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Weiser T, Hoch CC, Petry J, Shoykhet M, Schmidl B, Yazdi M, Hachani K, Mergner J, Theodoraki MN, Azimzadeh O, Multhoff G, Bashiri Dezfouli A, Wollenberg B. Head and neck squamous cell carcinoma-derived extracellular vesicles mediate Ca²⁺-dependent platelet activation and aggregation through tissue factor. Cell Commun Signal 2025; 23:210. [PMID: 40312345 PMCID: PMC12044835 DOI: 10.1186/s12964-025-02215-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: 02/12/2025] [Accepted: 04/25/2025] [Indexed: 05/03/2025] Open
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy, characterized by poor clinical outcomes, primarily driven by high rate of locoregional recurrence and metastasis. Extensive heterogeneity among the tumor cells as well as modulation of a highly immunosuppressive tumor microenvironment shape cancer progression. Shedding of extracellular vesicles (EVs) derived from tumor cells is a critical mediator of the disease initiating horizontal transfer of tumor components into platelets. This triggers platelet activation and thromboinflammation fueling tumor progression through multiple mechanisms. METHODS HNSCC-derived EVs isolated from HNSCC cell lines (SAS, UD-SCC 5) using size exclusion chromatography and characterized via flow cytometry, electron microscopy, nanoparticle tracking analysis and Western blotting, were used to induce platelet activation and aggregation, measured by aggregometry, flow cytometry, as well as the release of chemokines and Adenosine triphosphate, which were quantified using enzyme-linked immunosorbent assays (ELISA). Mechanistic investigations included inhibitor assays, thrombin activity measurements, and proteomic analyses. RESULTS We could show that EVs do not activate platelets through the FcγRIIa-IgG axis but platelet activation and aggregation is induced in a calcium-dependent manner, primarily mediated by EV-associated tissue factor. Proteomic analysis confirmed the presence of tissue factor in these vesicles, implicating its involvement in initiating the coagulation cascade, that leads to platelet activation and aggregation. This process was characterized by delayed aggregation kinetics and relied on thrombin activation, as the inhibition of thrombin and its receptors reduced platelet aggregation. HNSCC-derived EVs are pivotal in establishing a prothrombotic environment by promoting platelet activation and aggregation through tissue factor-dependent thrombin generation. CONCLUSION These findings indicate a therapeutic potential of targeting EV-mediated pathways as a therapeutic approach to alleviate thrombotic complications in HNSCC patients. Subsequent animal studies will be crucial to validate and extend these observations, providing deeper insight into their clinical implications.
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Affiliation(s)
- Tobias Weiser
- Department of Otolaryngology, Head and Neck Surgery, TUM School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Cosima C Hoch
- Department of Otolaryngology, Head and Neck Surgery, TUM School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Julie Petry
- Department of Otolaryngology, Head and Neck Surgery, TUM School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Maria Shoykhet
- Department of Otolaryngology, Head and Neck Surgery, TUM School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Benedikt Schmidl
- Department of Otolaryngology, Head and Neck Surgery, TUM School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Mina Yazdi
- Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität (LMU), Munich, Germany
| | - Khouloud Hachani
- Department of Otolaryngology, Head and Neck Surgery, TUM School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Julia Mergner
- Bavarian Center for Biomolecular Mass Spectrometry at Klinikum rechts der Isar (BayBioMS@MRI), TUM School of Medicine and Health, Technical University of Munich, Munich, Germany
| | - Marie-Nicole Theodoraki
- Department of Otolaryngology, Head and Neck Surgery, TUM School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Omid Azimzadeh
- Section Radiation Biology, Federal Office for Radiation Protection (BfS), Neuherberg, Germany
| | - Gabriele Multhoff
- Central Institute for Translational Cancer Research, Department of Radiation Oncology, TUM School of Medicine and Health, Technical University of Munich (TranslaTUM), Technical University of Munich, Munich, Germany
| | - Ali Bashiri Dezfouli
- Department of Otolaryngology, Head and Neck Surgery, TUM School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
- Central Institute for Translational Cancer Research, Department of Radiation Oncology, TUM School of Medicine and Health, Technical University of Munich (TranslaTUM), Technical University of Munich, Munich, Germany
| | - Barbara Wollenberg
- Department of Otolaryngology, Head and Neck Surgery, TUM School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany.
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Fu Y, Sun J, Yang C, Li W, Wang Y. Diversified nanocarrier design to optimize glucose oxidase-mediated anti-tumor therapy: Strategy and progress. Int J Biol Macromol 2025; 306:141581. [PMID: 40023419 DOI: 10.1016/j.ijbiomac.2025.141581] [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: 12/20/2024] [Revised: 02/08/2025] [Accepted: 02/26/2025] [Indexed: 03/04/2025]
Abstract
Given the inherent complexity and heterogeneity of tumors, current therapeutic approaches often fall short in meeting prognostic requirements. Starvation therapy (ST) utilizing glucose oxidase (GOx) has emerged as a promising strategy, specifically targeting tumor glucose consumption to disrupt nutrient supply. However, the therapeutic potential of GOx is significantly hampered by its inherent limitations as a protein, particularly its poor stability and short in vivo half-life. In recent years, the development of nanocarriors has provided an effective platform for intravenous and local tumor delivery of GOx. This review systematically examines three key strategies in GOx delivery: stimulus-response, biofilm modification, and local delivery. The progress in various carrier systems for GOx-mediated tumor therapy is comprehensively summarized, providing valuable insights for nanocarrier design. Furthermore, the existing challenges and future directions to advance the development of GOx-based tumor therapies are critically analyzed.
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Affiliation(s)
- Yuhan Fu
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China; Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin, Heilongjiang Province, China
| | - Jialin Sun
- Department of medicine, Heilongjiang Minzu College, Harbin, Heilongjiang Province, China
| | - Chunyu Yang
- Department of Pathology, Harbin 242 Hospital, Harbin, Heilongjiang Province, China
| | - Weinan Li
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China; Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin, Heilongjiang Province, China.
| | - Yanhong Wang
- School of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China; Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin, Heilongjiang Province, China.
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Khayer N, Shabani S, Jalessi M, Joghataei MT, Mahjoubi F. A dynamic co-expression approach reveals Gins2 as a potential upstream modulator of HNSCC metastasis. Sci Rep 2025; 15:3322. [PMID: 39865116 PMCID: PMC11770085 DOI: 10.1038/s41598-024-82668-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 12/09/2024] [Indexed: 01/28/2025] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer that is notably associated with a high risk of lymph node metastasis, a major cause of cancer mortality. Current therapeutic options remain limited to surgery supplemented by radio- or chemotherapy; however, these interventions often result in high-grade toxicities. Distant metastasis significantly contributed to the poor prognosis and decreased survival rates. However, the underlying molecular mechanisms remain poorly understood. Disease-related "omics" data provide a comprehensive overview of gene relationships, helping to decode the complex molecular mechanisms involved. Interactions between biological molecules are complex and highly dynamic across various cellular conditions, making traditional co-expression methods inadequate for understanding these intricate relationships. In the present study, a novel three-way interaction approach was employed to uncover dynamic co-expression relationships underlying the metastatic nature of HNSCC. Subsequently, the biologically relevant triples from statistically significant ones were defined through gene set enrichment analysis and reconstruction of the gene regulatory network. Finally, the validity of biologically relevant triplets was assessed at the protein level. The results highlighted the "PI3K/AKT/mTOR (PAM) signaling pathway" as a disrupted pathway involved in the metastatic nature of HNSCC. Notably, Gins2, identified as a switch gene, along with the gene pair {Akt2, Anxa2}, formed a statistically significant and biologically relevant triplet. It suggests that Gins2 could serve as a potential upstream modulator in the PAM signaling pathway, playing a crucial role in the distant metastasis of HNSCC. In addition, survival analysis of significant switch genes indicated that two genes, C19orf33 and Usp13, may be especially important for prognostic purposes in HNSCC.
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Affiliation(s)
- Nasibeh Khayer
- Skull Base Research Center, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Samira Shabani
- Department of Clinical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Maryam Jalessi
- Skull Base Research Center, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taghi Joghataei
- Cellular and Molecular Research Center , Iran University of Medical Sciences, Tehran, Iran.
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Frouzandeh Mahjoubi
- Department of Clinical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.
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Carney RP, Mizenko RR, Bozkurt BT, Lowe N, Henson T, Arizzi A, Wang A, Tan C, George SC. Harnessing extracellular vesicle heterogeneity for diagnostic and therapeutic applications. NATURE NANOTECHNOLOGY 2025; 20:14-25. [PMID: 39468355 PMCID: PMC11781840 DOI: 10.1038/s41565-024-01774-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 07/11/2024] [Indexed: 10/30/2024]
Abstract
Extracellular vesicles (EVs) are diverse nanoparticles with large heterogeneity in size and molecular composition. Although this heterogeneity provides high diagnostic value for liquid biopsy and confers many exploitable functions for therapeutic applications in cancer detection, wound healing and neurodegenerative and cardiovascular diseases, it has also impeded their clinical translation-hence heterogeneity acts as a double-edged sword. Here we review the impact of subpopulation heterogeneity on EV function and identify key cornerstones for addressing heterogeneity in the context of modern analytical platforms with single-particle resolution. We outline concrete steps towards the identification of key active biomolecules that determine EV mechanisms of action across different EV subtypes. We describe how such knowledge could accelerate EV-based therapies and engineering approaches for mimetic artificial nanovesicle formulations. This approach blunts one edge of the sword, leaving only a single razor-sharp edge on which EV heterogeneity can be exploited for therapeutic applications across many diseases.
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Affiliation(s)
- Randy P Carney
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA.
| | - Rachel R Mizenko
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA
| | - Batuhan T Bozkurt
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA
| | - Neona Lowe
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA
| | - Tanner Henson
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA
- Center for Surgical Bioengineering, Department of Surgery, University of California, Davis, School of Medicine, Sacramento, CA, USA
| | - Alessandra Arizzi
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA
| | - Aijun Wang
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA
- Center for Surgical Bioengineering, Department of Surgery, University of California, Davis, School of Medicine, Sacramento, CA, USA
| | - Cheemeng Tan
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA
| | - Steven C George
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA.
- Center for Surgical Bioengineering, Department of Surgery, University of California, Davis, School of Medicine, Sacramento, CA, USA.
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Zhang Y, Sun X, Guan Y, Sun Y. Exosome-Derived Cargos in Immune Microenvironment in Esophageal Carcinoma: A Mini-Review. Recent Pat Anticancer Drug Discov 2025; 20:137-144. [PMID: 38173209 DOI: 10.2174/0115748928280161231123060159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/09/2023] [Accepted: 11/16/2023] [Indexed: 01/05/2024]
Abstract
Esophageal carcinoma, a lethal malignancy with limited treatment options and poor prognosis, necessitates understanding its underlying mechanisms and identifying novel therapeutic targets. Recent studies have highlighted the critical role of the immune microenvironment in esophageal carcinoma, particularly the interplay between tumor cells and immune cells mediated by exosomes and their cargos. Exosomes, small extracellular vesicles secreted by various cells, including tumor cells, facilitate intercellular communication by transferring bioactive molecules such as proteins, nucleic acids, and lipids to recipient cells. In the context of esophageal carcinoma, tumor-derived exosomes have been shown to play a significant role in shaping the immune microenvironment. In esophageal carcinoma, exosomal cargos have been found to modulate immune cell function and impact tumor progression. These cargos can carry immune inhibitory molecules, such as programmed death-ligand 1 (PD-L1), to suppress T-cell activity and promote immune evasion by tumor cells. Furthermore, exosomal cargos can activate antigen- presenting cells, enhancing their ability to present tumor-specific antigens to T cells and thereby promoting anti-tumor immune responses. Additionally, the cargos of exosomes have been implicated in the induction of immune regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) within the esophageal carcinoma microenvironment. These immunosuppressive effectors inhibit the activity of T cells, contributing to tumor immune evasion and resistance to immune therapies. In summary, exosomes and their cargo play a crucial role in the immune microenvironment of esophageal carcinoma. Understanding the mechanisms by which exosomal cargos regulate immune cell function and tumor progression may reveal novel therapeutic targets for this devastating disease.
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Affiliation(s)
- Yakun Zhang
- Department of Oncology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao Municipal Hospital, Shandong University, Qingdao, Shandong, 266012, China
| | - Xiaoyan Sun
- Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, Shandong, 266012, China
| | - Yan Guan
- Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, 250117, Jinan, PR China
| | - Ying Sun
- Department of Oncology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, Shandong, 266012, China
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6
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Teles RHG, Villarinho NJ, Yamagata AS, Hiroki CT, de Oliveira MC, Terçarioli GR, Jaeger RG, Meybohm P, Burek M, Freitas VM. Valosin-containing protein (VCP), a component of tumor-derived extracellular vesicles, impairs the barrier integrity of brain microvascular endothelial cells. BBA ADVANCES 2024; 7:100130. [PMID: 39802400 PMCID: PMC11722580 DOI: 10.1016/j.bbadva.2024.100130] [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: 10/07/2024] [Revised: 12/06/2024] [Accepted: 12/10/2024] [Indexed: 01/16/2025] Open
Abstract
Metastases are the leading cause of cancer-related deaths, and their origin is not fully elucidated. Recently, studies have shown that extracellular vesicles (EVs), particularly small extracellular vesicles (sEV), can disrupt the homeostasis of organs, promoting the development of a secondary tumor. However, the role of sEV in brain endothelium and their association with metastasis related to breast cancer is unknown. Thus, this study aimed to investigate sEV-triggered changes in the phosphorylation state of proteins on the surface of brain endothelial cells, as they form the first barrier in contact with circulating tumor cells and EVs, and once identified, to modulate its interactors and effects from this through different functional assays. We used the most aggressive breast cancer cell line, MDA-MB-231, and its brain-seeking variant, MDA-MB-231-br. From these cells, small and large extracellular vesicles were harvested to treat hCMEC/D3 cells, an immortalized cell line from the human brain microvasculature. Higher levels of phosphorylation of VEGFR1 and VEGFR2 were found in hCMEC/D3 cells treated with MDA-MB-231-br sEV. By computational analysis, the Valosin-Containing Protein (VCP) was predicted to be an important sEV cargo affecting the VEGFR2 intracellular trafficking, validated by western blotting analysis. Then, VCP was modulated by cell transfection or chemical inhibition in hCMEC/D3 cells and assessed in different functional in vitro assays evidencing a significant effect on the functionality of these cells. Thus, this study demonstrates that the VCP-containing sEVs induce modifications at different phosphor sites of VEGFR2 and effectively modulate the state of brain microvascular endothelial cells.
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Affiliation(s)
- Ramon Handerson Gomes Teles
- University of São Paulo, Department of Cell and Developmental Biology, Institute of Biomedical Sciences (ICB), São Paulo, 05508-000, Brazil
- University Hospital Würzburg, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, 97080 Würzburg, Germany
- University Würzburg, Graduate School of Life Sciences, Campus Hubland Nord, 97074 Würzburg, Germany
| | - Nicolas Jones Villarinho
- University of São Paulo, Department of Cell and Developmental Biology, Institute of Biomedical Sciences (ICB), São Paulo, 05508-000, Brazil
| | - Ana Sayuri Yamagata
- University of São Paulo, Department of Cell and Developmental Biology, Institute of Biomedical Sciences (ICB), São Paulo, 05508-000, Brazil
| | - Camila Tamy Hiroki
- University of São Paulo, Department of Cell and Developmental Biology, Institute of Biomedical Sciences (ICB), São Paulo, 05508-000, Brazil
| | - Murilo Camargo de Oliveira
- University of São Paulo, Department of Cell and Developmental Biology, Institute of Biomedical Sciences (ICB), São Paulo, 05508-000, Brazil
| | - Gisela Ramos Terçarioli
- University of São Paulo, Department of Cell and Developmental Biology, Institute of Biomedical Sciences (ICB), São Paulo, 05508-000, Brazil
| | - Ruy Gastaldoni Jaeger
- University of São Paulo, Department of Cell and Developmental Biology, Institute of Biomedical Sciences (ICB), São Paulo, 05508-000, Brazil
| | - Patrick Meybohm
- University Hospital Würzburg, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, 97080 Würzburg, Germany
| | - Malgorzata Burek
- University Hospital Würzburg, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, 97080 Würzburg, Germany
| | - Vanessa Morais Freitas
- University of São Paulo, Department of Cell and Developmental Biology, Institute of Biomedical Sciences (ICB), São Paulo, 05508-000, Brazil
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Wang Q, Pang B, Bucci J, Jiang J, Li Y. The emerging role of extracellular vesicles and particles in prostate cancer diagnosis, and risk stratification. Biochim Biophys Acta Rev Cancer 2024; 1879:189210. [PMID: 39510450 DOI: 10.1016/j.bbcan.2024.189210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 10/29/2024] [Accepted: 10/31/2024] [Indexed: 11/15/2024]
Abstract
Current approaches for prostate cancer (PCa) diagnosis and risk stratification require greater accuracy. Extracellular vesicles and particles (EVPs) containing diverse cargos from parent cells are released into the extracellular microenvironment and play a critical role in intercellular communication. Accumulating evidence demonstrates that EVPs are emerging as a promising focus for the exploration of cancer biomarkers and therapeutic targets. However, the precise categorisation and nomenclature of EVP subpopulations remains challenging due to their compositional complexity, inherent heterogeneity in molecular composition, and structure. The recent identification of two novel non-vesicular extracellular particle subtypes, exomeres and supermeres, has altered our understanding of the distinct subpopulations of EVPs and their roles in biological and physiological processes. Here, we discuss recent advances in the field of EVPs, describe characteristics of EVP subpopulations, focus on the application and potential of EVPs in PCa diagnosis and risk stratification by liquid biopsy, and highlight the major challenges and prospects of EVP research in PCa area.
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Affiliation(s)
- Qi Wang
- St. George and Sutherland Clinical Campuses, School of Clinical Medicine, UNSW Sydney, Kensington, NSW 2052, Australia; Cancer Care Centre, St. George Hospital, Kogarah, NSW 2217, Australia
| | - Bairen Pang
- Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China; Ningbo Clinical Research Centre for Urological Disease, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China; Translational Research Laboratory for Urology, The Key Laboratory of Ningbo, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China; Zhejiang Engineering Research Centre of Innovative Technologies and Diagnostic and Therapeutic Equipment for Urinary System Diseases, Ningbo, Zhejiang 315010, China
| | - Joseph Bucci
- St. George and Sutherland Clinical Campuses, School of Clinical Medicine, UNSW Sydney, Kensington, NSW 2052, Australia; Cancer Care Centre, St. George Hospital, Kogarah, NSW 2217, Australia
| | - Junhui Jiang
- Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China; Ningbo Clinical Research Centre for Urological Disease, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China; Translational Research Laboratory for Urology, The Key Laboratory of Ningbo, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China; Zhejiang Engineering Research Centre of Innovative Technologies and Diagnostic and Therapeutic Equipment for Urinary System Diseases, Ningbo, Zhejiang 315010, China.
| | - Yong Li
- St. George and Sutherland Clinical Campuses, School of Clinical Medicine, UNSW Sydney, Kensington, NSW 2052, Australia; Cancer Care Centre, St. George Hospital, Kogarah, NSW 2217, Australia.
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8
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Sun S, Shao Y, Gu W. The roles of exosomes in esophageal cancer. Discov Oncol 2024; 15:371. [PMID: 39190048 DOI: 10.1007/s12672-024-01259-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 08/21/2024] [Indexed: 08/28/2024] Open
Abstract
The incidence and mortality rate of esophageal cancer (EC) are higher worldwide. Exosomes are nanoscale vesicles derived from various types of cells, exhibiting a stable presence in bodily fluids, and contain a plethora of bioactive components including proteins, DNA, and RNA. Exosomes can mediate cell-to-cell communication and signaling. Numerous studies conducted both domestically and internationally have indicated the significant involvement of exosomes in tumor development and their potential as novel diagnostic and prognostic biomarkers for liquid biopsy. This review seeks to consolidate the role of exosomes and bioactive substances in the progression of EC and elaborate on the opportunities and challenges associated with the clinical application of exosomes in EC.
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Affiliation(s)
- Shihong Sun
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, China
| | - Yingjie Shao
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, China.
| | - Wendong Gu
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, China.
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9
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Huang M, Li S, Zeng H, Zhu Y, Zhang F, Cai J. Exosomal miR-196a-5p contributes to esophageal squamous cell carcinoma malignant progression by inhibiting ITM2B. Pathol Int 2024; 74:464-474. [PMID: 38940569 DOI: 10.1111/pin.13459] [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: 12/21/2023] [Revised: 05/13/2024] [Accepted: 06/02/2024] [Indexed: 06/29/2024]
Abstract
Exosomes from cancer cells function as carriers to spread or transport specific microRNAs (miRNAs) to distant sites to exert their effects, but the mechanism of exosomal miRNA action in esophageal squamous cell carcinoma (ESCC) has not been fully explained. Therefore, in this study, we were interested in the impact of exosomal miR-196a-5p in ESCC progression. We found that miR-196a-5p was expressed enriched in clinical tissues, ESCC cells, and exosomes. Functionally, depletion of miR-196a-5p impeded ESCC cell growth, migration, and invasion, whereas overexpression of miR-196a-5p produced the opposite results. Moreover, enhancement of exosomal miR-196a-5p in recipient ESCC cells triggered more intense proliferation and migration. Mechanistically, we identified integral membrane protein 2B (ITM2B) as a direct target of miR-196a-5p. Silencing of ITM2B partially counteracted the inhibitory effect of miR-196a-5p inhibitors on the malignant phenotype of ESCC. Furthermore, in vivo, lower miR-196a-5p levels triggered by the introduction of antagomiR-196a-5p resulted in the generation of smaller volume and weight xenograft tumors. Thus, our results demonstrated novel mechanisms of exosomal and intracellular miR-196a-5p-mediated ESCC growth and migration and identify the interaction of miR-196a-5p with ITM2B. These works might provide new targets and basis for the development of clinical treatment options for ESCC.
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Affiliation(s)
- Min Huang
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
| | - Shuang Li
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
| | - Hai Zeng
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
| | - Yan Zhu
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
| | - Fan Zhang
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
| | - Jun Cai
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
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Bano A, Yadav P, Sharma M, Verma D, Vats R, Chaudhry D, Kumar P, Bhardwaj R. Extraction and characterization of exosomes from the exhaled breath condensate and sputum of lung cancer patients and vulnerable tobacco consumers-potential noninvasive diagnostic biomarker source. J Breath Res 2024; 18:046003. [PMID: 38988301 DOI: 10.1088/1752-7163/ad5eae] [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: 02/29/2024] [Accepted: 07/03/2024] [Indexed: 07/12/2024]
Abstract
Noninvasive sample sources of exosomes, such as exhaled breath and sputum, which are in close proximity to the tumor microenvironment and may contain biomarkers indicative of lung cancer, are far more permissive than invasive sample sources for biomarker screening. Standardized exosome extraction and characterization approaches for low-volume noninvasive samples are critically needed. We isolated and characterized exhaled breath condensate (EBC) and sputum exosomes from healthy nonsmokers (n= 30), tobacco smokers (n= 30), and lung cancer patients (n= 40) and correlated the findings with invasive sample sources. EBC samples were collected by using commercially available R-Tubes. To collect sputum samples the participants were directed to take deep breaths, hold their breath, and cough in a collection container. Dynamic light scattering, nanoparticle tracking analysis, and transmission electron microscopy were used to evaluate the exosome morphology. Protein isolation, western blotting, exosome quantification via EXOCET, and Fourier transform infrared spectroscopy were performed for molecular characterization. Exosomes were successfully isolated from EBC and sputum samples, and their yields were adequate and sufficiently pure for subsequent downstream processing and characterization. The exosomes were confirmed based on their size, shape, and surface marker expression. Remarkably, cancer exosomes were the largest in size not only in the plasma subgroups, but also in the EBC (p < 0.05) and sputum (p= 0.0036) subgroups, according to our findings. A significant difference in exosome concentrations were observed between the control sub-groups (p < 0.05). Our research confirmed that exosomes can be extracted from noninvasive sources, such as EBC and sputum, to investigate lung cancer diagnostic biomarkers for research, clinical, and early detection in smokers.
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Affiliation(s)
- Afsareen Bano
- Centre for Medical Biotechnology, Maharshi Dayanand University, Rohtak, Haryana 124001, India
| | - Pooja Yadav
- Centre for Medical Biotechnology, Maharshi Dayanand University, Rohtak, Haryana 124001, India
| | - Megha Sharma
- Centre for Medical Biotechnology, Maharshi Dayanand University, Rohtak, Haryana 124001, India
| | - Deepika Verma
- Department of Biochemistry, All India Institute of Medical Sciences, Delhi 110029, India
| | - Ravina Vats
- Centre for Medical Biotechnology, Maharshi Dayanand University, Rohtak, Haryana 124001, India
| | - Dhruva Chaudhry
- Department of Pulmonary & Critical Care Medicine, Pt. B. D. Sharma PGIMS, Rohtak, Haryana 124001, India
| | - Pawan Kumar
- Department of Pulmonary & Critical Care Medicine, Pt. B. D. Sharma PGIMS, Rohtak, Haryana 124001, India
| | - Rashmi Bhardwaj
- Centre for Medical Biotechnology, Maharshi Dayanand University, Rohtak, Haryana 124001, India
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11
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Maiyulan A, Matsumoto Y, Wang H, Murakami K, Toyozumi T, Otsuka R, Shiraishi T, Kinoshita K, Hu J, Iida S, Morishita H, Makiyama T, Nishioka Y, Kano M, Matsubara H. Hypoxia‑regulated exosomal miR‑185 inhibits esophageal squamous cell carcinoma progression and predicts prognosis. Oncol Lett 2024; 28:334. [PMID: 38827568 PMCID: PMC11140231 DOI: 10.3892/ol.2024.14467] [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: 01/18/2024] [Accepted: 04/18/2024] [Indexed: 06/04/2024] Open
Abstract
Despite advances in treatment and diagnosis, the prognosis of patients with esophageal squamous cell carcinoma (ESCC) remains poor. MicroRNAs (miRNAs/miRs) are associated with prognosis in esophageal cancer, indicating that they may help guide treatment decisions. The aim of the present study was to explore exosomal miR-185 as a candidate prognostic biomarker and therapeutic target in ESCC, to investigate its biological function and clinical significance, and to ascertain the applicability of circulating exosomal miR-185 for the development of targeted drugs for ESCC treatment. A GeneChip miRNA array was used to compare exosomal miRNA expression in ESCC cell lines under hypoxia with those under normoxia. Exosomal miR-185 expression was then confirmed by reverse transcription-quantitative PCR. Patient background and prognosis were compared between high and low miR-185 expression groups. Functional analyses were performed to evaluate the antitumor effects of miR-185 in ESCC cells. Global Gene Set Enrichment Analysis of The Cancer Genome Atlas data was also performed, and differentially expressed exosomal miRNAs under hypoxia were identified compared to those under normoxia. Hypoxia markedly decreased the expression of exosomal miR-185 in KYSE-960 and T.Tn cell culture media. Overexpression of miR-185 suppressed the migration, invasion and colony-forming abilities of ESCC lines, and also suppressed cell cycle progression and promoted apoptosis after cisplatin treatment. Notably, high miR-185 expression was associated with signaling pathways related to cell death, DNA damage and p53. Furthermore, circulating exosomal miR-185 levels were associated with cN and cStage, and could predict progression-free survival and disease-specific survival of patients with ESCC after initial treatment. In conclusion, miR-185 holds potential as a prognostic biomarker and therapeutic target in ESCC.
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Affiliation(s)
- Abula Maiyulan
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Yasunori Matsumoto
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Huan Wang
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Kentaro Murakami
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Takeshi Toyozumi
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Ryota Otsuka
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tadashi Shiraishi
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Kazuya Kinoshita
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Jie Hu
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Shinichiro Iida
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Hiroki Morishita
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tenshi Makiyama
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Yuri Nishioka
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Masayuki Kano
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
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12
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Christodoulidis G, Koumarelas KE, Kouliou MN. Pivotal role of exosomes in diagnosis and treatment of esophageal cancer in a new era of precision medicine. World J Methodol 2024; 14:90624. [PMID: 38577205 PMCID: PMC10989412 DOI: 10.5662/wjm.v14.i1.90624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 12/23/2023] [Accepted: 01/17/2024] [Indexed: 03/07/2024] Open
Abstract
In this editorial we comment on the article published by Ning et al, "Role of exosomes in metastasis and therapeutic resistance in esophageal cancer". Esophageal cancer (EC) represents a significant global health concern, being the seventh most common and sixth in terms of mortality worldwide. Despite the advances in therapeutic modalities, the management of patients with EC remains challenging, with a 5-year survival rate of only 25% and a limited eligibility for curative surgery due to its late diagnosis. Conventional screening methods are impractical for the early detection of EC, given their either invasive or insensitive nature. The advent of liquid biopsy, with a focus on circulating tumor cells, circulating tumor DNA, and exosomes, heralds a non-invasive avenue for cancer detection. Exosomes, small vesicles involved in intercellular communication, are highlighted as potential biomarkers for EC diagnosis and prognosis. Along with a diverse cargo encompassing various types of RNA, DNA molecules, proteins, and metabolites, exosomes emerge as key players in tumorigenesis, tumor development, and metastasis. Their significance extends to carrying distinctive biomarkers, including microRNAs (miRNAs), long non-coding RNAs, and circular RNAs, underscoring their potential diagnostic and prognostic value. Furthermore, exosomes may be utilized for therapeutic purposes in the context of EC treatment, serving as efficient delivery vehicles for therapeutic agents such as chemotherapeutic medicines and miRNAs. In this editorial we delve into the applications of exosomes for the early detection and treatment of EC, as well as the future perspectives.
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Boddu VK, Zamzow P, Kramer MW, Merseburger AS, Gorantla SP, Klinger M, Cramer L, Sauer T, Gemoll T, von Bubnoff N, Gieseler F, Darabi M. Targeting cancer-derived extracellular vesicles by combining CD147 inhibition with tissue factor pathway inhibitor for the management of urothelial cancer cells. Cell Commun Signal 2024; 22:129. [PMID: 38360687 PMCID: PMC10870545 DOI: 10.1186/s12964-024-01508-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: 08/28/2023] [Accepted: 01/31/2024] [Indexed: 02/17/2024] Open
Abstract
BACKGROUND Extracellular vesicles (EVs), including microvesicles, hold promise for the management of bladder urothelial carcinoma (BLCA), particularly because of their utility in identifying therapeutic targets and their diagnostic potential using easily accessible urine samples. Among the transmembrane glycoproteins highly enriched in cancer-derived EVs, tissue factor (TF) and CD147 have been implicated in promoting tumor progression. In this in vitro study, we explored a novel approach to impede cancer cell migration and metastasis by simultaneously targeting these molecules on urothelial cancer-derived EVs. METHODS Cell culture supernatants from invasive and non-invasive bladder cancer cell lines and urine samples from patients with BLCA were collected. Large, microvesicle-like EVs were isolated using sequential centrifugation and characterized by electron microscopy, nanoparticle tracking analysis, and flow cytometry. The impact of urinary or cell supernatant-derived EVs on cellular phenotypes was evaluated using cell-based assays following combined treatment with a specific CD147 inhibitor alone or in combination with a tissue factor pathway inhibitor (TFPI), an endogenous anticoagulant protein that can be released by low-molecular-weight heparins. RESULTS We observed that EVs obtained from the urine samples of patients with muscle-invasive BLCA and from the aggressive bladder cancer cell line J82 exhibited higher TF activity and CD147 expression levels than did their non-invasive counterparts. The shedding of GFP-tagged CD147 into isolated vesicles demonstrated that the vesicles originated from plasma cell membranes. EVs originating from invasive cancer cells were found to trigger migration, secretion of matrix metalloproteinases (MMPs), and invasion. The same induction of MMP activity was replicated using EVs obtained from urine samples of patients with invasive BLCA. EVs derived from cancer cell clones overexpressing TF and CD147 were produced in higher quantities and exhibited a higher invasive potential than those from control cancer cells. TFPI interfered with the effect when used in conjunction with the CD147 inhibitor, further suppressing homotypic EV-induced migration, MMP production, and invasion. CONCLUSIONS Our findings suggest that combining a CD147 inhibitor with low molecular weight heparins to induce TFPI release may be a promising therapeutic approach for urothelial cancer management. This combination can potentially suppress the tumor-promoting actions of cancer-derived microvesicle-like EVs, including collective matrix invasion.
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Affiliation(s)
- Vijay Kumar Boddu
- Department of Hematology and Oncology, Section for Experimental Oncology, University Hospital Schleswig-Holstein, Lübeck, Germany
| | - Piet Zamzow
- Department of Hematology and Oncology, Section for Experimental Oncology, University Hospital Schleswig-Holstein, Lübeck, Germany
| | | | - Axel S Merseburger
- Department of Urology, University Hospital Schleswig-Holstein, Lübeck, Germany
| | | | | | - Lena Cramer
- Department of Hematology and Oncology, Section for Experimental Oncology, University Hospital Schleswig-Holstein, Lübeck, Germany
| | - Thorben Sauer
- Department of Surgery, Section for Translational Surgical Oncology and Biobanking, University Hospital Schleswig-Holstein, Lübeck, Germany
| | - Timo Gemoll
- Department of Surgery, Section for Translational Surgical Oncology and Biobanking, University Hospital Schleswig-Holstein, Lübeck, Germany
| | - Nikolas von Bubnoff
- Department of Urology, University Hospital Schleswig-Holstein, Lübeck, Germany
- University Cancer Center Schleswig-Holstein (UCCSH), Lübeck, Germany
| | - Frank Gieseler
- Department of Hematology and Oncology, Section for Experimental Oncology, University Hospital Schleswig-Holstein, Lübeck, Germany
- University Cancer Center Schleswig-Holstein (UCCSH), Lübeck, Germany
| | - Masoud Darabi
- Department of Hematology and Oncology, Section for Experimental Oncology, University Hospital Schleswig-Holstein, Lübeck, Germany.
- University Cancer Center Schleswig-Holstein (UCCSH), Lübeck, Germany.
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14
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Gan X, Wang F, Luo J, Zhao Y, Wang Y, Yu C, Chen J. Proteolysis Targeting Chimeras (PROTACs) based on celastrol induce multiple protein degradation for triple-negative breast cancer treatment. Eur J Pharm Sci 2024; 192:106624. [PMID: 37898394 DOI: 10.1016/j.ejps.2023.106624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 10/23/2023] [Accepted: 10/25/2023] [Indexed: 10/30/2023]
Abstract
The pursuit of single drugs targeting multiple targets has become a prominent trend in modern cancer therapeutics. Natural products, known for their multi-targeting capabilities, accessibility, and cost-effectiveness, hold great potential for the development of multi-target drugs. However, their therapeutic efficacy is often hindered by complex structural modifications and limited anti-tumor activity. In this study, we present a novel approach using celastrol (CST)-based Proteolysis Targeting Chimeras (PROTACs) for breast cancer therapy. Through rational design, we have successfully developed compound 6a, a potent multiple protein degrader capable of selectively degrading GRP94 and CDK1/4 in tumor cells via the endogenous ubiquitin-proteasome system. Furthermore, compound 6a has demonstrated remarkable inhibitory effects on cell proliferation and migration, and induction of apoptosis in 4T1 cells through cell cycle arrest and activation of the Bcl-2/Bax/cleaved Caspase-3 apoptotic pathway. In vivo administration of compound 6a has effectively suppressed tumor growth with an acceptable safety profile. Our findings suggest that the CST-based PROTACs described herein can be readily extended to other natural products, offering a potential avenue for the development of natural product-based PROTACs for cancer treatment.
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Affiliation(s)
- Xuelan Gan
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy, Chongqing Medical University, No.1 Yixueyuan Road, Chongqing 400016, China
| | - Fan Wang
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy, Chongqing Medical University, No.1 Yixueyuan Road, Chongqing 400016, China
| | - Jianguo Luo
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy, Chongqing Medical University, No.1 Yixueyuan Road, Chongqing 400016, China
| | - Yunfei Zhao
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy, Chongqing Medical University, No.1 Yixueyuan Road, Chongqing 400016, China
| | - Yan Wang
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy, Chongqing Medical University, No.1 Yixueyuan Road, Chongqing 400016, China
| | - Chao Yu
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy, Chongqing Medical University, No.1 Yixueyuan Road, Chongqing 400016, China.
| | - Jun Chen
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy, Chongqing Medical University, No.1 Yixueyuan Road, Chongqing 400016, China.
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Co EL, Hameed M, Sebastian SA, Garg T, Sudan S, Bheemisetty N, Mohan B. Narrative Review of Probiotic Use on the Recovery of Postoperative Patients with Esophageal Cancer. Curr Nutr Rep 2023; 12:635-642. [PMID: 37605086 DOI: 10.1007/s13668-023-00490-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2023] [Indexed: 08/23/2023]
Abstract
PURPOSE OF REVIEW This narrative review discusses the significance of probiotic therapy in the postoperative care of patients with esophageal cancer and its role as an adjunct therapy to other treatment modalities for esophageal cancer. RECENT FINDINGS As such, there is an emerging need to address any malnutrition and gastrointestinal problems occurring in these patients which tend to have a strong negative impact on their prognosis. Probiotic effects on esophageal cancer biomarkers suggest that there is a positive correlation between these two factors. However, the beneficial effects remain controversial and warrant further investigation. Probiotics, now being widely utilized as postoperative therapy in some carcinomas of the gastrointestinal tract such as gastric cancer and colorectal cancer, have been shown in some clinical studies to positively impact the nutritional status of patients with esophageal cancer. Postoperative care among patients suffering from esophageal cancer is a very crucial aspect in the survival of these patients.
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Affiliation(s)
- Edzel Lorraine Co
- University of Santo Tomas Faculty of Medicine and Surgery, Manila, Philippines
| | - Maha Hameed
- Department of Internal Medicine, Florida State University/Sarasota Memorial Hospital, 1700 S Tamiami Trial, Sarasota, FL, 34239, USA.
| | | | - Tulika Garg
- Government Medical College and Hospital, Chandigarh, India
| | | | | | - Babu Mohan
- Department of Gastroenterology, University of Utah School of Medicine, Salt Lake City, UT, USA
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16
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Pooresmaeil F, Andi S, Hasannejad-Asl B, Takamoli S, Bolhassani A. Engineered exosomes: a promising vehicle in cancer therapy. Ther Deliv 2023; 14:775-794. [PMID: 38116620 DOI: 10.4155/tde-2023-0131] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2023] Open
Abstract
During the past few decades, researchers have attempted to discover an effective treatment for cancer. Exosomes are natural nanovesicles released by various cells and play a role in communication between cells. While natural exosomes have high clinical potential, their inherent limitations have prompted researchers to design exosomes with improved therapeutic properties. To achieve this purpose, researchers have undertaken exosome engineering to modify the surface properties or internal composition of exosomes. After these modifications, engineered exosomes can be used as carriers for delivery of chemotherapeutic agents, targeted drug delivery or development of cancer vaccines. The present study provides an overview of exosomes, including their biogenesis, biological functions, isolation techniques, engineering methods, and potential applications in cancer therapy.
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Affiliation(s)
- Farkhondeh Pooresmaeil
- Department of Hepatitis & AIDS, Pasteur Institute of Iran, Tehran, 1316943551, Iran
- Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Science, Tehran, Iran
| | - Sahar Andi
- Department of Molecular Medicine, School of Medicine, Qazvin University of Medical Science, Qazvin, Iran
| | - Behnam Hasannejad-Asl
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti, University of Medical Sciences, Tehran, Iran
| | - Shahla Takamoli
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
| | - Azam Bolhassani
- Department of Hepatitis & AIDS, Pasteur Institute of Iran, Tehran, 1316943551, Iran
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17
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Qiao X, Cheng Z, Xue K, Xiong C, Zheng Z, Jin X, Li J. Tumor-associated macrophage-derived exosomes LINC01592 induce the immune escape of esophageal cancer by decreasing MHC-I surface expression. J Exp Clin Cancer Res 2023; 42:289. [PMID: 37915049 PMCID: PMC10621170 DOI: 10.1186/s13046-023-02871-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 10/21/2023] [Indexed: 11/03/2023] Open
Abstract
BACKGROUND TAMs (tumor-associated macrophages) infiltration promotes the progression of esophageal cancer (EC). However, the underlying mechanisms remain unclear. METHODS Abnormal expression of LINC01592 from EC microarrays of the TCGA database was analyzed. LINC01592 expression level was validated in both EC cell lines and tissues. Stable LINC01592 knockdown and overexpression of EC cell lines were established. In vitro and in vivo trials were conducted to test the impact of LINC01592 knockdown and overexpression on EC cells. RNA binding protein immunoprecipitation (RIP), RNA pulldown assays, and Immunofluorescence (IF) were used to verify the combination of E2F6 and LINC01592. The combination of E2F6 and NBR1 was verified through the utilization of ChIP and dual luciferase reporter assays. RESULTS LINC01592 is carried and transferred by exosomes secreted by M2-TAMs to tumor cells. The molecular mechanism underlying the promotion of NBR1 transcription involves the direct binding of LINC01592 to E2F6, which facilitates the nuclear entry of E2F6. The collaborative action of LINC01592 and E2F6 results in improved NBR1 transcription. The elevation of NBR1 binding to the ubiquitinated protein MHC-I via the ubiquitin domain caused a higher degradation of MHC-I in autophagolysosomes and a reduction in MHC-I expression on the exterior of cancerous cell. Consequently, this caused cancerous cells to escape from CD8+ CTL immune attack. The tumor-promoting impacts of LINC01592, as well as the growth of M2-type macrophage-driven tumors, were significantly suppressed by the interruption of E2F6/NBR1/MHC-I signaling through the effect of siRNA or the corresponding antibody blockade. Significantly, the suppression of LINC01592 resulted in an upregulation of MHC-I expression on the tumor cell membrane, thereby enhancing the efficacy of CD8+ T cell reinfusion therapy. CONCLUSIONS The investigation conducted has revealed a significant molecular interaction between TAMs and EC via the LINC01592/E2F6/NBR1/MHC-I axis, which facilitates the progression of malignant tumors. This suggests that a therapeutic intervention targeting this axis may hold promise for the treatment of the disease.
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Affiliation(s)
- Xinwei Qiao
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China
| | - Zaixing Cheng
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China
| | - Kaming Xue
- Department of Traditional Chinese Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China
| | - Cui Xiong
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China
| | - Zhikun Zheng
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China
| | - Xin Jin
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Jinsong Li
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China.
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18
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Zhang S, Zhong J, Guo D, Zhang S, Huang G, Chen Y, Xu C, Chen W, Zhang Q, Zhao C, Liu S, Luo Z, Lin C. MIAT shuttled by tumor-secreted exosomes promotes paclitaxel resistance in esophageal cancer cells by activating the TAF1/SREBF1 axis. J Biochem Mol Toxicol 2023; 37:e23380. [PMID: 37132394 DOI: 10.1002/jbt.23380] [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: 09/26/2021] [Revised: 02/23/2023] [Accepted: 04/14/2023] [Indexed: 05/04/2023]
Abstract
Chemoresistance remains a major obstacle to the treatment of esophageal cancer (EC). Exosome-mediated transfer of long noncoding RNAs (lncRNAs) has recently been unveiled to correlate with the regulation of drug resistance in EC. This study aimed to investigate the physiological mechanisms by which exosome-encapsulated lncRNA myocardial infarction-associated transcript (MIAT) derived from tumor cells might mediate the paclitaxel (PTX) resistance of EC cells. First, MIAT was experimentally determined to be upregulated in PTX nonresponders and PTX-resistant EC cells. Silencing of MIAT in PTX-resistant EC cells decreased cell viability and enhanced apoptosis, corresponding to a reduced half-maximal inhibitory concentration (IC50 ) value. Next, exosomes were isolated from EC109 and EC109/T cells, and EC109 cells were cocultured with EC109/T-cell-derived exosomes. Accordingly, MIAT was revealed to be transmitted through exosomes from EC109/T cells to EC109 cells. Tumor-derived exosomes carrying MIAT increased the IC50 value of PTX and suppressed apoptosis in EC109 cells to promote PTX resistance. Furthermore, MIAT promoted the enrichment of TATA-box binding protein-associated Factor 1 (TAF1) in the promoter region of sterol regulatory element binding transcription factor 1 (SREBF1), as shown by a chromatin immunoprecipitation assay. This might be the mechanism by which MIAT could promote PTX resistance. Finally, in vivo experiments further confirmed that the knockdown of MIAT attenuated the resistance of EC cells to PTX. Collectively, these results indicate that tumor-derived exosome-loaded MIAT activates the TAF1/SREBF1 axis to induce PTX resistance in EC cells, providing a potential therapeutic target for overcoming PTX resistance in EC.
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Affiliation(s)
- Shuyao Zhang
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Guangzhou, P. R. China
- Department of Pharmacology, Shantou University Medical College, Shantou, P. R. China
| | - Junyong Zhong
- Department of Oncology, Longgang District Central Hospital of Shenzhen, Shenzhen, P. R. China
| | - Dainian Guo
- Good Clinical Practice, Cancer Hospital of Shantou University Medical College, Shantou, P. R. China
| | - Shengqi Zhang
- Dafeng Hospital of Chaoyang District in Shantou City, Shantou, P. R. China
- Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou, P. R. China
| | - Guifeng Huang
- Dafeng Hospital of Chaoyang District in Shantou City, Shantou, P. R. China
| | - Yun Chen
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Guangzhou, P. R. China
| | - Chengcheng Xu
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Guangzhou, P. R. China
- Department of Pharmacology, Shantou University Medical College, Shantou, P. R. China
| | - Wang Chen
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Guangzhou, P. R. China
| | - Qiuzhen Zhang
- Department of Pharmacology, Shantou University Medical College, Shantou, P. R. China
| | - Chengkuan Zhao
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Guangzhou, P. R. China
- Department of Pharmacology, Shantou University Medical College, Shantou, P. R. China
| | - Sulin Liu
- The First Affiliated Hospital of Shantou University Medical College, Shantou, P. R. China
| | - Zebin Luo
- Dafeng Hospital of Chaoyang District in Shantou City, Shantou, P. R. China
| | - Chaoxian Lin
- The First Affiliated Hospital of Shantou University Medical College, Shantou, P. R. China
- Shantou Chaonan Minsheng Hospital, Shantou, P. R. China
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19
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Si MY, Rao DY, Xia Y, Sang CP, Mao KY, Liu XJ, Zhang ZX, Tang ZX. Role of exosomal noncoding RNA in esophageal carcinoma. Front Oncol 2023; 13:1126890. [PMID: 37234976 PMCID: PMC10206631 DOI: 10.3389/fonc.2023.1126890] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 03/31/2023] [Indexed: 05/28/2023] Open
Abstract
Esophageal cancer is a common malignant tumor with a high degree of malignancy. Understanding its pathogenesis and identifying early diagnostic biomarkers can significantly improve the prognosis of esophageal cancer patients. Exosomes are small double-membrane vesicles found in various body fluids containing various components (DNA, RNA, and proteins) that mediate intercellular signal communication. Non-coding RNAs are a class of gene transcription products that encode polypeptide functions and are widely detected in exosomes. There is growing evidence that exosomal non-coding RNAs are involved in cancer growth, metastasis and angiogenesis, and can also be used as diagnostic and prognostic markers. This article reviews the recent progress in exosomal non-coding RNAs in esophageal cancer, including research progress, diagnostic value, proliferation, migration, invasion, and drug resistance, provide new ideas for the precise treatment of esophageal cancer.
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Affiliation(s)
- Mao-Yan Si
- First Clinical Medical College, Gannan Medical University, Ganzhou, China
| | - Ding-Yu Rao
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yao Xia
- First Clinical Medical College, Gannan Medical University, Ganzhou, China
| | - Cheng-Peng Sang
- Department of Cardiothoracic Surgery, The Affiliated Huaian Hospital of Xuzhou Medical University, Huai’an, Jiangsu, China
| | - Kai-Yun Mao
- First Clinical Medical College, Gannan Medical University, Ganzhou, China
| | - Xiang-Jin Liu
- First Clinical Medical College, Gannan Medical University, Ganzhou, China
| | - Zu-Xiong Zhang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Zhi-Xian Tang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
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Sariano PA, Mizenko RR, Shirure VS, Brandt AK, Nguyen BB, Nesiri C, Shergill BS, Brostoff T, Rocke DM, Borowsky AD, Carney RP, George SC. Convection and extracellular matrix binding control interstitial transport of extracellular vesicles. J Extracell Vesicles 2023; 12:e12323. [PMID: 37073802 PMCID: PMC10114097 DOI: 10.1002/jev2.12323] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 03/06/2023] [Accepted: 03/29/2023] [Indexed: 04/20/2023] Open
Abstract
Extracellular vesicles (EVs) influence a host of normal and pathophysiological processes in vivo. Compared to soluble mediators, EVs can traffic a wide range of proteins on their surface including extracellular matrix (ECM) binding proteins, and their large size (∼30-150 nm) limits diffusion. We isolated EVs from the MCF10 series-a model human cell line of breast cancer progression-and demonstrated increasing presence of laminin-binding integrins α3β1 and α6β1 on the EVs as the malignant potential of the MCF10 cells increased. Transport of the EVs within a microfluidic device under controlled physiological interstitial flow (0.15-0.75 μm/s) demonstrated that convection was the dominant mechanism of transport. Binding of the EVs to the ECM enhanced the spatial concentration and gradient, which was mitigated by blocking integrins α3β1 and α6β1. Our studies demonstrate that convection and ECM binding are the dominant mechanisms controlling EV interstitial transport and should be leveraged in nanotherapeutic design.
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Affiliation(s)
- Peter A. Sariano
- Department of Biomedical EngineeringUniversity of CaliforniaDavisCaliforniaUSA
| | - Rachel R. Mizenko
- Department of Biomedical EngineeringUniversity of CaliforniaDavisCaliforniaUSA
| | - Venktesh S. Shirure
- Department of Biomedical EngineeringUniversity of CaliforniaDavisCaliforniaUSA
| | - Abigail K. Brandt
- Department of Biomedical EngineeringUniversity of CaliforniaDavisCaliforniaUSA
| | - Bryan B. Nguyen
- Department of Biomedical EngineeringUniversity of CaliforniaDavisCaliforniaUSA
| | - Cem Nesiri
- Department of Biomedical EngineeringUniversity of CaliforniaDavisCaliforniaUSA
| | | | - Terza Brostoff
- Department of Biomedical EngineeringUniversity of CaliforniaDavisCaliforniaUSA
- Department of PathologyUniversity of CaliforniaSan DiegoCaliforniaUSA
| | - David M. Rocke
- Department of Biomedical EngineeringUniversity of CaliforniaDavisCaliforniaUSA
- Department of Public Health Sciences, Division of BiostatisticsUniversity of CaliforniaDavisCaliforniaUSA
| | - Alexander D. Borowsky
- Department of Pathology and Laboratory MedicineUniversity of CaliforniaDavis, SacramentoCaliforniaUSA
| | - Randy P. Carney
- Department of Biomedical EngineeringUniversity of CaliforniaDavisCaliforniaUSA
| | - Steven C. George
- Department of Biomedical EngineeringUniversity of CaliforniaDavisCaliforniaUSA
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21
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Guo J, Jiang G, Chen J, Zhang M, Xiang K, Wang C, Jiang T, Kang Y, Sun Y, Xu X, Yang X, Chen Z. Tumor tissue derived extracellular vesicles promote diabetic wound healing. J Diabetes Complications 2023; 37:108435. [PMID: 36933279 DOI: 10.1016/j.jdiacomp.2023.108435] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 02/15/2023] [Accepted: 02/15/2023] [Indexed: 02/22/2023]
Abstract
The diabetic wound nowadays remains a major public health challenge, which is characterized by overproduced reactive oxygen species (ROS). However, the current therapy for diabetic wounds is limited for reliable data in the general application. The growth of tumors has been revealed to share parallels with wound healing. Extracellular vesicles (EVs) derived from breast cancer have been reported to promote cell proliferation, migration and angiogenesis. The tumor tissue-derived EVs (tTi-EVs) of breast cancer performance a feature inheritance from original tissue and might accelerate the diabetic wound healing. We wonder whether the tumor-derived EVs are able to accelerate diabetic wound healing. In this study, tTi-EVs were extracted from breast cancer tissue via ultracentrifugation and size exclusion. Subsequently, tTi-EVs reversed the H2O2-induced inhibition of fibroblast proliferation and migration. Moreover, tTi-EVs significantly accelerated wound closure, collagen deposition and neovascularization, and finally promoted wound healing in diabetic mice. The tTi-EVs also reduced the level of oxidative stress in vitro and in vivo. Besides, the biosafety of tTi-EVs were preliminarily confirmed by blood tests and morphological analysis of major organs. Collectively, the present study proves that tTi-EVs can suppress oxidative stress and facilitate diabetic wound healing, which puts forward a novel function of tTi-EVs and provides potential treatment for diabetic wounds.
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Affiliation(s)
- Jiahe Guo
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Guoyong Jiang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jing Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Maojie Zhang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Kaituo Xiang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Cheng Wang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Tao Jiang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yu Kang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yue Sun
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST), Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430022, China
| | - Xiang Xu
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaofan Yang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Zhenbing Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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22
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Zhao L, Yu L, Wang X, He J, Zhu X, Zhang R, Yang A. Mechanisms of function and clinical potential of exosomes in esophageal squamous cell carcinoma. Cancer Lett 2023; 553:215993. [PMID: 36328162 DOI: 10.1016/j.canlet.2022.215993] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/05/2022] [Accepted: 10/27/2022] [Indexed: 11/20/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) remains one of the most lethal and widespread malignancies in China. Exosomes, a subset of tiny extracellular vesicles manufactured by all cells and present in all body fluids, contribute to intercellular communication and have become a focus of the search for new therapeutic strategies for cancer. A number of global analyses of exosome-mediated functions and regulatory mechanism in malignant diseases have recently been reported. There is extensive evidence that exosomes can be used as diagnostic and prognostic markers for cancer. However, our understanding of their clinical value and mechanisms of action in ESCC is still limited and has not been systematically reviewed. Here, we review current research specifically focused on the functions and mechanisms of action of ESCC tumor-derived exosomes and non-ESCC-derived exosomes in ESCC progression and describe opportunities and challenges in the clinical translation of exosomes.
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Affiliation(s)
- Lijun Zhao
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Lili Yu
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Xiangpeng Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Jangtao He
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Xiaofei Zhu
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
| | - Rui Zhang
- The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Angang Yang
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, China; The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
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23
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Shahverdi M, Darvish M. Exosomal microRNAs: A Diagnostic and Therapeutic Small Bio-molecule in Esophageal Cancer. Curr Mol Med 2023; 23:312-323. [PMID: 35319366 DOI: 10.2174/1566524022666220321125134] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 12/07/2021] [Accepted: 12/20/2021] [Indexed: 02/08/2023]
Abstract
Esophageal cancer (EC) is one of the major causes of cancer-related death worldwide. EC is usually diagnosed at a late stage, and despite aggressive therapy, the five-year survival rate of patients remains poor. Exosomes play important roles in cancer biology. Indeed, exosomes are implicated in tumor proliferation, angiogenesis, and invasion. They contain bioactive molecules such as lipids, proteins, and non-coding RNAs. Exosome research has recently concentrated on microRNAs, which are tiny noncoding endogenous RNAs that can alter gene expression and are linked to nearly all physiological and pathological processes, including cancer. It is suggested that deregulation of miRNAs results in cancer progression and directly induces tumor initiation. In esophageal cancer, miRNA dysregulation plays an important role in cancer prognosis and patients' responsiveness to therapy, indicating that miRNAs are important in tumorigenesis. In this review, we summarize the impact of exosomal miRNAs on esophageal cancer pathogenesis and their potential applications for EC diagnosis and therapy.
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Affiliation(s)
- Mahshid Shahverdi
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Maryam Darvish
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
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24
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Yunusova N, Dzhugashvili E, Yalovaya A, Kolomiets L, Shefer A, Grigor’eva A, Tupikin A, Kondakova I, Tamkovich S. Comparative Analysis of Tumor-Associated microRNAs and Tetraspanines from Exosomes of Plasma and Ascitic Fluids of Ovarian Cancer Patients. Int J Mol Sci 2022; 24:ijms24010464. [PMID: 36613908 PMCID: PMC9820379 DOI: 10.3390/ijms24010464] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/09/2022] [Accepted: 12/19/2022] [Indexed: 12/29/2022] Open
Abstract
Ovarian cancer (OC) is one of the most common and fatal types of gynecological cancer. In the early phase of OC detection, the current treatment and diagnostic methods are not efficient and sensitive enough. Therefore, it is crucial to explore the mechanisms of OC metastasis and discover valuable factors for early diagnosis of female cancers and novel therapeutic strategies for metastasis. Exosomes are known to be involved in the development, migration, and invasion of cancer cells, and their cargo could be useful for the non-invasive biopsy development. CD151- and Tspan8-positive exosomes are known to support the degradation of the extracellular matrix, and are involved in stroma remodeling, angiogenesis and cell motility, as well as the association of miR-24 and miR-101 with these processes. The objective of this study was to explore the relationship of these components of exosomal cargo, in patients with OC, to clarify the clinical significance of these markers in liquid biopsies. The levels of tetraspanins Tspan8+ and CD151+ exosomes were significantly higher in plasma exosomes of OC patients compared with healthy females (HFs). The relative levels of miR-24 and miR-101 in plasma exosomes of HFs were significantly higher than in plasma exosomes of OC patients, while the levels of these microRNAs in exosomes from plasma and ascites of ill females showed no difference. Our study revealed a strong direct correlation between the change in the ascites exosomes CD151+Tspan8+ subpopulation level and the expression levels of the ascites (R = 0.81, p < 0.05) and plasma exosomal miR-24 (R = 0.74, p < 0.05) in OC patients, which confirms the assumption that exosomal cargo act synergistically to increase cellular motility, affecting cellular processes and signaling. Bioinformatics analysis confirmed the involvement of CD151 and Tspan8 tetraspanins and genes controlled by miR-24-3p and miR-101 in signaling pathways, which are crucial for carcinogenesis, demonstrating that these tetraspanins and microRNAs are potential biomarkers for OC screening, and predictors of poor clinicopathological behavior in tumors.
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Affiliation(s)
- Natalia Yunusova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia
- Department of Biochemistry and Molecular Biology, Faculty of Medicine and Biology, Siberian State Medical University, 634050 Tomsk, Russia
| | - Ekaterina Dzhugashvili
- V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Alena Yalovaya
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Larisa Kolomiets
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia
| | - Aleksei Shefer
- V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, 630090 Novosibirsk, Russia
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Alina Grigor’eva
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Alexey Tupikin
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Irina Kondakova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia
| | - Svetlana Tamkovich
- V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, 630090 Novosibirsk, Russia
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia
- Correspondence:
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25
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Zhang S, Liu S, Ren J, Zhang H, Chen S, Chen Y, Zhang S, Chen W, Xu C, Zhong S, Liu S, Lin C. Tumor-derived extracellular vesicles confer 5-fluorouracil resistance in esophageal cancer via long noncoding RNA AC116025.2 delivery. Mol Carcinog 2022; 61:1177-1190. [PMID: 36239547 DOI: 10.1002/mc.23469] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 04/06/2022] [Accepted: 04/18/2022] [Indexed: 02/05/2023]
Abstract
5-Fluorouracil (5-FU) resistance is one of the main causes for treatment failure in esophageal cancer (EC). Here, we intended to elucidate the mechanism of tumor-derived extracellular vesicles (TEVs)-encapsulated long noncoding RNAs (lncRNAs) AC116025.2 in 5-FU resistance in EC. EVs were isolated from the serum samples of EC patients and HEEC, TE-1, and TE-1/5-FU cells, followed by RT-qPCR detection of AC116025.2 expression in EVs. The relationship among AC116025.2, microRNA (miR)-4496, and SEMA5A was evaluated. Next, EC cells were cocultured with EVs, followed by lentivirus transduction and plasmid transfection for studying the role of TEVs-AC116025.2 in EC cells in relation to miR-4496 and SEMA5A. Tumor formation in nude mice was applied for in vivo confirmation. Elevated AC116025.2 expression was seen in the EVs from the serum of 5-FU insensitive patients and from 5-FU-resistant EC cells. Mechanistically, AC116025.2 bound to miR-4496 that inversely targeted SEMA5A in EC cells. EVs-oe-AC116025.2 augmented EC cell viability, colony formation, and 5-FU resistance, but diminished their apoptosis through miR-4496-mediated SEMA5A. Furthermore, EVs-oe-AC116025.2 augmented tumor formation and 5-FU resistance of EC cells in vivo. Conclusively, our data offered evidence of the promoting mechanism of TEVs in the 5-FU resistance of EC by delivering AC116025.2.
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Affiliation(s)
- Shuyao Zhang
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Jinan University, Guangzhou, China
| | - Shaojie Liu
- Department of Gastrointestinal Surgery, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Jinan University, Guangzhou, China
| | - Jingqing Ren
- Department of Gastrointestinal Surgery, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Jinan University, Guangzhou, China
| | - Hanshuo Zhang
- Department of Gastrointestinal Surgery, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Jinan University, Guangzhou, China
| | - Song Chen
- Department of Medical Imaging, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Jinan University, Guangzhou, China
| | - Yun Chen
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Jinan University, Guangzhou, China
| | - Shengqi Zhang
- Dafeng Hospital of Chaoyang District in Shantou City, Shantou, China
- Department of Oncology, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Wang Chen
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Jinan University, Guangzhou, China
| | - Chengcheng Xu
- Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Jinan University, Guangzhou, China
| | - Shilong Zhong
- Department of Pharmacy, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Sulin Liu
- The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Chaoxian Lin
- Shantou Chaonan Minsheng Hospital, Shantou, China
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26
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Lucotti S, Kenific CM, Zhang H, Lyden D. Extracellular vesicles and particles impact the systemic landscape of cancer. EMBO J 2022; 41:e109288. [PMID: 36052513 PMCID: PMC9475536 DOI: 10.15252/embj.2021109288] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 02/16/2022] [Accepted: 03/23/2022] [Indexed: 11/09/2022] Open
Abstract
Intercellular cross talk between cancer cells and stromal and immune cells is essential for tumor progression and metastasis. Extracellular vesicles and particles (EVPs) are a heterogeneous class of secreted messengers that carry bioactive molecules and that have been shown to be crucial for this cell-cell communication. Here, we highlight the multifaceted roles of EVPs in cancer. Functionally, transfer of EVP cargo between cells influences tumor cell growth and invasion, alters immune cell composition and function, and contributes to stromal cell activation. These EVP-mediated changes impact local tumor progression, foster cultivation of pre-metastatic niches at distant organ-specific sites, and mediate systemic effects of cancer. Furthermore, we discuss how exploiting the highly selective enrichment of molecules within EVPs has profound implications for advancing diagnostic and prognostic biomarker development and for improving therapy delivery in cancer patients. Altogether, these investigations into the role of EVPs in cancer have led to discoveries that hold great promise for improving cancer patient care and outcome.
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Affiliation(s)
- Serena Lucotti
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Candia M Kenific
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Haiying Zhang
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - David Lyden
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
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27
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Li J, Wang X, Chen L, Zhang J, Zhang Y, Ren X, Sun J, Fan X, Fan J, Li T, Tong L, Yi L, Chen L, Liu J, Shang G, Ren X, Zhang H, Yu S, Ming H, Huang Q, Dong J, Zhang C, Yang X. TMEM158 promotes the proliferation and migration of glioma cells via STAT3 signaling in glioblastomas. Cancer Gene Ther 2022; 29:1117-1129. [PMID: 34992215 PMCID: PMC9395270 DOI: 10.1038/s41417-021-00414-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 11/20/2021] [Accepted: 12/02/2021] [Indexed: 12/16/2022]
Abstract
Glioblastoma is the most common primary intracranial malignant tumor in adults and has high morbidity and high mortality. TMEM158 has been reported to promote the progression of solid tumors. However, its potential role in glioma is still unclear. Here, we found that TMEM158 expression in human glioma cells in the tumor core was significantly higher than that in noncancerous cells at the tumor edge using bioinformatics analysis. Cancer cells in patients with primary GBMs harbored significantly higher expression of TMEM158 than those in patients with WHO grade II or III gliomas. Interestingly, regardless of tumor grading, human glioma samples that were IDH1-wild-type (IDH1-WT) exhibited higher expression of TMEM158 than those with IDH1-mutant (IDH1-Mut). We also illustrated that TMEM158 mRNA expression was correlated with poor overall survival in glioma patients. Furthermore, we demonstrated that silencing TMEM158 inhibited the proliferation of glioma cells and that TMEM158 overexpression promoted the migration and invasion of glioma cells by stimulating the EMT process. We found that the underlying mechanism involves STAT3 activation mediating TMEM158-driven glioma progression. In vivo results further confirmed the inhibitory effect of the TMEM158 downregulation on glioma growth. Collectively, these findings further our understanding of the oncogenic function of TMEM158 in gliomas, which represents a potential therapeutic target, especially for GBMs.
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Affiliation(s)
- Jiabo Li
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Xuya Wang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Lulu Chen
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Jinhao Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Yiming Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Xiao Ren
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Jinzhang Sun
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Xiaoguang Fan
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Jikang Fan
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Tao Li
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Luqing Tong
- Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Li Yi
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lei Chen
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Jie Liu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Guanjie Shang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Xiude Ren
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Hao Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Shengping Yu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Haolang Ming
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Qiang Huang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China
| | - Jun Dong
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Chen Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China.
| | - Xuejun Yang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
- Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin, China.
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28
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Wu F, Yang J, Shang G, Zhang Z, Niu S, Liu Y, Liu H, Jing J, Fang Y. Exosomal miR-224-5p from Colorectal Cancer Cells Promotes Malignant Transformation of Human Normal Colon Epithelial Cells by Promoting Cell Proliferation through Downregulation of CMTM4. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5983629. [PMID: 35814269 PMCID: PMC9262543 DOI: 10.1155/2022/5983629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 05/23/2022] [Indexed: 11/18/2022]
Abstract
Background Interactions between malignant cells and neighboring normal cells are important for carcinogenesis. In addition, cancer cell-derived exosomes have been shown to promote the malignant transformation of recipient cells, but the mechanisms remain unclear. Methods The level of miR-224-5p in CRC cell-derived exosomes was determined by RT-qPCR assay. In addition, PKH26 dye-labeled exosomes were used to assess the efficacy of the transfer of exosomes between SW620 and normal colon epithelial cell line CCD 841 CoN. Results In this study, we found that overexpression of miR-224-5p significantly promoted the proliferation, migration, and invasion and inhibited the oxidative stress of SW620 cells. In addition, miR-224-5p can be transferred from SW620 cells to CCD 841 CoN cells via exosomes. SW620 cell-derived exosomal miR-224-5p markedly promoted proliferation, migration, and invasion of CCD 841 CoN cells. Meanwhile, SW620 cell-derived exosomal miR-224-5p notably decreased the expression of CMTM4 in CCD 841 CoN cells. Furthermore, SW620 cell-derived exosomal miR-224-5p significantly promoted tumor growth in a xenograft model in vivo. Conclusion These findings suggested that SW620 cell-derived exosomal miR-224-5p could promote malignant transformation and tumorigenesis in vitro and in vivo via downregulation of CMTM4, suggesting that miR-224-5p might be a potential target for therapies in CRC.
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Affiliation(s)
- Feng Wu
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China
| | - Jiani Yang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China
| | - Guoyin Shang
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China
| | - Zhijia Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China
| | - Sijia Niu
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China
| | - Yang Liu
- Pharmacy Intravenous Admixture Services, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China
| | - Hongru Liu
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China
| | - Jing Jing
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, Heilongjiang 150000, China
| | - Yu Fang
- Department of Phase I Clinical Trial Ward, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, China
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29
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Yu F, Lin Y, Tan G, Ai M, Gong H, Liu W, Huang J, Zou Z. Tumor-derived exosomal microRNA-15b-5p augments laryngeal cancer by targeting TXNIP. Cell Cycle 2022; 21:730-740. [PMID: 35156506 PMCID: PMC8973331 DOI: 10.1080/15384101.2021.2022845] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Tumor-derived exosomes (EXO) are information carriers of microRNA (miR) in cancer development. Here, we explored the synergism of tumor-derived EXO and miR-15b-5p in laryngeal cancer (LCa). miR-15b-5p and thioredoxin-interacting protein (TXNIP) levels were firstly measured in clinical LCa tissues. The association between miR-15b-5p and TXNIP was determined. miR-15b-5p mimic was transfected into HEP-2 cells, and the corresponding exosomes were extracted. miR-15b-5p mimic-modified EXO were co-cultured with HEP-2 cells, and TXNIP low expression/high expression vector was transfected into HEP-2 cells Finally, cell growth was observed in vitro and in vivo. miR-15b-5p level was high while TXNIP level was low in LCa, and miR-15b-5p negatively modulated TXNIP expression. HEP-2 cells-derived EXO or inhibition of TXNIP enhanced HEP-2 cell growth in vitro and in vivo. Up-regulated miR-15b-5p further strengthened the pro-tumor effect of EXO, but this effect was reversed by overexpression of TXNIP. Overall, tumor-derived exosomal miR-15b-5p augments LCa through targeting down-regulation of TXNIP.
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Affiliation(s)
- Feng Yu
- Department of Otolaryngology Head and Neck Surgery, Guangzhou Red Cross Hospital, Institute of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, China,CONTACT Feng Yu Department of Otolaryngology Head and Neck Surgery, Guangzhou Red Cross Hospital, Institute of Otolaryngology Head and Neck Surgery,Jinan University, Department of Otolaryngology Head and Neck Surgery, Guangzhou Red Cross Hospital,No. 396 Tongfu Middle Road, Haizhu District, Guangzhou, Guangdong Province510220, China
| | - Ying Lin
- Department of Otolaryngology Head and Neck Surgery, Guangzhou Red Cross Hospital, Institute of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, China
| | - Guojie Tan
- Department of Otolaryngology Head and Neck Surgery, Guangzhou Twelfth People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Maomao Ai
- Department of Otolaryngology Head and Neck Surgery, Guangzhou Red Cross Hospital, Institute of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, China
| | - Huicheng Gong
- Department of Otolaryngology Head and Neck Surgery, Guangzhou Twelfth People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Wei Liu
- Department of Otolaryngology Head and Neck Surgery, Guangzhou Twelfth People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jiali Huang
- Department of Otolaryngology Head and Neck Surgery, Guangzhou Red Cross Hospital, Institute of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, China
| | - Zirou Zou
- Department of Otolaryngology Head and Neck Surgery, Guangzhou Red Cross Hospital, Institute of Otolaryngology Head and Neck Surgery, Jinan University, Guangzhou, China
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30
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Zhang J, Uchiyama J, Imami K, Ishihama Y, Kageyama R, Kobayashi T. Novel Roles of Small Extracellular Vesicles in Regulating the Quiescence and Proliferation of Neural Stem Cells. Front Cell Dev Biol 2021; 9:762293. [PMID: 34805169 PMCID: PMC8601375 DOI: 10.3389/fcell.2021.762293] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 10/22/2021] [Indexed: 12/12/2022] Open
Abstract
Neural stem cell (NSC) quiescence plays pivotal roles in avoiding exhaustion of NSCs and securing sustainable neurogenesis in the adult brain. The maintenance of quiescence and transition between proliferation and quiescence are complex processes associated with multiple niche signals and environmental stimuli. Exosomes are small extracellular vesicles (sEVs) containing functional cargos such as proteins, microRNAs, and mRNAs. The role of sEVs in NSC quiescence has not been fully investigated. Here, we applied proteomics to analyze the protein cargos of sEVs derived from proliferating, quiescent, and reactivating NSCs. Our findings revealed fluctuation of expression levels and functional clusters of gene ontology annotations of differentially expressed proteins especially in protein translation and vesicular transport among three sources of exosomes. Moreover, the use of exosome inhibitors revealed exosome contribution to entrance into as well as maintenance of quiescence. Exosome inhibition delayed entrance into quiescence, induced quiescent NSCs to exit from the G0 phase of the cell cycle, and significantly upregulated protein translation in quiescent NSCs. Our results suggest that NSC exosomes are involved in attenuating protein synthesis and thereby regulating the quiescence of NSCs.
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Affiliation(s)
- Jingtian Zhang
- Graduate School of Biostudies, Kyoto University, Kyoto, Japan.,Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Junki Uchiyama
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Koshi Imami
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.,PRESTO, Japan Science and Technology Agency (JST), Tokyo, Japan
| | - Yasushi Ishihama
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Ryoichiro Kageyama
- Graduate School of Biostudies, Kyoto University, Kyoto, Japan.,Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.,RIKEN Center for Brain Science, Wako, Japan
| | - Taeko Kobayashi
- Graduate School of Biostudies, Kyoto University, Kyoto, Japan.,Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
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31
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Xing C, Li H, Li RJ, Yin L, Zhang HF, Huang ZN, Cheng Z, Li J, Wang ZH, Peng HL. The roles of exosomal immune checkpoint proteins in tumors. Mil Med Res 2021; 8:56. [PMID: 34743730 PMCID: PMC8573946 DOI: 10.1186/s40779-021-00350-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 10/19/2021] [Indexed: 02/08/2023] Open
Abstract
Targeting immune checkpoints has achieved great therapeutic effects in the treatment of early-stage tumors. However, most patients develop adaptive resistance to this therapy. The latest evidence demonstrates that tumor-derived exosomes may play a key role in systemic immune suppression and tumor progression. In this article, we highlight the role of exosomal immune checkpoint proteins in tumor immunity, with an emphasis on programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), as well as emerging evidence on roles of T cell immunoglobulin-3 (TIM-3), arginase 1 (ARG1), and estrogen receptor binding fragment-associated antigen 9 (EBAG9) expressed by exosomes.
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Affiliation(s)
- Cheng Xing
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Heng Li
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Rui-Juan Li
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Le Yin
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Hui-Fang Zhang
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Zi-Neng Huang
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Zhao Cheng
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Ji Li
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Zhi-Hua Wang
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
| | - Hong-Ling Peng
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, 410011 China
- Institute of Molecular Hematology, Central South University, Changsha, 410011 China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, Changsha, 410011 China
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32
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Zhao Z, Yang S, Zhou A, Li X, Fang R, Zhang S, Zhao G, Li P. Small Extracellular Vesicles in the Development, Diagnosis, and Possible Therapeutic Application of Esophageal Squamous Cell Carcinoma. Front Oncol 2021; 11:732702. [PMID: 34527593 PMCID: PMC8435888 DOI: 10.3389/fonc.2021.732702] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/09/2021] [Indexed: 12/14/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) persists among the most lethal and broad-spreading malignancies in China. The exosome is a kind of extracellular vesicle (EV) from about 30 to 200 nm in diameter, contributing to the transfer of specific functional molecules, such as metabolites, proteins, lipids, and nucleic acids. The paramount role of exosomes in the formation and development of ESCC, which relies on promoting intercellular communication in the tumor microenvironment (TME), is manifested with immense amounts. Tumor-derived exosomes (TDEs) participate in most hallmarks of ESCC, including tumorigenesis, invasion, angiogenesis, immunologic escape, metastasis, radioresistance, and chemoresistance. Published reports have delineated that exosome-encapsulated cargos like miRNAs may have utility in the diagnosis, as prognostic biomarkers, and in the treatment of ESCC. This review summarizes the function of exosomes in the neoplasia, progression, and metastasis of ESCC, which improves our understanding of the etiology and pathogenesis of ESCC, and presents a promising target for early diagnostics in ESCC. However, recent studies of exosomes in the treatment of ESCC are sparse. Thus, we introduce the advances in exosome-based methods and indicate the possible applications for ESCC therapy in the future.
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Affiliation(s)
- Zheng Zhao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shuyue Yang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Anni Zhou
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiao Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Rui Fang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Guiping Zhao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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33
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Jing Z, Chen K, Gong L. The Significance of Exosomes in Pathogenesis, Diagnosis, and Treatment of Esophageal Cancer. Int J Nanomedicine 2021; 16:6115-6127. [PMID: 34511909 PMCID: PMC8423492 DOI: 10.2147/ijn.s321555] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/16/2021] [Indexed: 12/21/2022] Open
Abstract
Esophageal cancer is one of the most common malignancy in China with high mortality. Understanding pathogenesis and identifying early diagnosis biomarkers can significantly improve the prognosis of patients with esophageal cancer. Exosomes are small vesicular structures containing a variety of components (including DNA, RNA, and proteins) mediating cell-to-cell material exchange and signal communication. Growing evidences have shown that exosomes and its components are involved in growth, metastasis and angiogenesis in cancer, and could also be used as diagnostic and prognostic markers. In this review, we summarized recent progress to elucidate the significance of exosomes in the esophageal cancer progression, microenvironment remodeling, therapeutic resistance, and immunosuppression. We also discuss the utility of exosomes as diagnostic and prognostic biomarkers and therapeutic tool in esophageal cancer.
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Affiliation(s)
- Zhao Jing
- Department of Oncology, Zhejiang Hospital, Hangzhou, Zhejiang, People's Republic of China
| | - Kai Chen
- Department of Cardiovascular and Thoracic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Ling Gong
- Department of Infectious Disease (Liver Diseases), The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, People's Republic of China
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34
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Song J, Yang P, Li X, Zhu X, Liu M, Duan X, Liu R. Esophageal Cancer-Derived Extracellular Vesicle miR-21-5p Contributes to EMT of ESCC Cells by Disorganizing Macrophage Polarization. Cancers (Basel) 2021; 13:4122. [PMID: 34439276 PMCID: PMC8392810 DOI: 10.3390/cancers13164122] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 07/31/2021] [Accepted: 08/12/2021] [Indexed: 12/22/2022] Open
Abstract
The disorganized polarization of tumor-associated macrophages (TAMs) exerts a critical effect on tumor progression. MicroRNAs (miRNAs) in extracellular vesicles (EVs) secreted from cancer cells may contribute to this process. However, the relationship between TAMs and EVs-miRNAs-mediated regulation in esophageal squamous cell carcinoma (ESCC) remains unclear. In the present study, immunoaffinity magnetic beads combined with antiepithelial cell adhesion molecules (EpCAM) were used to isolate and identify EVs-miR-21-5p from the plasma of ESCC patients. An in vitro coculture system was designed to evaluate the effect of esophageal cancer cells with miR-21-5p overexpression on macrophage polarization. We found that phorbol myristate acetate-induced THP-1 macrophages took up EVs-miR-21-5p from EC109 or EC9706 cells and were transformed into M2 macrophages. This, in turn, contributed to the excessive migration and invasion of esophageal cancer cells. The mechanism underlying these changes may involve activation of M2 macrophages by upregulated ESCC-derived EVs-miR-21-5p through the PTEN/AKT/STAT6 pathway. This may result in esophageal cancer cell epithelial-mesenchymal transition (EMT) via TGF-β/Smad2 signaling. Our results indicate positive feedback between M2 macrophage polarization and EMT of esophageal cancer cells in the tumor microenvironment via shuttling of miR-21-5p in tumor-derived EVs.
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Affiliation(s)
- Jing Song
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China; (J.S.); (P.Y.); (M.L.)
- The Affiliated Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China; (X.L.); (X.Z.)
| | - Peiyan Yang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China; (J.S.); (P.Y.); (M.L.)
| | - Xiuwen Li
- The Affiliated Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China; (X.L.); (X.Z.)
| | - Xinyi Zhu
- The Affiliated Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China; (X.L.); (X.Z.)
| | - Mengxin Liu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China; (J.S.); (P.Y.); (M.L.)
| | - Xuexin Duan
- State Key Laboratory of Precision Measuring Technology & Instruments, College of Precision Instrument and Opto-electronics Engineering, Tianjin University, Tianjin 300072, China;
| | - Ran Liu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China; (J.S.); (P.Y.); (M.L.)
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35
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Matsumoto Y, Kano M, Murakami K, Toyozumi T, Suito H, Takahashi M, Sekino N, Shiraishi T, Kamata T, Ryuzaki T, Hirasawa S, Kinoshita K, Matsubara H. Tumor-derived exosomes influence the cell cycle and cell migration of human esophageal cancer cell lines. Cancer Sci 2020; 111:4348-4358. [PMID: 32969511 PMCID: PMC7734159 DOI: 10.1111/cas.14660] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 08/22/2020] [Accepted: 09/12/2020] [Indexed: 02/06/2023] Open
Abstract
Our laboratory previously reported the usefulness as biomarkers of exosomes in the plasma of esophageal squamous cell carcinoma (ESCC) patients. However, the influence of tumor‐derived exosomes on the tumor itself and underlying mechanisms remain unclear. We here report changes in the phenotype and gene expression when cancer cells exist in an environment with tumor‐derived exosomes. The exosomes were isolated from the culture medium of human ESCC cells (TE2, T.Tn) by ultracentrifugation; cell proliferation assay, wound‐healing assay, and fluorescence imaging of the cell cycle were performed to clarify the phenotypic changes in the high concentration of tumor‐derived exosomes. Gene expression changes were also assessed by mRNA microarray, and the data were analyzed by gene set enrichment analysis (GSEA). The data revealed that the proliferation of both TE2 and T.Tn was inhibited, and cell migration ability was upregulated in the exosome exposure group (P < .05). Fluorescence imaging using a fluorescent ubiquitination‐based cell cycle indicator expressing ESCC cells revealed that the ratio of G1‐phase cells was significantly increased in the exosome exposure group (P < .05). Findings of the GSEA clarified that high‐density exposure of cancer‐derived exosomes to their parent cancer cells downregulated the expression of genes related to cell proliferation and cell cycle, and upregulated the expression of genes related to actin filament length and extracellular structure organization. In conclusion, an environment of high‐density tumor‐derived exosomes induces changes in the gene expression and phenotype of tumor cells and may lead to tumor progression or malignant transformation.
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Affiliation(s)
- Yasunori Matsumoto
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masayuki Kano
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Kentaro Murakami
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Takeshi Toyozumi
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hiroshi Suito
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masahiko Takahashi
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Nobufumi Sekino
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Tadashi Shiraishi
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Toshiki Kamata
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Takahiro Ryuzaki
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Soichiro Hirasawa
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Kazuya Kinoshita
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
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