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Kasiński D, Szeliski K, Drewa T, Pokrywczyńska M. Extracellular vesicles-a new player in the development of urinary bladder cancer. Ther Adv Med Oncol 2025; 17:17588359241297529. [PMID: 39850919 PMCID: PMC11755519 DOI: 10.1177/17588359241297529] [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: 05/06/2024] [Accepted: 10/18/2024] [Indexed: 01/25/2025] Open
Abstract
Bladder cancer was the 10th most commonly diagnosed cancer worldwide in 2020. Extracellular vesicles (EVs) are nano-sized membranous structures secreted by all types of cells into the extracellular space. EVs can transport proteins, lipids, or nucleic acids to specific target cells. What brings more attention and potential implications is the fact that cancer cells secrete more EVs than non-malignant cells. EVs are widely studied for their role in cancer development. This publication summarizes the impact of EVs secreted by urinary bladder cancer cells on urinary bladder cancer development and metastasis. EVs isolated from urinary bladder cancer cells affect other lower-grade cancer cells or normal cells by inducing different metabolic pathways (transforming growth factor β/Smads pathway; phosphoinositide 3-kinase/Akt pathway) that promote epithelial-mesenchymal transition. The cargo carried by EVs can also induce angiogenesis, another critical element in the development of bladder cancer, and modulate the immune system response in a tumor-beneficial manner. In summary, the transfer of substances produced by tumor cells via EVs to the environment influences many stages of tumor progression. An in-depth understanding of the role EVs play in the development of urinary bladder cancer is crucial for the development of future anticancer therapies.
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Affiliation(s)
- Damian Kasiński
- Chair of Urology and Andrology, Department of Regenerative Medicine, Collegium Medicum, Nicolaus Copernicus University, Jagiellońska 13/15, 85-067 Bydgoszcz, Poland
| | - Kamil Szeliski
- Chair of Urology and Andrology, Department of Regenerative Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Tomasz Drewa
- Chair of Urology and Andrology, Department of Regenerative Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Marta Pokrywczyńska
- Chair of Urology and Andrology, Department of Regenerative Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
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Giannopoulos-Dimitriou A, Saiti A, Malousi A, Anagnostopoulos AK, Vatsellas G, Al-Maghrabi PM, Müllertz A, Fatouros DG, Vizirianakis IS. Molecular Profiling of A549 Cell-Derived Exosomes: Proteomic, miRNA, and Interactome Analysis for Identifying Potential Key Regulators in Lung Cancer. Cancers (Basel) 2024; 16:4123. [PMID: 39766023 PMCID: PMC11674491 DOI: 10.3390/cancers16244123] [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: 11/10/2024] [Revised: 11/28/2024] [Accepted: 12/05/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND/OBJECTIVES Exosomes, nano-sized extracellular vesicles released by all cells, play a key role in intercellular communication and carry tumorigenic properties that impact surrounding or distant cells. The complexity of the exosomal molecular interactome and its effects on recipient cells still remain unclear. This study aims to decipher the molecular profile and interactome of lung adenocarcinoma A549 cell-derived exosomes using multi-omics and bioinformatics approaches. METHODS We performed comprehensive morphological and physicochemical characterization of exosomes isolated from cell culture supernatant of A549 cells in vitro, using DLS, cryo-TEM, Western blot, and flow cytometry. Proteomic and miRNA high-throughput profiling, coupled with bioinformatics network analysis, were applied to elucidate the exosome molecular cargo. A comparative miRNA analysis was also conducted with exosomes derived from normal lung fibroblast MRC-5 cells. RESULTS Exosomes exhibited an average size of ~40 nm and disk-shaped lipid bilayer structures, with tetraspanins CD9 and CD63 validated as exosomal markers. Proteomic analysis identified 68 proteins, primarily linked to the extracellular matrix organization and metabolic processes. miRNA sequencing revealed 72 miRNAs, notably hsa-miR-619-5p, hsa-miR-122-5p, hsa-miR-9901, hsa-miR-7704, and hsa-miR-151a-3p, which are involved in regulating metabolic processes, gene expression, and tumorigenic pathways. Th integration of proteomic and miRNA data through a proteogenomics approach identified dually affected genes including ERBB2, CD44, and APOE, impacted by both exosomal miRNA targeting and protein interactions through synergistic or antagonistic interactions. Differential analysis revealed a distinct miRNA profile in A549 exosomes, associated with cancer-related biological processes, compared to MRC-5 exosomes; notably, hsa-miR-619-5p emerged as a promising candidate for future clinical biomarker studies. The network analysis also revealed genes targeted by multiple upregulated tumor-associated miRNAs in potential exosome-recipient cells. CONCLUSIONS This integrative study provides insights into the molecular interactome of lung adenocarcinoma A549 cell-derived exosomes, providing a foundation for future research on exosomal cargo and its role in tumor cell communication, growth, and progression.
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Affiliation(s)
| | - Aikaterini Saiti
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (A.G.-D.); (A.S.)
| | - Andigoni Malousi
- Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Athanasios K. Anagnostopoulos
- Proteomics Research Unit, Center of Basic Research II, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece;
| | - Giannis Vatsellas
- Greek Genome Center, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece;
| | - Passant M. Al-Maghrabi
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - Anette Müllertz
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - Dimitrios G. Fatouros
- Laboratory of Pharmaceutical Technology, Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Ioannis S. Vizirianakis
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (A.G.-D.); (A.S.)
- Department of Health Sciences, School of Life and Health Sciences, University of Nicosia, Nicosia 2417, Cyprus
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3
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Cheng W, Ren W, Ye P, He L, Bao D, Yue T, Lai J, Wu Y, Wei Y, Wu Z, Piao JG. Camouflaging nanoreactor traverse the blood-brain barrier to catalyze redox cascade for synergistic therapy of glioblastoma. Biomaterials 2024; 311:122702. [PMID: 39008916 DOI: 10.1016/j.biomaterials.2024.122702] [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: 05/17/2024] [Revised: 06/25/2024] [Accepted: 07/07/2024] [Indexed: 07/17/2024]
Abstract
The blood-brain barrier (BBB) is a complex and highly restrictive barrier that prevents most biomolecules and drugs from entering the brain. However, effective strategies for delivering drugs to the brain are urgently needed for the treatment of glioblastoma. Based on the efficient BBB penetration properties of exosomes derived from brain metastatic breast cancer cells (EB), this work prepared a nanoreactor (denoted as MAG@EB), which was constructed by self-assembly of Mn2+, arsenate and glucose oxidase (GOx) into nanoparticles wrapped with EB. MAG@EB can enhance the efficiency of traversing the BBB, target and accumulate at in situ glioblastoma sites. The GOx-driven glycolysis effectively cuts off the glucose supply while also providing an abundance of H2O2 and lowering pH. Meanwhile, the released Mn2+ mediated Fenton-like reaction converts elevated H2O2 into highly toxic ·OH. Besides, AsV was reduced to AsIII by glutathione, and the tumor suppressor gene P53 was activated by AsIII to kill glioblastoma cells. Glioblastoma succumbed to the redox cascade triggered by MAG@EB, as the results demonstrated in vivo and in vitro, yielding a remarkable therapeutic effect. This work provides a promising therapeutic option mediated by cascaded nanoreactors for the future treatment of glioblastoma.
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Affiliation(s)
- WeiYi Cheng
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - WeiYe Ren
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Peng Ye
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Li He
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Dandan Bao
- Department of Dermatology & Cosmetology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Tianxiang Yue
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Jianjun Lai
- Department of Oncology, Zhejiang Hospital, Hangzhou, 310030, China
| | - Yajun Wu
- Department of Pharmacy, Zhejiang Hospital, Hangzhou 310013, China
| | - YingHui Wei
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Zhibing Wu
- Department of Oncology, Zhejiang Hospital, Hangzhou, 310030, China.
| | - Ji-Gang Piao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
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Miceli RT, Chen T, Nose Y, Tichkule S, Brown B, Fullard JF, Saulsbury MD, Heyliger SO, Gnjatic S, Kyprianou N, Cordon‐Cardo C, Sahoo S, Taioli E, Roussos P, Stolovitzky G, Gonzalez‐Kozlova E, Dogra N. Extracellular vesicles, RNA sequencing, and bioinformatic analyses: Challenges, solutions, and recommendations. J Extracell Vesicles 2024; 13:e70005. [PMID: 39625409 PMCID: PMC11613500 DOI: 10.1002/jev2.70005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 09/20/2024] [Accepted: 10/07/2024] [Indexed: 12/06/2024] Open
Abstract
Extracellular vesicles (EVs) are heterogeneous entities secreted by cells into their microenvironment and systemic circulation. Circulating EVs carry functional small RNAs and other molecular footprints from their cell of origin, and thus have evident applications in liquid biopsy, therapeutics, and intercellular communication. Yet, the complete transcriptomic landscape of EVs is poorly characterized due to critical limitations including variable protocols used for EV-RNA extraction, quality control, cDNA library preparation, sequencing technologies, and bioinformatic analyses. Consequently, there is a gap in knowledge and the need for a standardized approach in delineating EV-RNAs. Here, we address these gaps by describing the following points by (1) focusing on the large canopy of the EVs and particles (EVPs), which includes, but not limited to - exosomes and other large and small EVs, lipoproteins, exomeres/supermeres, mitochondrial-derived vesicles, RNA binding proteins, and cell-free DNA/RNA/proteins; (2) examining the potential functional roles and biogenesis of EVPs; (3) discussing various transcriptomic methods and technologies used in uncovering the cargoes of EVPs; (4) presenting a comprehensive list of RNA subtypes reported in EVPs; (5) describing different EV-RNA databases and resources specific to EV-RNA species; (6) reviewing established bioinformatics pipelines and novel strategies for reproducible EV transcriptomics analyses; (7) emphasizing the significant need for a gold standard approach in identifying EV-RNAs across studies; (8) and finally, we highlight current challenges, discuss possible solutions, and present recommendations for robust and reproducible analyses of EVP-associated small RNAs. Overall, we seek to provide clarity on the transcriptomics landscape, sequencing technologies, and bioinformatic analyses of EVP-RNAs. Detailed portrayal of the current state of EVP transcriptomics will lead to a better understanding of how the RNA cargo of EVPs can be used in modern and targeted diagnostics and therapeutics. For the inclusion of different particles discussed in this article, we use the terms large/small EVs, non-vesicular extracellular particles (NVEPs), EPs and EVPs as defined in MISEV guidelines by the International Society of Extracellular Vesicles (ISEV).
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Affiliation(s)
- Rebecca T. Miceli
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Tzu‐Yi Chen
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Yohei Nose
- Department of ImmunologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Oncological SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Swapnil Tichkule
- Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Briana Brown
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - John F. Fullard
- Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Genetics and Genomics SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Center for Disease Neurogenetics, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Marilyn D. Saulsbury
- Department of Pharmaceutical Sciences, School of PharmacyHampton UniversityHamptonVirginiaUSA
| | - Simon O. Heyliger
- Department of Pharmaceutical Sciences, School of PharmacyHampton UniversityHamptonVirginiaUSA
| | - Sacha Gnjatic
- Department of ImmunologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Oncological SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Natasha Kyprianou
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Oncological SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of UrologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Carlos Cordon‐Cardo
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Susmita Sahoo
- Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Cardiovascular Research Institute, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Emanuela Taioli
- Department of Population Health and ScienceIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Thoracic SurgeryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Panos Roussos
- Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Genetics and Genomics SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Center for Disease Neurogenetics, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Center for Precision Medicine and Translational TherapeuticsJames J. Peters VA Medicinal CenterBronxNew YorkUSA
- Mental Illness Research Education and Clinical Center (MIRECC)James J. Peters VA Medicinal CenterBronxNew YorkUSA
| | - Gustavo Stolovitzky
- Department of Genetics and Genomics SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Biomedical Data Sciences Hub (Bio‐DaSH), Department of Pathology, NYU Grossman School of MedicineNew YorkNew YorkUSA
| | - Edgar Gonzalez‐Kozlova
- Department of ImmunologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Oncological SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Navneet Dogra
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Genetics and Genomics SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Icahn Genomics Institute, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- AI and Human HealthIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
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Chen JM, Huang QY, Chen WH, Wu JX, Zheng LT, You HJ, Shi YC, Lin S, Shi QR. Transcriptomics of tissue exosomes to investigate miR-195-5p's amelioration of endometrial fibrosis via the YAP-Smad7 pathway: an animal study. J Transl Med 2024; 22:1050. [PMID: 39574130 PMCID: PMC11580480 DOI: 10.1186/s12967-024-05871-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 11/09/2024] [Indexed: 11/25/2024] Open
Abstract
BACKGROUND A significant research gap exists regarding the role of tissue exosomes in intrauterine adhesions (IUAs). This study aims to investigate the involvement of miR-195-5p and its regulatory network in IUAs through the analysis of tissue exosomes. METHODS Exosomes from rat uterine tissue with intrauterine adhesions were analyzed via transcriptomics to identify downstream target genes of miR-195-5p, cross-referencing with the human endometrial transcriptomics database GSE224093. Dual luciferase labeling confirmed miRNA-target gene interactions. The therapeutic efficacy of a miR-195-5p agonist was assessed in vivo through HE staining, Masson staining, and mating tests. The mechanisms underlying extracellular matrix (ECM) deposition and myofibroblast transdifferentiation in endometrial fibrosis were investigated both in vitro and in vivo using RT-PCR, Western Blot, immunofluorescence, and immunohistochemistry. Migration ability of endometrial stromal cells was evaluated using CCK8, scratch tests, and Transwell assays. Finally, the clinical potential of miR-195-5p was compared with autologous adipose-derived mesenchymal stem cells. RESULTS The expression of miR-195-5p in uterine tissue exosomes from intrauterine adhesions was found to be decreased. Treatment with a miR-195-5p agonist resulted in improved endometrial health, reduced fibrosis, increased glandular density, and enhanced birth rates in rats. Both in vivo and in vitro experiments confirmed that miR-195-5p decreased ECM deposition, reduced myofibroblast transdifferentiation, and inhibited the migration of endometrial stromal cells. This was achieved through the downregulation of YAP expression in the Hippo pathway and the upregulation of Smad7. Notably, the therapeutic efficacy of miR-195-5p agonists was comparable to that of stem cell therapy, offering promising avenues for clinical application. CONCLUSIONS Differential expression of miR-195-5p in tissue exosomes can reduce ECM deposition and myofibroblast transdifferentiation, improving endometrial fibrosis by regulating the YAP-Smad7 pathway in the Hippo signaling cascade.
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Affiliation(s)
- Jia-Ming Chen
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian Province, China
| | - Qiao-Yi Huang
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian Province, China
| | - Wei-Hong Chen
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian Province, China
| | - Jin-Xiang Wu
- Department of Reproductive Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian Province, China
| | - Ling-Tao Zheng
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian Province, China
| | - Hui-Jie You
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian Province, China
| | - Yan-Chuan Shi
- Group of Neuroendocrinology, Garvan Institute of Medical Research, 384 Victoria St, Sydney, 999029, Australia
- St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, 999029, Australia
| | - Shu Lin
- Group of Neuroendocrinology, Garvan Institute of Medical Research, 384 Victoria St, Sydney, 999029, Australia.
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian Province, China.
| | - Qi-Rong Shi
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian Province, China.
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Mehrvar A, Akbari M, Khosroshahi EM, Nekavand M, Mokhtari K, Baniasadi M, Aghababaian M, Karimi M, Amiri S, Moazen A, Maghsoudloo M, Alimohammadi M, Rahimzadeh P, Farahani N, Vaghar ME, Entezari M, Hashemi M. The impact of exosomes on bone health: A focus on osteoporosis. Pathol Res Pract 2024; 263:155618. [PMID: 39362132 DOI: 10.1016/j.prp.2024.155618] [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: 08/29/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 10/05/2024]
Abstract
Osteoporosis is a widespread chronic condition. Although standard treatments are generally effective, they are frequently constrained by side effects and the risk of developing drug resistance. A promising area of research is the investigation of extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, which play a crucial role in bone metabolism. Exosomes, in particular, have shown significant potential in both the diagnosis and treatment of osteoporosis. EVs derived from osteoclasts, osteoblasts, mesenchymal stem cells, and other sources can influence bone metabolism, while exosomes from inflammatory and tumor cells may exacerbate bone loss, highlighting their dual role in osteoporosis pathology. This review offers a comprehensive overview of EV biogenesis, composition, and function in osteoporosis, focusing on their diagnostic and therapeutic potential. We examine the roles of various types of EVs and their cargo-proteins, RNAs, and lipids-in bone metabolism. Additionally, we explore the emerging applications of EVs as biomarkers and therapeutic agents, emphasizing the need for further research to address current challenges and enhance EV-based strategies for managing osteoporosis.
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Affiliation(s)
- Amir Mehrvar
- Assistant Professor, Department of Orthopedics, Taleghani Hospital Research Development Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadarian Akbari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrandokht Nekavand
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Midwifery, Faculty of nursing and midwifery, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Khatere Mokhtari
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Mojtaba Baniasadi
- Department of Orthopedic Surgery, Isfahan University of Medical Sciences, Isfahan, Iran; MD, Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Department of Orthopedic, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Majid Aghababaian
- Department of Orthopedic Surgery, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mansour Karimi
- MD, Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Department of Orthopedic, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shayan Amiri
- MD, Assistant Professor of Orthopaedic Surgery, Shohadaye Haftom-e-Tir Hospital, Department of Orthopedic, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Moazen
- Department of Orthopedics, Bone and Joint Reconstruction Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mazaher Maghsoudloo
- Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan 646000, PR China
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mohammad Eslami Vaghar
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of gynecology, Faculty of Medicine, Tehran Medical sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Najafzadeh M, Sajjadi SM, Kharazi S, Karimifard F, Safarpour H, Kharazinejad E. Interactions between cancer and stroma mediated by extracellular vesicles. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2024; 25:114. [DOI: 10.1186/s43042-024-00582-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 09/13/2024] [Indexed: 01/05/2025] Open
Abstract
AbstractExtracellular vehicles (EVs) are small membrane-bound particles that are released by both cancer and stromal cells. These vesicles have emerged as key mediators of intercellular communication within the tumor microenvironment. In particular, EVs have been shown to play a critical role in facilitating the interactions between cancer cells and the surrounding stroma. Through the transfer of various bioactive molecules, including proteins, lipids, and nucleic acids, EVs are able to modulate the behavior of recipient cells and promote tumorigenesis. Additionally, EVs can also contribute to the development of drug resistance and immune evasion, further highlighting their importance in cancer progression. This review will summarize the current knowledge regarding EV-mediated interactions between cancer and stromal cells, and discuss their implications for cancer diagnosis and therapy.
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8
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Zhang C, Zhang L, Huang Q, Jiang S, Peng T, Wang S, Xu X. Diagnostic and screening potential of plasma exosome miR‑99b‑5p and its combination with other miRNAs for colorectal cancer. Oncol Lett 2024; 28:461. [PMID: 39119230 PMCID: PMC11307556 DOI: 10.3892/ol.2024.14594] [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: 07/21/2023] [Accepted: 02/15/2024] [Indexed: 08/10/2024] Open
Abstract
Extracellular vesicles (EVs) secreted by tumor cells have been documented to hold viable biomarker potential. Therefore, the present study evaluated the potential clinical value of EV-microRNAs (miRNAs or miRs) in the plasma exosomes of patients with colorectal cancer (CRC) for the early diagnosis and screening of CRC. In total, 95 plasma samples were collected at The Third Affiliated Hospital of Guangzhou Medical University (Guangzhou, China) between 2017 and 2019. Specifically, 68 samples were from patients with CRC and 27 were from healthy control (HC) donors. High-throughput sequencing was used to detect the expression of miRNAs in the isolated plasma EVs, which was subsequently verified by reverse transcription-quantitative PCR. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic potential of single and combined miRNAs for CRC. Bioinformatics analysis was employed to predict the target genes of candidate miRNAs. Compared with those in the HC group, the CRC group expressed higher levels of miR-99b-5p and miR-409-3p, especially during the early stages of CRC. Clinicopathological analysis confirmed the higher expression levels of miR-99b-5p during the early stages, as well as higher expression levels in the colon compared with those in the rectum. ROC curve analysis revealed that the area under the curve (AUC) of miR-99b-5p for the diagnosis of early CRC was 73.5% (P=0.007). The early diagnostic capability of miR-99b-5p combined with miR-409-3p for CRC was evaluated, and the AUC was found to be 74.1% (P=0.006). In addition, the AUC of the combination of miR-99b-5p, miR-409-3p and carcinoembryonic antigen was 81.2% (P<0.001), indicating that this three-parameter combination displayed higher diagnostic power compared with any single miRNA for early CRC screening. The results from the present study suggest that the expression of miR-99b-5p in plasma exosomes is significantly upregulated in CRC, which holds potential for the early diagnosis of this cancer type. Such potential can be enhanced further by combining it with other miRNAs. Therefore, the present study provides a comprehensive but preliminary insight for the viability of miR-99b-5p (alone or combined with other miRNAs) for CRC diagnosis, which requires further exploration in the future.
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Affiliation(s)
- Chang Zhang
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Key Laboratory of Aerospace Medicine of Ministry of Education, Air Force Medical University, Xi'an, Shanxi 710032, P.R. China
- Department of Aviation Medicine, The First Affiliated Hospital, Air Force Medical University, Xi'an, Shanxi 710032, P.R. China
| | - Limei Zhang
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, P.R. China
| | - Qiyuan Huang
- Nursing School, Guangzhou Medical University, Guangzhou, Guangdong 510030, P.R. China
| | - Siyuan Jiang
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, P.R. China
| | - Tao Peng
- Sino-French Hoffmann Institute, Guangzhou Hoffman Institute of Immunology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China
| | - Shu Wang
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Republic of Singapore
| | - Xuehu Xu
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, P.R. China
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9
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Bhavsar V, Sahu A, Taware R. Stress-induced extracellular vesicles: insight into their altered proteomic composition and probable physiological role in cancer. Mol Cell Biochem 2024:10.1007/s11010-024-05121-x. [PMID: 39302488 DOI: 10.1007/s11010-024-05121-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 09/09/2024] [Indexed: 09/22/2024]
Abstract
EVs (extracellular vesicles) are phospholipid bilayer vesicles that can be released by both prokaryotic and eukaryotic cells in normal as well as altered physiological conditions. These vesicles also termed as signalosomes, possess a distinctive cargo comprising nucleic acids, proteins, lipids, and metabolites, enabling them to play a pivotal role in both local and long-distance intercellular communication. The composition, origin, and release of EVs can be influenced by different physiological conditions and a variety of stress factors, consequently affecting the contents carried within these vesicles. Therefore, identifying the modified contents of EVs can provide valuable insights into their functional role in stress-triggered communication. Particularly, this is important when EVs released from tumor microenvironment are investigated for their role in the development and dissemination of cancer. This review article emphasizes the importance of differential EV shedding and altered proteomic content in response to reduced oxygen concentration, altered levels of glucose and glutamine, pH variations, oxidative stress and Ca2+ ion concertation and it is subsequent effects on the behavior of recipient cells.
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Affiliation(s)
- Vaidehi Bhavsar
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Palaj, Gandhinagar, Gujarat, 382355, India
| | - Ashish Sahu
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad, Palaj, Gandhinagar, Gujarat, 382355, India
| | - Ravindra Taware
- Department of Natural Products, National Institute of Pharmaceutical Education and Research-Ahmedabad, Palaj, Gandhinagar, Gujarat, 382355, India.
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10
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Smirnova O, Efremov Y, Klyucherev T, Peshkova M, Senkovenko A, Svistunov A, Timashev P. Direct and cell-mediated EV-ECM interplay. Acta Biomater 2024; 186:63-84. [PMID: 39043290 DOI: 10.1016/j.actbio.2024.07.029] [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: 02/02/2024] [Revised: 07/07/2024] [Accepted: 07/17/2024] [Indexed: 07/25/2024]
Abstract
Extracellular vesicles (EV) are a heterogeneous group of lipid particles excreted by cells. They play an important role in regeneration, development, inflammation, and cancer progression, together with the extracellular matrix (ECM), which they constantly interact with. In this review, we discuss direct and indirect interactions of EVs and the ECM and their impact on different physiological processes. The ECM affects the secretion of EVs, and the properties of the ECM and EVs modulate EVs' diffusion and adhesion. On the other hand, EVs can affect the ECM both directly through enzymes and indirectly through the modulation of the ECM synthesis and remodeling by cells. This review emphasizes recently discovered types of EVs bound to the ECM and isolated by enzymatic digestion, including matrix-bound nanovesicles (MBV) and tissue-derived EV (TiEV). In addition to the experimental studies, computer models of the EV-ECM-cell interactions, from all-atom models to quantitative pharmacology models aiming to improve our understanding of the interaction mechanisms, are also considered. STATEMENT OF SIGNIFICANCE: Application of extracellular vesicles in tissue engineering is an actively developing area. Vesicles not only affect cells themselves but also interact with the matrix and change it. The matrix also influences both cells and vesicles. In this review, different possible types of interactions between vesicles, matrix, and cells are discussed. Furthermore, the united EV-ECM system and its regulation through the cellular activity are presented.
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Affiliation(s)
- Olga Smirnova
- Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
| | - Yuri Efremov
- Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
| | - Timofey Klyucherev
- Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
| | - Maria Peshkova
- Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia; World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov University, 119991 Moscow, Russia
| | - Alexey Senkovenko
- Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
| | | | - Peter Timashev
- Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia; World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov University, 119991 Moscow, Russia; Chemistry Department, Lomonosov Moscow State University, 119991 Moscow, Russia.
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11
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Zheng Y, Li J, Xu D, Liu L, Li Y, Yi J, Dong J, Pang D, Tang H. Tunneling nanotubes mediate KRas transport: Inducing tumor heterogeneity and altering cellular membrane mechanical properties. Acta Biomater 2024; 185:312-322. [PMID: 38969079 DOI: 10.1016/j.actbio.2024.06.046] [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: 02/11/2024] [Revised: 06/17/2024] [Accepted: 06/27/2024] [Indexed: 07/07/2024]
Abstract
Mutation in oncogene KRas plays a crucial role in the occurrence and progression of numerous malignant tumors. Malignancy involves changes in cell mechanics for extensive cellular deformation during metastatic dissemination. We hypothesize that oncogene KRas mutations are intrinsic to alterations in cellular mechanics that promote malignant tumor generation and progression. Here, we demonstrate the use of optical tweezers coupled with a confocal fluorescence imaging system and gene interference technique to reveal that the mutant KRas protein can be transported between homogeneous and heterogeneous tumor cells by tunneling nanotubes (TNTs), resulting in a significant reduction of membrane tension and acceleration of membrane phospholipid flow in the recipient cells. Simultaneously, the changes in membrane mechanical properties of the tumor cells also enhance the metastatic and invasive ability of the tumors, which further contribute to the deterioration of the tumors. This finding helps to clarify the association between oncogene mutations and changes in the mechanical properties of tumor cells, which provides a theoretical basis for the development of cancer treatment strategies. STATEMENT OF SIGNIFICANCE: Here, we present a laser confocal fluorescence system integrated with optical tweezers to observe the transfer of mutant KRasG12D protein from mutant cells to wild-type cells through TNTs. Malignancy involves changes in cell mechanics for extensive cellular deformation during metastatic dissemination. Our results demonstrate a significant decrease in membrane tension and an increase in membrane phospholipid flow in recipient cells. These alterations in mechanical properties augment the migration and invasive capabilities of tumor cells, contributing to tumor malignancy. Our findings propose that cellular mechanical properties could serve as new markers for tumor development, and targeting membrane tension may hold potential as a therapeutic strategy.
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Affiliation(s)
- Yawen Zheng
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, PR China
| | - Jiangtao Li
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, PR China
| | - Dadi Xu
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, PR China
| | - Liu Liu
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, PR China
| | - Yuyao Li
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, PR China
| | - Jing Yi
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, PR China
| | - Jiayao Dong
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, PR China
| | - Daiwen Pang
- College of Chemistry, Nankai University, Tianjin, 300071, PR China
| | - Hongwu Tang
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, PR China.
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12
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Katana Z, Sianidou K, Kaiopoulos G, Deligianni F, Tsetsakos S, Kouvatsi A, Sakellari I, Kritis A, Touraki M, Sotiropoulos D, Xagorari A. Molecular and biochemical evaluation of oxidative effects of cord blood CD34+ MPs on hematopoietic cells. Blood Cells Mol Dis 2024; 108:102871. [PMID: 39013336 DOI: 10.1016/j.bcmd.2024.102871] [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: 03/27/2024] [Revised: 06/22/2024] [Accepted: 06/24/2024] [Indexed: 07/18/2024]
Abstract
A graft source for allogeneic hematopoietic stem cell transplantation is umbilical cord blood, which contains umbilical cord blood mononuclear cells (MNCs and mesenchymal stem cells, both an excellent source of extracellular microparticles (MPs). MPs act as cell communication mediators, which are implicated in reactive oxygen species formation or detoxification depending on their origin. Oxidative stress plays a crucial role in both the development of cancer and its treatment by triggering apoptotic mechanisms, in which CD34+ cells are implicated. The aim of this work is to investigate the oxidative stress status and the apoptosis of HL-60 and mononuclear cells isolated from umbilical cord blood (UCB) following a 24- and 48-hour exposure to CD34 + microparticles (CD34 + MPs). The activity of superoxide dismutase, glutathione reductase, and glutathione S-transferase, as well as lipid peroxidation in the cells, were employed as oxidative stress markers. A 24- and 48-hour exposure of leukemic and mononuclear cells to CD34 + -MPs resulted in a statistically significant increase in the antioxidant activity and lipid peroxidation in both cells types. Moreover, CD34 + MPs affect the expression of BCL2 and FAS and related proteins and downregulate the hematopoietic differentiation program in both HL-60 and mononuclear cells. Our results indicate that MPs through activation of antioxidant enzymes in both homozygous and nonhomozygous cells might serve as a means for graft optimization and enhancement.
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Affiliation(s)
- Zoi Katana
- Public Cord Blood Bank, Hematology Department, G.H.G.Papanicolaou, Thessaloniki, Greece; Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kyriaki Sianidou
- Public Cord Blood Bank, Hematology Department, G.H.G.Papanicolaou, Thessaloniki, Greece; Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Gregory Kaiopoulos
- Public Cord Blood Bank, Hematology Department, G.H.G.Papanicolaou, Thessaloniki, Greece; Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Fani Deligianni
- Public Cord Blood Bank, Hematology Department, G.H.G.Papanicolaou, Thessaloniki, Greece; Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Sarantis Tsetsakos
- Public Cord Blood Bank, Hematology Department, G.H.G.Papanicolaou, Thessaloniki, Greece
| | - Anastasia Kouvatsi
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioanna Sakellari
- Public Cord Blood Bank, Hematology Department, G.H.G.Papanicolaou, Thessaloniki, Greece
| | - Aristeidis Kritis
- Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Maria Touraki
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Damianos Sotiropoulos
- Public Cord Blood Bank, Hematology Department, G.H.G.Papanicolaou, Thessaloniki, Greece
| | - Angeliki Xagorari
- Public Cord Blood Bank, Hematology Department, G.H.G.Papanicolaou, Thessaloniki, Greece.
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13
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Parashar D, Mukherjee T, Gupta S, Kumar U, Das K. MicroRNAs in extracellular vesicles: A potential role in cancer progression. Cell Signal 2024; 121:111263. [PMID: 38897529 DOI: 10.1016/j.cellsig.2024.111263] [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: 04/30/2024] [Revised: 06/07/2024] [Accepted: 06/12/2024] [Indexed: 06/21/2024]
Abstract
Intercellular communication, an essential biological process in multicellular organisms, is mediated by direct cell-to-cell contact and cell secretary molecules. Emerging evidence identifies a third mechanism of intercellular communication- the release of extracellular vesicles (EVs). EVs are membrane-enclosed nanosized bodies, released from cells into the extracellular environment, often found in all biofluids. The growing body of research indicates that EVs carry bioactive molecules in the form of proteins, DNA, RNAs, microRNAs (miRNAs), lipids, metabolites, etc., and upon transferring them, alter the phenotypes of the target recipient cells. Interestingly, the abundance of EVs is found to be significantly higher in different diseased conditions, most importantly cancer. In the past few decades, numerous studies have identified EV miRNAs as an important contributor in the pathogenesis of different types of cancer. However, the underlying mechanism behind EV miRNA-associated cancer progression and how it could be used as a targeted therapy remain ill-defined. The present review highlights how EV miRNAs influence essential processes in cancer, such as growth, proliferation, metastasis, angiogenesis, apoptosis, stemness, immune evasion, resistance to therapy, etc. A special emphasis has been given to the potential role of EV miRNAs as cancer biomarkers. The final section of the review delineates the ongoing clinical trials on the role of miRNAs in the progression of different types of cancer. Targeting EV miRNAs could be a potential therapeutic means in the treatment of different forms of cancer alongside conventional therapeutic approaches.
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Affiliation(s)
- Deepak Parashar
- Division of Hematology & Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
| | - Tanmoy Mukherjee
- Department of Cellular and Molecular Biology, The University of Texas at Tyler Health Science Center, Tyler, TX 75708, USA.
| | - Saurabh Gupta
- Department of Biotechnology, GLA University, Mathura 281406, Uttar Pradesh, India
| | - Umesh Kumar
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad 201015, Uttar Pradesh, India.
| | - Kaushik Das
- Biotechnology Research and Innovation Council-National Institute of Biomedical Genomics, Kalyani 741251, West Bengal, India.
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14
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Song Z, Tao Y, Liu Y, Li J. Advances in delivery systems for CRISPR/Cas-mediated cancer treatment: a focus on viral vectors and extracellular vesicles. Front Immunol 2024; 15:1444437. [PMID: 39281673 PMCID: PMC11392784 DOI: 10.3389/fimmu.2024.1444437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 07/30/2024] [Indexed: 09/18/2024] Open
Abstract
The delivery of CRISPR/Cas systems holds immense potential for revolutionizing cancer treatment, with recent advancements focusing on extracellular vesicles (EVs) and viral vectors. EVs, particularly exosomes, offer promising opportunities for targeted therapy due to their natural cargo transport capabilities. Engineered EVs have shown efficacy in delivering CRISPR/Cas components to tumor cells, resulting in inhibited cancer cell proliferation and enhanced chemotherapy sensitivity. However, challenges such as off-target effects and immune responses remain significant hurdles. Viral vectors, including adeno-associated viruses (AAVs) and adenoviral vectors (AdVs), represent robust delivery platforms for CRISPR/Cas systems. AAVs, known for their safety profile, have already been employed in clinical trials for gene therapy, demonstrating their potential in cancer treatment. AdVs, capable of infecting both dividing and non-dividing cells, offer versatility in CRISPR/Cas delivery for disease modeling and drug discovery. Despite their efficacy, viral vectors present several challenges, including immune responses and off-target effects. Future directions entail refining delivery systems to enhance specificity and minimize adverse effects, heralding personalized and effective CRISPR/Cas-mediated cancer therapies. This article underscores the importance of optimized delivery mechanisms in realizing the full therapeutic potential of CRISPR/Cas technology in oncology. As the field progresses, addressing these challenges will be pivotal for translating CRISPR/Cas-mediated cancer treatments from bench to bedside.
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Affiliation(s)
- Zhidu Song
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China
| | - Ying Tao
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yue Liu
- Department of Emergency and Critical Care, The Second Hospital of Jilin University, Changchun, China
| | - Jian Li
- Department of Emergency and Critical Care, The Second Hospital of Jilin University, Changchun, China
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15
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Espiau-Romera P, Gordo-Ortiz A, Ortiz-de-Solórzano I, Sancho P. Metabolic features of tumor-derived extracellular vesicles: challenges and opportunities. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2024; 5:455-470. [PMID: 39697624 PMCID: PMC11648520 DOI: 10.20517/evcna.2024.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 06/30/2024] [Accepted: 08/16/2024] [Indexed: 12/20/2024]
Abstract
Tumor-derived extracellular vesicles (TDEVs) play crucial roles in intercellular communication both in the local tumor microenvironment and systemically, facilitating tumor progression and metastatic spread. They carry a variety of molecules with bioactive properties, such as nucleic acids, proteins and metabolites, that trigger different signaling processes in receptor cells and induce, among other downstream effects, metabolic reprogramming. Interestingly, the cargo of TDEVs also reflects the metabolic status of the producing cells in a time- and context-dependent manner, providing information on the functionality and state of those cells. For these reasons, together with their ability to be detected in diverse biofluids, there is increasing interest in the study of TDEVs, particularly their metabolic cargo, as diagnostic and prognostic tools in cancer management. This review presents a compilation of metabolism-related molecules (enzymes and metabolites) described in cancer extracellular vesicles (EVs) with potential use as cancer biomarkers, and discusses the challenges arising in this rapidly evolving field.
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Affiliation(s)
| | | | | | - Patricia Sancho
- Hospital Universitario Miguel Servet, IIS Aragón, Zaragoza 50009, Spain
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16
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Surman M, Wilczak M, Bzowska M, Tylko G, Przybyło M. The Proangiogenic Effects of Melanoma-Derived Ectosomes Are Mediated by αvβ5 Integrin Rather than αvβ3 Integrin. Cells 2024; 13:1336. [PMID: 39195226 PMCID: PMC11352487 DOI: 10.3390/cells13161336] [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: 06/28/2024] [Revised: 07/28/2024] [Accepted: 08/10/2024] [Indexed: 08/29/2024] Open
Abstract
Ectosomes are carriers of proangiogenic factors during cancer progression. This study investigated whether the proangiogenic effect exerted by melanoma-derived ectosomes on recipient endothelial cells is mediated by ectosomal αvβ3 and αvβ5 integrins. Ectosomes were isolated from the conditioned culture media of four melanoma cell lines and melanocytes. Changes in gene and protein expression of αvβ3 and αvβ5 integrins, as well as VEGF and TNF-α were assessed in ectosome-treated endothelial cells. To confirm the functional involvement of ectosomal integrins in functional tests (Alamar Blue, wound healing and tube formation assays), ectosomes were also pretreated with anti-integrin antibodies and integrin-blocking peptides echistatin and cilengitide. Melanoma-derived ectosomes induced changes in the expression of αvβ3 and αvβ5 integrins in recipient endothelial cells, leading to increased viability, migratory properties, and tube formation potential. The extent of proangiogenic stimulation varied depending on the types of cells releasing ectosomes and the recipient cells. The use of anti-integrin antibodies and integrin-blocking peptides revealed a more significant role for the αvβ5 integrin/VEGF than the αvβ3 integrin/TNF-α pathway in the interactions between ectosomes and endothelial cells. The study demonstrated the functional role of ectosomal αvβ3 and αvβ5 integrins. It also provided a baseline understanding of ectosome-mediated αvβ3 integrin/TNF-α and αvβ5 integrin/VEGF signaling in angiogenesis.
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Affiliation(s)
- Magdalena Surman
- Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland; (M.S.); (M.W.)
| | - Magdalena Wilczak
- Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland; (M.S.); (M.W.)
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, 30-348 Krakow, Poland
| | - Małgorzata Bzowska
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland;
| | - Grzegorz Tylko
- Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland;
| | - Małgorzata Przybyło
- Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland; (M.S.); (M.W.)
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17
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Zhang W, Zhuang X, Wu C, Jin Y, Xing J, Hou M, Yang W, Feng Q, Wang H. Apigenin inhibits tumor angiogenesis by hindering microvesicle biogenesis via ARHGEF1. Cancer Lett 2024; 596:216961. [PMID: 38823764 DOI: 10.1016/j.canlet.2024.216961] [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: 02/14/2024] [Revised: 05/11/2024] [Accepted: 05/13/2024] [Indexed: 06/03/2024]
Abstract
Extracellular vesicles are essential for intercellular communication and are involved in tumor progression. Inhibiting the direct release of extracellular vesicles seems to be an effective strategy in inhibiting tumor progression, but lacks of investigation. Here, we report a natural flavonoid compound, apigenin, could significantly inhibit the growth of hepatocellular carcinoma by preventing microvesicle secretion. Mechanistically, apigenin primarily targets the guanine nucleotide exchange factor ARHGEF1, inhibiting the activity of small G protein Cdc42, which is essential in regulating the release of microvesicles from tumor cells. In turn, this inhibits tumor angiogenesis related to VEGF90K transported on microvesicles, ultimately impeding tumor progression. Collectively, these findings highlight the therapeutic potential of apigenin and shed light on its anticancer mechanisms through inhibiting microvesicle biogenesis, providing a solid foundation for the refinement and practical application of apigenin.
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Affiliation(s)
- Wanying Zhang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230036, China
| | - XiangJin Zhuang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230036, China
| | - Chenlong Wu
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230036, China
| | - Yong Jin
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230036, China
| | - Jiayu Xing
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230036, China
| | - Mei Hou
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230036, China
| | - Wen Yang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230036, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China; National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
| | - Qiyu Feng
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230036, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
| | - Hongyang Wang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230036, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200438, China; National Center for Liver Cancer, Naval Medical University (Second Military Medical University), Shanghai, 201805, China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, 200438, China.
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18
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Licari E, Cricrì G, Mauri M, Raimondo F, Dioni L, Favero C, Giussani A, Starace R, Nucera S, Biondi A, Piazza R, Bollati V, Dander E, D'Amico G. ActivinA modulates B-acute lymphoblastic leukaemia cell communication and survival by inducing extracellular vesicles production. Sci Rep 2024; 14:16083. [PMID: 38992199 PMCID: PMC11239915 DOI: 10.1038/s41598-024-66779-3] [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: 03/13/2024] [Accepted: 07/03/2024] [Indexed: 07/13/2024] Open
Abstract
Extracellular vesicles (EVs) are a new mechanism of cellular communication, by delivering their cargo into target cells to modulate molecular pathways. EV-mediated crosstalk contributes to tumor survival and resistance to cellular stress. However, the role of EVs in B-cell Acute Lymphoblastic Leukaemia (B-ALL) awaits to be thoroughly investigated. We recently published that ActivinA increases intracellular calcium levels and promotes actin polymerization in B-ALL cells. These biological processes guide cytoskeleton reorganization, which is a crucial event for EV secretion and internalization. Hence, we investigated the role of EVs in the context of B-ALL and the impact of ActivinA on this phenomenon. We demonstrated that leukemic cells release a higher number of EVs in response to ActivinA treatment, and they can actively uptake EVs released by other B-ALL cells. Under culture-induced stress conditions, EVs coculture promoted cell survival in B-ALL cells in a dose-dependent manner. Direct stimulation of B-ALL cells with ActivinA or with EVs isolated from ActivinA-stimulated cells was even more effective in preventing cell death. This effect can be possibly ascribed to the increase of vesiculation and modifications of EV-associated microRNAs induced by ActivinA. These data demonstrate that ActivinA boosts EV-mediated B-ALL crosstalk, improving leukemia survival in stress conditions.
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Affiliation(s)
- Eugenia Licari
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi, 20900, Monza, Italy
| | - Giulia Cricrì
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi, 20900, Monza, Italy
- Paediatric Nephrology, Dialysis and Transplant Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy
| | - Mario Mauri
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Francesca Raimondo
- Clinical Proteomics and Metabolomic Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Laura Dioni
- EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Chiara Favero
- EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Alice Giussani
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi, 20900, Monza, Italy
| | - Rita Starace
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi, 20900, Monza, Italy
| | - Silvia Nucera
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi, 20900, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Andrea Biondi
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Rocco Piazza
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Hematology Division and Bone Marrow Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Valentina Bollati
- EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
- CRC, Center for Environmental Health, University of Milan, Milan, Italy
- Occupational Health Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - Erica Dander
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi, 20900, Monza, Italy
| | - Giovanna D'Amico
- Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Via Pergolesi, 20900, Monza, Italy.
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19
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Lin Y, Wei D, He X, Huo L, Wang J, Zhang X, Wu Y, Zhang R, Gao Y, Kang T. RAB22A sorts epithelial growth factor receptor (EGFR) from early endosomes to recycling endosomes for microvesicles release. J Extracell Vesicles 2024; 13:e12494. [PMID: 39051763 PMCID: PMC11270584 DOI: 10.1002/jev2.12494] [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: 01/21/2024] [Revised: 06/15/2024] [Accepted: 06/27/2024] [Indexed: 07/27/2024] Open
Abstract
Microvesicles (MVs) containing proteins, nucleic acid or organelles are shed from the plasma membrane. Although the mechanisms of MV budding are well elucidated, the connection between endosomal trafficking and MV formation remains poorly understood. In this report, RAB22A is revealed to be crucial for EGFR-containing MVs formation by the RAB GTPase family screening. RAB22A recruits TBC1D2B, a GTPase-activating protein (GAP) of RAB7A, to inactivate RAB7A, thus preventing EGFR from being transported to late endosomes and lysosomes. RAB22A also engages SH3BP5L, a guanine-nucleotide exchange factor (GEF) of RAB11A, to activate RAB11A on early endosomes. Consequently, EGFR is recycled to the cell surface and packaged into MVs. Furthermore, EGFR can phosphorylate RAB22A at Tyr136, which in turn promotes EGFR-containing MVs formation. Our findings illustrate that RAB22A acts as a sorter on early endosomes to sort EGFR to recycling endosomes for MV shedding by both activating RAB11A and inactivating RAB7A.
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Affiliation(s)
- Yujie Lin
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Denghui Wei
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Xiaobo He
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Lanqing Huo
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Jingxuan Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Xia Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Yuanzhong Wu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Ruhua Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Ying Gao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouP. R. China
| | - Tiebang Kang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouP. R. China
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20
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Brown SR, Radcliffe ME, Danner JT, Andújar Cruz WJ, Lackey KH, Park HA, Weinman ST, Kim Y. Extracellular Vesicle-Mediated Modulation of Stem-like Phenotype in Breast Cancer Cells under Fluid Shear Stress. Biomolecules 2024; 14:757. [PMID: 39062471 PMCID: PMC11274421 DOI: 10.3390/biom14070757] [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: 05/20/2024] [Revised: 06/21/2024] [Accepted: 06/22/2024] [Indexed: 07/28/2024] Open
Abstract
Circulating tumor cells (CTCs) are some of the key culprits that cause cancer metastasis and metastasis-related deaths. These cells exist in a dynamic microenvironment where they experience fluid shear stress (FSS), and the CTCs that survive FSS are considered to be highly metastatic and stem cell-like. Biophysical stresses such as FSS are also known to cause the production of extracellular vesicles (EVs) that can facilitate cell-cell communication by carrying biomolecular cargos such as microRNAs. Here, we hypothesized that physiological FSS will impact the yield of EV production, and that these EVs will have biomolecules that transform the recipient cells. The EVs were isolated using direct flow filtration with and without FSS from the MDA-MB-231 cancer cell line, and the expression of key stemness-related genes and microRNAs was characterized. There was a significantly increased yield of EVs under FSS. These EVs also contained significantly increased levels of miR-21, which was previously implicated to promote metastatic progression and chemotherapeutic resistance. When these EVs from FSS were introduced to MCF-7 cancer cells, the recipient cells had a significant increase in their stem-like gene expression and CD44+/CD24- cancer stem cell-like subpopulation. There was also a correlated increased proliferation along with an increased ATP production. Together, these findings indicate that the presence of physiological FSS can directly influence the EVs' production and their contents, and that the EV-mediated transfer of miR-21 can have an important role in FSS-existing contexts, such as in cancer metastasis.
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Affiliation(s)
- Spenser R. Brown
- Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA (S.T.W.)
| | - Margaret E. Radcliffe
- Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA (S.T.W.)
| | - Joseph T. Danner
- Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA (S.T.W.)
| | - Wilmer J. Andújar Cruz
- Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA (S.T.W.)
| | - Kimberly H. Lackey
- Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA;
| | - Han-A Park
- Department of Human Nutrition and Hospitality Management, The University of Alabama, Tuscaloosa, AL 35487, USA;
| | - Steven T. Weinman
- Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA (S.T.W.)
| | - Yonghyun Kim
- Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA (S.T.W.)
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21
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Suwakulsiri W, Xu R, Rai A, Shafiq A, Chen M, Greening DW, Simpson RJ. Comparative proteomic analysis of three major extracellular vesicle classes secreted from human primary and metastatic colorectal cancer cells: Exosomes, microparticles, and shed midbody remnants. Proteomics 2024; 24:e2300057. [PMID: 37507836 DOI: 10.1002/pmic.202300057] [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: 05/02/2023] [Revised: 07/03/2023] [Accepted: 07/04/2023] [Indexed: 07/30/2023]
Abstract
Cell-derived extracellular vesicles (EVs) are evolutionary-conserved secretory organelles that, based on their molecular composition, are important intercellular signaling regulators. At least three classes of circulating EVs are known based on mechanism of biogenesis: exosomes (sEVs/Exos), microparticles (lEVs/MPs), and shed midbody remnants (lEVs/sMB-Rs). sEVs/Exos are of endosomal pathway origin, microparticles (lEVs/MPs) from plasma membrane blebbing and shed midbody remnants (lEVs/sMB-Rs) arise from symmetric cytokinetic abscission. Here, we isolate sEVs/Exos, lEVs/MPs, and lEVs/sMB-Rs secreted from human isogenic primary (SW480) and metastatic (SW620) colorectal cancer (CRC) cell lines in milligram quantities for label-free MS/MS-based proteomic profiling. Purified EVs revealed selective composition packaging of exosomal protein markers in SW480/SW620-sEVs/Exos, metabolic enzymes in SW480/SW620-lEVs/MPs, while centralspindlin complex proteins, nucleoproteins, splicing factors, RNA granule proteins, translation-initiation factors, and mitochondrial proteins selectively traffic to SW480/SW620- lEVs/sMB-Rs. Collectively, we identify 39 human cancer-associated genes in EVs; 17 associated with SW480-EVs, 22 with SW620-EVs. We highlight oncogenic receptors/transporters selectively enriched in sEVs/Exos (EGFR/FAS in SW480-sEVs/Exos and MET, TGFBR2, ABCB1 in SW620-sEVs/Exos). Interestingly, MDK, STAT1, and TGM2 are selectively enriched in SW480-lEVs/sMB-Rs, and ADAM15 to SW620-lEVs/sMB-Rs. Our study reveals sEVs/Exos, lEVs/MPs, and lEVs/sMB-Rs have distinct protein signatures that open potential diagnostic avenues of distinct types of EVs for clinical utility.
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Affiliation(s)
- Wittaya Suwakulsiri
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science (LIMS), School of Agriculture, Biomedicine and Environment (SABE), La Trobe University, Melbourne, Victoria, Australia
- Department of Psychiatry, School of Clinical Sciences at Monash Health, Monash Medical Centre, Monash University, Clayton, Victoria, Australia
| | - Rong Xu
- Nanobiotechnology Laboratory, Centre Clinical, Australia Centre for Blood Diseases, School, Monash University, Melbourne, Victoria, Australia
| | - Alin Rai
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Adnan Shafiq
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science (LIMS), School of Agriculture, Biomedicine and Environment (SABE), La Trobe University, Melbourne, Victoria, Australia
| | - Maoshan Chen
- Laboratory of Radiation Biology, Department of Blood Transfusion, Laboratory Medicine Centre, The Second Affiliated Hospital, Army Medical University, Chongqing, China
| | - David W Greening
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, Victoria, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Richard J Simpson
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science (LIMS), School of Agriculture, Biomedicine and Environment (SABE), La Trobe University, Melbourne, Victoria, Australia
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22
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Shams SGE, Ocampo RJ, Rahman S, Makhlouf MM, Ali J, Elnashar MM, Ebrahim HL, Abd Elmageed ZY. Decoding the secrets of small extracellular vesicle communications: exploring the inhibition of vesicle-associated pathways and interception strategies for cancer treatment. Am J Cancer Res 2024; 14:1957-1980. [PMID: 38859839 PMCID: PMC11162651 DOI: 10.62347/jwmx3035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 03/12/2024] [Indexed: 06/12/2024] Open
Abstract
Cancer disease is the second leading cause of death worldwide. In 2023, about 2 million new cancer cases and 609,820 cancer deaths are projected to occur in the United States. The driving forces of cancer progression and metastasis are widely varied and comprise multifactorial events. Although there is significant success in treating cancer, patients still present with tumors at advanced stages. Therefore, the discovery of novel oncologic pathways has been widely developed. Tumor cells communicate with each other through small extracellular vesicles (sEVs), which contribute to tumor-stromal interaction and promote tumor growth and metastasis. sEV-specific inhibitors are being investigated as a next-generation cancer therapy. A literature search was conducted to discuss different options for targeting sEV pathways in cancer cells. However, there are some challenges that need to be addressed in targeting sEVs: i) specificity and toxicity of sEV inhibitor, ii) targeted delivery of sEV inhibitors, iii) combination of sEV inhibitors with current standard chemotherapy to improve patients' clinical outcomes, and iv) data reproducibility and applicability at distinct levels of the disease. Despite these challenges, sEV inhibitors have immense potential for effectively treating cancer patients.
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Affiliation(s)
- Shams GE Shams
- Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College of Osteopathic Medicine (VCOM)Monroe, LA 71203, USA
| | - Ron-Joseph Ocampo
- Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College of Osteopathic Medicine (VCOM)Monroe, LA 71203, USA
| | - Sanna Rahman
- Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College of Osteopathic Medicine (VCOM)Monroe, LA 71203, USA
| | - Maysoon M Makhlouf
- Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College of Osteopathic Medicine (VCOM)Monroe, LA 71203, USA
| | - Jihad Ali
- School of Medicine, Medipol UniversityKavacik, Beykoz 34810, Istanbul, Turkey
| | - Magdy M Elnashar
- School of Medicine, Pharmacy and Biomedical Sciences, Curtin UniversityBentley, WA 6102, Australia
| | - Hassan L Ebrahim
- Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College of Osteopathic Medicine (VCOM)Monroe, LA 71203, USA
| | - Zakaria Y Abd Elmageed
- Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College of Osteopathic Medicine (VCOM)Monroe, LA 71203, USA
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23
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Agnihotram R, Dhar R, Dhar D, Purushothaman K, Narasimhan AK, Devi A. Fusion of Exosomes and Nanotechnology: Cutting-Edge Cancer Theranostics. ACS APPLIED NANO MATERIALS 2024; 7:8489-8506. [DOI: 10.1021/acsanm.4c01033] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Affiliation(s)
- Rohan Agnihotram
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu-603203, India
| | - Rajib Dhar
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu-603203, India
| | - Debolina Dhar
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu-603203, India
| | - Kaavya Purushothaman
- Department of Biomedical Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu-603203, India
| | - Ashwin Kumar Narasimhan
- Department of Biomedical Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu-603203, India
| | - Arikketh Devi
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu-603203, India
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24
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Lin M, Lei S, Chai Y, Xu J, Wang Y, Wu C, Jiang H, Yuan S, Wang J, Lyu J, Lu M, Deng J. Immunosuppressive microvesicles-mimetic derived from tolerant dendritic cells to target T-lymphocytes for inflammation diseases therapy. J Nanobiotechnology 2024; 22:201. [PMID: 38659058 PMCID: PMC11040880 DOI: 10.1186/s12951-024-02470-z] [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: 01/13/2024] [Accepted: 04/07/2024] [Indexed: 04/26/2024] Open
Abstract
The utilization of extracellular vesicles (EV) in immunotherapy, aiming at suppressing peripheral immune cells responsible for inflammation, has demonstrated significant efficacy in treating various inflammatory diseases. However, the clinical application of EV has faced challenges due to their inadequate targeting ability. In addition, most of the circulating EV would be cleared by the liver, resulting in a short biological half-life after systemic administration. Inspired by the natural microvesicles (MV, as a subset of large size EV) are originated and shed from the plasma membrane, we developed the immunosuppressive MV-mimetic (MVM) from endotoxin tolerant dendritic cells (DC) by a straightforward and effective extrusion approach, in which DC surface proteins were inherited for providing the homing ability to the spleen, while αCD3 antibodies were conjugated to the MVM membranes for specific targeting of T cells. The engineered MVM carried a large number of bioactive cargos from the parental cells, which exhibited a remarkable ability to promote the induction of regulatory T cells (Treg) and polarization of anti-inflammatory M2 macrophages. Mechanistically, the elevated Treg level by MVM was mediated due to the upregulation of miR-155-3p. Furthermore, it was observed that systemic and local immunosuppression was induced by MVM in models of sepsis and rheumatoid arthritis through the improvement of Treg and M2 macrophages. These findings reveal a promising cell-free strategy for managing inflammatory responses to infections or tissue injury, thereby maintaining immune homeostasis.
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Affiliation(s)
- Minghao Lin
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
- Wenzhou Traditional Chinese Medicine Hospital, Wenzhou, 325000, China
| | - Siyun Lei
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
| | - Yingqian Chai
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
| | - Jianghua Xu
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
| | - Youchao Wang
- Chimie ParisTech, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, PSL University, CNRS, Paris, 75005, France
| | - Chenghu Wu
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
| | - Hongyi Jiang
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
| | - Shanshan Yuan
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
| | - Jilong Wang
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China
| | - Jie Lyu
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China.
| | - Mingqin Lu
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China.
| | - Junjie Deng
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China.
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, Zhejiang, China.
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25
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Wang J, Shi R, Yin Y, Luo H, Cao Y, Lyu Y, Luo H, Zeng X, Wang D. Clinical significance of small extracellular vesicles in cholangiocarcinoma. Front Oncol 2024; 14:1334592. [PMID: 38665948 PMCID: PMC11043544 DOI: 10.3389/fonc.2024.1334592] [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: 11/07/2023] [Accepted: 03/28/2024] [Indexed: 04/28/2024] Open
Abstract
Cholangiocarcinoma is an aggressive and heterogeneous malignancy originating from the bile duct epithelium. It is associated with poor prognosis and high mortality. The global incidence of cholangiocarcinoma is rising, and there is an urgent need for effective early diagnosis and treatment strategies to reduce the burden of this devastating tumor. Small extracellular vesicles, including exosomes and microparticles, are nanoscale vesicles formed by membranes that are released both normally and pathologically from cells, mediating the intercellular transfer of substances and information. Recent studies have demonstrated the involvement of small extracellular vesicles in numerous biological processes, as well as the proliferation, invasion, and metastasis of tumor cells. The present review summarizes the tumorigenic roles of small extracellular vesicles in the cholangiocarcinoma microenvironment. Owing to their unique composition, accessibility, and stability in biological fluids, small extracellular vesicles have emerged as ideal biomarkers for use in liquid biopsies for diagnosing and outcome prediction of cholangiocarcinoma. Specific tissue tropism, theoretical biocompatibility, low clearance, and strong biological barrier penetration of small extracellular vesicles make them suitable drug carriers for cancer therapy. Furthermore, the potential value of small extracellular vesicle-based therapies for cholangiocarcinoma is also reviewed.
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Affiliation(s)
- Jianjun Wang
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Ruizi Shi
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Yuan Yin
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Hua Luo
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Yuan Cao
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Yun Lyu
- Departmant of Oncology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Huiwen Luo
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Xintao Zeng
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Decai Wang
- National Health Commission (NHC) Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
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26
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Freise C, Biskup K, Blanchard V, Schnorr J, Taupitz M. Inorganic Phosphate-Induced Extracellular Vesicles from Vascular Smooth Muscle Cells Contain Elevated Levels of Hyaluronic Acid, Which Enhance Their Interaction with Very Small Superparamagnetic Iron Oxide Particles. Int J Mol Sci 2024; 25:2571. [PMID: 38473817 DOI: 10.3390/ijms25052571] [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: 02/08/2024] [Revised: 02/18/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
Patients with chronic kidney disease (CKD) have a high prevalence of hyperphosphatemia, where uremic toxins like inorganic phosphate (Pi) induce a cardiovascular remodeling. Related disorders like atherosclerosis bear the risk of increased morbidity and mortality. We previously found that Pi stimulates the synthesis and sulfation of the negatively charged glycosaminoglycans (GAGs) heparan sulfate and chondroitin sulfate in vascular smooth muscle cells (VSMC). Similar GAG alterations were detected in VSMC-derived exosome-like extracellular vesicles (EV). These EV showed a strong interaction with very small superparamagnetic iron oxide particles (VSOP), which are used as imaging probes for experimental magnetic resonance imaging (MRI). Hyaluronic acid (HA) represents another negatively charged GAG which is supposed to function as binding motif for VSOP as well. We investigated the effects of Pi on the amounts of HA in cells and EV and studied the HA-dependent interaction between VSOP with cells and EV. Rat VSMC were treated with elevated concentrations of Pi. CKD in rats was induced by adenine feeding. EV were isolated from culture supernatants and rat plasma. We investigated the role of HA in binding VSOP to cells and EV via cell-binding studies, proton relaxometry, and analysis of cellular signaling, genes, proteins, and HA contents. Due to elevated HA contents, VSMC and EV showed an increased interaction with VSOP after Pi stimulation. Amongst others, Pi induced hyaluronan synthase (HAS)2 expression and activation of the Wnt pathway in VSMC. An alternative upregulation of HA by iloprost and an siRNA-mediated knockdown of HAS2 confirmed the importance of HA in cells and EV for VSOP binding. The in vitro-derived data were validated by analyses of plasma-derived EV from uremic rats. In conclusion, the inorganic uremic toxin Pi induces HA synthesis in cells and EV, which leads to an increased interaction with VSOP. HA might therefore be a potential molecular target structure for improved detection of pathologic tissue changes secondary to CKD like atherosclerosis or cardiomyopathy using EV, VSOP and MRI.
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Affiliation(s)
- Christian Freise
- Department of Radiology, Campus Mitte, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Karina Biskup
- Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Department of Human Medicine, Medical School Berlin, Rüdesheimer Str. 50, 14197 Berlin, Germany
| | - Véronique Blanchard
- Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Department of Human Medicine, Medical School Berlin, Rüdesheimer Str. 50, 14197 Berlin, Germany
| | - Jörg Schnorr
- Department of Radiology, Campus Mitte, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Matthias Taupitz
- Department of Radiology, Campus Mitte, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
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Gulati R, Mitra T, Rajiv R, Rajan EJE, Pierret C, Enninga EAL, Janardhanan R. Exosomal microRNAs in breast cancer: towards theranostic applications. Front Mol Biosci 2024; 11:1330144. [PMID: 38455764 PMCID: PMC10918471 DOI: 10.3389/fmolb.2024.1330144] [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: 10/30/2023] [Accepted: 01/29/2024] [Indexed: 03/09/2024] Open
Abstract
Breast cancer is one of the top two reproductive cancers responsible for high rates of morbidity and mortality among women globally. Despite the advancements in the treatment of breast cancer, its early diagnosis remains a challenge. Recent evidence indicates that despite the adroit use of numerous strategies to facilitate rapid and precision-oriented screening of breast cancer at the community level through the use of mammograms, Fine-needle aspiration cytology (FNAC) and biomarker tracking, no strategy has been unequivocally accepted as a gold standard for facilitating rapid screening for disease. This necessitates the need to identify novel strategies for the detection and triage of breast cancer lesions at higher rates of specificity, and sensitivity, whilst taking into account the epidemiologic and social-demographic features of the patients. Recent shreds of evidence indicate that exosomes could be a robust source of biomaterial for the rapid screening of breast cancer due to their high stability and their presence in body fluids. Increasing evidence indicates that the Exosomal microRNAs- play a significant role in modifying the tumour microenvironment of breast cancers, thereby potentially aiding in the proliferation, invasion and metastasis of breast cancer. In this review, we summarize the role of ExomiRs in the tumour microenvironment in breast cancer. These ExomiRs can also be used as candidate biomarkers for facilitating rapid screening and triaging of breast cancer patients for clinical intervention.
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Affiliation(s)
- Richa Gulati
- Division of Medical Research, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Tridip Mitra
- Division of Medical Research, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Rohan Rajiv
- Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PA, United States
| | - Emilda Judith Ezhil Rajan
- Division of Medical Research, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Chris Pierret
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States
| | | | - Rajiv Janardhanan
- Division of Medical Research, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
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Yu L, Zeng X, Hu X, Wen Q, Chen P. Advances and challenges in clinical applications of tumor cell-derived extracellular vesicles. Colloids Surf B Biointerfaces 2024; 234:113704. [PMID: 38113751 DOI: 10.1016/j.colsurfb.2023.113704] [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: 09/27/2023] [Revised: 12/05/2023] [Accepted: 12/07/2023] [Indexed: 12/21/2023]
Abstract
Extracellular vesicles (EVs) are a class of substances that feature vesicle-like structures. Initially deemed to be "biological waste", recent studies have highlighted the crucial role of EVs in mediating information communication between cells by transporting bioactive components. Specifically, tumor cell-derived extracellular vesicles (TEVs) contain components that can be utilized for disease diagnosis and as vaccines to activate the immune system. Moreover, since TEVs have a phospholipid bilayer shell and can transport exogenous substances, they are being increasingly explored as drug delivery vehicles in anti-tumor therapy. TEVs have proven highly compatible with their corresponding tumor cells, allowing for efficient drug delivery and exerting killing effects on tumor cells through various mechanisms such as domino effects, lysosomal pathways, and inhibition of drug efflux from tumor tissues. Despite these promising developments, challenges remain in the clinical applications of EVs derived from tumor cells. This paper outlines the current advances and limitations in this field, highlighting the potential of TEVs as a powerful tool for combating cancer.
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Affiliation(s)
- Li Yu
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Oncology, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, China
| | - Xiaonan Zeng
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Xiao Hu
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Oncology, the Second Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Qinglian Wen
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Ping Chen
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
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29
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Fang F, Yang J, Wang J, Li T, Wang E, Zhang D, Liu X, Zhou C. The role and applications of extracellular vesicles in osteoporosis. Bone Res 2024; 12:4. [PMID: 38263267 PMCID: PMC10806231 DOI: 10.1038/s41413-023-00313-5] [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: 09/14/2023] [Revised: 11/13/2023] [Accepted: 11/28/2023] [Indexed: 01/25/2024] Open
Abstract
Osteoporosis is a widely observed condition characterized by the systemic deterioration of bone mass and microarchitecture, which increases patient susceptibility to fragile fractures. The intricate mechanisms governing bone homeostasis are substantially impacted by extracellular vesicles (EVs), which play crucial roles in both pathological and physiological contexts. EVs derived from various sources exert distinct effects on osteoporosis. Specifically, EVs released by osteoblasts, endothelial cells, myocytes, and mesenchymal stem cells contribute to bone formation due to their unique cargo of proteins, miRNAs, and cytokines. Conversely, EVs secreted by osteoclasts and immune cells promote bone resorption and inhibit bone formation. Furthermore, the use of EVs as therapeutic modalities or biomaterials for diagnosing and managing osteoporosis is promising. Here, we review the current understanding of the impact of EVs on bone homeostasis, including the classification and biogenesis of EVs and the intricate regulatory mechanisms of EVs in osteoporosis. Furthermore, we present an overview of the latest research progress on diagnosing and treating osteoporosis by using EVs. Finally, we discuss the challenges and prospects of translational research on the use of EVs in osteoporosis.
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Affiliation(s)
- Fei Fang
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Jie Yang
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Jiahe Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Tiantian Li
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Erxiang Wang
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Demao Zhang
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Xiaoheng Liu
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China.
| | - Chenchen Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
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30
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Witz A, Dardare J, Betz M, Gilson P, Merlin JL, Harlé A. Tumor-derived cell-free DNA and circulating tumor cells: partners or rivals in metastasis formation? Clin Exp Med 2024; 24:2. [PMID: 38231464 PMCID: PMC10794481 DOI: 10.1007/s10238-023-01278-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 11/20/2023] [Indexed: 01/18/2024]
Abstract
The origin of metastases is a topic that has sparked controversy. Despite recent advancements, metastatic disease continues to pose challenges. The first admitted model of how metastases develop revolves around cells breaking away from the primary tumor, known as circulating tumor cells (CTCs). These cells survive while circulating through the bloodstream and subsequently establish themselves in secondary organs, a process often referred to as the "metastatic cascade". This intricate and dynamic process involves various steps, but all the mechanisms behind metastatic dissemination are not yet comprehensively elucidated. The "seed and soil" theory has shed light on the phenomenon of metastatic organotropism and the existence of pre-metastatic niches. It is now established that these niches can be primed by factors secreted by the primary tumor before the arrival of CTCs. In particular, exosomes have been identified as important contributors to this priming. Another concept then emerged, i.e. the "genometastasis" theory, which challenged all other postulates. It emphasizes the intriguing but promising role of cell-free DNA (cfDNA) in metastasis formation through oncogenic formation of recipient cells. However, it cannot be ruled out that all these theories are intertwined. This review outlines the primary theories regarding the metastases formation that involve CTCs, and depicts cfDNA, a potential second player in the metastasis formation. We discuss the potential interrelationships between CTCs and cfDNA, and propose both in vitro and in vivo experimental strategies to explore all plausible theories.
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Affiliation(s)
- Andréa Witz
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France.
| | - Julie Dardare
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
| | - Margaux Betz
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
| | - Pauline Gilson
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
| | - Jean-Louis Merlin
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
| | - Alexandre Harlé
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
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Catalano M, Limatola C, Trettel F. Non-neoplastic astrocytes: key players for brain tumor progression. Front Cell Neurosci 2024; 17:1352130. [PMID: 38293652 PMCID: PMC10825036 DOI: 10.3389/fncel.2023.1352130] [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: 12/07/2023] [Accepted: 12/26/2023] [Indexed: 02/01/2024] Open
Abstract
Astrocytes are highly plastic cells whose activity is essential to maintain the cerebral homeostasis, regulating synaptogenesis and synaptic transmission, vascular and metabolic functions, ions, neuro- and gliotransmitters concentrations. In pathological conditions, astrocytes may undergo transient or long-lasting molecular and functional changes that contribute to disease resolution or exacerbation. In recent years, many studies demonstrated that non-neoplastic astrocytes are key cells of the tumor microenvironment that contribute to the pathogenesis of glioblastoma, the most common primary malignant brain tumor and of secondary metastatic brain tumors. This Mini Review covers the recent development of research on non-neoplastic astrocytes as tumor-modulators. Their double-edged capability to promote cancer progression or to represent potential tools to counteract brain tumors will be discussed.
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Affiliation(s)
- Myriam Catalano
- Laboratory of Neuroimmunology, Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Cristina Limatola
- Laboratory of Neuroimmunology, Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
- IRCCS Neuromed, Pozzilli, Italy
| | - Flavia Trettel
- Laboratory of Neuroimmunology, Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
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Van Dorpe S, Tummers P, Denys H, Hendrix A. Towards the Clinical Implementation of Extracellular Vesicle-Based Biomarker Assays for Cancer. Clin Chem 2024; 70:165-178. [PMID: 38175582 DOI: 10.1093/clinchem/hvad189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 10/24/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Substantial research has been devoted to elucidating the role of extracellular vesicles (EVs) in the different hallmarks of cancer. Consequently, EVs are increasingly explored as a source of cancer biomarkers in body fluids. However, the heterogeneity in EVs, the complexity of body fluids, and the diversity in methods available for EV analysis, challenge the development and translation of EV-based biomarker assays. CONTENT Essential steps in EV-associated biomarker development are emphasized covering biobanking, biomarker discovery, verification and validation, and clinical implementation. A meticulous study design is essential and ideally results from close interactions between clinicians and EV researchers. A plethora of different EV preparation protocols exists which warrants quality control and transparency to ensure reproducibility and thus enable verification of EV-associated biomarker candidates identified in the discovery phase in subsequent independent cohorts. The development of an EV-associated biomarker assay requires thorough analytical and clinical validation. Finally, regulatory affairs must be considered for clinical implementation of EV-based biomarker assays. SUMMARY In this review, the current challenges that prevent us from exploiting the full potential of EV-based biomarker assays are identified. Guidelines and tools to overcome these hurdles are highlighted and are crucial to advance EV-based biomarker assays into clinical use.
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Affiliation(s)
- Sofie Van Dorpe
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
- Department of Gynecology, Ghent University Hospital, Ghent, Belgium
| | - Philippe Tummers
- Department of Gynecology, Ghent University Hospital, Ghent, Belgium
| | - Hannelore Denys
- Cancer Research Institute Ghent, Ghent, Belgium
- Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium
| | - An Hendrix
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent, Ghent, Belgium
- European Liquid Biopsy Society (ELBS), Hamburg, Germany
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Bolumar D, Moncayo-Arlandi J, Gonzalez-Fernandez J, Ochando A, Moreno I, Monteagudo-Sanchez A, Marin C, Diez A, Fabra P, Checa MA, Espinos JJ, Gardner DK, Simon C, Vilella F. Vertical transmission of maternal DNA through extracellular vesicles associates with altered embryo bioenergetics during the periconception period. eLife 2023; 12:RP88008. [PMID: 38149847 PMCID: PMC10752591 DOI: 10.7554/elife.88008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2023] Open
Abstract
The transmission of DNA through extracellular vesicles (EVs) represents a novel genetic material transfer mechanism that may impact genome evolution and tumorigenesis. We aimed to investigate the potential for vertical DNA transmission within maternal endometrial EVs to the pre-implantation embryo and describe any effect on embryo bioenergetics. We discovered that the human endometrium secretes all three general subtypes of EV - apoptotic bodies (ABs), microvesicles (MVs), and exosomes (EXOs) - into the human endometrial fluid (EF) within the uterine cavity. EVs become uniformly secreted into the EF during the menstrual cycle, with the proportion of different EV populations remaining constant; however, MVs contain significantly higher levels of mitochondrial (mt)DNA than ABs or EXOs. During the window of implantation, MVs contain an eleven-fold higher level of mtDNA when compared to cells-of-origin within the receptive endometrium, which possesses a lower mtDNA content and displays the upregulated expression of mitophagy-related genes. Furthermore, we demonstrate the internalization of EV-derived nuclear-encoded (n)DNA/mtDNA by trophoblast cells of murine embryos, which associates with a reduction in mitochondrial respiration and ATP production. These findings suggest that the maternal endometrium suffers a reduction in mtDNA content during the preconceptional period, that nDNA/mtDNA become packaged into secreted EVs that the embryo uptakes, and that the transfer of DNA to the embryo within EVs occurs alongside the modulation of bioenergetics during implantation.
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Affiliation(s)
- David Bolumar
- Igenomix Foundation, INCLIVA Health Research InstituteValenciaSpain
| | | | | | - Ana Ochando
- Carlos Simon Foundation, INCLIVA Health Research InstituteValenciaSpain
| | - Inmaculada Moreno
- Carlos Simon Foundation, INCLIVA Health Research InstituteValenciaSpain
| | | | - Carlos Marin
- Igenomix Foundation, INCLIVA Health Research InstituteValenciaSpain
| | - Antonio Diez
- Igenomix Foundation, INCLIVA Health Research InstituteValenciaSpain
| | | | - Miguel Angel Checa
- Clinica FerttyBarcelonaSpain
- Department of Medicine and Life Sciences, University Pompeu FabraBarcelonaSpain
| | - Juan Jose Espinos
- Clinica FerttyBarcelonaSpain
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, UABBellaterraSpain
| | - David K Gardner
- School of Biosciences, University of MelbourneParkvilleAustralia
- Melbourne IVFEast MelbourneAustralia
| | - Carlos Simon
- Carlos Simon Foundation, INCLIVA Health Research InstituteValenciaSpain
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of ValenciaValenciaSpain
- Department of Obstetrics and Gynecology, BIDMC, Harvard UniversityBostonUnited States
| | - Felipe Vilella
- Carlos Simon Foundation, INCLIVA Health Research InstituteValenciaSpain
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Wei YN, Yan CY, Zhao ML, Zhao XH. The role and application of vesicles in triple-negative breast cancer: Opportunities and challenges. Mol Ther Oncolytics 2023; 31:100752. [PMID: 38130701 PMCID: PMC10733704 DOI: 10.1016/j.omto.2023.100752] [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] [Indexed: 12/23/2023] Open
Abstract
Extracellular vesicles (EVs) carry DNA, RNA, protein, and other substances involved in intercellular crosstalk and can be used for the targeted delivery of drugs. Triple-negative breast cancer (TNBC) is rich in recurrent and metastatic disease and lacks therapeutic targets. Studies have proved the role of EVs in the different stages of the genesis and development of TNBC. Cancer cells actively secrete various biomolecules, which play a significant part establishing the tumor microenvironment via EVs. In this article, we describe the roles of EVs in the tumor immune microenvironment, metabolic microenvironment, and vascular remodeling, and summarize the application of EVs for objective delivery of chemotherapeutic drugs, immune antigens, and cancer vaccine adjuvants. EVs-based therapy may represent the next-generation tool for targeted drug delivery for the cure of a variety of diseases lacking effective drug treatment.
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Affiliation(s)
- Ya-Nan Wei
- Department of Clinical Oncology, Sheng jing Hospital of China Medical University, Shenyang 110022, People’s Republic of China
| | - Chun-Yan Yan
- Department of Clinical Oncology, Sheng jing Hospital of China Medical University, Shenyang 110022, People’s Republic of China
| | - Meng-Lu Zhao
- Department of Clinical Oncology, Sheng jing Hospital of China Medical University, Shenyang 110022, People’s Republic of China
| | - Xi-He Zhao
- Department of Clinical Oncology, Sheng jing Hospital of China Medical University, Shenyang 110022, People’s Republic of China
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35
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Schmidtmann M, D’Souza-Schorey C. Extracellular Vesicles: Biological Packages That Modulate Tumor Cell Invasion. Cancers (Basel) 2023; 15:5617. [PMID: 38067320 PMCID: PMC10705367 DOI: 10.3390/cancers15235617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 11/20/2023] [Accepted: 11/21/2023] [Indexed: 02/12/2024] Open
Abstract
Tumor progression, from early-stage invasion to the formation of distal metastases, relies on the capacity of tumor cells to modify the extracellular matrix (ECM) and communicate with the surrounding stroma. Extracellular vesicles (EVs) provide an important means to regulate cell invasion due to the selective inclusion of cargoes such as proteases and matrix proteins into EVs that can degrade or modify the ECM. EVs have also been shown to facilitate intercellular communication in the tumor microenvironment through paracrine signaling, which can impact ECM invasion by cancer cells. Here, we describe the current knowledge of EVs as facilitators of tumor invasion by virtue of their effects on proteolytic degradation and modification of the ECM, their ability to educate the stromal cells in the tumor microenvironment, and their role as mediators of long-range communication aiding in cell invasion and matrix remodeling at secondary sites.
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36
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Osten F, Löscher W, Gericke B. Human brain microvascular endothelial cells release different types of P-glycoprotein-containing extracellular vesicles upon exposure to doxorubicin. Toxicol Appl Pharmacol 2023; 479:116712. [PMID: 37820772 DOI: 10.1016/j.taap.2023.116712] [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: 05/05/2023] [Revised: 09/26/2023] [Accepted: 10/06/2023] [Indexed: 10/13/2023]
Abstract
In the brain, the efflux transporter P-glycoprotein (Pgp) is predominantly located on the luminal membrane of microvascular endothelial cells (BMECs) that form the blood-brain barrier. In addition, Pgp is localized in intracellular organelles involved in Pgp traffic and cycling and, by the release of extracellular vesicles (EVs), in intercellular Pgp transfer to cells with low Pgp expression. We recently described that drug exposure of a human BMEC line (hCMEC/D3) induces the release of Pgp-EGFP-containing EVs; however, the nature of the Pgp-enriched vesicles was not characterized. The two main categories of EVs are exosomes and microvesicles, which differ in origin, size, and molecular cargo. In the present study, we performed similar experiments with hCMEC/D3 cells in the absence and presence of doxorubicin and isolated and characterized the EVs released by the cells during the experiments by differential ultracentrifugation with/without subsequent sucrose gradient fractionation of EV pellets, proteomic profiling, EV size analysis, and confocal fluorescence microscopy. Using cocultures of hCMEC/D3 wildtype cells and cells transduced with MDR1-EGFP or monocultures of hCMEC/D3-MDR1-EGFP cells, we found release of both Pgp-enriched exosomes and microvesicles but analysis of the exosomal marker protein Rab7 indicated that doxorubicin increased particularly the release of exosomes. Transfer experiments with isolated EVs demonstrated EV endocytosis by recipient cells. EV release from BMECs in response to anticancer drugs such as doxorubicin likely serves different functions, including non-genetic intercellular transfer of a resistance phenotype to neighboring BMECs and a mechanism of drug extrusion that contributes to brain protection against potentially toxic chemotherapeutic drugs.
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Affiliation(s)
- Felix Osten
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany
| | - Wolfgang Löscher
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany; Translational Neuropharmacology Lab, NIFE, Department of Experimental Otology of the ENT Clinics, Hannover Medical School, Hannover, Germany.
| | - Birthe Gericke
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
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37
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Novais AA, Tamarindo GH, Chuffa LGDA, Zuccari DAPDC. Decoding Hidden Messengers: Proteomic Profiling of Exosomes in Mammary Cancer Research. Biomedicines 2023; 11:2839. [PMID: 37893211 PMCID: PMC10604896 DOI: 10.3390/biomedicines11102839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 10/11/2023] [Accepted: 10/14/2023] [Indexed: 10/29/2023] Open
Abstract
Cancer is a complex and heterogeneous disease, influenced by various factors that affect its progression and response to treatment. Although a histopathological diagnosis is crucial for identifying and classifying cancer, it may not accurately predict the disease's development and evolution in all cases. To address this limitation, liquid biopsy has emerged as a valuable tool, enabling a more precise and non-invasive analysis of cancer. Liquid biopsy can detect tumor DNA fragments, circulating tumor cells, and exosomes released by cancer cells into the bloodstream. Exosomes attracted significant attention in cancer research because of their specific protein composition, which can provide valuable insights into the disease. The protein profile of exosomes often differs from that of normal cells, reflecting the unique molecular characteristics of cancer. Analyzing these proteins can help identify cancer-associated markers that play important roles in tumor progression, invasion, and metastasis. Ongoing research and clinical validation are essential to advance and effectively utilize protein biomarkers in cancer. Nevertheless, their potential to improve diagnosis and treatment is highly promising. This review discusses several exosome proteins of interest in breast cancer, particularly focusing on studies conducted in mammary tissue and cell lines in humans and experimental animals. Unfortunately, studies conducted in canine species are scarce. This emphasis sheds light on the limited research available in this field. In addition, we present a curated selection of studies that explored exosomal proteins as potential biomarkers, aiming to achieve benefits in breast cancer diagnosis, prognosis, monitoring, and treatment.
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Affiliation(s)
- Adriana Alonso Novais
- Health Sciences Institute (ICS), Universidade Federal de Mato Grosso (UFMT), Sinop 78550-728, Brazil;
| | - Guilherme Henrique Tamarindo
- Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials (CNPEM), Campinas 13083-970, Brazil;
- Cancer Molecular Research Laboratory (LIMC), Department of Molecular Biology, Faculdade de Medicina de São José do Rio Preto/FAMERP (FAMERP), São José do Rio Preto 15090-000, Brazil
| | - Luiz Gustavo de Almeida Chuffa
- Department of Structural and Functional Biology, Institute of Biosciences, Universidade Estadual Paulista (UNESP), Botucatu 18618-689, Brazil;
| | - Debora Aparecida Pires de Campos Zuccari
- Cancer Molecular Research Laboratory (LIMC), Department of Molecular Biology, Faculdade de Medicina de São José do Rio Preto/FAMERP (FAMERP), São José do Rio Preto 15090-000, Brazil
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38
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Rani S, Lai A, Nair S, Sharma S, Handberg A, Carrion F, Möller A, Salomon C. Extracellular vesicles as mediators of cell-cell communication in ovarian cancer and beyond - A lipids focus. Cytokine Growth Factor Rev 2023; 73:52-68. [PMID: 37423866 DOI: 10.1016/j.cytogfr.2023.06.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 06/29/2023] [Indexed: 07/11/2023]
Abstract
Extracellular vesicles (EVs) are messengers that carry information in the form of proteins, lipids, and nucleic acids and are not only essential for intercellular communication but also play a critical role in the progression of various pathologies, including ovarian cancer. There has been recent substantial research characterising EV cargo, specifically, the lipid profile of EVs. Lipids are involved in formation and cargo sorting of EVs, their release and cellular uptake. Numerous lipidomic studies demonstrated the enrichment of specific classes of lipids in EVs derived from cancer cells suggesting that the EV associated lipids can potentially be employed as minimally invasive biomarkers for early diagnosis of various malignancies, including ovarian cancer. In this review, we aim to provide a general overview of the heterogeneity of EV, biogenesis, their lipid content, and function in cancer progression focussing on ovarian cancer.
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Affiliation(s)
- Shikha Rani
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, University of Queensland Centre for Clinical Research, Faculty of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, QLD 4029, Australia
| | - Andrew Lai
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, University of Queensland Centre for Clinical Research, Faculty of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, QLD 4029, Australia
| | - Soumya Nair
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, University of Queensland Centre for Clinical Research, Faculty of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, QLD 4029, Australia
| | - Shayna Sharma
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, University of Queensland Centre for Clinical Research, Faculty of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, QLD 4029, Australia
| | - Aase Handberg
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Flavio Carrion
- Departamento de Investigación, Postgrado y Educación Continua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago, Chile
| | - Andreas Möller
- Department of Otorhinolaryngology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong
| | - Carlos Salomon
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, University of Queensland Centre for Clinical Research, Faculty of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Brisbane, QLD 4029, Australia; Departamento de Investigación, Postgrado y Educación Continua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago, Chile.
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Lin W, Fang J, Wei S, He G, Liu J, Li X, Peng X, Li D, Yang S, Li X, Yang L, Li H. Extracellular vesicle-cell adhesion molecules in tumours: biofunctions and clinical applications. Cell Commun Signal 2023; 21:246. [PMID: 37735659 PMCID: PMC10512615 DOI: 10.1186/s12964-023-01236-8] [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: 04/09/2023] [Accepted: 07/18/2023] [Indexed: 09/23/2023] Open
Abstract
Cell adhesion molecule (CAM) is an umbrella term for several families of molecules, including the cadherin family, integrin family, selectin family, immunoglobulin superfamily, and some currently unclassified adhesion molecules. Extracellular vesicles (EVs) are important information mediators in cell-to-cell communication. Recent evidence has confirmed that CAMs transported by EVs interact with recipient cells to influence EV distribution in vivo and regulate multiple cellular processes. This review focuses on the loading of CAMs onto EVs, the roles of CAMs in regulating EV distribution, and the known and possible mechanisms of these actions. Moreover, herein, we summarize the impacts of CAMs transported by EVs to the tumour microenvironment (TME) on the malignant behaviour of tumour cells (proliferation, metastasis, immune escape, and so on). In addition, from the standpoint of clinical applications, the significance and challenges of using of EV-CAMs in the diagnosis and therapy of tumours are discussed. Finally, considering recent advances in the understanding of EV-CAMs, we outline significant challenges in this field that require urgent attention to advance research and promote the clinical applications of EV-CAMs. Video Abstract.
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Affiliation(s)
- Weikai Lin
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Jianjun Fang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Shibo Wei
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Guangpeng He
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Jiaxing Liu
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Xian Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Xueqiang Peng
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Dai Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Shuo Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Xinyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Liang Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China.
| | - Hangyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China.
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Löser R, Kuchar M, Wodtke R, Neuber C, Belter B, Kopka K, Santhanam L, Pietzsch J. Lysyl Oxidases as Targets for Cancer Therapy and Diagnostic Imaging. ChemMedChem 2023; 18:e202300331. [PMID: 37565736 DOI: 10.1002/cmdc.202300331] [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: 06/28/2023] [Revised: 08/10/2023] [Accepted: 08/11/2023] [Indexed: 08/12/2023]
Abstract
The understanding of the contribution of the tumour microenvironment to cancer progression and metastasis, in particular the interplay between tumour cells, fibroblasts and the extracellular matrix has grown tremendously over the last years. Lysyl oxidases are increasingly recognised as key players in this context, in addition to their function as drivers of fibrotic diseases. These insights have considerably stimulated drug discovery efforts towards lysyl oxidases as targets over the last decade. This review article summarises the biochemical and structural properties of theses enzymes. Their involvement in tumour progression and metastasis is highlighted from a biochemical point of view, taking into consideration both the extracellular and intracellular action of lysyl oxidases. More recently reported inhibitor compounds are discussed with an emphasis on their discovery, structure-activity relationships and the results of their biological characterisation. Molecular probes developed for imaging of lysyl oxidase activity are reviewed from the perspective of their detection principles, performance and biomedical applications.
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Affiliation(s)
- Reik Löser
- Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Mommsenstraße 4, 01069, Dresden, Germany
| | - Manuela Kuchar
- Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
| | - Robert Wodtke
- Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
| | - Christin Neuber
- Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
| | - Birgit Belter
- Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
| | - Klaus Kopka
- Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Mommsenstraße 4, 01069, Dresden, Germany
| | - Lakshmi Santhanam
- Departments of Anesthesiology and Critical Care Medicine and Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21287, USA
| | - Jens Pietzsch
- Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Mommsenstraße 4, 01069, Dresden, Germany
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Mitchell MI, Loudig O. Communicator Extraordinaire: Extracellular Vesicles in the Tumor Microenvironment Are Essential Local and Long-Distance Mediators of Cancer Metastasis. Biomedicines 2023; 11:2534. [PMID: 37760975 PMCID: PMC10526527 DOI: 10.3390/biomedicines11092534] [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: 06/16/2023] [Revised: 08/30/2023] [Accepted: 09/03/2023] [Indexed: 09/29/2023] Open
Abstract
Human tumors are increasingly being described as a complex "ecosystem", that includes many different cell types, secreted growth factors, extracellular matrix (ECM) components, and microvessels, that altogether create the tumor microenvironment (TME). Within the TME, epithelial cancer cells control the function of surrounding stromal cells and the non-cellular ECM components in an intricate orchestra of signaling networks specifically designed for cancer cells to exploit surrounding cells for their own benefit. Tumor-derived extracellular vesicles (EVs) released into the tumor microenvironment are essential mediators in the reprogramming of surrounding stromal cells, which include cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), and tumor endothelial cells (TECs), which are responsible for the promotion of neo-angiogenesis, immune cell evasion, and invasion which are essential for cancer progression. Perhaps most importantly, tumor-derived EVs play critical roles in the metastatic dissemination of tumor cells through their two-fold role in initiating cancer cell invasion and the establishment of the pre-metastatic niche, both of which are vital for tumor cell migration, homing, and colonization at secondary tumor sites. This review discusses extracellular vesicle trafficking within the tumor microenvironment and pre-metastatic niche formation, focusing on the complex role that EVs play in orchestrating cancer-to-stromal cell communication in order to promote the metastatic dissemination of cancer cells.
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Affiliation(s)
| | - Olivier Loudig
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA;
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Murillo Carrasco AG, Otake AH, Macedo-da-Silva J, Feijoli Santiago V, Palmisano G, Andrade LNDS, Chammas R. Deciphering the Functional Status of Breast Cancers through the Analysis of Their Extracellular Vesicles. Int J Mol Sci 2023; 24:13022. [PMID: 37629204 PMCID: PMC10455604 DOI: 10.3390/ijms241613022] [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: 06/30/2023] [Revised: 08/10/2023] [Accepted: 08/18/2023] [Indexed: 08/27/2023] Open
Abstract
Breast cancer (BC) accounts for the highest incidence of tumor-related mortality among women worldwide, justifying the growing search for molecular tools for the early diagnosis and follow-up of BC patients under treatment. Circulating extracellular vesicles (EVs) are membranous nanocompartments produced by all human cells, including tumor cells. Since minimally invasive methods collect EVs, which represent reservoirs of signals for cell communication, these particles have attracted the interest of many researchers aiming to improve BC screening and treatment. Here, we analyzed the cargoes of BC-derived EVs, both proteins and nucleic acids, which yielded a comprehensive list of potential markers divided into four distinct categories, namely, (i) modulation of aggressiveness and growth; (ii) preparation of the pre-metastatic niche; (iii) epithelial-to-mesenchymal transition; and (iv) drug resistance phenotype, further classified according to their specificity and sensitivity as vesicular BC biomarkers. We discuss the therapeutic potential of and barriers to the clinical implementation of EV-based tests, including the heterogeneity of EVs and the available technologies for analyzing their content, to present a consistent, reproducible, and affordable set of markers for further evaluation.
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Affiliation(s)
- Alexis Germán Murillo Carrasco
- Center for Translational Research in Oncology (LIM24), Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), São Paulo 01246-000, Brazil; (A.G.M.C.); (A.H.O.); (L.N.d.S.A.)
- Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo 01246-000, Brazil
| | - Andreia Hanada Otake
- Center for Translational Research in Oncology (LIM24), Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), São Paulo 01246-000, Brazil; (A.G.M.C.); (A.H.O.); (L.N.d.S.A.)
- Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo 01246-000, Brazil
| | - Janaina Macedo-da-Silva
- Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-000, Brazil; (J.M.-d.-S.); (V.F.S.); (G.P.)
| | - Veronica Feijoli Santiago
- Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-000, Brazil; (J.M.-d.-S.); (V.F.S.); (G.P.)
| | - Giuseppe Palmisano
- Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-000, Brazil; (J.M.-d.-S.); (V.F.S.); (G.P.)
- School of Natural Sciences, Macquarie University, Macquarie Park, NSW 2109, Australia
| | - Luciana Nogueira de Sousa Andrade
- Center for Translational Research in Oncology (LIM24), Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), São Paulo 01246-000, Brazil; (A.G.M.C.); (A.H.O.); (L.N.d.S.A.)
- Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo 01246-000, Brazil
| | - Roger Chammas
- Center for Translational Research in Oncology (LIM24), Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), São Paulo 01246-000, Brazil; (A.G.M.C.); (A.H.O.); (L.N.d.S.A.)
- Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo 01246-000, Brazil
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Hu X, Ma Z, Xu B, Li S, Yao Z, Liang B, Wang J, Liao W, Lin L, Wang C, Zheng S, Wu Q, Huang Q, Yu L, Wang F, Shi M. Glutamine metabolic microenvironment drives M2 macrophage polarization to mediate trastuzumab resistance in HER2-positive gastric cancer. Cancer Commun (Lond) 2023; 43:909-937. [PMID: 37434399 PMCID: PMC10397568 DOI: 10.1002/cac2.12459] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 01/04/2023] [Accepted: 06/21/2023] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND Trastuzumab is a first-line targeted therapy for human epidermal growth factor receptor-2 (HER2)-positive gastric cancer. However, the inevitable occurrence of acquired trastuzumab resistance limits the drug benefit, and there is currently no effective reversal measure. Existing researches on the mechanism of trastuzumab resistance mainly focused on tumor cells themselves, while the understanding of the mechanisms of environment-mediated drug resistance is relatively lacking. This study aimed to further explore the mechanisms of trastuzumab resistance to identify strategies to promote survival in these patients. METHODS Trastuzumab-sensitive and trastuzumab-resistant HER2-positive tumor tissues and cells were collected for transcriptome sequencing. Bioinformatics were used to analyze cell subtypes, metabolic pathways, and molecular signaling pathways. Changes in microenvironmental indicators (such as macrophage, angiogenesis, and metabolism) were verified by immunofluorescence (IF) and immunohistochemical (IHC) analyses. Finally, a multi-scale agent-based model (ABM) was constructed. The effects of combination treatment were further validated in nude mice to verify these effects predicted by the ABM. RESULTS Based on transcriptome sequencing, molecular biology, and in vivo experiments, we found that the level of glutamine metabolism in trastuzumab-resistant HER2-positive cells was increased, and glutaminase 1 (GLS1) was significantly overexpressed. Meanwhile, tumor-derived GLS1 microvesicles drove M2 macrophage polarization. Furthermore, angiogenesis promoted trastuzumab resistance. IHC showed high glutamine metabolism, M2 macrophage polarization, and angiogenesis in trastuzumab-resistant HER2-positive tumor tissues from patients and nude mice. Mechanistically, the cell division cycle 42 (CDC42) promoted GLS1 expression in tumor cells by activating nuclear factor kappa-B (NF-κB) p65 and drove GLS1 microvesicle secretion through IQ motif-containing GTPase-activating protein 1 (IQGAP1). Based on the ABM and in vivo experiments, we confirmed that the combination of anti-glutamine metabolism, anti-angiogenesis, and pro-M1 polarization therapy had the best effect in reversing trastuzumab resistance in HER2-positive gastric cancer. CONCLUSIONS This study revealed that tumor cells secrete GLS1 microvesicles via CDC42 to promote glutamine metabolism, M2 macrophage polarization, and pro-angiogenic function of macrophages, leading to acquired trastuzumab resistance in HER2-positive gastric cancer. A combination of anti-glutamine metabolism, anti-angiogenesis, and pro-M1 polarization therapy may provide a new insight into reversing trastuzumab resistance.
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Affiliation(s)
- Xingbin Hu
- Department of OncologyNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Zhenfeng Ma
- Department of OncologyNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Beibei Xu
- Department of OncologyNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Shulong Li
- School of Biomedical EngineeringSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Zhiqi Yao
- Department of OncologyNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Bishan Liang
- Department of OncologyNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Jiao Wang
- Department of OncologyNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Wangjun Liao
- Department of OncologyNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Li Lin
- Department of OncologyNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Chunling Wang
- Department of OncologyNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Siting Zheng
- Department of OncologyNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Qijing Wu
- Department of OncologyNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Qiong Huang
- Department of OncologyNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Le Yu
- School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Fenghua Wang
- Department of Medical OncologySun Yat‐sen University Cancer CenterState Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Min Shi
- Department of OncologyNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
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Bates ME, Libring S, Reinhart-King CA. Forces exerted and transduced by cancer-associated fibroblasts during cancer progression. Biol Cell 2023; 115:e2200104. [PMID: 37224184 PMCID: PMC10757454 DOI: 10.1111/boc.202200104] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 05/13/2023] [Accepted: 05/22/2023] [Indexed: 05/26/2023]
Abstract
Although it is well-known that cancer-associated fibroblasts (CAFs) play a key role in regulating tumor progression, the effects of mechanical tissue changes on CAFs are understudied. Myofibroblastic CAFs (myCAFs), in particular, are known to alter tumor matrix architecture and composition, heavily influencing the mechanical forces in the tumor microenvironment (TME), but much less is known about how these mechanical changes initiate and maintain the myCAF phenotype. Additionally, recent studies have pointed to the existence of CAFs in circulating tumor cell clusters, indicating that CAFs may be subject to mechanical forces beyond the primary TME. Due to their pivotal role in cancer progression, targeting CAF mechanical regulation may provide therapeutic benefit. Here, we will discuss current knowledge and summarize existing gaps in how CAFs regulate and are regulated by matrix mechanics, including through stiffness, solid and fluid stresses, and fluid shear stress.
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Affiliation(s)
- Madison E Bates
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA
| | - Sarah Libring
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA
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Soleymani T, Chen TY, Gonzalez-Kozlova E, Dogra N. The human neurosecretome: extracellular vesicles and particles (EVPs) of the brain for intercellular communication, therapy, and liquid-biopsy applications. Front Mol Biosci 2023; 10:1156821. [PMID: 37266331 PMCID: PMC10229797 DOI: 10.3389/fmolb.2023.1156821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 04/25/2023] [Indexed: 06/03/2023] Open
Abstract
Emerging evidence suggests that brain derived extracellular vesicles (EVs) and particles (EPs) can cross blood-brain barrier and mediate communication among neurons, astrocytes, microglial, and other cells of the central nervous system (CNS). Yet, a complete understanding of the molecular landscape and function of circulating EVs & EPs (EVPs) remain a major gap in knowledge. This is mainly due to the lack of technologies to isolate and separate all EVPs of heterogeneous dimensions and low buoyant density. In this review, we aim to provide a comprehensive understanding of the neurosecretome, including the extracellular vesicles that carry the molecular signature of the brain in both its microenvironment and the systemic circulation. We discuss the biogenesis of EVPs, their function, cell-to-cell communication, past and emerging isolation technologies, therapeutics, and liquid-biopsy applications. It is important to highlight that the landscape of EVPs is in a constant state of evolution; hence, we not only discuss the past literature and current landscape of the EVPs, but we also speculate as to how novel EVPs may contribute to the etiology of addiction, depression, psychiatric, neurodegenerative diseases, and aid in the real time monitoring of the "living brain". Overall, the neurosecretome is a concept we introduce here to embody the compendium of circulating particles of the brain for their function and disease pathogenesis. Finally, for the purpose of inclusion of all extracellular particles, we have used the term EVPs as defined by the International Society of Extracellular Vesicles (ISEV).
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Affiliation(s)
- Taliah Soleymani
- Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Tzu-Yi Chen
- Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Edgar Gonzalez-Kozlova
- Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Navneet Dogra
- Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Atobatele AG, Tonoli E, Vadakekolathu J, Savoca MP, Barr M, Kataria Y, Rossanese M, Burhan I, McArdle S, Caccamo D, Verderio EAM. Canonical and truncated transglutaminase-2 regulate mucin-1 expression and androgen independency in prostate cancer cell lines. Cell Death Dis 2023; 14:317. [PMID: 37160910 PMCID: PMC10170068 DOI: 10.1038/s41419-023-05818-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 04/13/2023] [Accepted: 04/19/2023] [Indexed: 05/11/2023]
Abstract
Androgen independency is associated with poor prostate cancer (PCa) survival. Here we report that silencing of transglutaminase-2 (TG2) expression by CRISPR-Cas9 is associated with upregulation of androgen receptor (AR) transcription in PCa cell lines. Knockout of TG2 reversed the migratory potential and anchorage independency of PC3 and DU145 cells and revealed a reduced level of mucin-1 (MUC1) RNA transcript through unbiased multi-omics profiling, which was restored by selective add-back of the truncated TG2 isoform (TGM2_v2). Silencing of AR resulted into increased MUC1 in TG2KO PC3 cells showing that TG2 affects transcriptional regulation of MUC1 via repressing AR expression. Treatment of PC3 WT cell line with TG2 inhibitor ZDON led to a significant increase in AR expression and decrease in MUC1. ZDON also blocked the formation of MUC1-multimers labelled with TG amine-donor substrates in reducing conditions, revealing for the first time a role for TG2, which we show to be externalised via extracellular vesicles, in MUC1 stabilisation via calcium-dependent transamidation. A specific antibody towards TGM2_v2 revealed its restricted nuclear location compared to the canonical long form of TG2 (TGM2_v1), which is predominantly cytosolic, suggesting that this form contributes to the previously suggested TG2-mediated NF-κB activation and AR transcriptional repression. As TGM2_v2 transcription was increased in biopsies of early-stage prostate adenocarcinoma (PRAD) patients compared to subjects presenting inflammatory prostatitis, and total TG2 protein expression significantly increased in PRAD versus normal tissue, the role of TG2 and its truncated form as a prostate malignancy marker is suggested. In conclusion, this investigation has provided the first unbiased discovery of a novel pathway mediated by TG2 via MUC1, which is shown to contribute to androgen insensitivity and malignancy of PCa cells and be upregulated in PCa biopsies, with potential relevance to cancer immune evasion.
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Affiliation(s)
- Adeola Grace Atobatele
- School of Science and Technology, Centre for Health, Ageing and Understanding of Disease, Nottingham Trent University, Nottingham, NG11 8NS, UK
- Department of Biological and Biomedical Sciences, Science Centre, School of Health, Science and Wellbeing, Staffordshire University, Leek Road, Stoke-on-Trent, ST4 2DF, UK
| | - Elisa Tonoli
- School of Science and Technology, Centre for Health, Ageing and Understanding of Disease, Nottingham Trent University, Nottingham, NG11 8NS, UK
| | - Jayakumar Vadakekolathu
- John van Geest Cancer Research Centre, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK
| | - Maria Pia Savoca
- School of Science and Technology, Centre for Health, Ageing and Understanding of Disease, Nottingham Trent University, Nottingham, NG11 8NS, UK
| | - Melissa Barr
- School of Science and Technology, Centre for Health, Ageing and Understanding of Disease, Nottingham Trent University, Nottingham, NG11 8NS, UK
| | - Yukti Kataria
- School of Science and Technology, Centre for Health, Ageing and Understanding of Disease, Nottingham Trent University, Nottingham, NG11 8NS, UK
| | - Marta Rossanese
- Department of Human and Paediatric Pathology, Polyclinic Hospital University, Via C. Valeria 1, 98125, Messina, Italy
| | - Izhar Burhan
- School of Science and Technology, Centre for Health, Ageing and Understanding of Disease, Nottingham Trent University, Nottingham, NG11 8NS, UK
| | - Stephanie McArdle
- John van Geest Cancer Research Centre, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK
| | - Daniela Caccamo
- Department of Biomedical Sciences, Dental Sciences & Morpho-Functional Imaging, Polyclinic Hospital University, Via C. Valeria 1, 98125, Messina, Italy
| | - Elisabetta A M Verderio
- School of Science and Technology, Centre for Health, Ageing and Understanding of Disease, Nottingham Trent University, Nottingham, NG11 8NS, UK.
- Biological Sciences Department (BiGeA), University of Bologna, Bologna, 40126, Italy.
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Lamanuzzi A, Saltarella I, Reale A, Melaccio A, Solimando AG, Altamura C, Tamma G, Storlazzi CT, Tolomeo D, Desantis V, Mariggiò MA, Desaphy JF, Spencer A, Vacca A, Apollonio B, Frassanito MA. Uptake-Dependent and -Independent Effects of Fibroblasts-Derived Extracellular Vesicles on Bone Marrow Endothelial Cells from Patients with Multiple Myeloma: Therapeutic and Clinical Implications. Biomedicines 2023; 11:biomedicines11051400. [PMID: 37239071 DOI: 10.3390/biomedicines11051400] [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: 01/04/2023] [Revised: 04/20/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Extracellular vesicles (EVs) have emerged as important players in cell-to-cell communication within the bone marrow (BM) of multiple myeloma (MM) patients, where they mediate several tumor-associated processes. Here, we investigate the contribution of fibroblasts-derived EVs (FBEVs) in supporting BM angiogenesis. We demonstrate that FBEVs' cargo contains several angiogenic cytokines (i.e., VEGF, HGF, and ANG-1) that promote an early over-angiogenic effect independent from EVs uptake. Interestingly, co-culture of endothelial cells from MM patients (MMECs) with FBEVs for 1 or 6 h activates the VEGF/VEGFR2, HGF/HGFR, and ANG-1/Tie2 axis, as well as the mTORC2 and Wnt/β-catenin pathways, suggesting that the early over-angiogenic effect is a cytokine-mediated process. FBEVs internalization occurs after longer exposure of MMECs to FBEVs (24 h) and induces a late over-angiogenic effect by increasing MMECs migration, chemotaxis, metalloproteases release, and capillarogenesis. FBEVs uptake activates mTORC1, MAPK, SRC, and STAT pathways that promote the release of pro-angiogenic cytokines, further supporting the pro-angiogenic milieu. Overall, our results demonstrate that FBEVs foster MM angiogenesis through dual time-related uptake-independent and uptake-dependent mechanisms that activate different intracellular pathways and transcriptional programs, providing the rationale for designing novel anti-angiogenic strategies.
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Affiliation(s)
- Aurelia Lamanuzzi
- Unit of Internal Medicine and Clinical Oncology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Ilaria Saltarella
- Unit of Internal Medicine and Clinical Oncology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy
- Unit of Pharmacology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Antonia Reale
- Myeloma Research Group, Australian Centre for Blood Diseases, Central Clinical School, Monash University-Alfred Health, Melbourne, VIC 3004, Australia
| | - Assunta Melaccio
- Unit of Internal Medicine and Clinical Oncology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Antonio Giovanni Solimando
- Unit of Internal Medicine and Clinical Oncology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Concetta Altamura
- Unit of Pharmacology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Grazia Tamma
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Clelia Tiziana Storlazzi
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Doron Tolomeo
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Vanessa Desantis
- Unit of Pharmacology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Maria Addolorata Mariggiò
- Unit of Clinical Pathology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Jean-François Desaphy
- Unit of Pharmacology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70121 Bari, Italy
| | - Andrew Spencer
- Myeloma Research Group, Australian Centre for Blood Diseases, Central Clinical School, Monash University-Alfred Health, Melbourne, VIC 3004, Australia
- Malignant Haematology and Stem Cell Transplantation, Department of Haematology, Alfred Hospital, Melbourne, VIC 3004, Australia
- Department of Clinical Hematology, Monash University, Melbourne, VIC 3004, Australia
| | - Angelo Vacca
- Unit of Internal Medicine and Clinical Oncology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Benedetta Apollonio
- Unit of Internal Medicine and Clinical Oncology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Maria Antonia Frassanito
- Unit of Clinical Pathology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70121 Bari, Italy
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48
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Li Q, Wang M, Liu L. The role of exosomes in the stemness maintenance and progression of acute myeloid leukemia. Biochem Pharmacol 2023; 212:115539. [PMID: 37024061 DOI: 10.1016/j.bcp.2023.115539] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/17/2023] [Accepted: 03/29/2023] [Indexed: 04/08/2023]
Abstract
Acute myeloid leukemia (AML) is an aggressive malignancy of myeloid hematopoietic cells, which is characterized by the aberrant clonal proliferation of immature myeloblasts and compromised hematopoiesis. The leukemic cell population is strongly heterogeneous. Leukemic stem cells (LSCs) are an important leukemic cell subset with stemness characteristics and self-renewal ability, which contribute to the development of refractory or relapsed AML. It is now acknowledged that LSCs develop from hematopoietic stem cells (HSCs) or phenotypically directed cell populations with transcriptional stemness characteristics under selective pressure from the bone marrow (BM) niche. Exosomes are extracellular vesicles containing bioactive substances involved in intercellular communication and material exchange under steady state and pathological conditions. Several studies have reported that exosomes mediate molecular crosstalk between LSCs, leukemic blasts, and stromal cells in the BM niche, promoting LSC maintenance and AML progression. This review briefly describes the process of LSC transformation and the biogenesis of exosomes, highlighting the role of leukemic-cell- and BM-niche-derived exosomes in the maintenance of LSCs and AML progression. In addition, we discuss the potential application of exosomes in the clinic as biomarkers, therapeutic targets, and carriers for targeted drug delivery.
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Affiliation(s)
- Qian Li
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Mengyuan Wang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lingbo Liu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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49
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Nguyen NM, Meyer D, Meyer L, Chand S, Jagadesan S, Miravite M, Guda C, Yelamanchili SV, Pendyala G. Identification of YWHAH as a Novel Brain-Derived Extracellular Vesicle Marker Post Long-Term Midazolam Exposure during Early Development. Cells 2023; 12:966. [PMID: 36980307 PMCID: PMC10047367 DOI: 10.3390/cells12060966] [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: 01/06/2023] [Revised: 02/10/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
Recently, the long-term use of sedative agents in the neonatal intensive care unit (NICU) has raised concerns about neurodevelopmental outcomes in exposed neonates. Midazolam (MDZ), a common neonatal sedative in the NICU, has been suggested to increase learning disturbances and cognitive impairment in children. However, molecular mechanisms contributing to such outcomes with long-term MDZ use during the early stages of life remain unclear. In this study, we for the first time elucidate the role of brain-derived extracellular vesicles (BDEVs), including mining the BDEV proteome post long-term MDZ exposure during early development. Employing our previously established rodent model system that mimics the exposure of MDZ in the NICU using an increasing dosage regimen, we isolated BDEVs from postnatal 21-days-old control and MDZ groups using a differential sucrose density gradient. BDEVs from the control and MDZ groups were then characterized using a ZetaView nanoparticle tracking analyzer and transmission electron microscopy analysis. Next, using RT-qPCR, we examined the expression of key ESCRT-related genes involved in EV biogenesis. Lastly, using quantitative mass spectrometry-based proteomics, we mined the BDEV protein cargo that revealed key differentially expressed proteins and associated molecular pathways to be altered post long-term MDZ exposure. Our study characterized the proteome in BDEV cargo from long-term MDZ exposure at early development. Importantly, we identified and validated the expression of YWHAH as a potential target for further characterization of its downstream mechanism and a potential biomarker for the early onset of neurodevelopment and neurodegenerative diseases. Overall, the present study demonstrated long-term exposure to MDZ at early development stages could influence BDEV protein cargo, which potentially impact neural functions and behavior at later stages of development.
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Affiliation(s)
- Nghi M. Nguyen
- Department of Anesthesiology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA
| | - Daniel Meyer
- Department of Anesthesiology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA
| | - Luke Meyer
- Department of Anesthesiology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA
| | - Subhash Chand
- Department of Anesthesiology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA
| | - Sankarasubramanian Jagadesan
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA
| | - Maireen Miravite
- Department of Anesthesiology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA
| | - Chittibabu Guda
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA
| | - Sowmya V. Yelamanchili
- Department of Anesthesiology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA
| | - Gurudutt Pendyala
- Department of Anesthesiology, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA
- Child Health Research Institute, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA
- National Strategic Research Institute, University of Nebraska Medical Center (UNMC), Omaha, NE 68198, USA
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50
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Zhu X, Gao M, Yang Y, Li W, Bao J, Li Y. The CRISPR/Cas9 System Delivered by Extracellular Vesicles. Pharmaceutics 2023; 15:pharmaceutics15030984. [PMID: 36986843 PMCID: PMC10053467 DOI: 10.3390/pharmaceutics15030984] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/14/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) systems can precisely manipulate DNA sequences to change the characteristics of cells and organs, which has potential in the mechanistic research on genes and the treatment of diseases. However, clinical applications are restricted by the lack of safe, targeted and effective delivery vectors. Extracellular vesicles (EVs) are an attractive delivery platform for CRISPR/Cas9. Compared with viral and other vectors, EVs present several advantages, including safety, protection, capacity, penetrating ability, targeting ability and potential for modification. Consequently, EVs are profitably used to deliver the CRISPR/Cas9 in vivo. In this review, the advantages and disadvantages of the delivery form and vectors of the CRISPR/Cas9 are concluded. The favorable traits of EVs as vectors, such as the innate characteristics, physiological and pathological functions, safety and targeting ability of EVs, are summarized. Furthermore, in terms of the delivery of the CRISPR/Cas9 by EVs, EV sources and isolation strategies, the delivery form and loading methods of the CRISPR/Cas9 and applications have been concluded and discussed. Finally, this review provides future directions of EVs as vectors of the CRISPR/Cas9 system in clinical applications, such as the safety, capacity, consistent quality, yield and targeting ability of EVs.
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Affiliation(s)
- Xinglong Zhu
- Key Laboratory of Transplant Engineering and Immunology, Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Mengyu Gao
- Key Laboratory of Transplant Engineering and Immunology, Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yongfeng Yang
- Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu 610041, China
- Precision Medicine Key Laboratory, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Weimin Li
- Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu 610041, China
- Precision Medicine Key Laboratory, West China Hospital, Sichuan University, Chengdu 610041, China
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ji Bao
- Key Laboratory of Transplant Engineering and Immunology, Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yi Li
- Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu 610041, China
- Precision Medicine Key Laboratory, West China Hospital, Sichuan University, Chengdu 610041, China
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