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1
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Wang L, Shi M, Sung AY, Yin CC, Bai Y, Chen M. Role of the bone marrow microenvironment in multiple myeloma: Impact of niches on drug resistance mechanisms. Semin Diagn Pathol 2025; 42:150916. [PMID: 40440932 DOI: 10.1016/j.semdp.2025.150916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 05/16/2025] [Indexed: 06/11/2025]
Abstract
Multiple myeloma (MM) is a blood cancer characterized by the uncontrolled growth of plasma cells in the bone marrow. These malignant plasma cells can proliferate locally and spread to other tissues and organs. The M-protein they produce can lead to various clinical symptoms, including anemia, hypercalcemia, bone pain, bone destruction, and kidney dysfunction. Despite significant advancements in treatment over the past two decades that have improved survival and outcomes for many patients, drug resistance remains a significant therapeutic challenge. This resistance is largely driven by the complex interactions between MM cells and the bone marrow microenvironment (BMME), making long-term disease control difficult. To improve treatment outcomes, it is essential to understand how the BMME supports MM cell growth and survival, as well as how these cells evade therapies. Investigating these processes will help identify key mechanisms behind drug resistance, offering a pathway to develop targeted therapies that can overcome this challenge. This review will explore the intricate relationship between MM cells and the BMME, focusing on how both cellular and non-cellular components of the microenvironment contribute to resistance mechanisms and prompt disease progression. These insights aim to inform future therapeutic strategies to enhance treatment options for MM patients.
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Affiliation(s)
- Lijie Wang
- Department of Hematology, Henan University People's Hospital & Henan Provincial People's Hospital, Henan, China
| | - Mingyue Shi
- Department of Pathology and Laboratory Medicine, UT Southwestern Medical Center, Dallas, TX 75390, United States; Department of Hematology, Zhengzhou University People's Hospital & Henan Provincial People's Hospital, Henan, China
| | - Andrew Y Sung
- Department of Pathology and Laboratory Medicine, UT Southwestern Medical Center, Dallas, TX 75390, United States
| | - C Cameron Yin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Yanliang Bai
- Department of Hematology, Zhengzhou University People's Hospital & Henan Provincial People's Hospital, Henan, China
| | - Mingyi Chen
- Department of Pathology and Laboratory Medicine, UT Southwestern Medical Center, Dallas, TX 75390, United States.
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2
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Hagiwara S, Ri M, Ebina T, Marumo Y, Nakamura T, Hirade K, Nakashima T, Asano A, Kinoshita S, Suzuki T, Narita T, Masaki A, Komatsu H, Iida S. Immunosuppressive Effects of Multiple Myeloma-Derived Extracellular Vesicles Through T Cell Exhaustion. Cancer Sci 2025. [PMID: 40344445 DOI: 10.1111/cas.70099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 04/17/2025] [Accepted: 05/02/2025] [Indexed: 05/11/2025] Open
Abstract
Extracellular vehicles (EVs) are reported to be involved in several processes relating to tumor progression, including angiogenesis, osteolysis, and drug resistance in multiple myeloma (MM). However, the role of EVs in the immune-suppressive milieu of MM is poorly understood. Here, we investigated the effects of MM-derived EVs on T cells, focusing on markers of T cell exhaustion. Using activated peripheral blood mononuclear cells from healthy donors, we observed immunosuppressive effects such as upregulated expression of immune checkpoint markers on CD8+ T cells treated with MM-derived EVs. Proteomic analysis identified several proteins, such as IL-8, SLC1A5, PIN2, and FSP1, associated with regulation of T cell exhaustion and chronic inflammation. Surprisingly, sphingosine kinase 1 (SPHK1) was enriched in MM cell line-derived EVs, implicating SPHK1/S1P signaling in the immunosuppressive effect of MM EVs. Thus, MM-derived EVs may promote T cell exhaustion via upregulating the expression of immune checkpoint markers and thereby contribute to the formation of the immune-suppressive milieu of MM, resulting in impaired T cell activity.
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Affiliation(s)
- Shinya Hagiwara
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan
| | - Masaki Ri
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan
- Department of Blood Transfusion and Cell Therapy, Nagoya City University Hospital, Nagoya, Japan
| | - Toru Ebina
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan
| | - Yoshiaki Marumo
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan
| | - Tomoyuki Nakamura
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan
| | - Kentaro Hirade
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan
| | - Takahiro Nakashima
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan
| | - Arisa Asano
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan
| | - Shiori Kinoshita
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan
| | - Tomotaka Suzuki
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan
| | - Tomoko Narita
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan
| | - Ayako Masaki
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan
- Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hirokazu Komatsu
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan
| | - Shinsuke Iida
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan
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3
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Wylie C, Rowan R, Malinova D, Crawford L. Extracellular vesicles in multiple myeloma: pathogenesis and therapeutic application. FEBS J 2025. [PMID: 40205752 DOI: 10.1111/febs.70093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 03/06/2025] [Accepted: 04/01/2025] [Indexed: 04/11/2025]
Abstract
Multiple myeloma (MM), characterised by the clonal proliferation of plasma cells in the bone marrow, is the second most common haematological malignancy worldwide. Although there is now an impressive artillery of therapeutics to tackle this condition, resistance remains a prevalent issue. The bone marrow microenvironment performs a crucial role in supporting MM pathogenesis and promoting the development of therapeutic resistance. Extracellular vesicles (EVs), small vesicles that carry bioactive molecules, are a key component of cell-to-cell communication within the bone marrow microenvironment. In this review, we summarise the contribution of EVs to disease progression and anticancer treatment resistance and discuss the potential therapeutic applications of EVs in MM.
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Affiliation(s)
- Chloe Wylie
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, UK
| | - Rebecca Rowan
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, UK
| | - Dessi Malinova
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, UK
| | - Lisa Crawford
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, UK
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4
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Semeradtova A, Liegertova M, Herma R, Capkova M, Brignole C, Del Zotto G. Extracellular vesicles in cancer´s communication: messages we can read and how to answer. Mol Cancer 2025; 24:86. [PMID: 40108630 PMCID: PMC11921637 DOI: 10.1186/s12943-025-02282-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 02/24/2025] [Indexed: 03/22/2025] Open
Abstract
Extracellular vesicles (EVs) are emerging as critical mediators of intercellular communication in the tumor microenvironment (TME), profoundly influencing cancer progression. These nano-sized vesicles, released by both tumor and stromal cells, carry a diverse cargo of proteins, nucleic acids, and lipids, reflecting the dynamic cellular landscape and mediating intricate interactions between cells. This review provides a comprehensive overview of the biogenesis, composition, and functional roles of EVs in cancer, highlighting their significance in both basic research and clinical applications. We discuss how cancer cells manipulate EV biogenesis pathways to produce vesicles enriched with pro-tumorigenic molecules, explore the specific contributions of EVs to key hallmarks of cancer, such as angiogenesis, metastasis, and immune evasion, emphasizing their role in shaping TME and driving therapeutic resistance. Concurrently, we submit recent knowledge on how the cargo of EVs can serve as a valuable source of biomarkers for minimally invasive liquid biopsies, and its therapeutic potential, particularly as targeted drug delivery vehicles and immunomodulatory agents, showcasing their promise for enhancing the efficacy and safety of cancer treatments. By deciphering the intricate messages carried by EVs, we can gain a deeper understanding of cancer biology and develop more effective strategies for early detection, targeted therapy, and immunotherapy, paving the way for a new era of personalized and precise cancer medicine with the potential to significantly improve patient outcomes.
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Affiliation(s)
- Alena Semeradtova
- Institute of Photonics and Electronics of the CAS, Chaberská 1014/57, Prague, 182 51, Czech Republic.
| | - Michaela Liegertova
- Centre for Nanomaterials and Biotechnology, Faculty of Science, Jan Evangelista Purkyně University in Ústí Nad Labem, Pasteurova 3632/15, Ústí Nad Labem, 40096, Czech Republic
| | - Regina Herma
- Centre for Nanomaterials and Biotechnology, Faculty of Science, Jan Evangelista Purkyně University in Ústí Nad Labem, Pasteurova 3632/15, Ústí Nad Labem, 40096, Czech Republic
| | - Magdalena Capkova
- Institute of Photonics and Electronics of the CAS, Chaberská 1014/57, Prague, 182 51, Czech Republic
| | - Chiara Brignole
- Laboratory of Experimental Therapies in Oncology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147, Genoa, Italy.
| | - Genny Del Zotto
- Core Facilities, Department of Research and Diagnostics, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
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5
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Shakerian N, Tafazoli A, Razavinia A, Sadrzadeh Aghajani Z, Bana N, Mard-Soltani M, Khalesi B, Hashemi ZS, Khalili S. Current Understanding of Therapeutic and Diagnostic Applications of Exosomes in Pancreatic Cancer. Pancreas 2025; 54:e255-e267. [PMID: 39661050 DOI: 10.1097/mpa.0000000000002414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2024]
Abstract
ABSTRACT Unusual symptoms, rapid progression, lack of reliable early diagnostic biomarkers, and lack of efficient treatment choices are the ongoing challenges of pancreatic cancer. Numerous research studies have demonstrated the correlation between exosomes and various aspects of pancreatic cancer. In light of these facts, exosomes possess the potential to play functional roles in the treatment, prognosis, and diagnosis of the pancreatic cancer. In the present study, we reviewed the most recent developments in approaches for exosome separation, modification, monitoring, and communication. Moreover, we discussed the clinical uses of exosomes as less invasive liquid biopsies and drug carriers and their contribution to the control of angiogenic activity of pancreatic cancer. Better investigation of exosome biology would help to effectively engineer therapeutic exosomes with certain nucleic acids, proteins, and even exogenous drugs as their cargo. Circulating exosomes have shown promise as reliable candidates for pancreatic cancer early diagnosis and monitoring in high-risk people without clinical cancer manifestation. Although we have tried to reflect the status of exosome applications in the treatment and detection of pancreatic cancer, it is evident that further studies and clinical trials are required before exosomes may be employed as a routine therapeutic and diagnostic tools for pancreatic cancer.
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Affiliation(s)
- Neda Shakerian
- From the Department of Clinical Biochemistry, Faculty of Medical Sciences, Dezful University of Medical Sciences, Dezful
| | - Aida Tafazoli
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz
| | - Amir Razavinia
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, IR
| | | | - Nikoo Bana
- Kish International Campus, University of Teheran
| | - Maysam Mard-Soltani
- From the Department of Clinical Biochemistry, Faculty of Medical Sciences, Dezful University of Medical Sciences, Dezful
| | - Bahman Khalesi
- Department of Research and Production of Poultry Viral Vaccine, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization, Karaj
| | - Zahra Sadat Hashemi
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran
| | - Saeed Khalili
- Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran
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6
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Chen J, Hu S, Liu J, Jiang H, Wang S, Yang Z. Exosomes: a double-edged sword in cancer immunotherapy. MedComm (Beijing) 2025; 6:e70095. [PMID: 39968497 PMCID: PMC11831209 DOI: 10.1002/mco2.70095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 01/08/2025] [Accepted: 01/10/2025] [Indexed: 02/20/2025] Open
Abstract
Over the past few decades, immunotherapy has emerged as a powerful strategy to overcome the limitations of conventional cancer treatments. The use of extracellular vesicles, particularly exosomes, which carry cargoes capable of modulating the immune response, has been extensively explored as a potential therapeutic approach in cancer immunotherapy. Exosomes can deliver their cargo to target cells, thereby influencing their phenotype and immunomodulatory functions. They exhibit either immunosuppressive or immune-activating characteristics, depending on their internal contents. These exosomes originate from diverse cell sources, and their internal contents can vary, suggesting that there may be a delicate balance between immune suppression and stimulation when utilizing them for immunotherapy. Therefore, a thorough understanding of the molecular mechanisms underlying the role of exosomes in cancer progression is essential. This review focuses on the molecular mechanisms driving exosome function and their impact on the tumor microenvironment (TME), highlighting the intricate balance between immune suppression and activation that must be navigated in exosome-based therapies. Additionally, it underscores the challenges and ongoing efforts to optimize exosome-based immunotherapies, thereby making a significant contribution to the advancement of cancer immunotherapy research.
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Affiliation(s)
- Jiayi Chen
- School of Life SciencesJilin UniversityChangchunChina
| | - Siyuan Hu
- School of Life SciencesJilin UniversityChangchunChina
| | - Jiayi Liu
- School of Life SciencesJilin UniversityChangchunChina
| | - Hao Jiang
- School of Life SciencesJilin UniversityChangchunChina
| | - Simiao Wang
- School of Life SciencesJilin UniversityChangchunChina
| | - Zhaogang Yang
- School of Life SciencesJilin UniversityChangchunChina
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7
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Rico LG, Salvia R, Bradford JA, Ward MD, Petriz J. PD-L1 expression in multiple myeloma myeloid derived suppressor cells. Methods Cell Biol 2025; 195:115-141. [PMID: 40180451 DOI: 10.1016/bs.mcb.2024.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
The Programmed Cell Death Protein 1/Programmed Cell Death Protein Ligand 1 (PD-1/PD-L1) axis stands as one of the most widely acknowledged targets for cancer immunotherapy. This ligand is considered a therapeutic target for this disease as it might play an important role in tumor immune evasion and drug resistance. In multiple myeloma (MM), PD-L1 is overexpressed in abnormal plasma cells and Myeloid-Derived Suppressor Cells (MDSCs). In MDSCs, unlike tumoral cells or derived cell lines, the PD-L1 protein is presented in a conformation not recognized by the monoclonal antibody. In contrast, when stimulating the sample with PMA, the PD-L1 molecule undergoes a conformational change that enables its recognition. Hence, we have developed a flow cytometric screening assay to determine PD-L1 conformational changes in MDSCs based on a minimal manipulation of the sample, to preserve the structure and functionality of the ligand. In this chapter, we provide detailed protocols to assess PD-L1 levels in MDSCs together with the representative results obtained in multiple myeloma patients. The obtained results enable the classification of MM patients based on the different PD-L1 detection after stimulation, which increases compared with unstimulated samples. We also provide protocols to assess kinetic analysis of PD-L1 expression over time and to compare PD-L1 cell surface expression with cytoplasmic expression. Finally, competitive experiments in the presence of durvalumab are also described to study its interaction with PD-L1. This approach can also be used to study the contribution of potential conformational changes in other proteins.
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Affiliation(s)
- Laura G Rico
- Functional Cytomics Lab, Germans Trias i Pujol Research Institute (IGTP), ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain; Department of Cellular Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Cerdanyola del Vallès, Spain
| | - Roser Salvia
- Functional Cytomics Lab, Germans Trias i Pujol Research Institute (IGTP), ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain; Department of Cellular Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Cerdanyola del Vallès, Spain
| | | | - Michael D Ward
- Thermo Fisher Scientific, Fort Collins, CO, United States
| | - Jordi Petriz
- Functional Cytomics Lab, Germans Trias i Pujol Research Institute (IGTP), ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain; Department of Cellular Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Cerdanyola del Vallès, Spain.
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8
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Fang Z, Fu J, Chen X. A combined immune and exosome-related risk signature as prognostic biomakers in acute myeloid leukemia. Hematology 2024; 29:2300855. [PMID: 38186215 DOI: 10.1080/16078454.2023.2300855] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 12/19/2023] [Indexed: 01/09/2024] Open
Abstract
OBJECTIVES Acute myeloid leukemia (AML) is one of the common hematological diseases with low survival rates. Studies have highlighted the dysregulated expression of immune-related and exosome-related genes (ERGs) in cancers. Nevertheless, it remains to be determined whether combining these genes have a prognostic significance in AML. METHODS Immune-ERG profiles for 151 AML patients from TCGA were analyzed. A risk model was constructed and optimized through the combination of univariate Cox regression and LASSO regression analysis. GEO datasets were utilized as the external validation for the robustness of the risk model. In addition, we performed KEGG and GO enrichment analyses to investigate the role played by these genes in AML. The variations in immune cell infiltrations among risk groups were assessed through four algorithms. Expression of hub gene in specific cell was analyzed by single-cell RNA seq. RESULTS A total of 85 immune-ERGs associated with prognosis were identified, enabling the construction of a risk model for AML. The risk model based on five immune-ERGs (CD37, NUCB2, LSP1, MGST1, and PLXNB1) demonstrated a correlation with the clinical outcomes. Additionally, age, FAB classification, cytogenetics risk, and risk score were identified as independent prognostic factors. The five immune-ERGs exhibited correlations with cytokine-cytokine receptor interaction, and antigen processing and presentation. Notably, the risk model demonstrated significant associations with immune responses and the expression of immune checkpoints. CONCLUSIONS An immune-ERG-based risk model was developed to effectively predict prognostic outcomes for AML patients. There is potential for immune therapy in AML targeting the five hub genes.
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Affiliation(s)
- Zenghui Fang
- Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People's Republic of China
| | - Jiali Fu
- Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People's Republic of China
| | - Xin Chen
- Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People's Republic of China
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9
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Xiao S, Chen L, Chen Z, Li Q. Therapeutically Harnessing Tumor Cell-Derived Extracellular Vesicles for Multiple Myeloma: Recent Advances and Future Perspectives. Pharmaceutics 2024; 16:1439. [PMID: 39598562 PMCID: PMC11597712 DOI: 10.3390/pharmaceutics16111439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 11/02/2024] [Accepted: 11/06/2024] [Indexed: 11/29/2024] Open
Abstract
Extracellular vesicles (EVs) have emerged as pivotal regulators for extensive intercellular crosstalk owing to capsuled diverse bioactive substances such as proteins, nucleic acids, and lipids. Recent studies have shown that tumor-derived EVs significantly influence the bone marrow microenvironment, contributing to the progression of multiple myeloma (MM). This highlights the robust potential of EVs as a promising avenue for developing more effective and precise diagnostic and therapeutic strategies for MM. In this review, we briefly discuss the multifaceted roles of EVs in MM progression, as well as the diagnostic and therapeutic value in MM management. Specifically, we focus on the latest research progress regarding the therapeutic potential of EVs for MM, particularly tumor cell-derived EVs, as we elaborate on three main aspects: (i) EVs as therapeutic targets, including the targeted inhibition of EV biogenesis and uptake, and the possibility of eliminating tumor-derived EVs; (ii) EVs as delivery nanovectors, where we discuss the latest anti-MM candidates and potential ways to optimize therapeutic efficiency; and (iii) engineered EVs as antitumor vaccines, focusing on the use of tumor cell-derived EVs in immunotherapy. Finally, we address the prospects and challenges of harnessing the therapeutic potential of EVs in clinical transformation.
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Affiliation(s)
- Shumei Xiao
- Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
| | - Lei Chen
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (L.C.); (Z.C.)
| | - Zhichao Chen
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (L.C.); (Z.C.)
| | - Qiubai Li
- Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
- Hubei Engineering Research Center for Application of Extracellular Vesicles, Hubei University of Science and Technology, Xianning 437100, China
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10
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Hsu CY, Ahmed AT, Bansal P, Hjazi A, Al-Hetty HRAK, Qasim MT, Sapaev I, Deorari M, Mustafa YF, Elawady A. MicroRNA-enriched exosome as dazzling dancer between cancer and immune cells. J Physiol Biochem 2024; 80:811-829. [PMID: 39316240 DOI: 10.1007/s13105-024-01050-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 09/11/2024] [Indexed: 09/25/2024]
Abstract
Exosomes are widely recognized for their roles in numerous biological processes and as intercellular communication mediators. Human cancerous and normal cells can both produce massive amounts of exosomes. They are extensively dispersed in tumor-modeling animals' pleural effusions, ascites, and plasma from people with cancer. Tumor cells interact with host cells by releasing exosomes, which allow them to interchange various biological components. Tumor growth, invasion, metastasis, and even tumorigenesis can all be facilitated by this delicate and complex system by modifying the nearby and remote surroundings. Due to the existence of significant levels of biomolecules like microRNA, exosomes can modulate the immune system's stimulation or repression, which in turn controls tumor growth. However, the role of microRNA in exosome-mediated communication between immunological and cancer cells is still poorly understood. This study aims to get the most recent information on the "yin and yang" of exosomal microRNA in the regulation of tumor immunity and immunotherapy, which will aid current cancer treatment and diagnostic techniques.
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Affiliation(s)
- Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, Arizona 85004, USA
| | - Abdulrahman T Ahmed
- Department of Nursing, Al-Maarif University College, Ramadi, AL-Anbar Governorate, Iraq
| | - Pooja Bansal
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, 560069, Karnataka, India
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | | | - Maytham T Qasim
- College of Health and Medical Technology, Al-Ayen University, Thi-Qar, 64001, Iraq
| | - Ibrokhim Sapaev
- Tashkent Institute of Irrigation and Agricultural Mechanization Engineers" National Research University, Tashkent, Uzbekistan
- School of Engineering, Central Asian University, Tashkent, 111221, Uzbekistan
- Western Caspian University, Scientific researcher, Baku, Azerbaijan
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Ahmed Elawady
- College of Technical Engineering, the Islamic University, Najaf, Iraq
- College of Technical Engineering, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, the Islamic University of Babylon, Babylon, Iraq
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11
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Quarato ER, Salama NA, Calvi LM. Interplay Between Skeletal and Hematopoietic Cells in the Bone Marrow Microenvironment in Homeostasis and Aging. Curr Osteoporos Rep 2024; 22:416-432. [PMID: 38782850 DOI: 10.1007/s11914-024-00874-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/05/2024] [Indexed: 05/25/2024]
Abstract
PURPOSE OF THE REVIEW In this review, we discuss the most recent scientific advances on the reciprocal regulatory interactions between the skeletal and hematopoietic stem cell niche, focusing on immunomodulation and its interplay with the cell's mitochondrial function, and how this impacts osteoimmune health during aging and disease. RECENT FINDINGS Osteoimmunology investigates interactions between cells that make up the skeletal stem cell niche and immune system. Much work has investigated the complexity of the bone marrow microenvironment with respect to the skeletal and hematopoietic stem cells that regulate skeletal formation and immune health respectively. It has now become clear that these cellular components cooperate to maintain homeostasis and that dysfunction in their interaction can lead to aging and disease. Having a deeper, mechanistic appreciation for osteoimmune regulation will lead to better research perspective and therapeutics with the potential to improve the aging process, skeletal and hematologic regeneration, and disease targeting.
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Affiliation(s)
- Emily R Quarato
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, USA.
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
| | - Noah A Salama
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA.
| | - Laura M Calvi
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
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12
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Bhowmick K, von Suskil M, Al-Odat OS, Elbezanti WO, Jonnalagadda SC, Budak-Alpdogan T, Pandey MK. Pathways to therapy resistance: The sheltering effect of the bone marrow microenvironment to multiple myeloma cells. Heliyon 2024; 10:e33091. [PMID: 39021902 PMCID: PMC11252793 DOI: 10.1016/j.heliyon.2024.e33091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 05/30/2024] [Accepted: 06/13/2024] [Indexed: 07/20/2024] Open
Abstract
Multiple Myeloma (MM) is a malignant expansion of plasma cells in the bone marrow (BM), resulting in a disease characterized by symptoms of end organ damage from light chain secretion, crowding of the BM, and bone lesions. Although the past two decades have been characterized by numerous novel therapies emerging, the disease remains incurable due to intrinsic or acquired drug resistance. A major player in MM's drug resistance arises from its intimate relationship with the BM microenvironment (BMME). Through stress-inducing conditions, soluble messengers, and physical adhesion to BM elements, the BMME activates numerous pathways in the myeloma cell. This not only propagates myeloma progression through survival and growth signals, but also specific mechanisms to circumvent therapeutic actions. In this review, we provide an overview of the BMME, the role of individual components in MM survival, and various therapy-specific resistance mechanisms reported in the literature.
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Affiliation(s)
- Kuntal Bhowmick
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
| | - Max von Suskil
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
| | - Omar S. Al-Odat
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
| | - Weam Othman Elbezanti
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
- Department of Hematology, MD Anderson Cancer Center at Cooper, Cooper University Health Care, Camden, NJ, USA
| | - Subash C. Jonnalagadda
- Department of Chemistry and Biochemistry, College of Science and Mathematics, Rowan University, Glassboro, NJ, USA
| | - Tulin Budak-Alpdogan
- Department of Hematology, MD Anderson Cancer Center at Cooper, Cooper University Health Care, Camden, NJ, USA
| | - Manoj K. Pandey
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
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13
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Wang H, Liu S, Zhan J, Liang Y, Zeng X. Shaping the immune-suppressive microenvironment on tumor-associated myeloid cells through tumor-derived exosomes. Int J Cancer 2024; 154:2031-2042. [PMID: 38500385 DOI: 10.1002/ijc.34921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 02/07/2024] [Accepted: 02/23/2024] [Indexed: 03/20/2024]
Abstract
Tumor-associated myeloid cells (TAMCs) play a crucial role in orchestrating the dynamics of the tumor immune microenvironment. This heterogeneous population encompasses myeloid-derived suppressor cells, tumor-associated macrophages and dendritic cells, all of which contribute to the establishment of an immunosuppressive milieu that fosters tumor progression. Tumor-derived exosomes (TEXs), small extracellular vesicles secreted by tumor cells, have emerged as central mediators in intercellular communication within the tumor microenvironment. In this comprehensive review, we explore the intricate mechanisms through which TEXs modulate immune-suppressive effects on TAMCs and their profound implications in cancer progression. We delve into the multifaceted ways in which TEXs influence TAMC functions, subsequently affecting tumor immune evasion. Furthermore, we elucidate various therapeutic strategies aimed at targeting TEX-mediated immune suppression, with the ultimate goal of bolstering antitumor immunity.
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Affiliation(s)
- Hongmei Wang
- Department of Pathology, Medical College, Jinhua Polytechnic, Jinhua, China
- Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang, China
| | - Shanshan Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang, China
| | - Jianhao Zhan
- Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang, China
- Department of Clinical Medcine, HuanKui Academy, Nanchang University, Nanchang, China
| | - Yuqing Liang
- Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang, China
| | - Xiaoping Zeng
- Department of Pathology, Medical College, Jinhua Polytechnic, Jinhua, China
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14
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Hammad M, Ashour HM. Single-cell transcriptomics unveil a unique molecular profile of mesenchymal stem/stromal cell-induced myeloid-derived immune suppressor cells. Mol Ther 2024; 32:1612-1613. [PMID: 38795702 PMCID: PMC11184375 DOI: 10.1016/j.ymthe.2024.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 05/09/2024] [Accepted: 05/09/2024] [Indexed: 05/28/2024] Open
Affiliation(s)
- Mohamed Hammad
- Developmental and Stem Cell Biology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Hossam M Ashour
- Department of Integrative Biology, College of Arts and Sciences, University of South Florida, St. Petersburg, FL, USA.
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15
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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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16
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Lin H, Liu C, Hu A, Zhang D, Yang H, Mao Y. Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives. J Hematol Oncol 2024; 17:31. [PMID: 38720342 PMCID: PMC11077829 DOI: 10.1186/s13045-024-01544-7] [Citation(s) in RCA: 59] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 04/10/2024] [Indexed: 05/12/2024] Open
Abstract
Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite the established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, and the exploration of emerging modalities such as immunotherapy and integration of medicine and engineering technology therapy, the efficacy of these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny of the inhibitory and immunosuppressive milieu within GBM has underscored the significance of cellular constituents of the GBM microenvironment and their interactions with malignant cells and neurons. Novel immune and targeted therapy strategies have emerged, offering promising avenues for advancing GBM treatment. One pivotal mechanism orchestrating immunosuppression in GBM involves the aggregation of myeloid-derived suppressor cells (MDSCs), glioma-associated macrophage/microglia (GAM), and regulatory T cells (Tregs). Among these, MDSCs, though constituting a minority (4-8%) of CD45+ cells in GBM, play a central component in fostering immune evasion and propelling tumor progression, angiogenesis, invasion, and metastasis. MDSCs deploy intricate immunosuppressive mechanisms that adapt to the dynamic tumor microenvironment (TME). Understanding the interplay between GBM and MDSCs provides a compelling basis for therapeutic interventions. This review seeks to elucidate the immune regulatory mechanisms inherent in the GBM microenvironment, explore existing therapeutic targets, and consolidate recent insights into MDSC induction and their contribution to GBM immunosuppression. Additionally, the review comprehensively surveys ongoing clinical trials and potential treatment strategies, envisioning a future where targeting MDSCs could reshape the immune landscape of GBM. Through the synergistic integration of immunotherapy with other therapeutic modalities, this approach can establish a multidisciplinary, multi-target paradigm, ultimately improving the prognosis and quality of life in patients with GBM.
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Affiliation(s)
- Hao Lin
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Chaxian Liu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Ankang Hu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Duanwu Zhang
- Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, People's Republic of China.
| | - Hui Yang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
- Institute for Translational Brain Research, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
| | - Ying Mao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
- National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
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17
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Song Y, Song Q, Hu D, Sun B, Gao M, Liang X, Qu B, Suo L, Yin Z, Wang L. The potential applications of artificially modified exosomes derived from mesenchymal stem cells in tumor therapy. Front Oncol 2024; 13:1299384. [PMID: 38250549 PMCID: PMC10798044 DOI: 10.3389/fonc.2023.1299384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 12/15/2023] [Indexed: 01/23/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have tumor-homing ability and play critical roles in tumor treatment, but their dual influences on tumor progression limit their therapeutic applications. Exosomes derived from MSCs (MSC-exosomes) exhibit great potential in targeted tumor treatment due to their advantages of high stability, low immunogenicity, good biocompatibility, long circulation time and homing characteristics. Furthermore, the artificial modification of MSC-exosomes could amplify their advantages and their inhibitory effect on tumors and could overcome the limit of tumor-promoting effect. In this review, we summarize the latest therapeutic strategies involving artificially modified MSC-exosomes in tumor treatment, including employing these exosomes as nanomaterials to carry noncoding RNAs or their inhibitors and anticancer drugs, and genetic engineering modification of MSC-exosomes. We also discuss the feasibility of utilizing artificially modified MSC-exosomes as an emerging cell-free method for tumor treatment and related challenges.
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Affiliation(s)
- Yilin Song
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Quanlin Song
- Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Daosheng Hu
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Binwen Sun
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Mingwei Gao
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiangnan Liang
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Boxin Qu
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Lida Suo
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zeli Yin
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Liming Wang
- Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
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18
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Lefebvre A, Trioën C, Renaud S, Laine W, Hennart B, Bouchez C, Leroux B, Allorge D, Kluza J, Werkmeister E, Grolez GP, Delhem N, Moralès O. Extracellular vesicles derived from nasopharyngeal carcinoma induce the emergence of mature regulatory dendritic cells using a galectin-9 dependent mechanism. J Extracell Vesicles 2023; 12:e12390. [PMID: 38117000 PMCID: PMC10731827 DOI: 10.1002/jev2.12390] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 11/02/2023] [Accepted: 11/13/2023] [Indexed: 12/21/2023] Open
Abstract
Nasopharyngeal carcinoma-derived small extracellular vesicles (NPCSEVs) have an immunosuppressive impact on the tumour microenvironment. In this study, we investigated their influence on the generation of tolerogenic dendritic cells and the potential involvement of the galectin-9 (Gal9) they carry in this process. We analysed the phenotype and immunosuppressive properties of NPCSEVs and explored the ability of DCs exposed to NPCSEVs (NPCSEV-DCs) to regulate T cell proliferation. To assess their impact at the pathophysiological level, we performed real-time fluorescent chemoattraction assays. Finally, we analysed phenotype and immunosuppressive functions of NPCSEV-DCs using a proprietary anti-Gal9 neutralising antibody to assess the role of Gal9 in this effect. We described that NPCSEV-DCs were able to inhibit T cell proliferation despite their mature phenotype. These mature regulatory DCs (mregDCs) have a specific oxidative metabolism and secrete high levels of IL-4. Chemoattraction assays revealed that NPCSEVs could preferentially recruit NPCSEV-DCs. Finally, and very interestingly, the reduction of the immunosuppressive function of NPCSEV-DCs using an anti-Gal9 antibody clearly suggested an important role for vesicular Gal9 in the induction of mregDCs. These results revealed for the first time that NPCSEVs promote the emergence of mregDCs using a galectin-9 dependent mechanism and open new perspectives for antitumour immunotherapy targeting NPCSEVs.
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Affiliation(s)
- Anthony Lefebvre
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
| | - Camille Trioën
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
| | - Sarah Renaud
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
| | - William Laine
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020‐U1277 ‐ CANTHER ‐ Cancer Heterogeneity Plasticity and Resistance to TherapiesLilleFrance
| | | | - Clément Bouchez
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
| | - Bertrand Leroux
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
| | | | - Jérôme Kluza
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020‐U1277 ‐ CANTHER ‐ Cancer Heterogeneity Plasticity and Resistance to TherapiesLilleFrance
| | - Elisabeth Werkmeister
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, US 41 – UAR 2014 – PLBSLilleFrance
| | - Guillaume Paul Grolez
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
| | - Nadira Delhem
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
| | - Olivier Moralès
- Univ. Lille, Inserm, CHU Lille U1189 – ONCO‐THAI – Assisted Laser Therapy and Immunotherapy for OncologyLilleFrance
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020‐U1277 ‐ CANTHER ‐ Cancer Heterogeneity Plasticity and Resistance to TherapiesLilleFrance
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19
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Mizuhara K, Shimura Y, Tsukamoto T, Kanai A, Kuwahara-Ota S, Yamaguchi J, Muramatsu A, Okamoto H, Taminishi-Katsuragawa Y, Kawaji-Kanayama Y, Isa R, Mizutani S, Inaba T, Kuroda J. Tumour-derived exosomes promote the induction of monocytic myeloid-derived suppressor cells from peripheral blood mononuclear cells by delivering miR-106a-5p and miR-146a-5p in multiple myeloma. Br J Haematol 2023; 203:426-438. [PMID: 37584109 DOI: 10.1111/bjh.19049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 07/17/2023] [Accepted: 08/07/2023] [Indexed: 08/17/2023]
Abstract
The shift of the tumour immune microenvironment to a suppressive state promotes not only the development and progression of the disease in multiple myeloma (MM) but also the development of resistance to immunotherapy. We previously demonstrated that myeloma cells can induce monocytic myeloid-derived suppressor cells (M-MDSCs) from healthy peripheral blood mononuclear cells (PBMCs) via the concomitant secretion of CC motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF), but an unknown mediator also promotes M-MDSC induction. This study demonstrates that miR-106a-5p and miR-146a-5p delivered by tumour-derived exosomes (TEXs) from myeloma cells play essential roles in M-MDSC induction in MM. MiR-106a-5p and miR-146a-5p upregulate various immunosuppressive/inflammatory molecules in PBMCs, such as IDO1, CD38, programmed death-ligand 1, CCL5 or MYD88, which are involved in interferon (IFN)-α response, IFN-γ response, inflammatory response, tumour necrosis factor-α signalling and Interleukin-6-JAK-STAT3 signalling. These molecular features mirror the increases in myeloid cellular compartments of PBMCs when co-cultured with myeloma cells. MiR-106a-5p and miR-146a-5p have a compensatory relationship, and these two miRNAs collaborate with CCL5 and MIF to promote M-MDSC induction. Collectively, novel therapeutic candidates may be involved in TEX-mediated sequential cellular and molecular events underlying M-MDSC induction, potentially improving the efficacy of immunotherapy.
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Affiliation(s)
- Kentaro Mizuhara
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuji Shimura
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Taku Tsukamoto
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Akinori Kanai
- Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
- Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | - Saeko Kuwahara-Ota
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Department of Hematology, Japan Community Health Care Organization, Kyoto Kuramaguchi Medical Center, Kyoto, Japan
| | - Junko Yamaguchi
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Department of Hematology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan
| | - Ayako Muramatsu
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Haruya Okamoto
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoko Taminishi-Katsuragawa
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuka Kawaji-Kanayama
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Reiko Isa
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shinsuke Mizutani
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshiya Inaba
- Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Junya Kuroda
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
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20
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Van Morckhoven D, Dubois N, Bron D, Meuleman N, Lagneaux L, Stamatopoulos B. Extracellular vesicles in hematological malignancies: EV-dence for reshaping the tumoral microenvironment. Front Immunol 2023; 14:1265969. [PMID: 37822925 PMCID: PMC10562589 DOI: 10.3389/fimmu.2023.1265969] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 09/04/2023] [Indexed: 10/13/2023] Open
Abstract
Following their discovery at the end of the 20th century, extracellular vesicles (EVs) ranging from 50-1,000 nm have proven to be paramount in the progression of many cancers, including hematological malignancies. EVs are a heterogeneous group of cell-derived membranous structures that include small EVs (commonly called exosomes) and large EVs (microparticles). They have been demonstrated to participate in multiple physiological and pathological processes by allowing exchange of biological material (including among others proteins, DNA and RNA) between cells. They are therefore a crucial way of intercellular communication. In this context, malignant cells can release these extracellular vesicles that can influence their microenvironment, induce the formation of a tumorigenic niche, and prepare and establish distant niches facilitating metastasis by significantly impacting the phenotypes of surrounding cells and turning them toward supportive roles. In addition, EVs are also able to manipulate the immune response and to establish an immunosuppressive microenvironment. This in turn allows for ideal conditions for heightened chemoresistance and increased disease burden. Here, we review the latest findings and reports studying the effects and therapeutic potential of extracellular vesicles in various hematological malignancies. The study of extracellular vesicles remains in its infancy; however, rapid advances in the analysis of these vesicles in the context of disease allow us to envision prospects to improve the detection and treatment of hematological malignancies.
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Affiliation(s)
- David Van Morckhoven
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Nathan Dubois
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Dominique Bron
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Departement of Hematology, Jules Bordet Institute, Brussels, Belgium
| | - Nathalie Meuleman
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Departement of Hematology, Jules Bordet Institute, Brussels, Belgium
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Basile Stamatopoulos
- Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium
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21
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Shokati E, Safari E. The immunomodulatory role of exosomal microRNA networks in the crosstalk between tumor-associated myeloid-derived suppressor cells and tumor cells. Int Immunopharmacol 2023; 120:110267. [PMID: 37276829 DOI: 10.1016/j.intimp.2023.110267] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 04/26/2023] [Accepted: 04/28/2023] [Indexed: 06/07/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are considered a heterogeneous group of immature myeloid cells engaging in aggressive tumor progression and metastasis in the tumor microenvironment (TME) of patients diagnosed with cancer, through downregulation of anti-tumor immune responses. Exosomes are small vesicles carrying specific cargos, including proteins, lipids, and MicroRNA (miRNAs). Such exosomal miRNAs delivered by MDSCs and tumor cells are short noncoding RNAs mediating some of the immunosuppressive characteristics of MDSCs in the TME. However, when it comes to cancer diseases, how these miRNAs interact with MDSCs and encourage MDSCs differentiation and function need further investigations. In this review, we discuss MDSC-derived exosomal miRNAs and those derived from tumor cells (TDE) could modulate anti-tumor immunity and regulate the interaction between tumor cells and MDSCs in the TME. Afterward, we focus on dividing miRNAs, as an important substance interacting with MDSCs and tumor cells in the TME, into those have an immunosuppressive or stimulating effect not only on MDSCs expansion, differentiation, and suppressive function but also on tumor evasion.
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Affiliation(s)
- Elham Shokati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Elahe Safari
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran
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22
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Wu Z, Fang ZX, Hou YY, Wu BX, Deng Y, Wu HT, Liu J. Exosomes in metastasis of colorectal cancers: Friends or foes? World J Gastrointest Oncol 2023; 15:731-756. [PMID: 37275444 PMCID: PMC10237026 DOI: 10.4251/wjgo.v15.i5.731] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/07/2023] [Accepted: 04/04/2023] [Indexed: 05/12/2023] Open
Abstract
Colorectal cancer (CRC), the third most common type of cancer worldwide, threaten human health and quality of life. With multidisciplinary, including surgery, chemotherapy and/or radiotherapy, patients with an early diagnosis of CRC can have a good prognosis. However, metastasis in CRC patients is the main risk factor causing cancer-related death. To elucidate the underlying molecular mechanisms of CRC metastasis is the difficult and research focus on the investigation of the CRC mechanism. On the other hand, the tumor microenvironment (TME) has been confirmed as having an essential role in the tumorigenesis and metastasis of malignancies, including CRCs. Among the different factors in the TME, exosomes as extracellular vesicles, function as bridges in the communication between cancer cells and different components of the TME to promote the progression and metastasis of CRC. MicroRNAs packaged in exosomes can be derived from different sources and transported into the TME to perform oncogenic or tumor-suppressor roles accordingly. This article focuses on CRC exosomes and illustrates their role in regulating the metastasis of CRC, especially through the packaging of miRNAs, to evoke exosomes as novel biomarkers for their impact on the metastasis of CRC progression.
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Affiliation(s)
- Zheng Wu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Ze-Xuan Fang
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yan-Yu Hou
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Bing-Xuan Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu Deng
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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23
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Jahromi FNA, Dowran R, Jafari R. Recent advances in the roles of exosomal microRNAs (exomiRs) in hematologic neoplasms: pathogenesis, diagnosis, and treatment. Cell Commun Signal 2023; 21:88. [PMID: 37127640 PMCID: PMC10152632 DOI: 10.1186/s12964-023-01102-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 03/15/2023] [Indexed: 05/03/2023] Open
Abstract
In clinical diagnosis, the capability of exosomes to serve as biomarkers is one of the most important biological functions of exosomes. The superior stability of exosome biomarkers makes them superior to those isolated from traditional samples such as serum and urine. Almost all body fluids contain exosomes, which contain proteins, nucleic acids, and lipids. Several molecular components of exosomes, including exosome proteins and microRNAs (miRNAs), are promising diagnostic biomarkers. These exosomes may carry genetic information by containing messenger RNA (mRNA) and miRNA. The miRNAs are small noncoding RNAs that regulate protein-coding genes by acting as translational repressors. It has been shown that miRNAs are mis-expressed in a range of conditions, including hematologic neoplasms. Additionally, miRNAs found within exosomes have been linked with specific diseases, including hematologic neoplasms. Numerous studies suggest that circulating exosomes contain miRNAs similar to those found in parental cancer cells. Exosomes contain miRNAs that are released by almost all kinds of cells. MiRNAs are packaged into exosomes and delivered to recipient cells, and manipulate its function. It has been recognized that exosomes are new therapeutic targets for immunotherapy and biomedicine of cancers. The current review discusses the current evidence around exosomal miRNAs involved in the pathogenesis, diagnosis, and treatment of hematologic neoplasms. Video Abstract.
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Affiliation(s)
- Faride Nam Avar Jahromi
- Department of Hematology, School of Paramedical, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Razieh Dowran
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Jafari
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, P.O. BoX: 1138, Shafa St., Ershad Blvd., 57147, Urmia, Iran.
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24
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Bhardwaj V, Ansell SM. Modulation of T-cell function by myeloid-derived suppressor cells in hematological malignancies. Front Cell Dev Biol 2023; 11:1129343. [PMID: 37091970 PMCID: PMC10113446 DOI: 10.3389/fcell.2023.1129343] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 03/15/2023] [Indexed: 04/08/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes that negatively regulate the immune response to cancer and chronic infections. Abnormal myelopoiesis and pathological activation of myeloid cells generate this heterogeneous population of myeloid-derived suppressor cells. They are characterized by their distinct transcription, phenotypic, biochemical, and functional features. In the tumor microenvironment (TME), myeloid-derived suppressor cells represent an important class of immunosuppressive cells that correlate with tumor burden, stage, and a poor prognosis. Myeloid-derived suppressor cells exert a strong immunosuppressive effect on T-cells (and a broad range of other immune cells), by blocking lymphocyte homing, increasing production of reactive oxygen and nitrogen species, promoting secretion of various cytokines, chemokines, and immune regulatory molecules, stimulation of other immunosuppressive cells, depletion of various metabolites, and upregulation of immune checkpoint molecules. Additionally, the heterogeneity of myeloid-derived suppressor cells in cancer makes their identification challenging. Overall, they serve as a major obstacle for many cancer immunotherapies and targeting them could be a favorable strategy to improve the effectiveness of immunotherapeutic interventions. However, in hematological malignancies, particularly B-cell malignancies, the clinical outcomes of targeting these myeloid-derived suppressor cells is a field that is still to be explored. This review summarizes the complex biology of myeloid-derived suppressor cells with an emphasis on the immunosuppressive pathways used by myeloid-derived suppressor cells to modulate T-cell function in hematological malignancies. In addition, we describe the challenges, therapeutic strategies, and clinical relevance of targeting myeloid-derived suppressor cells in these diseases.
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25
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Hess NJ, Kink JA, Hematti P. Exosomes, MDSCs and Tregs: A new frontier for GVHD prevention and treatment. Front Immunol 2023; 14:1143381. [PMID: 37063900 PMCID: PMC10090348 DOI: 10.3389/fimmu.2023.1143381] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
The development of graft versus host disease (GVHD) represents a long-standing complication of allogeneic hematopoietic cell transplantation (allo-HCT). Different approaches have been used to control the development of GVHD with most relying on variations of chemotherapy drugs to eliminate allo-reactive T cells. While these approaches have proven effective, it is generally accepted that safer, and less toxic GVHD prophylaxis drugs are required to reduce the health burden placed on allo-HCT recipients. In this review, we will summarize the emerging concepts revolving around three biologic-based therapies for GVHD using T regulatory cells (Tregs), myeloid-derived-suppressor-cells (MDSCs) and mesenchymal stromal cell (MSC) exosomes. This review will highlight how each specific modality is unique in its mechanism of action, but also share a common theme in their ability to preferentially activate and expand Treg populations in vivo. As these three GVHD prevention/treatment modalities continue their path toward clinical application, it is imperative the field understand both the biological advantages and disadvantages of each approach.
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Affiliation(s)
- Nicholas J. Hess
- Division of Hematology, Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
- University of Wisconsin Carbone Cancer Center, Madison, WI, United States
| | - John A. Kink
- Division of Hematology, Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
- University of Wisconsin Carbone Cancer Center, Madison, WI, United States
| | - Peiman Hematti
- Division of Hematology, Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
- University of Wisconsin Carbone Cancer Center, Madison, WI, United States
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26
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Alipoor SD, Chang H. Exosomal miRNAs in the Tumor Microenvironment of Multiple Myeloma. Cells 2023; 12:cells12071030. [PMID: 37048103 PMCID: PMC10092980 DOI: 10.3390/cells12071030] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/21/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023] Open
Abstract
Multiple myeloma (MM) is a malignancy of plasma cells in the bone marrow and is characterized by the clonal proliferation of B-cells producing defective monoclonal immunoglobulins. Despite the latest developments in treatment, drug resistance remains one of the major challenges in the therapy of MM. The crosstalk between MM cells and other components within the bone marrow microenvironment (BME) is the major determinant of disease phenotypes. Exosomes have emerged as the critical drivers of this crosstalk by allowing the delivery of informational cargo comprising multiple components from miniature peptides to nucleic acids. Such material transfers have now been shown to perpetuate drug-resistance development and disease progression in MM. MicroRNAs(miRNAs) specifically play a crucial role in this communication considering their small size that allows them to be readily packed within the exosomes and widespread potency that impacts the developmental trajectory of the disease inside the tumor microenvironment (TME). In this review, we aim to provide an overview of the current understanding of the role of exosomal miRNAs in the epigenetic modifications inside the TME and its pathogenic influence on the developmental phenotypes and prognosis of MM.
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Affiliation(s)
- Shamila D. Alipoor
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran P5X9+7F9, Iran
| | - Hong Chang
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Laboratory Hematology, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2M9, Canada
- Correspondence:
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27
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Ong KL, Davis MD, Purnell KK, Cutshall H, Pal HC, Connelly AN, Fay CX, Kuznetsova V, Brown EE, Hel Z. Distinct phenotype of neutrophil, monocyte, and eosinophil populations indicates altered myelopoiesis in a subset of patients with multiple myeloma. Front Oncol 2023; 12:1074779. [PMID: 36733370 PMCID: PMC9888259 DOI: 10.3389/fonc.2022.1074779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 12/09/2022] [Indexed: 01/19/2023] Open
Abstract
Hematologic malignancies, including multiple myeloma (MM), promote systemic immune dysregulation resulting in an alteration and increased plasticity of myeloid cell subsets. To determine the heterogeneity of the myeloid cell compartment in the peripheral blood of patients with MM, we performed a detailed investigation of the phenotype and function of myeloid subpopulations. We report that a subset of MM patients exhibits a specific myeloid cell phenotype indicative of altered myelopoiesis characterized by significant changes in the properties of circulating granulocytic, monocytic, and eosinophilic populations. The subset, referred to as MM2, is defined by a markedly elevated level of CD64 (FcγRI) on the surface of circulating neutrophils. Compared to healthy controls or MM1 patients displaying intermediate levels of CD64, neutrophils from MM2 patients exhibit a less differentiated phenotype, low levels of CD10 and CXC chemokine receptor 2 (CXCR2), increased capacity for the production of mitochondrial reactive oxygen species, and an expansion of CD16neg immature neutrophil subset. Classical and patrolling monocytes from MM2 patients express elevated levels of CD64 and activation markers. MM2 eosinophils display lower levels of C-C Chemokine receptor 3 (CCR3), Toll-like receptor 4 (TLR4, CD284), and tissue factor (TF, CD142). The MM2 (CD64high) phenotype is independent of age, race, sex, and treatment type. Characteristic features of the MM2 (CD64high) phenotype are associated with myeloma-defining events including elevated involved/uninvolved immunoglobulin free light chain (FLC) ratio at diagnosis. Detailed characterization of the altered myeloid phenotype in multiple myeloma will likely facilitate the identification of patients with an increased risk of disease progression and open new avenues for the rational design of novel therapeutic approaches.
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Affiliation(s)
- Krystle L. Ong
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Marcus D. Davis
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Kalyn K. Purnell
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Hannah Cutshall
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Harish C. Pal
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Ashley N. Connelly
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Christian X. Fay
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Valeriya Kuznetsova
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Elizabeth E. Brown
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States,O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Zdenek Hel
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States,O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States,Center for AIDS Research, University of Alabama at Birmingham, Birmingham, AL, United States,*Correspondence: Zdenek Hel,
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28
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Giannotta C, Autino F, Massaia M. The immune suppressive tumor microenvironment in multiple myeloma: The contribution of myeloid-derived suppressor cells. Front Immunol 2023; 13:1102471. [PMID: 36726975 PMCID: PMC9885853 DOI: 10.3389/fimmu.2022.1102471] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 12/27/2022] [Indexed: 01/18/2023] Open
Abstract
Myeloid derived suppressors cells (MDSC) play major roles in regulating immune homeostasis and immune responses in many conditions, including cancer. MDSC interact with cancer cells within the tumor microenvironment (TME) with direct and indirect mechanisms: production of soluble factors and cytokines, expression of surface inhibitory molecules, metabolic rewiring and exosome release. The two-way relationship between MDSC and tumor cells results in immune evasion and cancer outgrowth. In multiple myeloma (MM), MDSC play a major role in creating protumoral TME conditions. In this minireview, we will discuss the interplay between MDSC and MM TME and the possible strategies to target MDSC.
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Affiliation(s)
- Claudia Giannotta
- Laboratorio di Immunologia dei Tumori del Sangue (LITS), Centro Interdipartimentale di Biotecnologie Molecolari “Guido Tarone”, Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Torino, Italy
| | - Federica Autino
- Laboratorio di Immunologia dei Tumori del Sangue (LITS), Centro Interdipartimentale di Biotecnologie Molecolari “Guido Tarone”, Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Torino, Italy
| | - Massimo Massaia
- Laboratorio di Immunologia dei Tumori del Sangue (LITS), Centro Interdipartimentale di Biotecnologie Molecolari “Guido Tarone”, Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Torino, Italy,SC Ematologia, AO S.Croce e Carle, Cuneo, Italy,*Correspondence: Massimo Massaia,
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29
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Monoclonal Gammopathies and the Bone Marrow Microenvironment: From Bench to Bedside and Then Back Again. Hematol Rep 2023; 15:23-49. [PMID: 36648882 PMCID: PMC9844382 DOI: 10.3390/hematolrep15010004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 09/11/2022] [Accepted: 01/03/2023] [Indexed: 01/12/2023] Open
Abstract
Multiple myeloma (MM) is an incurable hematologic malignancy characterized by a multistep evolutionary pathway, with an initial phase called monoclonal gammopathy of undetermined significance (MGUS), potentially evolving into the symptomatic disease, often preceded by an intermediate phase called "smoldering" MM (sMM). From a biological point of view, genomic alterations (translocations/deletions/mutations) are already present at the MGUS phase, thus rendering their role in disease evolution questionable. On the other hand, we currently know that changes in the bone marrow microenvironment (TME) could play a key role in MM evolution through a progressive shift towards a pro-inflammatory and immunosuppressive shape, which may drive cancer progression as well as clonal plasma cells migration, proliferation, survival, and drug resistance. Along this line, the major advancement in MM patients' survival has been achieved by the introduction of microenvironment-oriented drugs (including immunomodulatory drugs and monoclonal antibodies). In this review, we summarized the role of the different components of the TME in MM evolution from MGUS as well as potential novel therapeutic targets/opportunities.
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30
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Aksoy O, Lind J, Sunder-Plaßmann V, Vallet S, Podar K. Bone marrow microenvironment- induced regulation of Bcl-2 family members in multiple myeloma (MM): Therapeutic implications. Cytokine 2023; 161:156062. [PMID: 36332463 DOI: 10.1016/j.cyto.2022.156062] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 09/19/2022] [Accepted: 09/30/2022] [Indexed: 11/23/2022]
Abstract
In Multiple Myeloma (MM) the finely tuned homeostasis of the bone marrow (BM) microenvironment is disrupted. Evasion of programmed cell death (apoptosis) represents a hallmark of cancer. Besides genetic aberrations, the supportive and protective MM BM milieu, which is constituted by cytokines and growth factors, intercellular and cell: extracellular matrix (ECM) interactions and exosomes, in particular, plays a key role in the abundance of pro-survival members of the Bcl-2 family (i.e., Mcl-1, Bcl-2, and Bcl-xL) in tumor cells. Moreover, microenvironmental cues have also an impact on stability- regulating post-translational modifications of anti-apoptotic proteins including de/phosphorylation, polyubiquitination; on their intracellular binding affinities, and localization. Advances of our molecular knowledge on the escape of cancer cells from apoptosis have informed the development of a new class of small molecules that mimic the action of BH3-only proteins. Indeed, approaches to directly target anti-apoptotic Bcl-2 family members are among today's most promising therapeutic strategies and BH3-mimetics (i.e., venetoclax) are currently revolutionizing not only the treatment of CLL and AML, but also hold great therapeutic promise in MM. Furthermore, approaches that activate apoptotic pathways indirectly via modification of the tumor microenvironment have already entered clinical practice. The present review article will summarize our up-to-date knowledge on molecular mechanisms by which the MM BM microenvironment, cytokines, and growth factors in particular, mediates tumor cell evasion from apoptosis. Moreover, it will discuss some of the most promising science- derived therapeutic strategies to overcome Bcl-2- mediated tumor cell survival in order to further improve MM patient outcome.
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Affiliation(s)
- Osman Aksoy
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria
| | - Judith Lind
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria
| | - Vincent Sunder-Plaßmann
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria
| | - Sonia Vallet
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria; Department of Internal Medicine 2, University Hospital Krems, Mitterweg 10, 3500 Krems an der Donau, Austria
| | - Klaus Podar
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500 Krems an der Donau, Austria; Department of Internal Medicine 2, University Hospital Krems, Mitterweg 10, 3500 Krems an der Donau, Austria.
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31
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Menu E, Vanderkerken K. Exosomes in multiple myeloma: from bench to bedside. Blood 2022; 140:2429-2442. [PMID: 35271699 PMCID: PMC10653045 DOI: 10.1182/blood.2021014749] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/10/2022] [Accepted: 02/23/2022] [Indexed: 12/16/2022] Open
Abstract
Multiple myeloma (MM) remains an incurable plasma cell malignancy that develops in the bone marrow (BM). This BM is partially responsible for protecting the MM cells against current standard-of-care therapies and for accommodating MM-related symptoms such as bone resorption and immune suppression. Increasing evidence has implicated extracellular vesicles (EV), including exosomes in the different processes within the BM. Exosomes are <150-nm-sized vesicles secreted by different cell types including MM cells. These vesicles contain protein and RNA cargo that they deliver to the recipient cell. In this way, they have been implicated in MM-related processes including osteolysis, angiogenesis, immune suppression, and drug resistance. Targeting exosome secretion could therefore potentially block these different processes. In this review, we will summarize the current findings of exosome-related processes in the BM and describe not only the current treatment strategies to counter them but also how exosomes can be harnessed to deliver toxic payloads. Finally, an overview of the different clinical studies that investigate EV cargo as potential MM biomarkers in liquid biopsies will be discussed.
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Affiliation(s)
- Eline Menu
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Karin Vanderkerken
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
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32
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Molecular Features of the Mesenchymal and Osteoblastic Cells in Multiple Myeloma. Int J Mol Sci 2022; 23:ijms232415448. [PMID: 36555090 PMCID: PMC9779562 DOI: 10.3390/ijms232415448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/02/2022] [Accepted: 12/04/2022] [Indexed: 12/12/2022] Open
Abstract
Multiple myeloma (MM) is a monoclonal gammopathy characterized by biological heterogeneity and unregulated proliferation of plasma cells (PCs) in bone marrow (BM). MM is a multistep process based on genomic instability, epigenetic dysregulation and a tight cross-talk with the BM microenvironment that plays a pivotal role supporting the proliferation, survival, drug-resistance and homing of PCs. The BM microenvironment consists of a hematopoietic and a non-hematopoietic compartment, which cooperate to create a tumor environment. Among the non-hematopoietic component, mesenchymal stromal cells (MSCs) and osteoblasts (OBs) appear transcriptionally and functionally different in MM patients compared to healthy donors (HDs) and to patients with pre-malignant monoclonal gammopathies. Alterations of both MSCs and OBs underly the osteolytic lesions that characterize myeloma-associated bone disease. In this review, we will discuss the different characteristics of MSCs and OBs in MM patients, analyzing the transcriptome, the deregulated molecular pathways and the role performed by miRNAs and exosome in the pathophysiology of MM.
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33
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Zhang W, Jiang Z, Tang D. The value of exosome-derived noncoding RNAs in colorectal cancer proliferation, metastasis, and clinical applications. Clin Transl Oncol 2022; 24:2305-2318. [PMID: 35921060 DOI: 10.1007/s12094-022-02908-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 07/23/2022] [Indexed: 11/26/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world today, and its incidence and mortality rates are increasing every year. The ease of proliferation and metastasis of CRC has long been an important reason for its high mortality rate. Exosomes serve as key mediators that mediate communication between tumor cells and various other cells. Non-coding RNAs (ncRNAs) have been shown to play a key role in apoptosis, immunosuppression and proliferation metastasis in cancer. ncRNAs are loaded on exosomes and initiate the onset of metastasis by promoting epithelial-mesenchymal transition (EMT) at the primary site of the tumor. Meanwhile, exosome-derived ncRNAs construct a pre-metastatic niche (PMN) for CRC metastasis by forming an inflammatory microenvironment in distant organs, immunosuppression, and promoting angiogenesis and remodeling of the extracellular matrix. Here, we summarize the specific mechanisms associated with exosome-derived ncRNAs promoting local invasion and metastasis in CRC. Finally, we focus on their value for clinical application in future CRC diagnosis and treatment.
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Affiliation(s)
- Wenjie Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China
| | - Zhengting Jiang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Clinical Medical College, Northern Jiangsu Province Hospital, Yangzhou University, Yangzhou, 225001, China.
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34
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Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity. Sci Rep 2022; 12:19660. [PMID: 36385153 PMCID: PMC9668840 DOI: 10.1038/s41598-022-24137-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 11/10/2022] [Indexed: 11/17/2022] Open
Abstract
Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite constantly evolving therapeutic approaches including various types of immunotherapy. Increased arginase activity has been associated with potent suppression of T-cell immune responses in different types of cancer. Here, we investigated the role of arginase 1 (ARG1) in Vκ*MYC model of MM in mice. ARG1 expression in myeloid cells correlated with tumor progression and was accompanied by a systemic drop in ʟ-arginine levels. In MM-bearing mice antigen-induced proliferation of adoptively transferred T-cells was strongly suppressed and T-cell proliferation was restored by pharmacological arginase inhibition. Progression of Vκ*MYC tumors was significantly delayed in mice with myeloid-specific ARG1 deletion. Arginase inhibition effectively inhibited tumor progression although it failed to augment anti-myeloma effects of bortezomib. However, arginase inhibitor completely prevented development of bortezomib-induced cardiotoxicity in mice. Altogether, these findings indicate that arginase inhibitors could be further tested as a complementary strategy in multiple myeloma to mitigate adverse cardiac events without compromising antitumor efficacy of proteasome inhibitors.
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Iskrzak J, Zygmunciak P, Misiewicz-Krzemińska I, Puła B. Extracellular Vesicles in Multiple Myeloma-Cracking the Code to a Better Understanding of the Disease. Cancers (Basel) 2022; 14:cancers14225575. [PMID: 36428668 PMCID: PMC9688731 DOI: 10.3390/cancers14225575] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Multiple myeloma (MM) is a plasma cell-derived malignancy that stands for around 1.5% of newly discovered cancer cases. Despite constantly improving treatment methods, the disease is incurable with over 13,000 deaths in the US and over 30,000 in Europe. Recent studies suggest that extracellular vesicles (EVs) might play a significant role in the pathogenesis and evolution of MM. Further investigation of their role could prove to be beneficial in establishing new therapies and hence, improve the prognosis of MM patients. What is more, EVs might serve as novel markers in diagnosing and monitoring the disease. Great advancements concerning the position of EVs in the pathophysiology of MM have recently been shown in research and in this review, we would like to delve into the still expanding state of knowledge.
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Affiliation(s)
- Justyna Iskrzak
- Medical University of Warsaw, 02-091 Warsaw, Poland
- Institute of Hematology and Transfusion Medicine, Indira Gandhi Str. 14, 02-776 Warsaw, Poland
| | - Przemysław Zygmunciak
- Medical University of Warsaw, 02-091 Warsaw, Poland
- Institute of Hematology and Transfusion Medicine, Indira Gandhi Str. 14, 02-776 Warsaw, Poland
| | - Irena Misiewicz-Krzemińska
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Chocimska Str. 5, 00-791 Warsaw, Poland
| | - Bartosz Puła
- Department of Hematology, Institute of Hematology and Transfusion Medicine, Indira Gandhi Str. 14, 02-776 Warsaw, Poland
- Correspondence: ; Tel.: +48-223-496-302; Fax: +48-223-496-335
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Zhang L, Xiang J, Zhang F, Liu L, Hu C. MSCs can be a double-edged sword in tumorigenesis. Front Oncol 2022; 12:1047907. [PMID: 36439438 PMCID: PMC9685321 DOI: 10.3389/fonc.2022.1047907] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/14/2022] [Indexed: 08/10/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been used to treat various diseases including Alzheimer's disease and cancer. In particular, the immunomodulatory function of MSCs plays a major role in cancer therapy using stem cells. However, MSCs exert promotive and inhibitory effects on cancer. The immunomodulatory effects of MSCs in the tumor microenvironment (TME) are ambiguous, which is the primary reason for the different outcomes of MSCs therapies for tumors. This review discusses the use of MSCs in cancer immunotherapy and their immunomodulatory mechanisms in cancers.
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Affiliation(s)
- Lu Zhang
- Oncology Laboratory, Chongqing Key Laboratory of Translational Research for Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Junyu Xiang
- Department of Biomedical Materials Science, Third Military Medical University, Chongqing, China
| | - Fang Zhang
- Oncology Laboratory, Chongqing Key Laboratory of Translational Research for Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Limei Liu
- Oncology Laboratory, Chongqing Key Laboratory of Translational Research for Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Chongling Hu
- Hematological Oncology Center, Chongqing University Cancer Hospital, Chongqing, China
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Marín-Payá JC, Clara-Trujillo S, Cordón L, Gallego Ferrer G, Sempere A, Gómez Ribelles JL. Protein-Functionalized Microgel for Multiple Myeloma Cells’ 3D Culture. Biomedicines 2022; 10:biomedicines10112797. [PMID: 36359316 PMCID: PMC9687145 DOI: 10.3390/biomedicines10112797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 10/27/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
Multiple myeloma is a hematologic neoplasm caused by an uncontrolled clonal proliferation of neoplastic plasma cells (nPCs) in the bone marrow. The development and survival of this disease is tightly related to the bone marrow environment. Proliferation and viability of nPCs depend on their interaction with the stromal cells and the extracellular matrix components, which also influences the appearance of drug resistance. Recapitulating these interactions in an in vitro culture requires 3D environments that incorporate the biomolecules of interest. In this work, we studied the proliferation and viability of three multiple myeloma cell lines in a microgel consisting of biostable microspheres with fibronectin (FN) on their surfaces. We also showed that the interaction of the RPMI8226 cell line with FN induced cell arrest in the G0/G1 cell cycle phase. RPMI8226 cells developed a significant resistance to dexamethasone, which was reduced when they were treated with dexamethasone and bortezomib in combination.
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Affiliation(s)
- Juan Carlos Marín-Payá
- Centre for Biomaterials and Tissue Engineering, CBIT, Universitat Politècnica de València, 46022 Valencia, Spain
| | - Sandra Clara-Trujillo
- Centre for Biomaterials and Tissue Engineering, CBIT, Universitat Politècnica de València, 46022 Valencia, Spain
- Biomedical Research Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Valencia, Spain
| | - Lourdes Cordón
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Carlos III, 20029 Madrid, Spain
- Hematology Research Group, Instituto de Investigación Sanitaria La Fe (IISLAFE), 46026 Valencia, Spain
| | - Gloria Gallego Ferrer
- Centre for Biomaterials and Tissue Engineering, CBIT, Universitat Politècnica de València, 46022 Valencia, Spain
- Biomedical Research Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Valencia, Spain
| | - Amparo Sempere
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Carlos III, 20029 Madrid, Spain
- Haematology Department, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
| | - José Luis Gómez Ribelles
- Centre for Biomaterials and Tissue Engineering, CBIT, Universitat Politècnica de València, 46022 Valencia, Spain
- Biomedical Research Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Valencia, Spain
- Correspondence:
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Extracellular Vesicles in Haematological Disorders: A Friend or a Foe? Int J Mol Sci 2022; 23:ijms231710118. [PMID: 36077514 PMCID: PMC9455998 DOI: 10.3390/ijms231710118] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 11/17/2022] Open
Abstract
Extracellular vesicles (EVs) have emerged as important mediators of homeostasis, immune modulation and intercellular communication. They are released by every cell of the human body and accordingly detected in a variety of body fluids. Interestingly, their expression can be upregulated under various conditions, such as stress, hypoxia, irradiation, inflammation, etc. Their cargo, which is variable and may include lipids, proteins, RNAs and DNA, reflects that of the parental cell, which offers a significant diagnostic potential to EVs. In line with this, an increasing number of studies have reported the important contribution of cancer-derived EVs in altering the tumour microenvironment and allowing for cancer progression and metastasis. As such, cancer-derived EVs may be used to monitor the development and progression of disease and to evaluate the potential response to treatment, which has generated much excitement in the field of oncology and particularly in haemato-oncology. Finally, EVs are able to transfer their cargo to target cells, modifying the properties of the recipient cell, which offers great therapeutic potential for EVs (either by specific drug delivery or by delivery of siRNAs and other inhibitory proteins). In this manuscript, we review the potential diagnostic use and therapeutic options of EVs in the context of haematological malignancies.
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Hervás-Salcedo R, Martín-Antonio B. A Journey through the Inter-Cellular Interactions in the Bone Marrow in Multiple Myeloma: Implications for the Next Generation of Treatments. Cancers (Basel) 2022; 14:3796. [PMID: 35954459 PMCID: PMC9367481 DOI: 10.3390/cancers14153796] [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: 07/04/2022] [Revised: 07/29/2022] [Accepted: 08/02/2022] [Indexed: 02/05/2023] Open
Abstract
Tumors are composed of a plethora of extracellular matrix, tumor and non-tumor cells that form a tumor microenvironment (TME) that nurtures the tumor cells and creates a favorable environment where tumor cells grow and proliferate. In multiple myeloma (MM), the TME is the bone marrow (BM). Non-tumor cells can belong either to the non-hematological compartment that secretes soluble mediators to create a favorable environment for MM cells to grow, or to the immune cell compartment that perform an anti-MM activity in healthy conditions. Indeed, marrow-infiltrating lymphocytes (MILs) are associated with a good prognosis in MM patients and have served as the basis for developing different immunotherapy strategies. However, MM cells and other cells in the BM can polarize their phenotype and activity, creating an immunosuppressive environment where immune cells do not perform their cytotoxic activity properly, promoting tumor progression. Understanding cell-cell interactions in the BM and their impact on MM proliferation and the performance of tumor surveillance will help in designing efficient anti-MM therapies. Here, we take a journey through the BM, describing the interactions of MM cells with cells of the non-hematological and hematological compartment to highlight their impact on MM progression and the development of novel MM treatments.
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Affiliation(s)
| | - Beatriz Martín-Antonio
- Department of Experimental Hematology, Instituto de Investigación Sanitaria-Fundación Jiménez Diaz (IIS-FJD), University Autonomous of Madrid (UAM), 28040 Madrid, Spain
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Yu S, Ren X, Li L. Myeloid-derived suppressor cells in hematologic malignancies: two sides of the same coin. Exp Hematol Oncol 2022; 11:43. [PMID: 35854339 PMCID: PMC9295421 DOI: 10.1186/s40164-022-00296-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 07/13/2022] [Indexed: 12/15/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of bone marrow cells originating from immature myeloid cells. They exert potent immunosuppressive activity and are closely associated with the development of various diseases such as malignancies, infections, and inflammation. In malignant tumors, MDSCs, one of the most dominant cellular components comprising the tumor microenvironment, play a crucial role in tumor growth, drug resistance, recurrence, and immune escape. Although the role of MDSCs in solid tumors is currently being extensively studied, little is known about their role in hematologic malignancies. In this review, we comprehensively summarized and reviewed the different roles of MDSCs in hematologic malignancies and hematopoietic stem cell transplantation, and finally discussed current targeted therapeutic strategies.Affiliation: Kindly check and confirm the processed affiliations are correct. Amend if any.correct
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Affiliation(s)
- Shunjie Yu
- Department of Hematology, Tianjin Medical University General Hospital, Heping district 154 Anshan Road, Tianjin, China
| | - Xiaotong Ren
- Department of Hematology, Tianjin Medical University General Hospital, Heping district 154 Anshan Road, Tianjin, China
| | - Lijuan Li
- Department of Hematology, Tianjin Medical University General Hospital, Heping district 154 Anshan Road, Tianjin, China.
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Du Z, Feng Y, Zhang H, Liu J, Wang J. Melanoma-derived small extracellular vesicles remodel the systemic onco-immunity via disrupting hematopoietic stem cell proliferation and differentiation. Cancer Lett 2022; 545:215841. [DOI: 10.1016/j.canlet.2022.215841] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/18/2022] [Accepted: 07/23/2022] [Indexed: 02/08/2023]
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Ferreira BV, Carneiro EA, Pestana C, Barahona F, Caetano J, Lopes R, Lúcio P, Neves M, Beck HC, Carvalho AS, Matthiesen R, Costa-Silva B, João C. Patient-Derived Extracellular Vesicles Proteins as New Biomarkers in Multiple Myeloma - A Real-World Study. Front Oncol 2022; 12:860849. [PMID: 35800053 PMCID: PMC9254863 DOI: 10.3389/fonc.2022.860849] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 05/16/2022] [Indexed: 12/14/2022] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy of clonal antibody–secreting plasma cells (PCs). MM diagnosis and risk stratification rely on bone marrow (BM) biopsy, an invasive procedure prone to sample bias. Liquid biopsies, such as extracellular vesicles (EV) in peripheral blood (PB), hold promise as new minimally invasive tools. Real-world studies analyzing patient-derived EV proteome are rare. Here, we characterized a small EV protein content from PB and BM samples in a cohort of 102 monoclonal gammopathies patients routinely followed in the clinic and 223 PB and 111 BM samples were included. We investigated whether EV protein and particle concentration could predict an MM patient prognosis. We found that a high EV protein/particle ratio, or EV cargo >0.6 µg/108 particles, is related to poorer survival and immune dysfunction. These results were supported at the protein level by mass spectrometry. We report a set of PB EV-proteins (PDIA3, C4BPA, BTN1A1, and TNFSF13) with a new biomarker potential for myeloma patient outcomes. The high proteomic similarity between PB and BM matched pairs supports the use of circulating EV as a counterpart of the BM EV proteome. Overall, we found that the EV protein content is related to patient outcomes, such as survival, immune dysfunction, and possibly treatment response.
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Affiliation(s)
- Bruna Velosa Ferreira
- Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal
- NOVA Medical School (NMS), NOVA University Lisbon, Lisbon, Portugal
- Hemato-Oncology Unit, Champalimaud Clinical Centre, Champalimaud Foundation, Lisbon, Portugal
| | - Emilie Arnault Carneiro
- Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal
| | - Carolina Pestana
- Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal
- Centre of Statistics and its Applications, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
| | - Filipa Barahona
- Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal
- NOVA Medical School (NMS), NOVA University Lisbon, Lisbon, Portugal
| | - Joana Caetano
- Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal
- NOVA Medical School (NMS), NOVA University Lisbon, Lisbon, Portugal
- Hemato-Oncology Unit, Champalimaud Clinical Centre, Champalimaud Foundation, Lisbon, Portugal
| | - Raquel Lopes
- Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal
- Faculty of Medicine, University of Lisbon, Lisbon, Portugal
| | - Paulo Lúcio
- Hemato-Oncology Unit, Champalimaud Clinical Centre, Champalimaud Foundation, Lisbon, Portugal
| | - Manuel Neves
- Hemato-Oncology Unit, Champalimaud Clinical Centre, Champalimaud Foundation, Lisbon, Portugal
| | - Hans Christian Beck
- Centre for Clinical Proteomics, Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
| | - Ana Sofia Carvalho
- NOVA Medical School (NMS), Faculdade de Ciências Médicas (FCM), Universidade Nova de Lisboa, Lisboa, Portugal
| | - Rune Matthiesen
- NOVA Medical School (NMS), Faculdade de Ciências Médicas (FCM), Universidade Nova de Lisboa, Lisboa, Portugal
| | - Bruno Costa-Silva
- Systems Oncology Group, Champalimaud Physiology and Cancer Programme, Champalimaud Foundation, Lisbon, Portugal
- *Correspondence: Bruno Costa-Silva, ; Cristina João,
| | - Cristina João
- Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal
- NOVA Medical School (NMS), NOVA University Lisbon, Lisbon, Portugal
- Hemato-Oncology Unit, Champalimaud Clinical Centre, Champalimaud Foundation, Lisbon, Portugal
- *Correspondence: Bruno Costa-Silva, ; Cristina João,
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Amin AH, Sharifi LMA, Kakhharov AJ, Opulencia MJC, Alsaikhan F, Bokov DO, Majdi HS, Jawad MA, Hammid AT, Shalaby MN, Mustafa YF, Siahmansouri H. Role of Acute Myeloid Leukemia (AML)-Derived exosomes in tumor progression and survival. Biomed Pharmacother 2022; 150:113009. [PMID: 35486974 DOI: 10.1016/j.biopha.2022.113009] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/17/2022] [Accepted: 04/19/2022] [Indexed: 02/07/2023] Open
Abstract
Acute myeloid leukemia (AML) is a quickly aggressive hematopoietic disorder that progress due to the accumulation and clonal expansion of immature myeloid cells. Despite the latest developments in AML treatment, repeated relapses and drug resistance remain one of the major challenges in treatment of leukemia. Currently, it is well known that the components of the tumor microenvironment such as cellular and non-cellular elements play a critical function in treatment failures of AML, also they are most common cause of complications including suppression of hematopoiesis. Exosomes are membrane-bound extracellular vesicles (EVs) that transfer signaling molecules and have attracted a large amount of attention due to their important role in inter-cellular communication in health and disease. Exosomes participate in the survival and chemoresistance of many leukemia through transferring their rich cargos of molecules including miRNAs, growth factors, and cytokines. The key producers of exosomes that mainly participate to AML pathogenesis are bone marrow mesenchymal stem cell (BMSCs) and AML cell themselves. These cells release an enormous number of exosomes that affect several target cells such as natural killer (NK) and hematopoietic stem cells to the development of leukemia proliferation and progression. In the present study, a comprehensive review of the literature has been done to briefly discuss the biology of exosomes and highlight the role of exosomes derived from AML in the progress of acute myeloid leukemia.
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Affiliation(s)
- Ali H Amin
- Deanship of Scientific Research, Umm Al-Qura University, Makkah, Saudi Arabia; Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | | | - Alisher Jamoliddinovich Kakhharov
- Department of Oncology and Medical Radiology, Tashkent State Dental Institute, Tashkent, Uzbekistan; Department of Oncology and Medical Radiology, Samarkand State Dental Institute, Samarkand, Uzbekistan.
| | | | - Fahad Alsaikhan
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow 119991, Russian Federation; Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, 2/14 Ustyinsky pr., Moscow 109240, Russian Federation
| | - Hasan Sh Majdi
- Department of Chemical Engineering and Petroleum Industries, Al-Mustaqbal University College, Babylon 51001, Iraq
| | | | - Ali Thaeer Hammid
- Computer Engineering Department, Imam Ja'afar Al-Sadiq University, Baghdad, Iraq
| | - Mohammed Nader Shalaby
- Biological Sciences and Sports Health Department, Faculty of Physical Education, Suez Canal University, Egypt
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Homayoon Siahmansouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Wang G, Ji X, Li P, Wang W. Human bone marrow mesenchymal stem cell-derived exosomes containing microRNA-425 promote migration, invasion and lung metastasis by down-regulating CPEB1. Regen Ther 2022; 20:107-116. [PMID: 35582707 PMCID: PMC9061616 DOI: 10.1016/j.reth.2022.03.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/24/2022] [Accepted: 03/17/2022] [Indexed: 01/23/2023] Open
Abstract
Objective Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) could mediate the malignancy of tumor cells by transmitting targeted cargo. Therein, this study intends to explore the function of BMSC-Exos transmitting microRNA-425 (miR-425)/cytoplasmic polyadenylation binding protein 1 (CPEB1) in lung cancer growth. Methods miR-425 and CPEB1 levels in cancer tissues and cells were measured. BMSCs and their exosomes were collected and identified. After intervention with BMSC-Exos, miR-425 or CPEB1, invasion and migration of A549 and NCI-H1299 cells in vitro, and lung metastasis of A549 cells in vivo were observed. The relationship between miR-425 and CPEB1 was verified. Results miR-425 was highly expressed while CPEB1 was lowly expressed in lung cancer tissues of patients. CPEB1 was the direct target of miR-425. Down-regulating miR-425 or up-regulating CPEB1 decreased cell invasion and migration ability of A549 and NCI-H1299 cells, as well as decreased the number of lung metastasis lesions in vivo. After co-culture with BMSC-Exos, A549 and NCI-H1299 cells showed promoted migration and invasion in vitro and A549 cells demonstrated increased lung metastasis in vivo. Down-regulated miR-425 or up-regulated CPEB1 reversed the promotion of BMSC-Exos on lung cancer cell invasion, migration and lung metastasis. Conclusion BMSC-Exos could deliver miR-425 to inhibit CPEB1 expression in lung cancer cells, thereby promoting the malignant biological properties of lung cancer cells and their metastasis in vivo.
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Affiliation(s)
- Guoqiang Wang
- Department of Oncology, Binzhou Central Hospital, Binzhou, Shandong 251700, PR China
| | - Xiuli Ji
- Department of Respiratory, Jinan Municipal Hospital of Traditional Chinese Medicine, Jinan, Shandong 250012, PR China
| | - Pan Li
- Department of Oncology, Binzhou Central Hospital, Binzhou, Shandong 251700, PR China
| | - Wei Wang
- School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China
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System Xc− inhibition blocks bone marrow-multiple myeloma exosomal crosstalk, thereby countering bortezomib resistance. Cancer Lett 2022; 535:215649. [DOI: 10.1016/j.canlet.2022.215649] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 02/28/2022] [Accepted: 03/15/2022] [Indexed: 12/27/2022]
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Hao Q, Wu Y, Wu Y, Wang P, Vadgama JV. Tumor-Derived Exosomes in Tumor-Induced Immune Suppression. Int J Mol Sci 2022; 23:1461. [PMID: 35163380 PMCID: PMC8836190 DOI: 10.3390/ijms23031461] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/19/2022] [Accepted: 01/25/2022] [Indexed: 02/07/2023] Open
Abstract
Exosomes are a class of small membrane-bound extracellular vesicles released by almost all cell types and present in all body fluids. Based on the studies of exosome content and their interactions with recipient cells, exosomes are now thought to mediate "targeted" information transfer. Tumor-derived exosomes (TEX) carry a cargo of molecules different from that of normal cell-derived exosomes. TEX functions to mediate distinct biological effects such as receptor discharge and intercellular cross-talk. The immune system defenses, which may initially restrict tumor progression, are progressively blunted by the broad array of TEX molecules that activate suppressive pathways in different immune cells. Herein, we provide a review of the latest research progress on TEX in the context of tumor-mediated immune suppression and discuss the potential as well as challenges of TEX as a target of immunotherapy.
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Affiliation(s)
- Qiongyu Hao
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
| | - Yong Wu
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Yanyuan Wu
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Piwen Wang
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
| | - Jaydutt V. Vadgama
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
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Biomimetic 3D Environment Based on Microgels as a Model for the Generation of Drug Resistance in Multiple Myeloma. MATERIALS 2021; 14:ma14237121. [PMID: 34885273 PMCID: PMC8658353 DOI: 10.3390/ma14237121] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/13/2021] [Accepted: 11/15/2021] [Indexed: 12/11/2022]
Abstract
The development of three-dimensional environments to mimic the in vivo cellular response is a problem in the building of disease models. This study aimed to synthesize and validate three-dimensional support for culturing monoclonal plasma cells (mPCs) as a disease model for multiple myeloma. The three-dimensional environment is a biomimetic microgel formed by alginate microspheres and produced on a microfluidic device whose surface has been functionalized by a layer-by-layer process with components of the bone marrow’s extracellular matrix, which will interact with mPC. As a proof of concept, RPMI 8226 cell line cells were cultured in our 3D culture platform. We proved that hyaluronic acid significantly increased cell proliferation and corroborated its role in inducing resistance to dexamethasone. Despite collagen type I having no effect on proliferation, it generated significant resistance to dexamethasone. Additionally, it was evidenced that both biomolecules were unable to induce resistance to bortezomib. These results validate the functionalized microgels as a 3D culture system that emulates the interaction between tumoral cells and the bone marrow extracellular matrix. This 3D environment could be a valuable culture system to test antitumoral drugs efficiency in multiple myeloma.
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Role of Extracellular Vesicle-Based Cell-to-Cell Communication in Multiple Myeloma Progression. Cells 2021; 10:cells10113185. [PMID: 34831408 PMCID: PMC8625088 DOI: 10.3390/cells10113185] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/04/2021] [Accepted: 11/12/2021] [Indexed: 02/07/2023] Open
Abstract
Multiple myeloma (MM) progression closely depends on the bidirectional crosstalk between tumor cells and the surrounding microenvironment, which leads to the creation of a tumor supportive niche. Extracellular vesicles (EVs) have emerged as key players in the pathological interplay between the malignant clone and near/distal bone marrow (BM) cells through their biologically active cargo. Here, we describe the role of EVs derived from MM and BM cells in reprogramming the tumor microenvironment and in fostering bone disease, angiogenesis, immunosuppression, drug resistance, and, ultimately, tumor progression. We also examine the emerging role of EVs as new therapeutic agents for the treatment of MM, and their potential use as clinical biomarkers for early diagnosis, disease classification, and therapy monitoring.
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Allegra A, Di Gioacchino M, Tonacci A, Petrarca C, Musolino C, Gangemi S. Multiple Myeloma Cell-Derived Exosomes: Implications on Tumorigenesis, Diagnosis, Prognosis and Therapeutic Strategies. Cells 2021; 10:2865. [PMID: 34831088 PMCID: PMC8616233 DOI: 10.3390/cells10112865] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 12/16/2022] Open
Abstract
Multiple myeloma (MM) is a hematological disease that is still not curable. The bone marrow milieu, with cellular and non-cellular elements, participate in the creation of a pro-tumoral environment enhancing growth and survival of MM plasma cells. Exosomes are vesicles oscillating in dimension between 50 nm and 100 nm in size that can be released by various cells and contribute to the pathogenesis and progression of MM. Exosomes enclose proteins, cytokines, lipids, microRNAs, long noncoding RNAs, and circular RNAs able to regulate interactions between MM plasma cells and adjacent cells. Through exosomes, mesenchymal stem cells confer chemoresistance to MM cells, while myeloma cells promote angiogenesis, influence immune response, cause bone lesions, and have an impact on the outcome of MM patients. In this review, we analyze the role played by exosomes in the progression of monoclonal gammopathies and the effects on the proliferation of neoplastic plasma cells, and discuss the possible employment of exosomes as potential targets for the treatment of MM patients.
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Affiliation(s)
- Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy;
| | - Mario Di Gioacchino
- Center for Advanced Studies and Technology, G. D’Annunzio University, 66100 Chieti, Italy;
- Institute for Clinical Immunotherapy and Advanced Biological Treatments, 65100 Pescara, Italy
| | - Alessandro Tonacci
- National Research Council of Italy (IFC-CNR), Clinical Physiology Institute, 56124 Pisa, Italy;
| | - Claudia Petrarca
- Center for Advanced Studies and Technology, G. D’Annunzio University, 66100 Chieti, Italy;
- Institute for Clinical Immunotherapy and Advanced Biological Treatments, 65100 Pescara, Italy
- National Research Council of Italy (IFC-CNR), Clinical Physiology Institute, 56124 Pisa, Italy;
- Department of Medicine and Science of Ageing, G. D’Annunzio University, 66100 Chieti, Italy
| | - Caterina Musolino
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy;
| | - Sebastiano Gangemi
- Department of Clinical and Experimental Medicine, Unit and School of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy;
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New insights into exosome mediated tumor-immune escape: Clinical perspectives and therapeutic strategies. Biochim Biophys Acta Rev Cancer 2021; 1876:188624. [PMID: 34487817 DOI: 10.1016/j.bbcan.2021.188624] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 08/30/2021] [Accepted: 09/01/2021] [Indexed: 12/13/2022]
Abstract
Recent advances in extracellular vesicle biology have uncovered a substantial role in maintaining cell homeostasis in health and disease conditions by mediating intercellular communication, thus catching the scientific community's attention worldwide. Extracellular microvesicles, some called exosomes, functionally transfer biomolecules such as proteins and non-coding RNAs from one cell to another, influencing the local environment's biology. Although numerous advancements have been made in treating cancer patients with immune therapy, controlling the disease remains a challenge in the clinic due to tumor-driven interference with the immune response and inability of immune cells to clear cancer cells from the body. The present review article discusses the recent findings and knowledge gaps related to the role of exosomes derived from tumors and the tumor microenvironment cells in tumor escape from immunosurveillance. Further, we highlight examples where exosomal non-coding RNAs influence immune cells' response within the tumor microenvironment and favor tumor growth and progression. Therefore, exosomes can be used as a therapeutic target for the treatment of human cancers.
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