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Zheng S, Zhang Y, Cai R, Cai B, Luo S, He S, Peng T, Wang W, Cui H, Li H, Lu X. The untold story of CD82: Exploring its non-canonical roles in cancer. Pathol Res Pract 2025; 270:155979. [PMID: 40252385 DOI: 10.1016/j.prp.2025.155979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 04/06/2025] [Accepted: 04/13/2025] [Indexed: 04/21/2025]
Abstract
CD82, traditionally recognized as a metastasis suppressor within the tetraspanin family, has emerged as a key player in diverse cancer-related processes beyond its canonical functions. This review highlights recent research on the non-canonical roles of CD82 in cancer progression, with a particular focus on its regulation of immune cell interactions, its impact on tumor microenvironment modulation, and its potential as both a therapeutic target and a biomarker. By examining the novel functions of CD82 in immune modulation and its influence on key signaling pathways, we propose that CD82 offers promising avenues for therapeutic interventions in cancer. This paper provides a comprehensive synthesis of the current understanding of CD82's expanded roles, underscoring its potential in improving cancer diagnosis and therapy.
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Affiliation(s)
- Shutao Zheng
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China
| | - Yao Zhang
- Beijing Beanstalk International Bilingual School, Beijing 100016, PR China
| | - Ren Cai
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China
| | - Bangwu Cai
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China
| | - Shujuan Luo
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China
| | - Shuo He
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China
| | - Tianyuan Peng
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China
| | - Wei Wang
- Department of Digestive Internal Medicine, the Affiliated Tumor Hospital of Xinjiang Medical University, PR China
| | - Hong Cui
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China
| | - Huifang Li
- Department of Breast Surgery, the First Affiliated Hospital of Xinjiang Medical University, PR China
| | - Xiaomei Lu
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, PR China.
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Delshad M, Sanaei MJ, Mohammadi MH, Sadeghi A, Bashash D. Exosomal Biomarkers: A Comprehensive Overview of Diagnostic and Prognostic Applications in Malignant and Non-Malignant Disorders. Biomolecules 2025; 15:587. [PMID: 40305328 PMCID: PMC12024574 DOI: 10.3390/biom15040587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 05/02/2025] Open
Abstract
Exosomes are small extracellular vesicles, ranging from 30 to 150 nm, that are essential in cell biology, mediating intercellular communication and serving as biomarkers due to their origin from cells. Exosomes as biomarkers for diagnosing various illnesses have gained significant investigation due to the high cost and invasive nature of current diagnostic procedures. Exosomes have a clear advantage in the diagnosis of diseases because they include certain signals that are indicative of the genetic and proteomic profile of the ailment. This feature gives them the potential to be useful liquid biopsies for real-time, noninvasive monitoring, enabling early cancer identification for the creation of individualized treatment plans. According to our analysis, the trend toward utilizing exosomes as diagnostic and prognostic tools has raised since 2012. In this regard, the proportion of malignant indications is higher compared with non-malignant ones. To be precise, exosomes have been used the most in gastrointestinal, thoracic, and urogenital cancers, along with cardiovascular, diabetic, breathing, infectious, and brain disorders. To the best of our knowledge, this is the first research to examine all registered clinical trials that look at exosomes as a diagnostic and prognostic biomarker.
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Affiliation(s)
- Mahda Delshad
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
- Department of Laboratory Sciences, School of Allied Medical Sciences, Zanjan University of Medical Sciences, Zanjan 1411718541, Iran
| | - Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
| | - Mohammad Hossein Mohammadi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
| | - Amir Sadeghi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717411, Iran;
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran; (M.D.); (M.-J.S.); (M.H.M.)
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Gao J, Yang R, Zhu X, Shi J, Wang S, Jing A. An Electrochemical Immunosensor for Sensitive Detection of Exosomes Based on Au/MXenes and AuPtPdCu. MICROMACHINES 2025; 16:280. [PMID: 40141891 PMCID: PMC11944654 DOI: 10.3390/mi16030280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/24/2025] [Accepted: 02/26/2025] [Indexed: 03/28/2025]
Abstract
Exosomes are important biomarkers for liquid biopsy in early cancer screening which play important roles in many biological processes, including apoptosis, inflammatory response, and tumor metastasis. In this study, an electrochemical aptamer immunosensor based on Au/MXene and AuPtPdCu was constructed for the sensitive detection of colorectal cancer-derived exosomes. AuNPs were deposited in situ on the surface of MXenes as a sensing platform due to their large specific area, excellent conductivity, and higher number of active sites for aptamer immobilization. The aptamer CD63 immobilized on Au/MXene can specifically capture target exosomes. Therefore, the AuPtPdCu-Apt nanoprobe further enhanced the sensitivity and accuracy of the immunosensor. A low limit of detection of 19 particles μL-1 was achieved in the linear range of 50 to 5 × 104 particles μL-1 under optimal conditions. The immunosensor developed herein showed satisfactory electrochemical stability and anti-interference ability for the detection of exosomes in real serum samples.
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Affiliation(s)
- Jie Gao
- School of Secondary Vocational Education, The Open University of China, Beijing 100031, China;
| | - Rong Yang
- School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang 471023, China; (R.Y.); (J.S.); (S.W.)
| | - Xiaorui Zhu
- Collaboration Innovative Center of Henan Province for Energy-Saving Building Materials, Xinyang Normal University, Xinyang 464000, China;
| | - Jiling Shi
- School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang 471023, China; (R.Y.); (J.S.); (S.W.)
| | - Sufei Wang
- School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang 471023, China; (R.Y.); (J.S.); (S.W.)
| | - Aihua Jing
- School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang 471023, China; (R.Y.); (J.S.); (S.W.)
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Ochiya T, Hashimoto K, Shimomura A. Prospects for liquid biopsy using microRNA and extracellular vesicles in breast cancer. Breast Cancer 2025; 32:10-15. [PMID: 38554234 PMCID: PMC11717869 DOI: 10.1007/s12282-024-01563-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 02/29/2024] [Indexed: 04/01/2024]
Abstract
Among the analytes circulating in body fluids, microRNAs, a type of non-coding RNA and known to exist 2655 in primates, have attracted attention as a novel biomarker for cancer screening. MicroRNAs are signaling molecules with important gene expression regulatory functions that can simultaneously control many gene functions and multiple different pathways in living organisms. These microRNAs are transported in extracellular vesicles (EVs), which are lipid bilayers with 50-150 nm in diameter, and are used as communication tools between cells. Furthermore, the EVs that carry these microRNAs circulate in the bloodstream and have other important implications for understanding the pathogenesis and diagnosis of breast cancer. The greatest benefit from cancer screening is the reduction in breast cancer mortality rate through early detection. Other benefits include reduced incidence of breast cancer, improved quality of life, prognosis prediction, contribution to personalized medicine, and relative healthcare cost containment. This paper outlines the latest developments in liquid biopsy for breast cancer, especially focusing on microRNA and EV diagnostics.
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Affiliation(s)
- Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Center for Future Medical Research, Institute of Medical Science, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjyuku-ku, Tokyo, 160-0023, Japan.
| | - Kazuki Hashimoto
- Department of Breast Surgery, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan
| | - Akihiko Shimomura
- Department of Breast and Medical Oncology, Genetic Medicine, General Medical Oncology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan
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Moni ZA, Hasan Z, Alam MS, Roy N, Islam F. Diagnostic and Prognostic Significance of Exosomes and Their Components in Patients With Cancers. Cancer Med 2025; 14:e70569. [PMID: 39757782 DOI: 10.1002/cam4.70569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 12/15/2024] [Accepted: 12/21/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND Cancer is the second leading cause of human mortality worldwide. Extracellular vesicles (EVs) from liquid biopsy samples are used in early cancer detection, characterization, and surveillance. Exosomes are a subset of EVs produced by all cells and present in all body fluids. They play an important role in the development of cancer because they are active transporters capable of carrying the contents of any type of cell. The objective of this review was to provide a brief overview of the clinical implication of exosomes or exosomal components in cancer diagnosis and prognosis. METHODS An extensive review of the current literature of exosomes and their components in cancer diagnosis and prognosis were carried out in the current study. RESULTS Tumor cells release exosomes that contribute to the formation of the pre-metastatic microenvironment, angiogenesis, invasion, and treatment resistance. On the contrary, tumor cells release more exosomes than normal cells, and these tumor-specific exosomes can carry the genomic and proteomic signature contents of the tumor cells, which can act as tools for the diagnosis and prognosis of patients with cancers. CONCLUSION This information may help clinicians to improve the management of cancer patients in clinical settings in the future.
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Affiliation(s)
- Zinnat Ara Moni
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Zahid Hasan
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Md Shaheen Alam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Nitai Roy
- Department of Biochemistry and Molecular Biology, Patuakhali Science and Technology University, Patuakhali, Bangladesh
| | - Farhadul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
- School of Medicine and Dentistry, Griffith University, Gold Coast, Queensland, Australia
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Jin K, Lan H, Han Y, Qian J. Exosomes in cancer diagnosis based on the Latest Evidence: Where are We? Int Immunopharmacol 2024; 142:113133. [PMID: 39278058 DOI: 10.1016/j.intimp.2024.113133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 08/09/2024] [Accepted: 09/07/2024] [Indexed: 09/17/2024]
Abstract
Exosomes are small extracellular vesicles (EVs) derived from various cellular sources and have emerged as favorable biomarkers for cancer diagnosis and prognosis. These vesicles contain a variety of molecular components, including nucleic acids, proteins, and lipids, which can provide valuable information for cancer detection, classification, and monitoring. However, the clinical application of exosomes faces significant challenges, primarily related to the standardization and scalability of their use. In order to overcome these challenges, sophisticated methods such as liquid biopsy and imaging are being combined to augment the diagnostic capabilities of exosomes. Additionally, a deeper understanding of the interaction between exosomes and immune system components within the tumor microenvironment (TME) is essential. This review discusses the biogenesis and composition of exosomes, addresses the current challenges in their clinical translation, and highlights recent technological advancements and integrative approaches that support the role of exosomes in cancer diagnosis and prognosis.
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Affiliation(s)
- Ketao Jin
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310003, China.
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, China; Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang 310006, China.
| | - Yuejun Han
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310003, China
| | - Jun Qian
- Department of Colorectal Surgery, Xinchang People's Hospital, Affiliated Xinchang Hospital, Wenzhou Medical University, Xinchang, Zhejiang 312500, China.
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Ye J, Li D, Jie Y, Luo H, Zhang W, Qiu C. Exosome-based nanoparticles and cancer immunotherapy. Biomed Pharmacother 2024; 179:117296. [PMID: 39167842 DOI: 10.1016/j.biopha.2024.117296] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 08/06/2024] [Accepted: 08/09/2024] [Indexed: 08/23/2024] Open
Abstract
Over the past decades, cancer immunotherapy has encountered challenges such as immunogenicity, inefficiency, and cytotoxicity. Consequently, exosome-based cancer immunotherapy has gained rapid traction as a promising alternative. Exosomes, a type of extracellular vesicles (EVs) ranging from 50 to 150 nm, are self-originating and exhibit fewer side effects compared to traditional therapies. Exosome-based immunotherapy encompasses three significant areas: cancer vaccination, co-inhibitory checkpoints, and adoptive T-cell therapy. Each of these fields leverages the inherent advantages of exosomes, demonstrating substantial potential for individualized tumor therapy and precision medicine. This review aims to elucidate the reasons behind the promise of exosome-based nanoparticles as cancer therapies by examining their characteristics and summarizing the latest research advancements in cancer immunotherapy.
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Affiliation(s)
- Jiarong Ye
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang University, Jiangxi Province, 330000 China.
| | - Danni Li
- Second Clinical Medical School, Nanchang University, Jiangxi Province 330000, China
| | - Yiting Jie
- Second Clinical Medical School, Nanchang University, Jiangxi Province 330000, China
| | - Hongliang Luo
- Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, China
| | - Wenjun Zhang
- Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Jiangxi Province 330000, China
| | - Cheng Qiu
- Gastrointestinal Surgery, Pingxiang People's Hospital, Jiangxi Province 330000, China.
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Bandu R, Oh JW, Kim KP. Extracellular vesicle proteins as breast cancer biomarkers: Mass spectrometry-based analysis. Proteomics 2024; 24:e2300062. [PMID: 38829178 DOI: 10.1002/pmic.202300062] [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: 06/11/2023] [Revised: 02/20/2024] [Accepted: 03/18/2024] [Indexed: 06/05/2024]
Abstract
Extracellular vesicles (EVs) are membrane-surrounded vesicles released by various cell types into the extracellular microenvironment. Although EVs vary in size, biological function, and components, their importance in cancer progression and the potential use of EV molecular species to serve as novel cancer biomarkers have become increasingly evident. Cancer cells actively release EVs into surrounding tissues, which play vital roles in cancer progression and metastasis, including invasion and immune modulation. EVs released by cancer cells are usually chosen as a gateway in the search for biomarkers for cancer. In this review, we mainly focused on molecular profiling of EV protein constituents from breast cancer, emphasizing mass spectrometry (MS)-based proteomic approaches. To further investigate the potential use of EVs as a source of breast cancer biomarkers, we have discussed the use of these proteins as predictive marker candidates. Besides, we have also summarized the key characteristics of EVs as potential therapeutic targets in breast cancer and provided significant information on their implications in breast cancer development and progression. Information provided in this review may help understand the recent progress in understanding EV biology and their potential role as new noninvasive biomarkers as well as emerging therapeutic opportunities and associated challenges.
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Affiliation(s)
- Raju Bandu
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, Republic of Korea
- Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, Republic of Korea
- Department of Neurology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jae Won Oh
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, Republic of Korea
- Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, Republic of Korea
| | - Kwang Pyo Kim
- Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, Republic of Korea
- Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, Republic of Korea
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Loggenberg S, Twilley D, Lall N. Evaluating the effects of various ethanolic medicinal plant extracts on metastatic breast cancer proliferation, invasion, and expression of a novel potential drug target; CD82 metastatic suppressor protein, and on in vivo angiogenesis using the ex ovo yolk sac membrane (YSM) assay. J Cancer Res Clin Oncol 2024; 150:257. [PMID: 38753184 PMCID: PMC11098903 DOI: 10.1007/s00432-024-05751-0] [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: 01/18/2024] [Accepted: 04/15/2024] [Indexed: 05/19/2024]
Abstract
PURPOSE Breast cancer metastasis relies on cellular invasion and angiogenesis facilitated by the downregulation of metastatic suppressor proteins like Cluster of Differentiation 82 (CD82). Currently, no medicines target multiple systems to prevent metastatic progression through CD82 upregulation. This study screened for plant extracts displaying effects on cell proliferation, invasion, and CD82 expression in breast cancer cells, and in vivo angiogenesis, and further correlated between the biological activities and effect on CD82 expression. METHODS Seventeen ethanolic plant extracts were screened for their effect on cell proliferation (against MDA-MB-231 and MCF-7 breast cancer and Hek293 kidney cells), cell invasion and effect on CD82 expression in metastatic MDA-MB-231 cells. Selected extracts were further evaluated for in vivo anti-angiogenesis. RESULTS Extracts displayed varying antiproliferative activity against the different cell lines, and those that showed selectivity indexes (SI) > 0.5 against MDA-MB-231 were selected for anti-invasion evaluation. Buddleja saligna Willd. (BS), Combretum apiculatum Sond. (CA), Foeniculum vulgare, Greyia radlkoferi, Gunnera perpensa and Persicaria senegalensis (Meisn.) Soják (PS) displayed 50% inhibitory concentration (IC50) values of 44.46 ± 3.46, 74.00 ± 4.48, 180.43 ± 4.51, 96.97 ± 2.29, 55.29 ± 9.88 and 243.60 ± 2.69 µg/mL, respectively against MDA-MB-231, and compared to Hek293 showed SI of 0.9, 0.7, 1.4, 1.1, 2.2 and 0.5. Significant invasion inhibition was observed at both 20 and 40 µg/mL for BS (94.10 ± 0.74 and 96.73 ± 0.95%) and CA (87.42 ± 6.54 and 98.24 ± 0.63%), whereas GR (14.91 ± 1.62 and 41 ± 1.78%) and PS (36.58 ± 0.54 and 51.51 ± 0.83%), only showed significant inhibition at 40 µg/mL, and FV (< 5% inhibition) and GP (10 ± 1.03 and 22 ± 1.31%) did not show significant inhibition at both concentrations. Due to the significant anti-invasive activity of BS, CA and PS at 40 µg/mL, these extracts were further evaluated for their potential to stimulate CD82. BS showed significant (p < 0.05) reduction in CD82 at 20 and 40 µg/mL (13.2 ± 2.2% and 20.3 ± 1.5% decrease, respectively), whereas both CA and PS at 20 µg/mL increased (p < 0.05) CD82 expression (16.4 ± 0.8% and 5.4 ± 0.6% increase, respectively), and at 40 µg/mL significantly reduced CD82 expression (23.4 ± 3.1% and 11.2 ± 2.9% decrease, respectively). Using the yolk sac membrane assay, BS (59.52 ± 4.12 and 56.72 ± 3.13% newly formed vessels) and CA (83.33 ± 3.17 and 74.00 ± 2.12%) at both 20 and 40 µg/egg showed significant (p < 0.001) angiogenesis inhibition, with BS showing statistical similar activity to the positive control, combretastatin A4 (10 nmol/egg), whereas PS only displayed significant (p < 0.001) angiogenesis stimulation at 40 µg/egg (120.81 ± 3.34% newly formed vessels). CONCLUSION BS exhibits antiproliferative, anti-invasive, and anti-angiogenic activity despite inhibiting CD82, suggesting an alternative mode of action. CA at 20 µg/mL shows moderate anti-invasive and anti-angiogenic potential by stimulating CD82, while at 40 µg/mL it still displays these properties but inhibits CD82, suggesting an additional mode of action. PS, with the least antiproliferative activity, stimulates CD82 and inhibits angiogenesis at 20 µg/mL but inhibits CD82 and increases angiogenesis at 40 µg/mL, indicating CD82 targeting as a major mode of action. Future studies should explore breast cancer xenograft models to assess the extracts' impact on CD82 expression and angiogenesis in the tumor microenvironment, along with isolating bioactive compounds from the extracts.
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Affiliation(s)
- Samantha Loggenberg
- Department of Plant and Soil Sciences, University of Pretoria, Pretoria, 0002, South Africa
| | - Danielle Twilley
- Department of Plant and Soil Sciences, University of Pretoria, Pretoria, 0002, South Africa
| | - Namrita Lall
- Department of Plant and Soil Sciences, University of Pretoria, Pretoria, 0002, South Africa.
- School of Natural Resources, University of Missouri, Columbia, MO, 65211, USA.
- College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, 570015, India.
- Bio-Tech Research and Development Institute, University of the West Indies, Kingston, Jamaica.
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Wang H, Wang R, Shen K, Huang R, Wang Z. Biological Roles and Clinical Applications of Exosomes in Breast Cancer: A Brief Review. Int J Mol Sci 2024; 25:4620. [PMID: 38731840 PMCID: PMC11083446 DOI: 10.3390/ijms25094620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/20/2024] [Accepted: 04/22/2024] [Indexed: 05/13/2024] Open
Abstract
Breast cancer (BC) is a global health risk for women and has a high prevalence rate. The drug resistance, recurrence, and metastasis of BC affect patient prognosis, thus posing a challenge to scientists. Exosomes are extracellular vesicles (EVs) that originate from various cells; they have a double-layered lipid membrane structure and contain rich biological information. They mediate intercellular communication and have pivotal roles in tumor development, progression, and metastasis and drug resistance. Exosomes are important cell communication mediators in the tumor microenvironment (TME). Exosomes are utilized as diagnostic and prognostic biomarkers for estimating the treatment efficacy of BC and have the potential to function as tools to enable the targeted delivery of antitumor drugs. This review introduces recent progress in research on how exosomes influence tumor development and the TME. We also present the research progress on the application of exosomes as prognostic and diagnostic biomarkers and drug delivery tools.
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Affiliation(s)
| | | | | | - Renhong Huang
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (H.W.); (R.W.); (K.S.)
| | - Zheng Wang
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; (H.W.); (R.W.); (K.S.)
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Maralbashi S, Aslan C, Kahroba H, Asadi M, Soltani-Zangbar MS, Haghnavaz N, Jadidi F, Salari F, Kazemi T. Docosahexaenoic acid (DHA) impairs hypoxia-induced cellular and exosomal overexpression of immune-checkpoints and immunomodulatory molecules in different subtypes of breast cancer cells. BMC Nutr 2024; 10:41. [PMID: 38439112 PMCID: PMC10910708 DOI: 10.1186/s40795-024-00844-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Accepted: 02/16/2024] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND Tumor cells express immune-checkpoint molecules to suppress anti-tumor immune responses. In part, immune evasion takes place by secreting exosomes bearing immune-checkpoint and immunomodulatory molecules and their inducing and/or regulating agents e.g., microRNAs (miRs). This study aimed to evaluate the effects of omega-3 fatty acid, docosahexaenoic acid (DHA), on the expression of some selected immune-checkpoint and immunomodulatory molecules and their regulating miRs under both normoxic and hypoxic conditions in triple negative (TNBC) invasive and triple positive non-invasive breast cancer cell lines. METHODS MDA-MB-231 and BT-474 cells were treated with 100 µM DHA under hypoxic and normoxic conditions for 24 h. Exosomes were isolated by ultracentrifuge and confirmed by electron microscope and anti-CD9, -CD63, -CD81 immunoblotting. Total RNA from cells and exosomes were extracted and expression of CD39, CD73, CD47, CD80, PD-L1, B7-H3, B7-H4 genes and their related miRs were evaluated by quantitative Real-time PCR. RESULTS This study showed significant over-expression of immune-checkpoint and immunomodulatory molecules under hypoxic condition. Treatment with DHA resulted in a significant decrease in immune-checkpoint and immunomodulatory molecule expression as well as an upregulation of their regulatory miRNA expression. CONCLUSION DHA supplementation may be utilized in breast cancer therapy for down-regulation of cellular and exosomal immune escape-related molecules.
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Affiliation(s)
- Sepideh Maralbashi
- Applied drug research center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Kermanshah University of Medical Science, Kermanshah, Iran
| | - Cynthia Aslan
- Immunology Research Center, Tabriz University of Medical Science, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran
| | - Houman Kahroba
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
- Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium
| | - Milad Asadi
- Department of Basic Oncology, Health Institute of Ege University, Izmir, Turkey
| | | | - Navideh Haghnavaz
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Farhad Jadidi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Farhad Salari
- Department of Immunology, Faculty of Medicine, Kermanshah University of Medical Science, Kermanshah, Iran.
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Science, Tabriz, Iran.
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran.
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Sahoo RK, Tripathi SK, Biswal S, Panda M, Mathapati SS, Biswal BK. Transforming native exosomes to engineered drug vehicles: A smart solution to modern cancer theranostics. Biotechnol J 2024; 19:e2300370. [PMID: 38375578 DOI: 10.1002/biot.202300370] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 12/13/2023] [Accepted: 12/22/2023] [Indexed: 02/21/2024]
Abstract
Exosomes have been the hidden treasure of the cell in terms of cellular interactions, transportation and therapy. The native exosomes (NEx) secreted by the parent cells hold promising aspects in cancer diagnosis and therapy. NEx has low immunogenicity, high biocompatibility, low toxicity and high stability which enables them to be an ideal prognostic biomarker in cancer diagnosis. However, due to heterogeneity, NEx lacks specificity and accuracy to be used as therapeutic drug delivery vehicle in cancer therapy. Transforming these NEx with their innate structure and multiple receptors to engineered exosomes (EEx) can provide better opportunities in the field of cancer theranostics. The surface of the NEx exhibits numeric receptors which can be modified to pave the direction of its therapeutic drug delivery in cancer therapy. Through surface membrane, EEx can be modified with increased drug loading potentiality and higher target specificity to act as a therapeutic nanocarrier for drug delivery. This review provides insights into promising aspects of NEx as a prognostic biomarker and drug delivery tool along with its need for the transformation to EEx in cancer theranostics. We have also highlighted different methods associated with NEx transformations, their nano-bio interaction with recipient cells and major challenges of EEx for clinical application in cancer theranostics.
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Affiliation(s)
- Rajeev Kumar Sahoo
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, India
| | - Surya Kant Tripathi
- Lineberger Comprehensive Cancer Centre, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Stuti Biswal
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, India
| | - Munmun Panda
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, India
| | - Santosh S Mathapati
- Translational Health Science and Technology Institute Faridabad, Faridabad, Haryana, India
| | - Bijesh Kumar Biswal
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, India
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13
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Keup C, Kimmig R, Kasimir-Bauer S. The Diversity of Liquid Biopsies and Their Potential in Breast Cancer Management. Cancers (Basel) 2023; 15:5463. [PMID: 38001722 PMCID: PMC10670968 DOI: 10.3390/cancers15225463] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 11/10/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
Analyzing blood as a so-called liquid biopsy in breast cancer (BC) patients has the potential to adapt therapy management. Circulating tumor cells (CTCs), extracellular vesicles (EVs), cell-free DNA (cfDNA) and other blood components mirror the tumoral heterogeneity and could support a range of clinical decisions. Multi-cancer early detection tests utilizing blood are advancing but are not part of any clinical routine yet. Liquid biopsy analysis in the course of neoadjuvant therapy has potential for therapy (de)escalation.Minimal residual disease detection via serial cfDNA analysis is currently on its way. The prognostic value of blood analytes in early and metastatic BC is undisputable, but the value of these prognostic biomarkers for clinical management is controversial. An interventional trial confirmed a significant outcome benefit when therapy was changed in case of newly emerging cfDNA mutations under treatment and thus showed the clinical utility of cfDNA analysis for therapy monitoring. The analysis of PIK3CA or ESR1 variants in plasma of metastatic BC patients to prescribe targeted therapy with alpesilib or elacestrant has already arrived in clinical practice with FDA-approved tests available and is recommended by ASCO. The translation of more liquid biopsy applications into clinical practice is still pending due to a lack of knowledge of the analytes' biology, lack of standards and difficulties in proving clinical utility.
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Affiliation(s)
- Corinna Keup
- Department of Gynecology and Obstetrics, University Hospital of Essen, 45147 Essen, Germany
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14
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Li L, Song X, Chen G, Zhang Z, Zheng B, Zhang Q, Wang S, Xie L. Plasma exosomal protein PLG and SERPINA1 in colorectal cancer diagnosis and coagulation abnormalities. J Cancer Res Clin Oncol 2023; 149:8507-8519. [PMID: 37093347 DOI: 10.1007/s00432-023-04776-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 04/10/2023] [Indexed: 04/25/2023]
Abstract
PURPOSE Early diagnosis of colorectal cancer (CRC) is critical to patient prognosis; however, there is lack of non-invasive biomarkers that are extremely sensitive and specific for early screening and diagnosis. Exosomes are a novel tool applied to the diagnosis and treatment of cancer. Changes in plasma exosomal proteins have a certain relationship with the development of various diseases including tumors. Here, we aimed to find exosomal biomarkers for early diagnosis of CRC. METHODS Exosomes obtained by ultracentrifugation from CRC patients and healthy donors were characterized by transmission electron microscopy (TEM), qNano and western blotting. Proteomic and functional enrichment analyses confirmed differences in the specific expression of exosomal proteins in plasma between CRC patients and healthy donors. Western blotting with enzyme-linked immunosorbent assay (ELISA) was used to verify the difference proteins. Statistical methods were used to analyze the relationship between protein levels and CRC. RESULTS The expression levels of serpin peptidase inhibitor clade A member 1 (SERPINA1) and fibrinogen (PLG) in CRC patients were significantly higher than those in healthy groups. Receptor operating characteristic (ROC) curves analysis was superior to CEA and CA19-9 for the diagnosis of colorectal cancer and early-stage colorectal cancer. The two were related to TNM staging and coagulation, and the difference was statistically significant. CONCLUSION The results of this study have potential value in advancing the clinical diagnosis of colorectal cancer.
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Affiliation(s)
- Lei Li
- School of Medical Laboratory, Weifang Medical University, Weifang, China
- Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, 440 Ji-Yan Road, Jinan, 250117, Shandong Province, People's Republic of China
| | - Xingguo Song
- Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, 440 Ji-Yan Road, Jinan, 250117, Shandong Province, People's Republic of China
| | - Guanxuan Chen
- Department of Intensive Care Unit, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, Shandong, People's Republic of China
| | - Zhe Zhang
- Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, 440 Ji-Yan Road, Jinan, 250117, Shandong Province, People's Republic of China
| | - Baibing Zheng
- Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, 440 Ji-Yan Road, Jinan, 250117, Shandong Province, People's Republic of China
| | - Qianru Zhang
- Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, 440 Ji-Yan Road, Jinan, 250117, Shandong Province, People's Republic of China
| | - Shiwen Wang
- Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, 440 Ji-Yan Road, Jinan, 250117, Shandong Province, People's Republic of China
| | - Li Xie
- Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, 440 Ji-Yan Road, Jinan, 250117, Shandong Province, People's Republic of China.
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15
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Loric S, Denis JA, Desbene C, Sabbah M, Conti M. Extracellular Vesicles in Breast Cancer: From Biology and Function to Clinical Diagnosis and Therapeutic Management. Int J Mol Sci 2023; 24:7208. [PMID: 37108371 PMCID: PMC10139222 DOI: 10.3390/ijms24087208] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/03/2023] [Accepted: 04/09/2023] [Indexed: 04/29/2023] Open
Abstract
Breast cancer (BC) is the first worldwide most frequent cancer in both sexes and the most commonly diagnosed in females. Although BC mortality has been thoroughly declining over the past decades, there are still considerable differences between women diagnosed with early BC and when metastatic BC is diagnosed. BC treatment choice is widely dependent on precise histological and molecular characterization. However, recurrence or distant metastasis still occurs even with the most recent efficient therapies. Thus, a better understanding of the different factors underlying tumor escape is mainly mandatory. Among the leading candidates is the continuous interplay between tumor cells and their microenvironment, where extracellular vesicles play a significant role. Among extracellular vesicles, smaller ones, also called exosomes, can carry biomolecules, such as lipids, proteins, and nucleic acids, and generate signal transmission through an intercellular transfer of their content. This mechanism allows tumor cells to recruit and modify the adjacent and systemic microenvironment to support further invasion and dissemination. By reciprocity, stromal cells can also use exosomes to profoundly modify tumor cell behavior. This review intends to cover the most recent literature on the role of extracellular vesicle production in normal and cancerous breast tissues. Specific attention is paid to the use of extracellular vesicles for early BC diagnosis, follow-up, and prognosis because exosomes are actually under the spotlight of researchers as a high-potential source of liquid biopsies. Extracellular vesicles in BC treatment as new targets for therapy or efficient nanovectors to drive drug delivery are also summarized.
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Affiliation(s)
- Sylvain Loric
- INSERM U538, CRSA, Saint-Antoine University Hospital, 75012 Paris, France; (J.A.D.)
| | | | - Cédric Desbene
- INSERM U538, CRSA, Saint-Antoine University Hospital, 75012 Paris, France; (J.A.D.)
| | - Michèle Sabbah
- INSERM U538, CRSA, Saint-Antoine University Hospital, 75012 Paris, France; (J.A.D.)
| | - Marc Conti
- INSERM U538, CRSA, Saint-Antoine University Hospital, 75012 Paris, France; (J.A.D.)
- INTEGRACELL SAS, 91160 Longjumeau, France
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Araujo-Abad S, Manresa-Manresa A, Rodríguez-Cañas E, Fuentes-Baile M, García-Morales P, Mallavia R, Saceda M, de Juan Romero C. New therapy for pancreatic cancer based on extracellular vesicles. Biomed Pharmacother 2023; 162:114657. [PMID: 37023623 DOI: 10.1016/j.biopha.2023.114657] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/29/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC), is the most common aggressive cancer of the pancreas. The standard care of PDAC includes tumor resection and chemotherapy, but the lack of early diagnosis and the limited response to the treatment worsens the patient's condition. In order to improve the efficiency of chemotherapy, we look for more efficient systems of drug delivery. We isolated and fully characterized small Extracellular Vesicles (EVs) from the RWP-1 cell line. Our study indicates that the direct incubation method was the most efficient loading protocol and that a minimum total amount of drug triggers an effect on tumor cells. Therefore, we loaded the small EVs with two chemotherapeutic drugs (Temozolomide and EPZ015666) by direct incubation method and the amount of drug loaded was measured by high-performance liquid chromatography (HPLC). Finally, we tested their antiproliferative effect on different cancer cell lines. Moreover, the system is highly dependent on the drug structure and therefore RWP-1 small EVsTMZ were more efficient than RWP-1 small EVsEPZ015666. RWP-1 derived small EVs represent a promising drug delivery tool that can be further investigated in preclinical studies and its combination with PRMT5 inhibitor can be potentially developed in clinical trials for the treatment of PDAC.
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Affiliation(s)
- Salomé Araujo-Abad
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, 03203 Alicante, Spain; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain; Centro de Biotecnología, Universidad Nacional de Loja, Avda. Pio Jaramillo Alvarado s/n, Loja, 110111 Loja, Ecuador
| | - Antonio Manresa-Manresa
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, 03203 Alicante, Spain
| | - Enrique Rodríguez-Cañas
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain
| | - María Fuentes-Baile
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, 03203 Alicante, Spain
| | - Pilar García-Morales
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain
| | - Ricardo Mallavia
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain
| | - Miguel Saceda
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, 03203 Alicante, Spain; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain
| | - Camino de Juan Romero
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, 03203 Alicante, Spain; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain.
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Araujo-Abad S, Manresa-Manresa A, Rodríguez-Cañas E, Fuentes-Baile M, García-Morales P, Mallavia R, Saceda M, de Juan Romero C. Glioblastoma-Derived Small Extracellular Vesicles: Nanoparticles for Glioma Treatment. Int J Mol Sci 2023; 24:ijms24065910. [PMID: 36982984 PMCID: PMC10054028 DOI: 10.3390/ijms24065910] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 03/14/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
Glioblastoma (GBM), characterized by fast growth and invasion into adjacent tissue, is the most aggressive cancer of brain origin. Current protocols, which include cytotoxic chemotherapeutic agents, effectively treat localized disease; however, these aggressive therapies present side effects due to the high doses administered. Therefore, more efficient ways of drug delivery have been studied to reduce the therapeutic exposure of the patients. We have isolated and fully characterized small extracellular vesicles (EVs) from seven patient-derived GBM cell lines. After loading them with two different drugs, Temozolomide (TMZ) and EPZ015666, we observed a reduction in the total amount of drugs needed to trigger an effect on tumor cells. Moreover, we observed that GBM-derived small EVs, although with lower target specificity, can induce an effect on pancreatic cancer cell death. These results suggest that GBM-derived small EVs represent a promising drug delivery tool for further preclinical studies and potentially for the clinical development of GBM treatments.
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Affiliation(s)
- Salomé Araujo-Abad
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, 03202 Alicante, Spain
- Centro de Biotecnología, Universidad Nacional de Loja, Loja 110111, Ecuador
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Unidad de Investigación, 03203 Alicante, Spain
| | - Antonio Manresa-Manresa
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Unidad de Investigación, 03203 Alicante, Spain
| | - Enrique Rodríguez-Cañas
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, 03202 Alicante, Spain
| | - María Fuentes-Baile
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Unidad de Investigación, 03203 Alicante, Spain
| | - Pilar García-Morales
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, 03202 Alicante, Spain
| | - Ricardo Mallavia
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, 03202 Alicante, Spain
| | - Miguel Saceda
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, 03202 Alicante, Spain
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Unidad de Investigación, 03203 Alicante, Spain
| | - Camino de Juan Romero
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, 03202 Alicante, Spain
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Unidad de Investigación, 03203 Alicante, Spain
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Caputo V, Ciardiello F, Corte CMD, Martini G, Troiani T, Napolitano S. Diagnostic value of liquid biopsy in the era of precision medicine: 10 years of clinical evidence in cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:102-138. [PMID: 36937316 PMCID: PMC10017193 DOI: 10.37349/etat.2023.00125] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 11/13/2022] [Indexed: 03/06/2023] Open
Abstract
Liquid biopsy is a diagnostic repeatable test, which in last years has emerged as a powerful tool for profiling cancer genomes in real-time with minimal invasiveness and tailoring oncological decision-making. It analyzes different blood-circulating biomarkers and circulating tumor DNA (ctDNA) is the preferred one. Nevertheless, tissue biopsy remains the gold standard for molecular evaluation of solid tumors whereas liquid biopsy is a complementary tool in many different clinical settings, such as treatment selection, monitoring treatment response, cancer clonal evolution, prognostic evaluation, as well as the detection of early disease and minimal residual disease (MRD). A wide number of technologies have been developed with the aim of increasing their sensitivity and specificity with acceptable costs. Moreover, several preclinical and clinical studies have been conducted to better understand liquid biopsy clinical utility. Anyway, several issues are still a limitation of its use such as false positive and negative results, results interpretation, and standardization of the panel tests. Although there has been rapid development of the research in these fields and recent advances in the clinical setting, many clinical trials and studies are still needed to make liquid biopsy an instrument of clinical routine. This review provides an overview of the current and future clinical applications and opening questions of liquid biopsy in different oncological settings, with particular attention to ctDNA liquid biopsy.
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Affiliation(s)
- Vincenza Caputo
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Napoli, Italy
| | - Fortunato Ciardiello
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Napoli, Italy
| | - Carminia Maria Della Corte
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Napoli, Italy
| | - Giulia Martini
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Napoli, Italy
| | - Teresa Troiani
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Napoli, Italy
| | - Stefania Napolitano
- Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Napoli, Italy
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Irmer B, Chandrabalan S, Maas L, Bleckmann A, Menck K. Extracellular Vesicles in Liquid Biopsies as Biomarkers for Solid Tumors. Cancers (Basel) 2023; 15:cancers15041307. [PMID: 36831648 PMCID: PMC9953862 DOI: 10.3390/cancers15041307] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/10/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Extracellular vesicles (EVs) are secreted by all living cells and are ubiquitous in every human body fluid. They are quite heterogeneous with regard to biogenesis, size, and composition, yet always reflect their parental cells with their cell-of-origin specific cargo loading. Since numerous studies have demonstrated that EV-associated proteins, nucleic acids, lipids, and metabolites can represent malignant phenotypes in cancer patients, EVs are increasingly being discussed as valuable carriers of cancer biomarkers in liquid biopsy samples. However, the lack of standardized and clinically feasible protocols for EV purification and characterization still limits the applicability of EV-based cancer biomarker analysis. This review first provides an overview of current EV isolation and characterization techniques that can be used to exploit patient-derived body fluids for biomarker quantification assays. Secondly, it outlines promising tumor-specific EV biomarkers relevant for cancer diagnosis, disease monitoring, and the prediction of cancer progression and therapy resistance. Finally, we summarize the advantages and current limitations of using EVs in liquid biopsy with a prospective view on strategies for the ongoing clinical implementation of EV-based biomarker screenings.
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Affiliation(s)
- Barnabas Irmer
- Department of Medicine A, Hematology, Oncology, and Pneumology, University of Münster, 48149 Munster, Germany
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149 Munster, Germany
| | - Suganja Chandrabalan
- Department of Medicine A, Hematology, Oncology, and Pneumology, University of Münster, 48149 Munster, Germany
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149 Munster, Germany
| | - Lukas Maas
- Department of Medicine A, Hematology, Oncology, and Pneumology, University of Münster, 48149 Munster, Germany
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149 Munster, Germany
| | - Annalen Bleckmann
- Department of Medicine A, Hematology, Oncology, and Pneumology, University of Münster, 48149 Munster, Germany
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149 Munster, Germany
- West German Cancer Center, University Hospital Münster, 48149 Munster, Germany
| | - Kerstin Menck
- Department of Medicine A, Hematology, Oncology, and Pneumology, University of Münster, 48149 Munster, Germany
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, 48149 Munster, Germany
- Correspondence:
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Lee Y, Ni J, Beretov J, Wasinger VC, Graham P, Li Y. Recent advances of small extracellular vesicle biomarkers in breast cancer diagnosis and prognosis. Mol Cancer 2023; 22:33. [PMID: 36797736 PMCID: PMC9933347 DOI: 10.1186/s12943-023-01741-x] [Citation(s) in RCA: 63] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 02/06/2023] [Indexed: 02/18/2023] Open
Abstract
Current clinical tools for breast cancer (BC) diagnosis are insufficient but liquid biopsy of different bodily fluids has recently emerged as a minimally invasive strategy that provides a real-time snapshot of tumour biomarkers for early diagnosis, active surveillance of progression, and post-treatment recurrence. Extracellular vesicles (EVs) are nano-sized membranous structures 50-1000 nm in diameter that are released by cells into biological fluids. EVs contain proteins, nucleic acids, and lipids which play pivotal roles in tumourigenesis and metastasis through cell-to-cell communication. Proteins and miRNAs from small EVs (sEV), which range in size from 50-150 nm, are being investigated as a potential source for novel BC biomarkers using mass spectrometry-based proteomics and next-generation sequencing. This review covers recent developments in sEV isolation and single sEV analysis technologies and summarises the sEV protein and miRNA biomarkers identified for BC diagnosis, prognosis, and chemoresistance. The limitations of current sEV biomarker research are discussed along with future perspective applications.
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Affiliation(s)
- Yujin Lee
- grid.1005.40000 0004 4902 0432St. George and Sutherland Clinical Campuses, School of Clinical Medicine, UNSW Sydney, Kensington, NSW 2052 Australia ,grid.416398.10000 0004 0417 5393Cancer Care Centre, St. George Hospital, Kogarah, NSW 2217 Australia
| | - Jie Ni
- grid.1005.40000 0004 4902 0432St. George and Sutherland Clinical Campuses, School of Clinical Medicine, UNSW Sydney, Kensington, NSW 2052 Australia ,grid.416398.10000 0004 0417 5393Cancer Care Centre, St. George Hospital, Kogarah, NSW 2217 Australia
| | - Julia Beretov
- grid.1005.40000 0004 4902 0432St. George and Sutherland Clinical Campuses, School of Clinical Medicine, UNSW Sydney, Kensington, NSW 2052 Australia ,grid.416398.10000 0004 0417 5393Cancer Care Centre, St. George Hospital, Kogarah, NSW 2217 Australia ,grid.416398.10000 0004 0417 5393Anatomical Pathology, NSW Health Pathology, St. George Hospital, Kogarah, NSW 2217 Australia
| | - Valerie C. Wasinger
- grid.1005.40000 0004 4902 0432Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Kensington, NSW 2052 Australia ,grid.1005.40000 0004 4902 0432School of Medical Science, UNSW Sydney, Kensington, NSW 2052 Australia
| | - Peter Graham
- grid.1005.40000 0004 4902 0432St. George and Sutherland Clinical Campuses, School of Clinical Medicine, UNSW Sydney, Kensington, NSW 2052 Australia ,grid.416398.10000 0004 0417 5393Cancer Care Centre, St. George Hospital, Kogarah, NSW 2217 Australia
| | - 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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The Roles of Exosomal Proteins: Classification, Function, and Applications. Int J Mol Sci 2023; 24:ijms24043061. [PMID: 36834471 PMCID: PMC9961790 DOI: 10.3390/ijms24043061] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 02/09/2023] Open
Abstract
Exosome, a subpopulation of extracellular vesicles, plays diverse roles in various biological processes. As one of the most abundant components of exosomes, exosomal proteins have been revealed to participate in the development of many diseases, such as carcinoma, sarcoma, melanoma, neurological disorders, immune responses, cardiovascular diseases, and infection. Thus, understanding the functions and mechanisms of exosomal proteins potentially assists clinical diagnosis and targeted delivery of therapies. However, current knowledge about the function and application of exosomal proteins is still limited. In this review, we summarize the classification of exosomal proteins, and the roles of exosomal proteins in exosome biogenesis and disease development, as well as in the clinical applications.
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22
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Feng L, Guo L, Tanaka Y, Su L. Tumor-Derived Small Extracellular Vesicles Involved in Breast Cancer Progression and Drug Resistance. Int J Mol Sci 2022; 23:ijms232315236. [PMID: 36499561 PMCID: PMC9736664 DOI: 10.3390/ijms232315236] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/28/2022] [Accepted: 12/01/2022] [Indexed: 12/09/2022] Open
Abstract
Breast cancer is one of the most serious and terrifying threats to the health of women. Recent studies have demonstrated that interaction among cancer cells themselves and those with other cells, including immune cells, in a tumor microenvironment potentially and intrinsically regulate and determine cancer progression and metastasis. Small extracellular vesicles (sEVs), a type of lipid-bilayer particles derived from cells, with a size of less than 200 nm, are recognized as one form of important mediators in cell-to-cell communication. sEVs can transport a variety of bioactive substances, including proteins, RNAs, and lipids. Accumulating evidence has revealed that sEVs play a crucial role in cancer development and progression, with a significant impact on proliferation, invasion, and metastasis. In addition, sEVs systematically coordinate physiological and pathological processes, such as coagulation, vascular leakage, and stromal cell reprogramming, to bring about premetastatic niche formation and to determine metastatic organ tropism. There are a variety of oncogenic factors in tumor-derived sEVs that mediate cellular communication between local stromal cells and distal microenvironment, both of which are important in cancer progression and metastasis. Tumor-derived sEVs contain substances that are similar to parental tumor cells, and as such, sEVs could be biomarkers in cancer progression and potential therapeutic targets, particularly for predicting and preventing future metastatic development. Here, we review the mechanisms underlying the regulation by tumor-derived sEVs on cancer development and progression, including proliferation, metastasis, drug resistance, and immunosuppression, which coordinately shape the pro-metastatic microenvironment. In addition, we describe the application of sEVs to the development of cancer biomarkers and potential therapeutic modalities and discuss how they can be engineered and translated into clinical practice.
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Affiliation(s)
- Lingyun Feng
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Lijuan Guo
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Yoshimasa Tanaka
- Center for Medical Innovation, Nagasaki University, 1-7-1, Sakamoto, Nagasaki 852-8588, Japan
- Correspondence: (Y.T.); (L.S.); Tel.: +81-95-819-7063 (Y.T.); +86-27-8779-2024 (L.S.); Fax: +81-95-819-2189 (Y.T.); +86-27-8779-2072 (L.S.)
| | - Li Su
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
- Correspondence: (Y.T.); (L.S.); Tel.: +81-95-819-7063 (Y.T.); +86-27-8779-2024 (L.S.); Fax: +81-95-819-2189 (Y.T.); +86-27-8779-2072 (L.S.)
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23
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Tenchov R, Sasso JM, Wang X, Liaw WS, Chen CA, Zhou QA. Exosomes─Nature's Lipid Nanoparticles, a Rising Star in Drug Delivery and Diagnostics. ACS NANO 2022; 16:17802-17846. [PMID: 36354238 PMCID: PMC9706680 DOI: 10.1021/acsnano.2c08774] [Citation(s) in RCA: 262] [Impact Index Per Article: 87.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 10/21/2022] [Indexed: 05/03/2023]
Abstract
Exosomes are a subgroup of nanosized extracellular vesicles enclosed by a lipid bilayer membrane and secreted by most eukaryotic cells. They represent a route of intercellular communication and participate in a wide variety of physiological and pathological processes. The biological roles of exosomes rely on their bioactive cargos, including proteins, nucleic acids, and lipids, which are delivered to target cells. Their distinctive properties─innate stability, low immunogenicity, biocompatibility, and good biomembrane penetration capacity─allow them to function as superior natural nanocarriers for efficient drug delivery. Another notably favorable clinical application of exosomes is in diagnostics. They hold various biomolecules from host cells, which are indicative of pathophysiological conditions; therefore, they are considered vital for biomarker discovery in clinical diagnostics. Here, we use data from the CAS Content Collection and provide a landscape overview of the current state and delineate trends in research advancement on exosome applications in therapeutics and diagnostics across time, geography, composition, cargo loading, and development pipelines. We discuss exosome composition and pathway, from their biogenesis and secretion from host cells to recipient cell uptake. We assess methods for exosome isolation and purification, their clinical applications in therapy and diagnostics, their development pipelines, the exploration goals of the companies, the assortment of diseases they aim to treat, development stages of their research, and publication trends. We hope this review will be useful for understanding the current knowledge in the field of medical applications of exosomes, in an effort to further solve the remaining challenges in fulfilling their potential.
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Affiliation(s)
- Rumiana Tenchov
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Janet M. Sasso
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Xinmei Wang
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Wen-Shing Liaw
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Chun-An Chen
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Qiongqiong Angela Zhou
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
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24
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Khan SU, Khan MU, Gao Y, Khan MI, Puswal SM, Zubair M, Khan MA, Farwa R, Gao S, Ali R, Hussain N. Unique therapeutic potentialities of exosomes based nanodrug carriers to target tumor microenvironment in cancer therapy. OPENNANO 2022. [DOI: 10.1016/j.onano.2022.100091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
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25
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Chen X, Feng J, Chen W, Shao S, Chen L, Wan H. Small extracellular vesicles: from promoting pre-metastatic niche formation to therapeutic strategies in breast cancer. Cell Commun Signal 2022; 20:141. [PMID: 36096820 PMCID: PMC9465880 DOI: 10.1186/s12964-022-00945-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 07/23/2022] [Indexed: 12/04/2022] Open
Abstract
Breast cancer is the most common cancer in females, and to date, the mortality rate of breast cancer metastasis cannot be ignored. The metastasis of breast cancer is a complex, staged process, and the pattern of metastatic spread is not random. The pre-metastatic niche, as an organ-specific home for metastasis, is a favourable environment for tumour cell colonization. As detection techniques improve, the role of the pre-metastatic niche in breast cancer metastasis is being uncovered. sEVs (small extracellular vesicles) can deliver cargo, which is vital for the formation of pre-metastatic niches. sEVs participate in multiple aspects of creating a distant microenvironment to promote tumour invasion, including the secretion of inflammatory molecules, immunosuppression, angiogenesis and enhancement of vascular permeability, as well as regulation of the stromal environment. Here, we discuss the multifaceted mechanisms through which breast cancer-derived sEVs contribute to pre-metastatic niches. In addition, sEVs as biomarkers and antimetastatic therapies are also discussed, particularly their use in transporting exosomal microRNAs. The study of sEVs may provide insight into immunotherapy and targeted therapies for breast cancer, and we also provide an overview of their potential role in antitumour metastasis.
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