10.1016/j.canlet.2025.217792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 04/21/2025] [Accepted: 05/11/2025] [Indexed: 05/25/2025]
Abstract
Gastric cancer ranks fifth among the most prevalent cancers globally, with a dismal prognosis. In recent years, immunotherapy, particularly immune checkpoint inhibitors, has emerged as a glimmer of hope for advanced gastric cancer patients. However, not all patients can benefit from this treatment modality, as the tumor microenvironment significantly influences treatment efficacy. Exosomes, pivotal mediators of intercellular communication, exert intricate and diverse effects in shaping and regulating the tumor microenvironment. This review provides a comprehensive overview of the functional mechanisms of exosomes within the gastric cancer tumor microenvironment. It delves into their biogenesis, functions, and impact on innate and adaptive immune cells (such as dendritic cells, myeloid-derived suppressor cells, and T cells) and cancer-associated fibroblasts. Additionally, the potential applications of exosomes in gastric cancer immunotherapy are explored, including their use as biomarkers to predict responses to immune checkpoint inhibitors, and drug delivery vectors, and in the development of exosome-based vaccines and gene therapy. Notably, this review emphasizes the dual nature of exosomes: they can facilitate tumor immune escape, yet they also serve as promising targets for innovative therapeutic strategies. It also compares potential exosome-based strategies with existing immunotherapies like ICIs and emerging CAR-T cell therapies. Finally, insights into the future of exosomes in precision immunotherapy for gastric cancer are offered, presenting a forward-looking perspective on this emerging field.
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Affiliation(s)
- Zhao Jin
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Cell & Gene Therapy for Solid Tumor, Department of GI Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
| | - Cheng Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Cell & Gene Therapy for Solid Tumor, Department of GI Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
| | - Lin Shen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Cell & Gene Therapy for Solid Tumor, Department of GI Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
| | - Yanshuo Cao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Cell & Gene Therapy for Solid Tumor, Department of GI Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
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Liu J, Gao S, Liu X, Dong J, Zhen D, Liu T. Exosomes: their role and therapeutic potential in overcoming drug resistance of gastrointestinal cancers. Front Oncol 2025; 15:1540643. [PMID: 40432919 PMCID: PMC12106034 DOI: 10.3389/fonc.2025.1540643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 04/18/2025] [Indexed: 05/29/2025] Open
Abstract
Gastrointestinal cancers are prevalent malignant neoplasms in clinical medicine. The development of drug resistance in gastrointestinal cancers result in tumor recurrence and metastasis and greatly diminish the efficacy of treatment. Exosomes, as the shuttle of intercellular molecular cargoes in tumor micro-environment, secreted from tumor and stromal cells mediate drug resistance by regulating epithelial-mesenchymal transition, drug efflux, stem-like phenotype and cell metabolism. Meanwhile, exosomes have already received tremendous attention in biomedical study as potential drug resistant biomarkers as well as treatment strategy in gastrointestinal cancers. Primary challenge to implement this potential is the ability to obtain high-grade exosomes efficiently; however, exosomes lack standard protocols for their processing and characterization. Furthermore, this field suffers from insufficient standardized reference materials and workflow for purification, detection and analysis of exosomes with defined biological properties. This review summarize the unique biogenesis, composition and novel detection methods of exosomes and informed the underlying correlation between exosomes and drug resistance of gastrointestinal cancers. Moreover, the clinical applications of exosomes are also summarized, might providing novel therapy for the individual treatment of gastrointestinal cancers.
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Affiliation(s)
- Jiulian Liu
- Department of Anorectal Surgery, The Fourth People’s Hospital of Jinan, Jinan, China
| | - Shanyu Gao
- Department of Anorectal Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaoming Liu
- Department of Health Care, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jiaxin Dong
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Dingwei Zhen
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Tong Liu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
- Department of Clinical Laboratory, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, China
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3
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Zhang Y, Wang B, Chen J, Li T. Role of exosomal miRNAs and macrophage polarization in gastric cancer: A novel therapeutic strategy. Eur J Pharmacol 2025; 990:177268. [PMID: 39805486 DOI: 10.1016/j.ejphar.2025.177268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 01/09/2025] [Accepted: 01/09/2025] [Indexed: 01/16/2025]
Abstract
Gastric cancer (GC) is one of the most common gastrointestinal cancers worldwide, with consistently high morbidity and mortality rates and poor prognosis. Most patients are diagnosed at an advanced stage due to the lack of specific presentation in the early stages. Exosomes are a class of extracellular vesicles (EVs) widely found in body fluids and can release genetic material or multiple proteins to facilitate intercellular communication. In recent years, exosomal miRNAs have gained attention for their role in various cancers. These exosomal miRNAs can impact GC development and progression by targeting specific genes or influencing signaling pathways and cytokines involved in Angiogenesis, epithelial-mesenchymal transition (EMT), drug resistance, and immune regulation. They show great potential in terms of diagnosis, prognosis, and treatment of GC. Notably, the gastrointestinal tract has the largest number of macrophages, which play a significant role in GC progression. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and can influence macrophage programming through various mediators, including macrophage polarization. Macrophage polarization is involved in inflammatory responses and significantly impacts the GC process.
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Affiliation(s)
- Yun Zhang
- School of Clinical Medicine, Ningxia Medical University, Ningxia, China; General Hospital of Ningxia Medical University, Ningxia, China
| | - Baozhen Wang
- School of Clinical Medicine, Ningxia Medical University, Ningxia, China; General Hospital of Ningxia Medical University, Ningxia, China
| | - Jing Chen
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
| | - Tao Li
- Department of Surgical Oncology, Tumor Hospital, The General Hospital of Ningxia Medical University, Ningxia, China.
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Tang L, Zhang W, Qi T, Jiang Z, Tang D. Exosomes play a crucial role in remodeling the tumor microenvironment and in the treatment of gastric cancer. Cell Commun Signal 2025; 23:82. [PMID: 39948541 PMCID: PMC11827163 DOI: 10.1186/s12964-024-02009-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 12/21/2024] [Indexed: 02/16/2025] Open
Abstract
Gastric cancer (GC) is a common and frequent malignant cancer of the digestive system with a poor prognosis. In addition to common therapies such as surgical resection and chemotherapy, novel biological interventions are quite valuable for research. Exosomes are extracellular vesicles (EVs) that originate from various cell types and contain proteins, RNA, DNA, and other components that transmit biological signals and mediate intercellular communication. Numerous studies have shown that exosomes shape the tumor microenvironment (TME) by affecting hypoxia, inflammation, immunity, metabolism, and interstitial changes in the tumor, playing a crucial role in the development and metastasis of GC. This article reviews the important role of exosomes in the TME of GC and explores their potential clinical applications in GC treatment.
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Affiliation(s)
- Lingyun Tang
- Clinical Medical College, Yangzhou University, Yangzhou, 225000, China
| | - Wenjie Zhang
- School of Medicine, Chongqing University, Chongqing, 400030, China
| | - Teng Qi
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, 225000, China
| | - Zhengting Jiang
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, 225000, China.
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Northern Jiangsu People's Hospital; The Yangzhou Clinical Medical College of Xuzhou Medical University; The Yangzhou School of Clinical Medicine of Dalian Medical University; The Yangzhou School of Clinical Medicine of Nanjing Medical University; Northern Jiangsu People's Hospital, Clinical Teaching Hospital of Medical School, Nanjing University, Yangzhou, 225000, China.
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5
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Yang S, Wei S, Wei F. Extracellular vesicles mediated gastric cancer immune response: tumor cell death or immune escape? Cell Death Dis 2024; 15:377. [PMID: 38816455 PMCID: PMC11139918 DOI: 10.1038/s41419-024-06758-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 05/16/2024] [Accepted: 05/16/2024] [Indexed: 06/01/2024]
Abstract
Gastric cancer (GC) is a major global health issue, being the fifth most prevalent cancer and the third highest contributor to cancer-related deaths. Although treatment strategies for GC have diversified, the prognosis for advanced GC remains poor. Hence, there is a critical need to explore new directions for GC treatment to enhance diagnosis, treatment, and patient prognosis. Extracellular vesicles (EVs) have emerged as key players in tumor development and progression. Different sources of EVs carry different molecules, resulting in distinct biological functions. For instance, tumor-derived EVs can promote tumor cell proliferation, alter the tumor microenvironment and immune response, while EVs derived from immune cells carry molecules that regulate immune function and possess tumor-killing capabilities. Numerous studies have demonstrated the crucial role of EVs in the development, immune escape, and immune microenvironment remodeling in GC. In this review, we discuss the role of GC-derived EVs in immune microenvironment remodeling and EVs derived from immune cells in GC development. Furthermore, we provide an overview of the potential uses of EVs in immunotherapy for GC.
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Affiliation(s)
- Shuo Yang
- Department of the Seventh General surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110000̥, Liaoning Province, PR China
| | - Shibo Wei
- Department of the Seventh General surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110000̥, Liaoning Province, PR China.
| | - Fang Wei
- Department of the Seventh General surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110000̥, Liaoning Province, PR China.
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Javdani-Mallak A, Salahshoori I. Environmental pollutants and exosomes: A new paradigm in environmental health and disease. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 925:171774. [PMID: 38508246 DOI: 10.1016/j.scitotenv.2024.171774] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 02/16/2024] [Accepted: 03/15/2024] [Indexed: 03/22/2024]
Abstract
This study investigates the intricate interplay between environmental pollutants and exosomes, shedding light on a novel paradigm in environmental health and disease. Cellular stress, induced by environmental toxicants or disease, significantly impacts the production and composition of exosomes, crucial mediators of intercellular communication. The heat shock response (HSR) and unfolded protein response (UPR) pathways, activated during cellular stress, profoundly influence exosome generation, cargo sorting, and function, shaping intercellular communication and stress responses. Environmental pollutants, particularly lipophilic ones, directly interact with exosome lipid bilayers, potentially affecting membrane stability, release, and cellular uptake. The study reveals that exposure to environmental contaminants induces significant changes in exosomal proteins, miRNAs, and lipids, impacting cellular function and health. Understanding the impact of environmental pollutants on exosomal cargo holds promise for biomarkers of exposure, enabling non-invasive sample collection and real-time insights into ongoing cellular responses. This research explores the potential of exosomal biomarkers for early detection of health effects, assessing treatment efficacy, and population-wide screening. Overcoming challenges requires advanced isolation techniques, standardized protocols, and machine learning for data analysis. Integration with omics technologies enhances comprehensive molecular analysis, offering a holistic understanding of the complex regulatory network influenced by environmental pollutants. The study underscores the capability of exosomes in circulation as promising biomarkers for assessing environmental exposure and systemic health effects, contributing to advancements in environmental health research and disease prevention.
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Affiliation(s)
- Afsaneh Javdani-Mallak
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Iman Salahshoori
- Department of Polymer Processing, Iran Polymer and Petrochemical Institute, Tehran, Iran; Department of Chemical Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran.
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Al-Hawary SIS, Almajidi YQ, Bansal P, Ahmad I, Kaur H, Hjazi A, Deorari M, Zwamel AH, Hamzah HF, Mohammed BA. Dendritic cell-derived exosome (DEX) therapy for digestive system cancers: Recent advances and future prospect. Pathol Res Pract 2024; 257:155288. [PMID: 38653088 DOI: 10.1016/j.prp.2024.155288] [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: 02/15/2024] [Revised: 03/10/2024] [Accepted: 03/31/2024] [Indexed: 04/25/2024]
Abstract
Tumor-mediated immunosuppression is a fundamental obstacle to the development of dendritic cell (DC)-based cancer vaccines, which despite their ability to stimulate host anti-tumor CD8 T cell immunity, have not been able to generate meaningful therapeutic responses. Exosomes are inactive membrane vesicles that are nanoscale in size and are produced by the endocytic pathway. They are essential for intercellular communication. Additionally, DC-derived exosomes (DEXs) contained MHC class I/II (MHCI/II), which is frequently complexed with antigens and co-stimulatory molecules and is therefore able to prime CD4 and CD8 T cells that are specific to particular antigens. Indeed, vaccines with DEXs have been shown to exhibit better anti-tumor efficacy in eradicating tumors compared to DC vaccines in pre-clinical models of digestive system tumors. Also, there is room for improvement in the tumor antigenic peptide (TAA) selection process. DCs release highly targeted exosomes when the right antigenic peptide is chosen, which could aid in the creation of DEX-based antitumor vaccines that elicit more targeted immune responses. Coupled with their resistance to tumor immunosuppression, DEXs-based cancer vaccines have been heralded as the superior alternative cell-free therapeutic vaccines over DC vaccines to treat digestive system tumors. In this review, current studies of DEXs cancer vaccines as well as potential future directions will be deliberated.
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Affiliation(s)
| | - Yasir Qasim Almajidi
- Department of pharmacy (pharmaceutics), Baghdad College of Medical Sciences, Baghdad, Iraq.
| | - Pooja Bansal
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, Karnataka 560069, India; Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Harpreet Kaur
- School of Basic & Applied Sciences, Shobhit University, Gangoh, Uttar Pradesh 247341, India; Department of Health & Allied Sciences, Arka Jain University, Jamshedpur, Jharkhand 831001, India
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University Al-Kharj 11942, Saudi Arabia
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Ahmed Hussein Zwamel
- Department of Medical Laboratory Technology, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Hamza Fadhel Hamzah
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
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8
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Guan XL, Guan XY, Zhang ZY. Roles and application of exosomes in the development, diagnosis and treatment of gastric cancer. World J Gastrointest Oncol 2024; 16:630-642. [PMID: 38577463 PMCID: PMC10989387 DOI: 10.4251/wjgo.v16.i3.630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 12/18/2023] [Accepted: 01/15/2024] [Indexed: 03/12/2024] Open
Abstract
As important messengers of intercellular communication, exosomes can regulate local and distant cellular communication by transporting specific exosomal contents and can also promote or suppress the development and progression of gastric cancer (GC) by regulating the growth and proliferation of tumor cells, the tumor-related immune response and tumor angiogenesis. Exosomes transport bioactive molecules including DNA, proteins, and RNA (coding and noncoding) from donor cells to recipient cells, causing reprogramming of the target cells. In this review, we will describe how exosomes regulate the cellular immune response, tumor angiogenesis, proliferation and metastasis of GC cells, and the role and mechanism of exosome-based therapy in human cancer. We will also discuss the potential application value of exosomes as biomarkers in the diagnosis and treatment of GC and their relationship with drug resistance.
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Affiliation(s)
- Xiao-Li Guan
- Department of General Medicine, The Second Hospital of Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Xiao-Ying Guan
- Department of Pathology, The Second Hospital of Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Zheng-Yi Zhang
- Department of General Medicine, The Second Hospital of Lanzhou University, Lanzhou 730030, Gansu Province, China
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Li Y, Tian L, Zhao T, Zhang J. A nanotherapeutic system for gastric cancer suppression by synergistic chemotherapy and immunotherapy based on iPSCs and DCs exosomes. Cancer Immunol Immunother 2023; 72:1673-1683. [PMID: 36622422 DOI: 10.1007/s00262-022-03355-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 12/21/2022] [Indexed: 01/10/2023]
Abstract
BACKGROUND Chemotherapeutic drugs, the indispensable therapy in the treatment of gastric cancer, contain many problems such as high organ toxicity and insufficient therapeutic effect. The development of nanodrug delivery carriers with both tumor targeting function and immune stimulation ability possesses the potential to remedy these practical defects. METHODS AND RESULTS In this study, a tumor targeting nanosystem that combines chemotherapy with immunotherapy was applied to the treatment and prognosis of gastric cancer. The fusion vector of iPSCs and DCs exosomes, which simultaneously possess the ability of tumor targeting and immune factor recruitment, effectively improved the in vivo efficacy of chemotherapy drugs and released the suppressed T lymphocytes under the action of modified PD-1 antibody to dredge the immunotherapy process. In addition, extensive recruitment of immune cells to clean the environment while exposing vast tumor antigens efficiently amplified the anti-tumor immune effect and ensured the good prognosis. CONCLUSIONS Nanodrug delivery system DOX@aiPS-DCexo could effectively inhibit the expansion process of gastric cancer MFC through synergistic chemotherapy and immunotherapy and demonstrated the capacity of improving prognosis. Scheme: schematic illustration of the nanostructure DOX@aiPS-DCexo and the mechanism of action.
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Affiliation(s)
- Yezhou Li
- Department of Vascular Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, Jilin, China
| | - Leilei Tian
- Department of Operating Room, China-Japan Union Hospital of Jilin University, Changchun, 130033, Jilin, China
| | - Tiancheng Zhao
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, 130033, Jilin, China.
| | - Jiayu Zhang
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, Jilin, China.
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10
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Haque E, Esmail A, Muhsen I, Salah H, Abdelrahim M. Recent Trends and Advancements in the Diagnosis and Management of Gastric Cancer. Cancers (Basel) 2022; 14:5615. [PMID: 36428707 PMCID: PMC9688354 DOI: 10.3390/cancers14225615] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/10/2022] [Accepted: 11/10/2022] [Indexed: 11/17/2022] Open
Abstract
Gastric cancer is an enigmatic malignancy that has recently been shown to be increasing in incidence globally. There has been recent progress in emerging technologies for the diagnosis and treatment of the disease. Improvements in non-invasive diagnostic techniques with serological tests and biomarkers have led to decreased use of invasive procedures such as endoscopy. A multidisciplinary approach is used to treat gastric cancer, with recent significant advancements in systemic therapies used in combination with cytotoxic chemotherapies. New therapeutic targets have been identified and clinical trials are taking place to assess their efficacy and safety. In this review, we provide an overview of the current and emerging treatment strategies and diagnostic techniques for gastric cancer.
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Affiliation(s)
- Emaan Haque
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Abdullah Esmail
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA
| | - Ibrahim Muhsen
- Section of Hematology and Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Haneen Salah
- Department of Pathology, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Maen Abdelrahim
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA
- Cockrell Center for Advanced Therapeutic Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA
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11
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Yang X, Gao M, Xu R, Tao Y, Luo W, Wang B, Zhong W, He L, He Y. Hyperthermia combined with immune checkpoint inhibitor therapy in the treatment of primary and metastatic tumors. Front Immunol 2022; 13:969447. [PMID: 36032103 PMCID: PMC9412234 DOI: 10.3389/fimmu.2022.969447] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/27/2022] [Indexed: 11/29/2022] Open
Abstract
According to the difference in temperature, thermotherapy can be divided into thermal ablation and mild hyperthermia. The main advantage of thermal ablation is that it can efficiently target tumors in situ, while mild hyperthermia has a good inhibitory effect on distant metastasis. There are some similarities and differences between the two therapies with respect to inducing anti-tumor immune responses, but neither of them results in sustained systemic immunity. Malignant tumors (such as breast cancer, pancreatic cancer, nasopharyngeal carcinoma, and brain cancer) are recurrent, highly metastatic, and highly invasive even after treatment, hence a single therapy rarely resolves the clinical issues. A more effective and comprehensive treatment strategy using a combination of hyperthermia and immune checkpoint inhibitor (ICI) therapies has gained attention. This paper summarizes the relevant preclinical and clinical studies on hyperthermia combined with ICI therapies and compares the efficacy of two types of hyperthermia combined with ICIs, in order to provide a better treatment for the recurrence and metastasis of clinically malignant tumors.
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Affiliation(s)
- Ximing Yang
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Miaozhi Gao
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Runshi Xu
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Yangyang Tao
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Wang Luo
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Binya Wang
- Medical School, Hunan University of Chinese Medicine, Changsha, China
| | - Wenliang Zhong
- Medical School, Hunan University of Chinese Medicine, Changsha, China
- Hunan Provincial Ophthalmology and Otolaryngology Diseases Prevention and Treatment with Traditional Chinese Medicine and Visual Function Protection Engineering and Technological Research Center, Changsha, China
| | - Lan He
- Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, China
- The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Yingchun He
- Medical School, Hunan University of Chinese Medicine, Changsha, China
- Hunan Provincial Ophthalmology and Otolaryngology Diseases Prevention and Treatment with Traditional Chinese Medicine and Visual Function Protection Engineering and Technological Research Center, Changsha, China
- Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, China
- *Correspondence: Yingchun He,
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12
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Su H, Ren W, Zhang D. Research progress on exosomal proteins as diagnostic markers of gastric cancer (review article). Clin Exp Med 2022; 23:203-218. [DOI: 10.1007/s10238-022-00793-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 01/04/2022] [Indexed: 12/20/2022]
Abstract
AbstractGastric cancer (GC) is one of the most common types of tumors and the most common cause of cancer mortality worldwide. The diagnosis of GC is critical to its prevention and treatment. Available tumor markers are the crucial step for GC diagnosis. Recent studies have shown that proteins in exosomes are potential diagnostic and prognostic markers for GC. Exosomes, secreted by cells, are cup-shaped with a diameter of 30–150 nm under the electron microscope. They are also surrounded by lipid bilayers and are widely found in various body fluids. Exosomes contain proteins, lipids and nucleic acid. The examination of exosomal proteins has the advantages of quickness, easy sampling, and low pain and cost, as compared with the routine inspection method of GC, which may lead to marked developments in GC diagnosis. This article summarized the exosomal proteins with a diagnostic and prognostic potential in GC, as well as exosomal proteins involved in GC progression.
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13
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Cen Y, Lou Y, Wang J, Wang S, Peng P, Zhang A, Liu P. Supplementation with Serum-Derived Extracellular Vesicles Reinforces Antitumor Immunity Induced by Cryo-Thermal Therapy. Int J Mol Sci 2021; 22:ijms222011021. [PMID: 34681680 PMCID: PMC8539038 DOI: 10.3390/ijms222011021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/26/2021] [Accepted: 09/29/2021] [Indexed: 11/16/2022] Open
Abstract
Effective cancer therapies should reshape immunosuppression and trigger antitumor immunity. Previously, we developed a novel cryo-thermal therapy through applying local rapid cooling followed by rapid heating of tumor tissue. It could not only ablate local tumors, but also, subsequently, induce systemic long-term antitumor immunity. Hyperthermia can induce the release of extracellular vesicles (EVs) to stimulate antitumor immunity. We examine whether EVs are released after cryo-thermal therapy and whether they could improve the efficacy of cryo-thermal therapy in the 4T1 model. In this study, serum extracellular vesicles (sEVs) are isolated and characterized 3 h after cryo-thermal therapy of subcutaneous tumors. sEV phagocytosis is observed in vitro and in vivo by using laser confocal microscopy and flow cytometry. After cryo-thermal therapy, sEVs are administered to mice via the tail vein, and changes in immune cells are investigated by using flow cytometry. After cryo-thermal therapy, a large number of sEVs are released to the periphery carrying danger signals and tumor antigens, and these sEVs could be phagocytosed by peripheral blood monocytes and differentiated macrophages. After cryo-thermal therapy, supplementation with sEVs released after treatment promotes the differentiation of myeloid-derived suppressor cells (MDSCs), monocytes into macrophages and CD4+ T cells into the Th1 subtype, as well as prolonging the long-term survival of the 4T1 subcutaneous tumor-bearing mice. sEVs released after cryo-thermal tumor treatment could clinically serve as an adjuvant in subsequent cryo-thermal therapy to improve the therapeutic effects on malignant tumors.
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Affiliation(s)
- Yinuo Cen
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (Y.C.); (Y.L.); (J.W.); (S.W.); (P.P.); (A.Z.)
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Yue Lou
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (Y.C.); (Y.L.); (J.W.); (S.W.); (P.P.); (A.Z.)
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Junjun Wang
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (Y.C.); (Y.L.); (J.W.); (S.W.); (P.P.); (A.Z.)
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Shicheng Wang
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (Y.C.); (Y.L.); (J.W.); (S.W.); (P.P.); (A.Z.)
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Peng Peng
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (Y.C.); (Y.L.); (J.W.); (S.W.); (P.P.); (A.Z.)
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Aili Zhang
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (Y.C.); (Y.L.); (J.W.); (S.W.); (P.P.); (A.Z.)
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Ping Liu
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (Y.C.); (Y.L.); (J.W.); (S.W.); (P.P.); (A.Z.)
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China
- Correspondence: ; Tel.: +86-(21)-6293-2304
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14
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Day NB, Wixson WC, Shields CW. Magnetic systems for cancer immunotherapy. Acta Pharm Sin B 2021; 11:2172-2196. [PMID: 34522583 PMCID: PMC8424374 DOI: 10.1016/j.apsb.2021.03.023] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/05/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
Immunotherapy is a rapidly developing area of cancer treatment due to its higher specificity and potential for greater efficacy than traditional therapies. Immune cell modulation through the administration of drugs, proteins, and cells can enhance antitumoral responses through pathways that may be otherwise inhibited in the presence of immunosuppressive tumors. Magnetic systems offer several advantages for improving the performance of immunotherapies, including increased spatiotemporal control over transport, release, and dosing of immunomodulatory drugs within the body, resulting in reduced off-target effects and improved efficacy. Compared to alternative methods for stimulating drug release such as light and pH, magnetic systems enable several distinct methods for programming immune responses. First, we discuss how magnetic hyperthermia can stimulate immune cells and trigger thermoresponsive drug release. Second, we summarize how magnetically targeted delivery of drug carriers can increase the accumulation of drugs in target sites. Third, we review how biomaterials can undergo magnetically driven structural changes to enable remote release of encapsulated drugs. Fourth, we describe the use of magnetic particles for targeted interactions with cellular receptors for promoting antitumor activity. Finally, we discuss translational considerations of these systems, such as toxicity, clinical compatibility, and future opportunities for improving cancer treatment.
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Key Words
- BW, body weight
- Biomaterials
- CpG, cytosine-phosphate-guanine
- DAMP, damage associated molecular pattern
- Drug delivery
- EPR, enhanced permeability and retention
- FFR, field free region
- HS-TEX, heat-stressed tumor cell exosomes
- HSP, heat shock protein
- ICD, immunogenic cell death
- IVIS, in vivo imaging system
- Immunotherapy
- MICA, MHC class I-related chain A
- MPI, magnetic particle imaging
- Magnetic hyperthermia
- Magnetic nanoparticles
- Microrobotics
- ODNs, oligodeoxynucleotides
- PARP, poly(adenosine diphosphate-ribose) polymerase
- PDMS, polydimethylsiloxane
- PEG, polyethylene glycol
- PLGA, poly(lactic-co-glycolic acid)
- PNIPAM, poly(N-isopropylacrylamide)
- PVA, poly(vinyl alcohol)
- SDF, stromal cell derived-factor
- SID, small implantable device
- SLP, specific loss power
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Affiliation(s)
- Nicole B Day
- Department of Chemical & Biological Engineering, University of Colorado, Boulder, CO 80303, USA
| | - William C Wixson
- Department of Chemical & Biological Engineering, University of Colorado, Boulder, CO 80303, USA
| | - C Wyatt Shields
- Department of Chemical & Biological Engineering, University of Colorado, Boulder, CO 80303, USA
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15
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Regimbeau M, Abrey J, Vautrot V, Causse S, Gobbo J, Garrido C. Heat shock proteins and exosomes in cancer theranostics. Semin Cancer Biol 2021; 86:46-57. [PMID: 34343652 DOI: 10.1016/j.semcancer.2021.07.014] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/21/2021] [Accepted: 07/21/2021] [Indexed: 01/19/2023]
Abstract
Heat shock proteins (HSPs) are a superfamily of molecular chaperones that were discovered through their ability to be induced by different stresses including heat shock. Other than their function as chaperones in proteins homeostasis, HSPs have been shown to inhibit different forms of cell death and to participate in cell proliferation and differentiation processes. Because cancer cells have to rewire their metabolism, they require a high amount of these stress-inducible chaperones for their survival. Therefore, HSPs are unusually abundant in cancer cells where they have oncogene-like functions. In cancer, HSPs have been involved in the regulation of apoptosis, immune responses, angiogenesis, metastasis and treatment resistance. Recently, HSPs have been shown to be secreted through exosomes by cancer cells. These tumor-derived exosomes can be used as circulating markers: HSP-exosomes have been reported as biomarkers of cancer dissemination, response to therapy and/or patient outcome. A new range of functions, mostly in modulation of anticancer immune responses, have been described for these extracellular HSPs. In this review, we will describe those recently reported functions of HSP-exosomes that makes them both targets for anticancer therapeutics and biomarkers for the monitoring of the disease. We will also discuss their emerging interest in cancer vaccines.
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Affiliation(s)
- Mathilde Regimbeau
- INSERM, UMR 1231, Label Ligue Nationale Contre le Cancer and LipSTIC. 7 blvd Jeanne d'Arc, 21000, Dijon, France; Université. Bourgogne Franche-Comté, 21000, Dijon, France
| | - Jimena Abrey
- INSERM, UMR 1231, Label Ligue Nationale Contre le Cancer and LipSTIC. 7 blvd Jeanne d'Arc, 21000, Dijon, France; Université. Bourgogne Franche-Comté, 21000, Dijon, France
| | - Valentin Vautrot
- INSERM, UMR 1231, Label Ligue Nationale Contre le Cancer and LipSTIC. 7 blvd Jeanne d'Arc, 21000, Dijon, France; Université. Bourgogne Franche-Comté, 21000, Dijon, France; Anticancer Center Georges François Leclerc, Dijon, France
| | - Sebastien Causse
- INSERM, UMR 1231, Label Ligue Nationale Contre le Cancer and LipSTIC. 7 blvd Jeanne d'Arc, 21000, Dijon, France; Université. Bourgogne Franche-Comté, 21000, Dijon, France
| | - Jessica Gobbo
- INSERM, UMR 1231, Label Ligue Nationale Contre le Cancer and LipSTIC. 7 blvd Jeanne d'Arc, 21000, Dijon, France; Anticancer Center Georges François Leclerc, Dijon, France; Early Phase Unit INCa CLIP², Department of Oncology, Georges-François Leclerc Centre, Dijon, France; Centre d'investigation Clinique INSERM 1432, CHU Dijon-Bourgogne, Dijon, France
| | - Carmen Garrido
- INSERM, UMR 1231, Label Ligue Nationale Contre le Cancer and LipSTIC. 7 blvd Jeanne d'Arc, 21000, Dijon, France; Université. Bourgogne Franche-Comté, 21000, Dijon, France; Anticancer Center Georges François Leclerc, Dijon, France.
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16
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Tang XH, Guo T, Gao XY, Wu XL, Xing XF, Ji JF, Li ZY. Exosome-derived noncoding RNAs in gastric cancer: functions and clinical applications. Mol Cancer 2021; 20:99. [PMID: 34330299 PMCID: PMC8323226 DOI: 10.1186/s12943-021-01396-6] [Citation(s) in RCA: 112] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/20/2021] [Indexed: 02/07/2023] Open
Abstract
Exosomes are a subpopulation of the tumour microenvironment (TME) that transmit various biological molecules to promote intercellular communication. Exosomes are derived from nearly all types of cells and exist in all body fluids. Noncoding RNAs (ncRNAs) are among the most abundant contents in exosomes, and some ncRNAs with biological functions are specifically packaged into exosomes. Recent studies have revealed that exosome-derived ncRNAs play crucial roles in the tumorigenesis, progression and drug resistance of gastric cancer (GC). In addition, regulating the expression levels of exosomal ncRNAs can promote or suppress GC progression. Moreover, the membrane structures of exosomes protect ncRNAs from degradation by enzymes and other chemical substances, significantly increasing the stability of exosomal ncRNAs. Specific hallmarks within exosomes that can be used for exosome identification, and specific contents can be used to determine their origin. Therefore, exosomal ncRNAs are suitable for use as diagnostic and prognostic biomarkers or therapeutic targets. Regulating the biogenesis of exosomes and the expression levels of exosomal ncRNAs may represent a new way to block or eradicate GC. In this review, we summarized the origins and characteristics of exosomes and analysed the association between exosomal ncRNAs and GC development.
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Affiliation(s)
- Xiao-Huan Tang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China.,Department of Gastrointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China
| | - Ting Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China
| | - Xiang-Yu Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China.,Department of Gastrointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China
| | - Xiao-Long Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China.,Department of Gastrointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China
| | - Xiao-Fang Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China.
| | - Jia-Fu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China. .,Department of Gastrointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China.
| | - Zi-Yu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China. .,Department of Gastrointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China.
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17
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Role of Extracellular Vesicles in Compromising Cellular Resilience to Environmental Stressors. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9912281. [PMID: 34337063 PMCID: PMC8321721 DOI: 10.1155/2021/9912281] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 06/16/2021] [Accepted: 07/07/2021] [Indexed: 12/17/2022]
Abstract
Extracellular vesicles (EVs), like exosomes, are nanosized membrane-enveloped vesicles containing different bioactive cargo, such as proteins, lipids, mRNA, miRNA, and other small regulatory RNAs. Cell-derived EVs, including EVs originating from stem cells, may capture components from damaged cells or cells impacted by therapeutic treatments. Interestingly, EVs derived from stem cells can be preconditioned to produce and secrete EVs with different therapeutic properties, particularly with respect to heat-shock proteins and other molecular cargo contents. This behavior is consistent with stem cells that also respond differently to various microenvironments. Heat-shock proteins play roles in cellular protection and mediate cellular resistance to radiotherapy, chemotherapy, and heat shock. This review highlights the possible roles EVs play in mediating cellular plasticity and survival when exposed to different physical and chemical stressors, with a special focus on the respiratory distress due to the air pollution.
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18
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Gao J, Li S, Xu Q, Zhang X, Huang M, Dai X, Liu L. Exosomes Promote Pre-Metastatic Niche Formation in Gastric Cancer. Front Oncol 2021; 11:652378. [PMID: 34109113 PMCID: PMC8180914 DOI: 10.3389/fonc.2021.652378] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 05/05/2021] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer has a high rate of metastasis, during which pre-metastatic niches (PMN) provide a supportive environment for the upcoming tumor cells. Exosomes are bilayer vesicles secreted by cells containing biological information that mediates communication between cells. Using exosomes, gastric cancer cells establish PMN remotely in multifarious perspectives, including immunosuppression, stroma remodeling, angiogenesis, mesothelial mesenchymal transformation, and organotropism. In turn, the cell components in PMN secrete exosomes that interact with each other and provide onco-promoting signals. In this review, we highlight the role of exosomes in PMN formation in gastric cancer and discuss their potential values in gastric cancer metastasis diagnosis, prevention, and treatment.
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Affiliation(s)
- Jing Gao
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Song Li
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qian Xu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xue Zhang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Miao Huang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xin Dai
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lian Liu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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19
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Hyperthermia by near infrared radiation induced immune cells activation and infiltration in breast tumor. Sci Rep 2021; 11:10278. [PMID: 33986437 PMCID: PMC8119485 DOI: 10.1038/s41598-021-89740-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 04/30/2021] [Indexed: 02/04/2023] Open
Abstract
Breast cancer is the most common cancer that causes death in women. Conventional therapies, including surgery and chemotherapy, have different therapeutic effects and are commonly associated with risks and side effects. Near infrared radiation is a technique with few side effects that is used for local hyperthermia, typically as an adjuvant to other cancer therapies. The understanding of the use of near NIR as a monotherapy, and its effects on the immune cells activation and infiltration, are limited. In this study, we investigate the effects of HT treatment using NIR on tumor regression and on the immune cells and molecules in breast tumors. Results from this study demonstrated that local HT by NIR at 43 °C reduced tumor progression and significantly increased the median survival of tumor-bearing mice. Immunohistochemical analysis revealed a significant reduction in cells proliferation in treated tumor, which was accompanied by an abundance of heat shock protein 70 (Hsp70). Increased numbers of activated dendritic cells were observed in the draining lymph nodes of the mice, along with infiltration of T cells, NK cells and B cells into the tumor. In contrast, tumor-infiltrated regulatory T cells were largely diminished from the tumor. In addition, higher IFN-γ and IL-2 secretion was observed in tumor of treated mice. Overall, results from this present study extends the understanding of using local HT by NIR to stimulate a favourable immune response against breast cancer.
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20
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Sun B, Li G, Yu Q, Liu D, Tang X. HSP60 in cancer: a promising biomarker for diagnosis and a potentially useful target for treatment. J Drug Target 2021; 30:31-45. [PMID: 33939586 DOI: 10.1080/1061186x.2021.1920025] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Heat shock proteins (HSPs), most of which are molecular chaperones, are highly conserved proteins produced by cells under physiological stress or pathological conditions. HSP60 (57-69 kDa) can promote or inhibit cell apoptosis through different mechanisms, and its abnormal expression is also related to tumour cell metastasis and drug resistance. In recent years, HSP60 has received increasing attention in the field of cancer research due to its potential as a diagnostic and prognostic biomarker or therapeutic target. However, in different types of cancer, the specific mechanisms of abnormally expressed HSP60 in tumour carcinogenesis and drug resistance are complicated and still require further study. In this article, we comprehensively review the regulative mechanisms of HSP60 on apoptosis, its applications as a cancer diagnostic biomarker and a therapeutic target, evidence of involvement in tumour resistance and the applications of exosomal HSP60 in liquid biopsy. By evaluating the current findings of HSP60 in cancer research, we highlight some core issues that need to be addressed for the use of HSP60 as a diagnostic or prognostic biomarker and therapeutic target in certain types of cancer.
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Affiliation(s)
- Bo Sun
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Ganghui Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Qing Yu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Dongchun Liu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, PR China
| | - Xing Tang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, PR China
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21
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Li Z, Deng J, Sun J, Ma Y. Hyperthermia Targeting the Tumor Microenvironment Facilitates Immune Checkpoint Inhibitors. Front Immunol 2020; 11:595207. [PMID: 33240283 PMCID: PMC7680736 DOI: 10.3389/fimmu.2020.595207] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 10/09/2020] [Indexed: 12/12/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have ushered in a new era of cancer therapy; however, ICIs are only effective in selective patients. The efficacy of ICIs is closely related to the tumor microenvironment. Fever for a long time was thought to directly regulate the immune response, and artificial “fever” from hyperthermia modulates the tumor immune microenvironment by providing danger signals with heat shock proteins (HSPs) as well as subsequent activation of immune systems. Encouraging results have been achieved in preclinical studies focused on potential synergetic effects by combining hyperthermia with ICIs. In this review, we summarized a cluster of immune-related factors that not only make hyperthermia a treatment capable of defending against cancer but also make hyperthermia a reliable treatment that creates a type I-like tumor microenvironment (overexpression of PD-L1 and enrichment of tumor infiltrating lymphocytes) in complementary for the enhancement of the ICIs. Then we reviewed recent preclinical data of the combination regimens involving hyperthermia and ICIs that demonstrated the combined efficacy and illustrated possible approaches to further boost the effectiveness of this combination.
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Affiliation(s)
- Zihui Li
- Oncology Department, The Third People's Hospital of Hubei Province, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Jie Deng
- Oncology Department, The Third People's Hospital of Hubei Province, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Jianhai Sun
- Oncology Department, The Third People's Hospital of Hubei Province, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Yanling Ma
- Oncology Department, The Third People's Hospital of Hubei Province, Affiliated Hospital of Jianghan University, Wuhan, China
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22
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Cabeza L, Perazzoli G, Peña M, Cepero A, Luque C, Melguizo C, Prados J. Cancer therapy based on extracellular vesicles as drug delivery vehicles. J Control Release 2020; 327:296-315. [PMID: 32814093 DOI: 10.1016/j.jconrel.2020.08.018] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/11/2020] [Accepted: 08/14/2020] [Indexed: 02/07/2023]
Abstract
Extracellular vesicles (EVs) are lipid bilayer vesicles of nanometric size secreted by cells to communicate with other cells, either nearby or remotely. Their physicochemical properties make them a promising nanomedicine for drug transport and release in cancer therapy. In this review, we present the different types and biogenesis of EVs and highlight the importance of adequately selecting the cell of origin in cancer therapy. Furthermore, the main methodologies followed for the isolation of EVs and drug loading, as well as the modification and functionalization of these vesicles to generate EV-based nanocarriers are discussed. Finally, we review some of the main studies using drug-loaded exosomes in tumor therapy both in in vitro and in vivo models (even in resistant tumors). These investigations show promising results, achieving significant improvement in the antitumor effect of drugs in most cases. However, the number of clinical trials and patents based on these nanoformulations is still low, thus further research is still warranted in this area.
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Affiliation(s)
- Laura Cabeza
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain; Biosanitary Research Institute ibs.GRANADA, 18012 Granada, Spain; Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
| | - Gloria Perazzoli
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain; Biosanitary Research Institute ibs.GRANADA, 18012 Granada, Spain
| | - Mercedes Peña
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
| | - Ana Cepero
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
| | - Cristina Luque
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
| | - Consolacion Melguizo
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain; Biosanitary Research Institute ibs.GRANADA, 18012 Granada, Spain; Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain.
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain; Biosanitary Research Institute ibs.GRANADA, 18012 Granada, Spain; Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
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23
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Li C, Donninger H, Eaton J, Yaddanapudi K. Regulatory Role of Immune Cell-Derived Extracellular Vesicles in Cancer: The Message Is in the Envelope. Front Immunol 2020; 11:1525. [PMID: 32765528 PMCID: PMC7378739 DOI: 10.3389/fimmu.2020.01525] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/09/2020] [Indexed: 12/28/2022] Open
Abstract
Extracellular vesicles (EVs) are a heterogenous group of membrane-surrounded structures. Besides serving as a harbor for the unwanted material exocytosed by cells, EVs play a critical role in conveying intact protein, genetic, and lipid contents that are important for intercellular communication. EVs, broadly comprised of microvesicles and exosomes, are released to the extracellular environment from nearly all cells either via shedding from the plasma membrane or by originating from the endosomal system. Exosomes are 40–150 nm, endosome-derived small EVs (sEVs) that are released by cells into the extracellular environment. This review focuses on the biological properties of immune cell-derived sEVs, including composition and cellular targeting and mechanisms by which these immune cell-derived sEVs influence tumor immunity either by suppressing or promoting tumor growth, are discussed. The final section of this review discusses how the biological properties of immune cell-derived sEVs can be manipulated to improve their immunogenicity.
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Affiliation(s)
- Chi Li
- Experimental Therapeutics Group, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States.,Department of Medicine, University of Louisville, Louisville, KY, United States
| | - Howard Donninger
- Experimental Therapeutics Group, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States.,Department of Medicine, University of Louisville, Louisville, KY, United States
| | - John Eaton
- Department of Medicine, University of Louisville, Louisville, KY, United States.,Immuno-Oncology Group, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States
| | - Kavitha Yaddanapudi
- Immuno-Oncology Group, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States.,Division of Immunotherapy, Department of Surgery, University of Louisville, Louisville, KY, United States.,Department of Microbiology and Immunology, University of Louisville, Louisville, KY, United States
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24
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Srinivasan ES, Sankey EW, Grabowski MM, Chongsathidkiet P, Fecci PE. The intersection between immunotherapy and laser interstitial thermal therapy: a multipronged future of neuro-oncology. Int J Hyperthermia 2020; 37:27-34. [PMID: 32672126 PMCID: PMC11229985 DOI: 10.1080/02656736.2020.1746413] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 03/04/2020] [Accepted: 03/15/2020] [Indexed: 10/23/2022] Open
Abstract
The rise of immunotherapy (IT) in oncological treatment has greatly improved outcomes in a number of disease states. However, its use in tumors of the central nervous system (CNS) remains limited for multiple reasons related to the unique immunologic tumor microenvironment. As such, it is valuable to consider the intersection of IT with additional treatment methods that may improve access to the CNS and effectiveness of existing IT modalities. One such combination is the pairing of IT with localized hyperthermia (HT) generated through technologies such as laser interstitial thermal therapy (LITT). The wide-ranging immunomodulatory effects of localized and whole-body HT have been investigated for some time. Hyperthermia has demonstrated immunostimulatory effects at the level of tumor cells, immune cells, and the broader environment governing potential immune surveillance. A thorough understanding of these effects as well as the current and upcoming investigations of such in combination with IT is important in considering the future directions of neuro-oncology.
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Affiliation(s)
- Ethan S Srinivasan
- Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA
| | - Eric W Sankey
- Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA
- Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA
| | | | | | - Peter E Fecci
- Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA
- Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA
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25
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Behrouzi A, Ashrafian F, Mazaheri H, Lari A, Nouri M, Riazi Rad F, Hoseini Tavassol Z, Siadat SD. The importance of interaction between MicroRNAs and gut microbiota in several pathways. Microb Pathog 2020; 144:104200. [PMID: 32289465 DOI: 10.1016/j.micpath.2020.104200] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 04/04/2020] [Accepted: 04/06/2020] [Indexed: 12/17/2022]
Abstract
The human gut harbors diverse microbes that play a fundamental role in the well-being of their host. Microbiota disruption affects the immune function, metabolism, and causes several diseases. Therefore, understanding how the microbiome is adjusted, and identifying methods for manipulating it is critical. Studies have found that there is an inverse association between MicroRNAs (miRNAs) abundance and microbe abundance. miRNAs are known to be engaged in post-transcription regulation of cell-autonomous gene expression. Recently, they have gained great attention for their proposed roles in cell-to-cell communication, and as biomarkers for human disease. Here, we review recent studies on the role of miRNAs as a component of outer membrane vesicles (OMVs) in the composition of gut microbiota and their significance in the human situation of health and diseases and discuss their effect on inflammatory responses and dysbiosis. Further, we explain how probiotics exert influence on the expression of miRNAs.
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Affiliation(s)
- Ava Behrouzi
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran; Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Fatemeh Ashrafian
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran; Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Hoora Mazaheri
- Department of Molecular Biology, Pasteur Institute of Iran, Tehran, Iran
| | - Arezou Lari
- Systems Biomedicine Unit, Pasteur Institute of Iran, Tehran, Iran
| | - Matineh Nouri
- Department of Immunology, Pasteur Institute of Iran, Tehran, Iran
| | - Farhad Riazi Rad
- Department of Immunology, Pasteur Institute of Iran, Tehran, Iran
| | - Zahra Hoseini Tavassol
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran; Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Seyed Davar Siadat
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran; Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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26
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Kothandan VK, Kothandan S, Kim DH, Byun Y, Lee YK, Park IK, Hwang SR. Crosstalk between Stress Granules, Exosomes, Tumour Antigens, and Immune Cells: Significance for Cancer Immunity. Vaccines (Basel) 2020; 8:E172. [PMID: 32276342 PMCID: PMC7349635 DOI: 10.3390/vaccines8020172] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 03/29/2020] [Accepted: 04/04/2020] [Indexed: 02/07/2023] Open
Abstract
RNA granules and exosomes produced by tumour cells under various stresses in the microenvironment act as critical determinants of cell survival by promoting angiogenesis, cancer metastasis, chemoresistance, and immunosuppression. Meanwhile, developmental cancer/testis (CT) antigens that are normally sequestered in male germ cells of the testes, but which are overexpressed in malignant tumour cells, can function as tumour antigens triggering immune responses. As CT antigens are potential vaccine candidates for use in cancer immunotherapy, they could be targeted together with crosstalk between stress granules, exosomes, and immune cells for a synergistic effect. In this review, we describe the effects of exosomes and exosomal components presented to the recipient cells under different types of stresses on immune cells and cancer progression. Furthermore, we discuss their significance for cancer immunity, as well as the outlook for their future application.
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Affiliation(s)
- Vinoth Kumar Kothandan
- Department of Biomedical Sciences, Graduate School, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Korea
| | - Sangeetha Kothandan
- Department of Industrial Biotechnology, Bharath Institute of Higher Education and Research, Chennai 600073, India
| | - Do Hee Kim
- Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea
| | - Youngro Byun
- College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea
| | - Yong-kyu Lee
- Department of Chemical and Biological Engineering, Korea National University of Transportation, 50 Daehak-ro, Chungju, Chungbuk 27469, Korea
| | - In-Kyu Park
- Department of Biomedical Sciences, Chonnam National University Medical School, 322 Seoyang-ro, Hwasun 58128, Korea
| | - Seung Rim Hwang
- Department of Biomedical Sciences, Graduate School, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Korea
- College of Pharmacy, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Korea
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27
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Wang M, Su Z, Amoah Barnie P. Crosstalk among colon cancer-derived exosomes, fibroblast-derived exosomes, and macrophage phenotypes in colon cancer metastasis. Int Immunopharmacol 2020; 81:106298. [PMID: 32058925 DOI: 10.1016/j.intimp.2020.106298] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 02/05/2020] [Accepted: 02/06/2020] [Indexed: 12/13/2022]
Abstract
Cellular crosstalk is an important mechanism in the pathogenesis of inflammatory disorders and cancers. One significant means by which cells communicate with each other is through the release of exosomes. Exosomes are extracellular vesicles formed by the outward budding of plasma membranes, which are then released from cells into the extracellular space. Many studies have suggested that microvesicles released by colon cancer cells initiate crosstalk and modulate the fibroblast activities and macrophage phenotypes. Interestingly, crosstalk among colon cancer cells, macrophages and cancer-associated fibroblasts maximizes the mechanical composition of the stromal extracellular matrix (ECM). Exosomes contribute to cancer cell migration and invasion, which are critical for colon cancer progression to metastasis. The majority of the studies on colorectal cancers (CRCs) have focused on developing exosomal biomarkers for the early detection and prediction of CRC prognosis. This study highlights the crosstalk among colon cancer-derived exosomes, macrophage phenotypes and fibroblasts during colon cancer metastasis.
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Affiliation(s)
- Meiyun Wang
- Department of Nephrology, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu Province, PR China.
| | - Zhaoliang Su
- International Genome Center, Jiangsu University, Zhenjiang 212013, Jiangsu Province, PR China.
| | - Prince Amoah Barnie
- International Genome Center, Jiangsu University, Zhenjiang 212013, Jiangsu Province, PR China; Department of Biomedical Sciences, School of Allied Health Sciences, University of Cape Coast, Cape Coast, Ghana.
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28
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Markov O, Oshchepkova A, Mironova N. Immunotherapy Based on Dendritic Cell-Targeted/-Derived Extracellular Vesicles-A Novel Strategy for Enhancement of the Anti-tumor Immune Response. Front Pharmacol 2019; 10:1152. [PMID: 31680949 PMCID: PMC6798004 DOI: 10.3389/fphar.2019.01152] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 09/06/2019] [Indexed: 12/12/2022] Open
Abstract
Dendritic cell (DC)-based anti-tumor vaccines have great potential for the treatment of cancer. To date, a large number of clinical trials involving DC-based vaccines have been conducted with a view to treating tumors of different histological origins. However, DC-based vaccines had several drawbacks, including problems with targeted delivery of tumor antigens to DCs and prolong storage of cellular vaccines. Therefore, the development of other immunotherapeutic approaches capable of enhancing the immunogenicity of existing DC-based vaccines or directly triggering anti-tumor immune responses is of great interest. Extracellular vesicles (EVs) are released by almost all types of eukaryotic cells for paracrine signaling. EVs can interact with target cells and change their functional activity by delivering different signaling molecules including mRNA, non-coding RNA, proteins, and lipids. EVs have potential benefits as natural vectors for the delivery of RNA and other therapeutic molecules targeted to DCs, T-lymphocytes, and tumor cells; therefore, EVs are a promising entity for the development of novel cell-free anti-tumor vaccines that may be a favourable alternative to DC-based vaccines. In the present review, we discuss the anti-tumor potential of EVs derived from DCs, tumors, and other cells. Methods of EV isolation are systematized, and key molecules carried by EVs that are necessary for the activation of a DC-mediated anti-tumor immune response are analyzed with a focus on the RNA component of EVs. Characteristics of anti-tumor immune responses induced by EVs in vitro and in vivo are reviewed. Finally, perspectives and challenges with the use of EVs for the development of anti-tumor cell-free vaccines are considered.
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Affiliation(s)
- Oleg Markov
- Laboratory of Nucleic Acids Biochemistry, Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia
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29
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Different Types of Cellular Stress Affect the Proteome Composition of Small Extracellular Vesicles: A Mini Review. Proteomes 2019; 7:proteomes7020023. [PMID: 31126168 PMCID: PMC6631412 DOI: 10.3390/proteomes7020023] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 05/14/2019] [Accepted: 05/19/2019] [Indexed: 12/27/2022] Open
Abstract
Extracellular vesicles (EVs) are well-known mediators of the cellular response to different stress factors, yet the exact mechanism of their action remains unclear. Hence, the characterization of their cargo, consisting of proteins, nucleic acids, and different classes of metabolites, helps to elucidate an understanding of their function in stress-related communication. The unexpected diversity and complexity of these vesicles requires the incorporation of multiple technologically advanced approaches in EV-oriented studies. This mini review focuses on the invaluable role of proteomics, especially mass spectrometry-based tools, in the investigation of the role of small EVs in their response to stress. Though relatively few experimental works address this issue to date, the available data indicate that stress conditions would affect the composition of protein cargo of vesicles released by stressed cells, as evidenced by the functional importance of such changes in the context of the response of recipient cells.
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30
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Huang T, Song C, Zheng L, Xia L, Li Y, Zhou Y. The roles of extracellular vesicles in gastric cancer development, microenvironment, anti-cancer drug resistance, and therapy. Mol Cancer 2019; 18:62. [PMID: 30925929 PMCID: PMC6441168 DOI: 10.1186/s12943-019-0967-5] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 02/21/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the leading causes of cancer-related death in both men and women due to delayed diagnosis and high metastatic frequency. Extracellular vesicles (EVs) are membrane-bound nanovesicles which are released by cells into body fluids such as plasma, saliva, breast milk, cerebrospinal fluid, semen, urine, lymphatic fluid, amniotic fluid, sputum and synovial fluid. EVs deliver almost all types of biomolecules such as proteins, nucleic acids, metabolites, and even pharmacological compounds. These bioactive molecules can be delivered to recipient cells to influence their biological properties, modify surrounding microenvironment and distant targets. The extensive exploration of EVs enhances our comprehension of GC biology referring to tumor growth, metastasis, immune response and evasion, chemoresistance and treatment. In this review, we will sum up the effects of GC-derived EVs to the tumor microenvironment. Moreover, we will also summarize the function of microenvironment-derived EVs in GC and discuss how the bidirectional communication between tumor and microenvironment affect GC growth, metastatic behavior, immune response, and drug resistance. At last, we prospect the clinical application viewpoint of EVs in GC.
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Affiliation(s)
- Tingting Huang
- Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Baoan District, Shenzhen, 518020, Guangdong, People's Republic of China.
| | - Chunli Song
- Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Baoan District, Shenzhen, 518020, Guangdong, People's Republic of China
| | - Lei Zheng
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, No.1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Ligang Xia
- Department of Gastrointestinal Surgery, Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, 518020, Guangdong, People's Republic of China
| | - Yang Li
- Department of Gastrointestinal Surgery, Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, 518020, Guangdong, People's Republic of China.
| | - Yiwen Zhou
- Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Baoan District, Shenzhen, 518020, Guangdong, People's Republic of China.
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31
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Fu M, Gu J, Jiang P, Qian H, Xu W, Zhang X. Exosomes in gastric cancer: roles, mechanisms, and applications. Mol Cancer 2019; 18:41. [PMID: 30876419 PMCID: PMC6419325 DOI: 10.1186/s12943-019-1001-7] [Citation(s) in RCA: 174] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 03/11/2019] [Indexed: 12/24/2022] Open
Abstract
Exosomes are nanosized extracellular vesicles that can be released by almost all types of cells. Initially considered as the garbage bins acting to discard unwanted products of cells, exosomes are now recognized as an important way for cellular communication by transmitting bioactive molecules including proteins, DNA, mRNAs, and non-coding RNAs. The recent studies have shown that exosomes are critically involved in human health and diseases including cancer. Exosomes have been suggested to participate in the promotion of tumorigenesis, tumor growth and metastasis, tumor angiogenesis, tumor immune escape, and tumor therapy resistance. Increasing evidence indicate that exosomes play important roles in gastric cancer development and progression. In this review, we summarized the current understanding of exosomes in gastric cancer with an emphasis on the biological roles of exosomes in gastric cancer and their potential as biomarkers for gastric cancer diagnosis as well as potential targets for gastric cancer therapy.
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Affiliation(s)
- Min Fu
- Institute of Digestive Diseases, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China.,Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Jianmei Gu
- Departmemt of Clinical Laboratory Medicine, Nantong Tumor Hospital, 30 Tongyang North Road, Nantong, 226361, Jiangsu, China
| | - Pengcheng Jiang
- Institute of Digestive Diseases, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China
| | - Hui Qian
- Institute of Digestive Diseases, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China.,Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Wenrong Xu
- Institute of Digestive Diseases, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China.,Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Xu Zhang
- Institute of Digestive Diseases, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China. .,Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China.
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32
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O'Neill CP, Gilligan KE, Dwyer RM. Role of Extracellular Vesicles (EVs) in Cell Stress Response and Resistance to Cancer Therapy. Cancers (Basel) 2019; 11:cancers11020136. [PMID: 30682793 PMCID: PMC6406503 DOI: 10.3390/cancers11020136] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 01/16/2019] [Accepted: 01/22/2019] [Indexed: 12/30/2022] Open
Abstract
Extracellular vesicles (EVs) are nanosized particles released by all cells that have been heralded as novel regulators of cell-to-cell communication. It is becoming increasingly clear that in response to a variety of stress conditions, cells employ EV-mediated intercellular communication to transmit a pro-survival message in the tumor microenvironment and beyond, supporting evasion of cell death and transmitting resistance to therapy. Understanding changes in EV cargo and secretion pattern during cell stress may uncover novel, targetable mechanisms underlying disease progression, metastasis and resistance to therapy. Further, the profile of EVs released into the circulation may provide a circulating biomarker predictive of response to therapy and indicative of microenvironmental conditions linked to disease progression, such as hypoxia. Continued progress in this exciting and rapidly expanding field of research will be dependent upon widespread adoption of transparent reporting standards and implementation of guidelines to establish a consensus on methods of EV isolation, characterisation and nomenclature employed.
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Affiliation(s)
- Clodagh P O'Neill
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway (NUIG), Galway H91 YR71, Ireland.
| | - Katie E Gilligan
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway (NUIG), Galway H91 YR71, Ireland.
| | - Róisín M Dwyer
- Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway (NUIG), Galway H91 YR71, Ireland.
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33
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Li LM, Liu H, Liu XH, Hu HB, Liu SM. Clinical significance of exosomal miRNAs and proteins in three human cancers with high mortality in China. Oncol Lett 2018; 17:11-22. [PMID: 30655733 PMCID: PMC6313090 DOI: 10.3892/ol.2018.9631] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 08/30/2018] [Indexed: 02/06/2023] Open
Abstract
Cancer is the second leading cause of mortality worldwide. More importantly, the mortality rates for cancer are increasing. In China, lung cancer, liver cancer and gastric cancer are the top three leading causes of mortality in males, whereas lung cancer, gastric cancer and liver cancer are ranked the top three causes of mortality in females. Exosomes are extracellular vesicles that are produced and released by many different cells; these vesicles have a size range between 30 and 100 nm in diameter, and contain a lipid bilayer. Exosomes exist in various bodily fluids, contain plentiful amounts of nucleic acids and proteins, and shuttle these materials between cells to mediate the development of cancers. The present review summarizes the composition of exosomes and methods for their isolation and then intensively highlights the latest findings on the contributions of exosomal microRNAs (miRNAs) and proteins to lung cancer, liver cancer and gastric cancer. Taken together, exosomal miRNAs and proteins may be used as noninvasive, novel biomarkers for cancer diagnosis, prognosis or precision treatment owing to their ability to promote tumor progression and metastasis, and their ability to regulate the immune response and tumor cell sensitivity to chemotherapy drugs.
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Affiliation(s)
- Li-Man Li
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Huan Liu
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Xing-Hui Liu
- Department of Clinical Laboratory, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai 200135, P.R. China
| | - Hong-Bin Hu
- Department of Blood Transfusion, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430016, P.R. China
| | - Song-Mei Liu
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
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34
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Nair S, Tang KD, Kenny L, Punyadeera C. Salivary exosomes as potential biomarkers in cancer. Oral Oncol 2018; 84:31-40. [PMID: 30115473 DOI: 10.1016/j.oraloncology.2018.07.001] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 05/21/2018] [Accepted: 07/09/2018] [Indexed: 12/12/2022]
Abstract
Over the past decade, there has been emerging research in the field of extracellular vesicles, especially those originating from endosomes, referred to as 'exosomes. Exosomes are membrane-bound nanovesicles secreted by most cell types upon fusion of multivesicular bodies (MVBs) to the cell plasma membrane. These vesicles are present in almost all body fluids such as blood, urine, saliva, breast milk, cerebrospinal and peritoneal fluids. Exosomes participate in intercellular communication by transferring the biologically active molecules like proteins, nucleic acids, and lipids to neighboring cells. Exosomes are enriched in the tumour microenvironment and growing evidence demonstrates that exosomes mediate cancer progression and metastasis. Given the important biological role played by these nanovesicles in cancer pathogenesis, these can be used as ideal non-invasive biomarkers in detecting and monitoring tumours as well as therapeutic targets. The scope of the current review is to provide an overview of exosomes with a special focus on salivary exosomes as potential biomarkers in head and neck cancers.
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Affiliation(s)
- Soumyalekshmi Nair
- The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Australia; Translational Research Institute, Brisbane, Australia
| | - Kai Dun Tang
- The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Australia; Translational Research Institute, Brisbane, Australia; The Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Liz Kenny
- School of Medicine, University of Queensland, Queensland, Australia; Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Central Integrated Regional Cancer Service, Queensland Health, Queensland, Australia
| | - Chamindie Punyadeera
- The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD, Australia; Translational Research Institute, Brisbane, Australia; The Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Woolloongabba, Queensland, Australia.
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35
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Li W, Ng JMK, Wong CC, Ng EKW, Yu J. Molecular alterations of cancer cell and tumour microenvironment in metastatic gastric cancer. Oncogene 2018; 37:4903-4920. [PMID: 29795331 PMCID: PMC6127089 DOI: 10.1038/s41388-018-0341-x] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 05/07/2018] [Accepted: 05/08/2018] [Indexed: 02/07/2023]
Abstract
The term metastasis is widely used to describe the endpoint of the process by which tumour cells spread from the primary location to an anatomically distant site. Achieving successful dissemination is dependent not only on the molecular alterations of the cancer cells themselves, but also on the microenvironment through which they encounter. Here, we reviewed the molecular alterations of metastatic gastric cancer (GC) as it reflects a large proportion of GC patients currently seen in clinic. We hope that further exploration and understanding of the multistep metastatic cascade will yield novel therapeutic targets that will lead to better patient outcomes.
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Affiliation(s)
- Weilin Li
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong, Hong Kong.,Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Jennifer Mun-Kar Ng
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Chi Chun Wong
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Enders Kwok Wai Ng
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
| | - Jun Yu
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
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36
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The histone deacetylase inhibitor SAHA induces HSP60 nitration and its extracellular release by exosomal vesicles in human lung-derived carcinoma cells. Oncotarget 2018; 7:28849-67. [PMID: 26700624 PMCID: PMC5045361 DOI: 10.18632/oncotarget.6680] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 11/22/2015] [Indexed: 12/14/2022] Open
Abstract
HSP60 undergoes changes in quantity and distribution in some types of tumors suggesting a participation of the chaperonin in the mechanism of transformation and cancer progression. Suberoylanilide hydroxamic acid (SAHA), a member of a family of histone deacetylase inhibitors (HDACi), has anti-cancer potential but its interaction, if any, with HSP60 has not been elucidated. We investigated the effects of SAHA in a human lung-derived carcinoma cell line (H292). We analysed cell viability and cycle; oxidative stress markers; mitochondrial integrity; HSP60 protein and mRNA levels; and HSP60 post-translational modifications, and its secretion. We found that SAHA is cytotoxic for H292 cells, interrupting the cycle at the G2/M phase, which is followed by death; cytotoxicity is associated with oxidative stress, mitochondrial damage, and diminution of intracellular levels of HSP60; HSP60 undergoes a post-translational modification and becomes nitrated; and nitrated HSP60 is exported via exosomes. We propose that SAHA causes ROS overproduction and mitochondrial dysfunction, which leads to HSP60 nitration and release into the intercellular space and circulation to interact with the immune system. These successive steps might constitute the mechanism of the anti-tumor action of SAHA and provide a basis to design supplementary therapeutic strategies targeting HSP60, which would be more efficacious than the compound alone.
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37
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Feingold PL, Klemen ND, Kwong MLM, Hashimoto B, Rudloff U. Adjuvant intraperitoneal chemotherapy for the treatment of colorectal cancer at risk for peritoneal carcinomatosis: a systematic review. Int J Hyperthermia 2017; 34:501-511. [PMID: 29214884 DOI: 10.1080/02656736.2017.1401742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The peritoneal surface is the second most common site of disease recurrence, after the liver, following definitive surgery for colorectal cancer. Adjuvant intraperitoneal (IP) chemotherapy delivered at time of surgical resection has the potential to delay or prevent future spread to the peritoneal surface and improve clinical outcome. The exact role of adjuvant IP chemotherapy in colorectal cancer, including its associated morbidity and mortality, is not well defined. STUDY DESIGN Systematic review and pooled random effect analysis of comparative trials examining the addition of adjuvant IP chemotherapy compared to surgery alone in colorectal cancer. The primary outcome was overall survival, and the secondary outcomes were of post-operative morbidity and mortality. RESULTS In nine colorectal cancer studies identified, seven were two-arm trials comparing adjuvant IP chemotherapy to surgery alone. Of these, four trials had outcome reporting and met criteria that allowed inclusion into a random effects model. Heterogeneity was measured by Cochran's Q-test (Q = 13.9; p = 0.01) and random effect models were utilised. Pooling eligible trials together revealed a 0.55 odds ratio of death associated with the administration of IP chemotherapy compared to surgery alone (CI = 0.31, 0.98; p = 0.04). Trials selecting patients at elevated risk for the development of peritoneal carcinomatosis by clinicopathological biomarkers for administration of adjuvant IP chemotherapy reported more favourable overall outcomes. There was no increase in mortalities or IP chemotherapy-related abdominal complication rates among patients undergoing IP chemotherapy (OR = 1.4; CI = 0.52, 3.8; p = 0.5). CONCLUSIONS This systematic review supports the use of adjuvant IP chemotherapy in resectable colorectal cancer at risk for peritoneal spread. Future trials should seek to standardise inclusion criteria and IP chemotherapy modalities to better define the role of this treatment in patients with resectable colorectal cancer.
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Affiliation(s)
- Paul L Feingold
- a Thoracic and Gastrointestinal Oncology Branch , National Cancer Institute, National Institutes of Health , Bethesda , MD , USA
| | - Nicholas D Klemen
- a Thoracic and Gastrointestinal Oncology Branch , National Cancer Institute, National Institutes of Health , Bethesda , MD , USA
| | - Mei Li M Kwong
- a Thoracic and Gastrointestinal Oncology Branch , National Cancer Institute, National Institutes of Health , Bethesda , MD , USA
| | - Barry Hashimoto
- b Department of International Studies , American University of Sharjah, Sharjah, UAE
| | - Udo Rudloff
- a Thoracic and Gastrointestinal Oncology Branch , National Cancer Institute, National Institutes of Health , Bethesda , MD , USA
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Barteneva NS, Baiken Y, Fasler-Kan E, Alibek K, Wang S, Maltsev N, Ponomarev ED, Sautbayeva Z, Kauanova S, Moore A, Beglinger C, Vorobjev IA. Extracellular vesicles in gastrointestinal cancer in conjunction with microbiota: On the border of Kingdoms. Biochim Biophys Acta Rev Cancer 2017; 1868:372-393. [DOI: 10.1016/j.bbcan.2017.06.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 06/26/2017] [Accepted: 06/26/2017] [Indexed: 12/16/2022]
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Lässer C, Shelke GV, Yeri A, Kim DK, Crescitelli R, Raimondo S, Sjöstrand M, Gho YS, Van Keuren Jensen K, Lötvall J. Two distinct extracellular RNA signatures released by a single cell type identified by microarray and next-generation sequencing. RNA Biol 2016; 14:58-72. [PMID: 27791479 PMCID: PMC5270547 DOI: 10.1080/15476286.2016.1249092] [Citation(s) in RCA: 109] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Cells secrete extracellular RNA (exRNA) to their surrounding environment and exRNA has been found in many body fluids such as blood, breast milk and cerebrospinal fluid. However, there are conflicting results regarding the nature of exRNA. Here, we have separated 2 distinct exRNA profiles released by mast cells, here termed high-density (HD) and low-density (LD) exRNA. The exRNA in both fractions was characterized by microarray and next-generation sequencing. Both exRNA fractions contained mRNA and miRNA, and the mRNAs in the LD exRNA correlated closely with the cellular mRNA, whereas the HD mRNA did not. Furthermore, the HD exRNA was enriched in lincRNA, antisense RNA, vault RNA, snoRNA, and snRNA with little or no evidence of full-length 18S and 28S rRNA. The LD exRNA was enriched in mitochondrial rRNA, mitochondrial tRNA, tRNA, piRNA, Y RNA, and full-length 18S and 28S rRNA. The proteomes of the HD and LD exRNA-containing fractions were determined with LC-MS/MS and analyzed with Gene Ontology term finder, which showed that both proteomes were associated with the term extracellular vesicles and electron microscopy suggests that at least a part of the exRNA is associated with exosome-like extracellular vesicles. Additionally, the proteins in the HD fractions tended to be associated with the nucleus and ribosomes, whereas the LD fraction proteome tended to be associated with the mitochondrion. We show that the 2 exRNA signatures released by a single cell type can be separated by floatation on a density gradient. These results show that cells can release multiple types of exRNA with substantial differences in RNA species content. This is important for any future studies determining the nature and function of exRNA released from different cells under different conditions.
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Affiliation(s)
- Cecilia Lässer
- a Krefting Research Center, Department of Internal Medicine and Clinical Nutrition , University of Gothenburg , Gothenburg , Sweden
| | - Ganesh Vilas Shelke
- a Krefting Research Center, Department of Internal Medicine and Clinical Nutrition , University of Gothenburg , Gothenburg , Sweden
| | | | - Dae-Kyum Kim
- c Department of Life Sciences , Pohang University of Science and Technology , Pohang , Gyeongbuk , Republic of Korea
| | - Rossella Crescitelli
- a Krefting Research Center, Department of Internal Medicine and Clinical Nutrition , University of Gothenburg , Gothenburg , Sweden
| | - Stefania Raimondo
- a Krefting Research Center, Department of Internal Medicine and Clinical Nutrition , University of Gothenburg , Gothenburg , Sweden.,d Department of Biopathology, and Medical Biotechnologies , Section of Biology and Genetics, Università di Palermo , Palermo , Italy
| | - Margareta Sjöstrand
- a Krefting Research Center, Department of Internal Medicine and Clinical Nutrition , University of Gothenburg , Gothenburg , Sweden
| | - Yong Song Gho
- c Department of Life Sciences , Pohang University of Science and Technology , Pohang , Gyeongbuk , Republic of Korea
| | | | - Jan Lötvall
- a Krefting Research Center, Department of Internal Medicine and Clinical Nutrition , University of Gothenburg , Gothenburg , Sweden
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Abstract
Many Gram-negative bacterial species release outer membrane vesicles (OMVs) that interact with the host by delivering virulence factors. Here, we report for the first time that RNA is among the wide variety of bacterial components that are associated with OMVs. To characterize the RNA profiles of bacterial OMVs, we performed RNA deep sequencing analysis using OMV samples isolated from a wild type Vibrio cholerae O1 El Tor strain. The results showed that RNAs originating from intergenic regions were the most abundant. Our findings reveal a hitherto unrecognised feature of OMVs mimicking eukaryotic exosomes and highlight a need to evaluate the potential role of RNA-containing bacterial membrane vesicles in bacteria-host interactions.
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Campanella C, Rappa F, Sciumè C, Marino Gammazza A, Barone R, Bucchieri F, David S, Curcurù G, Caruso Bavisotto C, Pitruzzella A, Geraci G, Modica G, Farina F, Zummo G, Fais S, Conway de Macario E, Macario AJL, Cappello F. Heat shock protein 60 levels in tissue and circulating exosomes in human large bowel cancer before and after ablative surgery. Cancer 2015; 121:3230-3239. [PMID: 26060090 DOI: 10.1002/cncr.29499] [Citation(s) in RCA: 117] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Revised: 04/24/2015] [Accepted: 05/12/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND Heat shock protein 60 (Hsp60) is a chaperonin involved in tumorigenesis, but its participation in tumor development and progression is not well understood and its value as a tumor biomarker has not been fully elucidated. In the current study, the authors presented evidence supporting the theory that Hsp60 has potential as a biomarker as well as a therapeutic target in patients with large bowel cancer. METHODS The authors studied a population of 97 subjects, including patients and controls. Immunomorphology, Western blot analysis, and quantitative real-time polymerase chain reaction were performed on tissue specimens. Exosomes were isolated from blood and characterized by electron microscopy, biochemical tests, and Western blot analysis. RESULTS Hsp60 was found to be increased in cancerous tissue, in which it was localized in the tumor cell plasma membrane, and in the interstitium associated with cells of the immune system, in which it was associated with exosomes liberated by tumor cells and, as such, circulated in the blood. An interesting finding was that these parameters returned to normal shortly after tumor removal. CONCLUSIONS The data from the current study suggested that Hsp60 is a good candidate for theranostics applied to patients with large bowel carcinoma and encourage similar research among patients with other tumors in which Hsp60 has been implicated.
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Affiliation(s)
- Claudia Campanella
- Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
| | - Francesca Rappa
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
- Department of Legal Science, Society and Sports, University of Palermo, Palermo, Italy
| | - Carmelo Sciumè
- Department of Oncological Surgery, University of Palermo, Palermo, Italy
| | - Antonella Marino Gammazza
- Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
| | - Rosario Barone
- Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
| | - Fabio Bucchieri
- Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
| | - Sabrina David
- Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy
| | - Giuseppe Curcurù
- Department of Chemical, Management, Informatics and Mechanical Engineering, University of Palermo, Palermo, Italy
| | - Celeste Caruso Bavisotto
- Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
| | - Alessandro Pitruzzella
- Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
| | - Girolamo Geraci
- Department of Oncological Surgery, University of Palermo, Palermo, Italy
| | - Giuseppe Modica
- Department of Oncological Surgery, University of Palermo, Palermo, Italy
| | - Felicia Farina
- Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy
| | - Giovanni Zummo
- Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy
| | - Stefano Fais
- Department of Therapeutic Research and Medicines Evaluation, National Institute of Health, Rome, Italy
| | - Everly Conway de Macario
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland
- Institute of Marine and Environmental Technology, Baltimore, Maryland
| | - Alberto J L Macario
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland
- Institute of Marine and Environmental Technology, Baltimore, Maryland
| | - Francesco Cappello
- Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
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Yang Y, Chen Y, Zhang F, Zhao Q, Zhong H. Increased anti-tumour activity by exosomes derived from doxorubicin-treated tumour cells via heat stress. Int J Hyperthermia 2015; 31:498-506. [PMID: 25955015 DOI: 10.3109/02656736.2015.1036384] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
PURPOSE Tumour-cell-derived exosomes (Exo) have been proposed as a new kind of drug carrier, and heat stress can promote release of exosomes from tumour cells. This study investigated the impact of heat stress on the quantity of doxorubicin in exosomes from the same number of doxorubicin-treated MFC-7 tumour cells and their anti-tumour effects. MATERIALS AND METHODS Exosomes were isolated from phosphate-buffered saline (Exo), doxorubicin (Exo-Dox) or doxorubicin combined with heat-stress-treated (Exo-Dox-HS) MCF-7 cells. The content of doxorubicin in the exosomes was determined by flow cytometry. The effects of individual types of exosomes on the MCF-7 cell proliferation and apoptosis as well as the tumour growth were determined by MTT assay, flow cytometry and murine xenograft tumour modelling. RESULTS We found that the amount of Exo-Dox-HS was higher than that of Exo-Dox from the same number of MCF-7 cells, and Exo-Dox-HS contained higher levels of doxorubicin than Exo-Dox from the same number of cells. Exo-Dox and Exo-Dox-HS, but not Exo or 10 µg/mL doxorubicin, significantly inhibited the MCF-7 cell proliferation and triggered MCF-7 cell apoptosis, associated with increased levels of cleaved caspase-3 and -8 and morphological changes in MCF-7 cells. Treatment with Exo-Dox and Exo-Dox-HS inhibited the growth of implanted breast tumours in mice. CONCLUSIONS Our study indicated that heat stress increased the quantity of doxorubicin-containing exosomes from tumour cells, and enhanced the anti-tumour effect of exosomes from the doxorubicin-treated tumour cells. Our findings may aid in designing new strategies for cancer therapy by combination of chemotherapy and hyperthermia.
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Affiliation(s)
- Yunshan Yang
- Department of Chemotherapy, Zhejiang Cancer Hospital , Hangzhou
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Yuan P, Yue TH, Xiao YH, Zhu LJ, Li S, Chen BA. Clinical effects of hyperthermic intraperitoneal chemotherapy for gastric cancer with malignant ascites. Shijie Huaren Xiaohua Zazhi 2014; 22:4825-4829. [DOI: 10.11569/wcjd.v22.i31.4825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the clinical effects of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of gastric cancer with malignant ascites.
METHODS: Seventy patients with gastric cancer with malignant ascites were randomly divided into either a study group or a control group. The study group was treated by HIPEC combined with thermal therapy, and the control group was treated by non-hyperthermic peritoneal perfusion chemotherapy. The clinical effects, Kamofsky score and adverse reactions were compared for the two groups. The temperature and vital signs at different points of HIPEC were recorded.
RESULTS: The total effective rate was significantly higher in the experiment group than in the control group (77.14% vs 37.14%, P < 0.05). Posttreatment Kamofsky scores for the two groups were significantly higher than prior-treatment values (77.92 ± 6.83 vs 54.44 ± 5.47, 62.08 ± 6.17 vs 53.89 ± 5.56, P < 0.05). Posttreatment Kamofsky score was significantly higher in the experiment group than in the control group (77.92 ± 6.83 vs 62.08 ± 6.17, P < 0.05). There were no significant difference in the shell temperature, tympanic temperature, rectal temperature, blood pressure, heart rate, breath, or oxyhemoglobin saturation for the experiment group at different time points (36.18 ℃ ± 0.42 ℃ vs 36.42 ℃ ± 0.27 ℃ vs 37.13 ℃ ± 1.72 ℃, 35.66 ℃ ± 0.23 ℃ vs 35.94 ℃ ± 0.37 ℃ vs 36.60 ℃ ± 0.22 ℃, 36.34 ℃ ± 0.12 ℃ vs 36.64 ℃ ± 0.27 ℃ vs 37.10 ℃ ± 0.30 ℃, 117 mmHg ± 6.2 mmHg vs 116 mmHg ± 6.5 mmHg vs 116 mmHg ± 6.4 mmHg, 62 mmHg ± 4.9 mmHg vs 69 mmHg ± 6.8 mmHg vs 72 mmHg ± 5.3 mmHg, 68/min ± 4.3/min vs 72/min ± 5.3/min vs 73/min ± 4.5/min, 14/min ± 2.5/min vs 13/min ± 1.8/min vs 14/min ± 1.7/min, 98% ± 1.8% vs 97% ± 0.9% vs 98% ± 1.3%, P > 0.05). The rate of fatty scleroma for the experiment group was significantly higher than that for the control group (14.29% vs 0.00%, P < 0.05).
CONCLUSION: HIPEC can improve Kamofsky score and has high safety in patients with gastric cancer with malignant ascites.
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Zhang B, Yin Y, Lai RC, Lim SK. Immunotherapeutic potential of extracellular vesicles. Front Immunol 2014; 5:518. [PMID: 25374570 PMCID: PMC4205852 DOI: 10.3389/fimmu.2014.00518] [Citation(s) in RCA: 137] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 10/04/2014] [Indexed: 12/20/2022] Open
Abstract
Extracellular vesicle or EV is a term that encompasses all classes of secreted lipid membrane vesicles. Despite being scientific novelties, EVs are gaining importance as a mediator of important physiological and pathological intercellular activities possibly through the transfer of their cargo of protein and RNA between cells. In particular, exosomes, the currently best characterized EVs have been notable for their in vitro and in vivo immunomodulatory activities. Exosomes are nanometer-sized endosome-derived vesicles secreted by many cell types and their immunomodulatory potential is independent of their cell source. Besides immune cells such as dendritic cells, macrophages, and T cells, cancer and stem cells also secrete immunologically active exosomes that could influence both physiological and pathological processes. The immunological activities of exosomes affect both innate and adaptive immunity and include antigen presentation, T cell activation, T cell polarization to regulatory T cells, immune suppression, and anti-inflammation. As such, exosomes carry much immunotherapeutic potential as a therapeutic agent and a therapeutic target.
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Affiliation(s)
- Bin Zhang
- Exosome and Secreted Nano-vesicle Group, ASTAR Institute of Medical Biology , Singapore
| | - Yijun Yin
- Exosome and Secreted Nano-vesicle Group, ASTAR Institute of Medical Biology , Singapore
| | - Ruenn Chai Lai
- Exosome and Secreted Nano-vesicle Group, ASTAR Institute of Medical Biology , Singapore
| | - Sai Kiang Lim
- Exosome and Secreted Nano-vesicle Group, ASTAR Institute of Medical Biology , Singapore ; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore , Singapore
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Zhu L, Qu XH, Sun YL, Qian YM, Zhao XH. Novel method for extracting exosomes of hepatocellular carcinoma cells. World J Gastroenterol 2014; 20:6651-6657. [PMID: 24914390 PMCID: PMC4047354 DOI: 10.3748/wjg.v20.i21.6651] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Revised: 02/08/2014] [Accepted: 03/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop a novel method for the rapid and efficient extraction of exosomes secreted by tumor cells.
METHODS: Unlike the traditional extraction method, the supernatants of cell cultures were concentrated, and the exosomes were isolated promptly and effectively using a novel nanomaterial called ExoQuick. Coomassie brilliant blue staining was used for protein quantification, and the morphology of the exosomes extracted by both methods was visualized by transmission electron microscopy. Exosome marker proteins were detected by Western blot analysis. Two potential hepatoma-associated proteins, tissue transglutaminase 2 (TGM2) and annexin A2, were analyzed.
RESULTS: The exosomes separated by the new extraction assay based on the nanomaterial were disc-shaped, intact vesicles with lipid bilayer membranes. They were approximately 30-100 nm in diameter, which is similar to the diameter of exosomes isolated by the traditional method. The protein concentration of exosomes extracted by the new method was approximately 780 μg/108 cells, and therefore, it was 19 times higher than that of exosomes extracted in the traditional manner. There were differences between the total proteins of Huh-7 cells and the exosomal proteins. Typical exosome proteins, such as the transmembrane protein CD63 and heat shock protein 70, were confirmed. Two potential hepatoma-associated proteins were also identified. TGM2 was first found to exist in the exosomes of human liver cancer cells, but annexin A2 was not secreted into exosomes.
CONCLUSION: The new extraction method based on the nanomaterial is quick and efficient. The cancer-associated protein TGM2 can be secreted through an exosome-mediated non-classical secretion pathway, and it may be a valuable tumor marker.
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Cappello F, Marino Gammazza A, Palumbo Piccionello A, Campanella C, Pace A, Conway de Macario E, Macario AJL. Hsp60 chaperonopathies and chaperonotherapy: targets and agents. Expert Opin Ther Targets 2013; 18:185-208. [PMID: 24286280 DOI: 10.1517/14728222.2014.856417] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Hsp60 (Cpn60) assembles into a tetradecamer that interacts with the co-chaperonin Hsp10 (Cpn10) to assist client polypeptides to fold, but it also has other roles, including participation in pathogenic mechanisms. AREA COVERED Hsp60 chaperonopathies are pathological conditions, inherited or acquired, in which the chaperone plays a determinant etiologic-pathogenic role. These diseases justify selection of Hsp60 as a target for developing agents that interfere with its pathogenic effects. We provide information on how to proceed. EXPERT OPINION The information available encourages the development of ways to improve Hsp60 activity (positive chaperonotherapy) when deficient or to block it (negative chaperonotherapy) when pathogenic. Many questions are still unanswered and obstacles are obvious. More information is needed to establish when and why autologous Hsp60 becomes a pathogenic autoantigen, or induces cytokine formation and inflammation, or favors carcinogenesis. Clarification of these points will take considerable time. However, analysis of the Hsp60 molecule and a search for active compounds aimed at structural sites that will affect its functioning should continue without interruption. No doubt that some of these compounds will offer therapeutic hopes and will also be instrumental for dissecting structure-function relationships at the biochemical and biological (using animal models and cultured cells) levels.
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Affiliation(s)
- Francesco Cappello
- Euro-Mediterranean Institute of Science and Technology (IEMEST) , Palermo , Italy
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Huang X, Yuan T, Tschannen M, Sun Z, Jacob H, Du M, Liang M, Dittmar RL, Liu Y, Liang M, Kohli M, Thibodeau SN, Boardman L, Wang L. Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genomics 2013; 14:319. [PMID: 23663360 PMCID: PMC3653748 DOI: 10.1186/1471-2164-14-319] [Citation(s) in RCA: 802] [Impact Index Per Article: 66.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Accepted: 05/02/2013] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Exosomes, endosome-derived membrane microvesicles, contain specific RNA transcripts that are thought to be involved in cell-cell communication. These RNA transcripts have great potential as disease biomarkers. To characterize exosomal RNA profiles systemically, we performed RNA sequencing analysis using three human plasma samples and evaluated the efficacies of small RNA library preparation protocols from three manufacturers. In all we evaluated 14 libraries (7 replicates). RESULTS From the 14 size-selected sequencing libraries, we obtained a total of 101.8 million raw single-end reads, an average of about 7.27 million reads per library. Sequence analysis showed that there was a diverse collection of the exosomal RNA species among which microRNAs (miRNAs) were the most abundant, making up over 42.32% of all raw reads and 76.20% of all mappable reads. At the current read depth, 593 miRNAs were detectable. The five most common miRNAs (miR-99a-5p, miR-128, miR-124-3p, miR-22-3p, and miR-99b-5p) collectively accounted for 48.99% of all mappable miRNA sequences. MiRNA target gene enrichment analysis suggested that the highly abundant miRNAs may play an important role in biological functions such as protein phosphorylation, RNA splicing, chromosomal abnormality, and angiogenesis. From the unknown RNA sequences, we predicted 185 potential miRNA candidates. Furthermore, we detected significant fractions of other RNA species including ribosomal RNA (9.16% of all mappable counts), long non-coding RNA (3.36%), piwi-interacting RNA (1.31%), transfer RNA (1.24%), small nuclear RNA (0.18%), and small nucleolar RNA (0.01%); fragments of coding sequence (1.36%), 5' untranslated region (0.21%), and 3' untranslated region (0.54%) were also present. In addition to the RNA composition of the libraries, we found that the three tested commercial kits generated a sufficient number of DNA fragments for sequencing but each had significant bias toward capturing specific RNAs. CONCLUSIONS This study demonstrated that a wide variety of RNA species are embedded in the circulating vesicles. To our knowledge, this is the first report that applied deep sequencing to discover and characterize profiles of plasma-derived exosomal RNAs. Further characterization of these extracellular RNAs in diverse human populations will provide reference profiles and open new doors for the development of blood-based biomarkers for human diseases.
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Affiliation(s)
- Xiaoyi Huang
- Department of Pathology and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Tiezheng Yuan
- Department of Pathology and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Michael Tschannen
- Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Zhifu Sun
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, 55905, USA
| | - Howard Jacob
- Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Meijun Du
- Department of Pathology and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Meihua Liang
- Department of Endocrinology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Rachel L Dittmar
- Department of Pathology and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Yong Liu
- Department of Physiology, Medical College of Wisconsi, Milwaukee, WI, 53226, USA
| | - Mingyu Liang
- Department of Physiology, Medical College of Wisconsi, Milwaukee, WI, 53226, USA
| | - Manish Kohli
- Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Stephen N Thibodeau
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Lisa Boardman
- Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Liang Wang
- Department of Pathology and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
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Lässer C. Identification and analysis of circulating exosomal microRNA in human body fluids. Methods Mol Biol 2013; 1024:109-28. [PMID: 23719946 DOI: 10.1007/978-1-62703-453-1_9] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Exosomes are 40-100 nm sized vesicles released from cells when multivesicular bodies fuse with the plasma membrane. These vesicles take part in cell-to-cell communication by binding and signalling through membrane receptors on cells or by transferring proteins, RNA, and lipids into the cells. Exosomal RNA in body fluids, such as plasma and urine, has been associated with malignancies, making the exosomal RNA a potential biomarker for early detection of these diseases. This has increased the interest in the field of extracellular RNA and in particular, the interest in exosomal RNA.In this chapter, a well-established exosome isolation method is described, as well as how to characterize the isolated vesicles by electron microscopy. Furthermore, two types of RNA isolation methods are described with a focus on isolating RNA from body fluids, which can be more viscous than cell culture media.
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Affiliation(s)
- Cecilia Lässer
- Krefting Research Centre, Department of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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