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Abdulmonem WA, Ahsan M, Mallick AK, Mohamed AH, Waggiallah HA, Shafie A, Alzahrani HS, Ashour AA, Rab SO, Mirdad MT, Ali HTO. The Role of Exosomal miRNAs in Female Infertility: Therapeutic Potential and Mechanisms of Action. Stem Cell Rev Rep 2025:10.1007/s12015-025-10869-w. [PMID: 40126819 DOI: 10.1007/s12015-025-10869-w] [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] [Accepted: 03/17/2025] [Indexed: 03/26/2025]
Abstract
Reproductive disorders, including preeclampsia (PE), endometriosis, premature ovarian failure (POF), and polycystic ovary syndrome (PCOS), present substantial challenges to women's reproductive health. Exosomes (EXOs) are cell-derived vesicles containing molecules that influence target cells' gene expression and cellular behavior. Among their cargo, microRNAs (miRNAs)-short, non-coding RNAs typically 19-25 nucleotides in length-play a crucial role in post-transcriptional gene regulation and have been extensively studied for their therapeutic potential. miRNAs are considered therapeutic targets because they regulate key cellular pathways such as proliferation, apoptosis, angiogenesis, and tissue repair. This review examines the role of exosomal miRNAs from sources such as mesenchymal stem cells (MSCs), plasma, and amniotic fluid in female reproductive disorders, including PE, POF, PCOS, and endometriosis. We discuss their biological origins, mechanisms of miRNA sorting and packaging, and their therapeutic applications in modulating disease progression. By categorizing miRNAs according to their beneficial or detrimental effects in specific conditions, we aim to simplify the understanding of their roles in female infertility.
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Affiliation(s)
- Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Marya Ahsan
- Department of Pharmacology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, 13317, Saudi Arabia
| | - Ayaz Khurram Mallick
- Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Asma'a H Mohamed
- Department of Optometry Techniques, Technical College Al-Mussaib, Al-Furat Al-Awsat Technical University, Najaf, Iraq.
| | - Hisham Ali Waggiallah
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Alkharj, 11942, Saudi Arabia
| | - Alaa Shafie
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O.Box 11099, Taif, 21944, Saudi Arabia
| | - Hassan Swed Alzahrani
- Counseling Healthy Marriage, Jeddah Regional Laboratory, Jeddah First Cluster , Jeddah, Saudi Arabia
| | - Amal Adnan Ashour
- Department of Oral & Maxillofacial Surgery and Diagnostic Sciences, Faculty of Dentistry, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Mohammed Tarek Mirdad
- Medical Intern MBBS, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Hatim T O Ali
- Obstetrics and Gynecology, College of Medicine, King Khalid University, Abha, Saudi Arabia
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Cong F, Huang J, Wu C, Zhong H, Qiu G, Luo T, Tang W. Integrin α6 and integrin β4 in exosomes promote lung metastasis of colorectal cancer. J Cancer Res Ther 2024; 20:2082-2093. [PMID: 39792419 DOI: 10.4103/jcrt.jcrt_230_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 10/23/2024] [Indexed: 01/12/2025]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common cancers worldwide. The mechanisms underlying metastasis, which contributes to poor outcomes, remain elusive. METHODS We used the Cancer Genome Atlas dataset to compare mRNA expression patterns of integrin α6 (ITGA6) and integrin β4 (ITGB4) in patients with CRC. We measured ITGA6 and ITGB4 expression levels in highly metastatic (i.e., HCT116 and SW620) and lowly metastatic (i.e., SW480 and Caco2) CRC cell lines. Exosomes were isolated from cell culture media and characterized using western blotting and nanoparticle analyses. The role of exosomes in lung metastasis was investigated using xenograft experiments in mice models, which received CRC cell injection and were treated with exosomes. RESULTS ITGA6 and ITGB4 were significantly overexpressed in CRC tissues, and ITGA6 was associated with the American Joint Committee on Cancer (AJCC) stage and outcome. ITGA6 and ITGB4, as well as exosomal ITGA6 and ITGB4, were significantly more highly expressed in HCT116 and SW620 cells than in SW480 and Caco2 cells. The proliferation and tubulogenesis of vascular endothelial cells were markedly decreased by disruption of ITGA6 and ITGB4 but were markedly increased by ectopic expression of ITGA6 and ITGB4. Exosomal ITGA6 and ITGB4 promoted CRC metastasis to the lung in vivo. CONCLUSIONS Taken together, our findings suggested that exosomal ITGA6 and ITGB4 displayed organotropism to the lung and upregulated proliferation and tubulogenic capacities, which might help reduce lung metastasis from CRC. These findings provided new insights into the mechanisms of CRC metastasis and provided novel potential therapeutic targets.
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Affiliation(s)
- Fengyun Cong
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jiahao Huang
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Changtao Wu
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Huage Zhong
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Guangxi Key Laboratory of Basic and Translational Research for Colorectal Cancer, China
| | - Guanhua Qiu
- Department of Ultrasound, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Tao Luo
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Guangxi Key Laboratory of Basic and Translational Research for Colorectal Cancer, China
| | - Weizhong Tang
- Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Guangxi Key Laboratory of Basic and Translational Research for Colorectal Cancer, China
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An J, Park H, Ju M, Woo Y, Seo Y, Min J, Lee T. An updated review on the development of a nanomaterial-based field-effect transistor-type biosensors to detect exosomes for cancer diagnosis. Talanta 2024; 279:126604. [PMID: 39068827 DOI: 10.1016/j.talanta.2024.126604] [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: 03/29/2024] [Revised: 06/24/2024] [Accepted: 07/22/2024] [Indexed: 07/30/2024]
Abstract
Cancer, a life-threatening genetic disease caused by abnormalities in normal cell growth regulatory functions, poses a significant challenge that current medical technologies cannot fully overcome. The current desired breakthrough is to diagnose cancer as early as possible and increase survival rates through treatments tailored to the prognosis and appropriate follow-up. From a perspective that reflects this contemporary paradigm of cancer diagnostics, exosomes are emerging as promising biomarkers. Exosomes, serving as mobile biological information repositories of cancer cells, have been known to create a microtumor environment in surrounding cells, and significant insight into the clinical significance of cancer diagnosis targeting them has been reported. Therefore, there are growing interests in constructing a system that enables continuous screening with a focus on patient-friendly and flexible diagnosis, aiming to improve cancer screening rates through exosome detection. This review focuses on a proposed exosome-embedded biological information-detecting platform employing a field-effect transistor (FET)-based biosensor that leverages portability, cost-effectiveness, and rapidity to minimize the stages of sacrifice attributable to cancer. The FET-applied biosensing technique, stemming from variations in an electric field, is considered an early detection system, offering high sensitivity and a prompt response frequency for the qualitative and quantitative analysis of biomolecules. Hence, an in-depth discussion was conducted on the understanding of various exosome-based cancer biomarkers and the clinical significance of recent studies on FET-based biosensors applying them.
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Affiliation(s)
- Jeongyun An
- Department of Chemical Engineering, Kwangwoon University, 20 Kwangwoon-Ro, Nowon-Gu, Seoul, 01897, Republic of Korea
| | - Hyunjun Park
- Department of Chemical Engineering, Kwangwoon University, 20 Kwangwoon-Ro, Nowon-Gu, Seoul, 01897, Republic of Korea
| | - Minyoung Ju
- Department of Chemical Engineering, Kwangwoon University, 20 Kwangwoon-Ro, Nowon-Gu, Seoul, 01897, Republic of Korea
| | - Yeeun Woo
- Department of Chemical Engineering, Kwangwoon University, 20 Kwangwoon-Ro, Nowon-Gu, Seoul, 01897, Republic of Korea
| | - Yoshep Seo
- Department of Chemical Engineering, Kwangwoon University, 20 Kwangwoon-Ro, Nowon-Gu, Seoul, 01897, Republic of Korea
| | - Junhong Min
- School of Integrative Engineering, Chung-Ang University, Dongjak-Gu, Seoul, 06974, Republic of Korea.
| | - Taek Lee
- Department of Chemical Engineering, Kwangwoon University, 20 Kwangwoon-Ro, Nowon-Gu, Seoul, 01897, Republic of Korea.
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Lawrence SR, Shah KM. Prospects and Current Challenges of Extracellular Vesicle-Based Biomarkers in Cancer. BIOLOGY 2024; 13:694. [PMID: 39336121 PMCID: PMC11428408 DOI: 10.3390/biology13090694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 08/31/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024]
Abstract
Cancer continues to impose a substantial global health burden, particularly among the elderly, where the ongoing global demographic shift towards an ageing population underscores the growing need for early cancer detection. This is essential for enabling personalised cancer care and optimised treatment throughout the disease course to effectively mitigate the increasing societal impact of cancer. Liquid biopsy has emerged as a promising strategy for cancer diagnosis and treatment monitoring, offering a minimally invasive method for the isolation and molecular profiling of circulating tumour-derived components. The expansion of the liquid biopsy approach to include the detection of tumour-derived extracellular vesicles (tdEVs) holds significant therapeutic opportunity. Evidence suggests that tdEVs carry cargo reflecting the contents of their cell-of-origin and are abundant within the blood, exhibiting superior stability compared to non-encapsulated tumour-derived material, such as circulating tumour nucleic acids and proteins. However, despite theoretical promise, several obstacles hinder the translation of extracellular vesicle-based cancer biomarkers into clinical practice. This critical review assesses the current prospects and challenges facing the adoption of tdEV biomarkers in clinical practice, offering insights into future directions and proposing strategies to overcome translational barriers. By addressing these issues, EV-based liquid biopsy approaches could revolutionise cancer diagnostics and management.
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Affiliation(s)
- Samuel R Lawrence
- Division of Clinical Medicine, School of Medicine & Population Health, The University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK
| | - Karan M Shah
- Division of Clinical Medicine, School of Medicine & Population Health, The University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK
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Monteleone MC, Billi SC, Abarzúa-Catalán L, Henzi R, Fernández EM, Kaehne T, Wyneken U, Brocco MA. Bulk serum extracellular vesicles from stressed mice show a distinct proteome and induce behavioral and molecular changes in naive mice. PLoS One 2024; 19:e0308976. [PMID: 39146369 PMCID: PMC11326636 DOI: 10.1371/journal.pone.0308976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 08/02/2024] [Indexed: 08/17/2024] Open
Abstract
Chronic stress can trigger several pathologies including mood disorders for which no clear diagnostic molecular markers have been established yet. Attractive biomarker sources are extracellular vesicles (EVs). Evs are released by cells in health and disease and contain genetic material, proteins and lipids characteristic of the cell state. Here we show that Evs recovered from the blood of animals exposed to a repeated interrupted stress protocol (RIS) have a different protein profile compared to those obtained from control animals. Proteomic analysis indicated that proteins differentially present in bulk serum Evs from stressed animals were implicated in metabolic and inflammatory pathways and several of them were previously related to psychiatric disorders. Interestingly, these serum Evs carry brain-enriched proteins including the stress-responsive neuronal protein M6a. Then, we used an in-utero electroporation strategy to selectively overexpress M6a-GFP in brain neurons and found that M6a-GFP could also be detected in bulk serum Evs suggesting a neuronal origin. Finally, to determine if these Evs could have functional consequences, we administered Evs from control and RIS animals intranasally to naïve mice. Animals receiving stress EVs showed changes in behavior and brain M6a levels similar to those observed in physically stressed animals. Such changes could therefore be attributed, or at least in part, to EV protein transfer. Altogether these findings show that EVs may participate in stress signaling and propose proteins carried by EVs as a valuable source of biomarkers for stress-induced diseases.
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Affiliation(s)
- Melisa C Monteleone
- Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín (UNSAM)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Martín, Argentina
- Escuela de Bio y Nanotecnologías (EByN), Universidad Nacional de San Martín, San Martín, Argentina
| | - Silvia C Billi
- Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín (UNSAM)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Martín, Argentina
- Escuela de Bio y Nanotecnologías (EByN), Universidad Nacional de San Martín, San Martín, Argentina
| | - Lorena Abarzúa-Catalán
- Facultad de Medicina, Centro de Investigación e Innovación Biomédica CiiB, Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Roberto Henzi
- Facultad de Medicina, Centro de Investigación e Innovación Biomédica CiiB, Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Eliana M Fernández
- Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín (UNSAM)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Martín, Argentina
- Escuela de Bio y Nanotecnologías (EByN), Universidad Nacional de San Martín, San Martín, Argentina
| | - Thilo Kaehne
- Institute of Experimental Internal Medicine, Medical School, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Ursula Wyneken
- Facultad de Medicina, Centro de Investigación e Innovación Biomédica CiiB, Universidad de los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Marcela A Brocco
- Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín (UNSAM)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Martín, Argentina
- Escuela de Bio y Nanotecnologías (EByN), Universidad Nacional de San Martín, San Martín, Argentina
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Jiang Y, Wang W, Tang F, Zhang W, Chen S, Gu X, Chen P, Xu X, Nian B, Li Z, Chen C, Yin H, Su L, Sun H, Chen W, Zhang D, Li Y. Identifying MiR-140-3p as a stable internal reference to normalize MicroRNA qRT-PCR levels of plasma small extracellular vesicles in lung cancer patients. Genomics 2024; 116:110875. [PMID: 38849018 DOI: 10.1016/j.ygeno.2024.110875] [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: 05/31/2023] [Revised: 03/13/2024] [Accepted: 04/12/2024] [Indexed: 06/09/2024]
Abstract
Exploration of a stably expressed gene as a reference is critical for the accurate evaluation of miRNAs isolated from small extracellular vesicles (sEVs). In this study, we analyzed small RNA sequencing on plasma sEV miRNAs in the training dataset (n = 104) and found that miR-140-3p was the most stably expressed candidate reference for sEV miRNAs. We further demonstrated that miR-140-3p expressed most stably in the validation cohort (n = 46) when compared to two other reference miRNAs, miR-451a and miR-1228-3p, and the commonly-used miRNA reference U6. Finally, we compared the capability of miR-140-3p and U6 as the internal reference for sEV miRNA expression by evaluating key miRNAs expression in lung cancer patients and found that miR-140-3p was more suitable as a sEV miRNA reference gene. Taken together, our data indicated miR-140-3p as a stable internal reference miRNA of plasma sEVs to evaluate miRNA expression profiles in lung cancer patients.
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Affiliation(s)
- Yuan Jiang
- Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Weiwei Wang
- Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Faqing Tang
- Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Wei Zhang
- 3D Medicines Inc., Shanghai 201114, China
| | - Sheng Chen
- 3D Medicines Inc., Shanghai 201114, China
| | - Xiumei Gu
- Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Ping Chen
- Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Xiaoya Xu
- 3D Medicines Inc., Shanghai 201114, China
| | | | - Zhikuan Li
- 3D Medicines Inc., Shanghai 201114, China
| | | | - Hanbing Yin
- Shenxian People's Hospital, Liaocheng 252411, China
| | - Linlin Su
- Shenxian People's Hospital, Liaocheng 252411, China
| | - Honghou Sun
- Shenxian Maternal and Child Health Hospital, Liaocheng 252499, China
| | - Wei Chen
- 3D Medicines Inc., Shanghai 201114, China
| | | | - Yuejin Li
- Department of Clinical Laboratory, Hui Ya Hospital of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
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De Sota RE, Quake SR, Sninsky JJ, Toden S. Decoding bioactive signals of the RNA secretome: the cell-free messenger RNA catalogue. Expert Rev Mol Med 2024; 26:e12. [PMID: 38682644 PMCID: PMC11140549 DOI: 10.1017/erm.2024.12] [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: 08/08/2023] [Revised: 01/18/2024] [Accepted: 03/18/2024] [Indexed: 05/01/2024]
Abstract
Despite gene-expression profiling being one of the most common methods to evaluate molecular dysregulation in tissues, the utilization of cell-free messenger RNA (cf-mRNA) as a blood-based non-invasive biomarker analyte has been limited compared to other RNA classes. Recent advancements in low-input RNA-sequencing and normalization techniques, however, have enabled characterization as well as accurate quantification of cf-mRNAs allowing direct pathological insights. The molecular profile of the cell-free transcriptome in multiple diseases has subsequently been characterized including, prenatal diseases, neurological disorders, liver diseases and cancers suggesting this biological compartment may serve as a disease agnostic platform. With mRNAs packaged in a myriad of extracellular vesicles and particles, these signals may be used to develop clinically actionable, non-invasive disease biomarkers. Here, we summarize the recent scientific developments of extracellular mRNA, biology of extracellular mRNA carriers, clinical utility of cf-mRNA as disease biomarkers, as well as proposed functions in cell and tissue pathophysiology.
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Affiliation(s)
- Rhys E. De Sota
- Superfluid Dx., 259 E Grand Avenue, South San Francisco, CA 94080, USA
| | - Stephen R. Quake
- Department of Bioengineering and Department of Applied Physics, Stanford University, Stanford, CA, USA
- Chan Zuckerberg Biohub, San Francisco, CA, USA
| | - John J. Sninsky
- Superfluid Dx., 259 E Grand Avenue, South San Francisco, CA 94080, USA
| | - Shusuke Toden
- Superfluid Dx., 259 E Grand Avenue, South San Francisco, CA 94080, USA
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Gupta R, Gupta J, Roy S. Exosomes: Key Players for Treatment of Cancer and Their Future Perspectives. Assay Drug Dev Technol 2024; 22:118-147. [PMID: 38407852 DOI: 10.1089/adt.2023.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/27/2024] Open
Affiliation(s)
- Reena Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura, India
| | - Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura, India
| | - Suchismita Roy
- Institute of Pharmaceutical Research, GLA University, Mathura, India
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Yaman M, Pirim D. Investigation of Common Pathways and Putative Biomarker Candidates of Colorectal Cancer and Insomnia by Using Integrative In-Silico Approaches. IRANIAN JOURNAL OF BIOTECHNOLOGY 2024; 22:e3827. [PMID: 39220338 PMCID: PMC11364928 DOI: 10.30498/ijb.2024.422185.3827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 03/09/2024] [Indexed: 09/04/2024]
Abstract
Background Colorectal cancer (CRC) is one of the leading causes of cancer-related mortalities across the globe. Accumulating evidence shows that individuals having sleep disorders such as insomnia are at high risk of developing CRC, yet the association of sleep disorders with CRC risk is still unclear. Here, we investigated the potential molecular connections between CRC and insomnia using integrative in silico approaches. Objective This study aims to explore the potential molecular connections between CRC and insomnia utilizing integrative in-silico methodologies. Methods and Methods Gene expression microarray datasets for CRC and insomnia samples were retrieved from the NCBI-GEO database and analyzed using R. Functional enrichment analysis of common differentially expressed genes (DEGs) was performed by the g: Profiler tool. Cytoscape software was used to construct a protein-protein interaction network and hub gene identification. Expression profiles of hub genes in TCGA datasets were also determined, and predicted miRNAs targeting hub genes were analyzed by miRNA target prediction tools. Results Our results revealed a total of 113 shared DEGs between the CRC and insomnia datasets. Six genes (HSP8A, GAPDH, HSP90AA1, EEF1G, RPS6, and RPLP0), which were also differently expressed in TCGA datasets, were prioritized as hub genes and were found to be enriched in pathways related to protein synthesis. hsa-miR-324-3p, hsa-miR-769-3p, and hsa-miR-16-5p were identified as promising miRNA biomarkers for two diseases. Conclusions Our in-silico analysis provides promising evidence of the molecular link between CRC and insomnia and highlights multiple potential molecular biomarkers and pathways. Validation of the results by wet lab work can be utilized for novel translational and precision medicine applications to alleviate the public health burden of CRC.
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Affiliation(s)
- Metehan Yaman
- Institute of Natural and Applied Sciences, Department of Molecular Biology and Genetics, Bursa Uludag University, Bursa, Türkiye
| | - Dilek Pirim
- Institute of Natural and Applied Sciences, Department of Molecular Biology and Genetics, Bursa Uludag University, Bursa, Türkiye
- Institute of Health Sciences, Department of Translational Medicine, Bursa Uludag University, Bursa, Türkiye
- Department of Molecular Biology and Genetics, Bursa Uludag University, Bursa, Türkiye
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Chiba M, Uehara H, Kuwata H, Niiyama I. Extracellular miRNAs in the serum and feces of mice exposed to high‑dose radiation. Biomed Rep 2024; 20:55. [PMID: 38357239 PMCID: PMC10865170 DOI: 10.3892/br.2024.1744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 01/19/2024] [Indexed: 02/16/2024] Open
Abstract
Exposure to high-dose radiation causes life-threatening intestinal damage. Histopathology is the most accurate method of judging the extent of intestinal damage following death. However, it is difficult to predict the extent of intestinal damage. The present study investigated extracellular microRNAs (miRNAs or miRs) in serum and feces using a radiation-induced intestinal injury mouse model. A peak of 25-200 nucleotide small RNAs was detected in mouse serum and feces by bioanalyzer, indicating the presence of miRNAs. Microarray analysis detected four miRNAs expressed in the small intestine and increased by >2-fold in serum and 19 in feces following 10 Gy radiation exposure. Increased miR-375-3p in both serum and feces suggests leakage due to radiation-induced intestinal injury and may be a candidate for high-dose radiation biomarkers.
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Affiliation(s)
- Mitsuru Chiba
- Department of Bioscience and Laboratory Medicine, Graduate School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
- Research Center for Biomedical Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
| | - Haruka Uehara
- Department of Medical Technology, School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
| | - Haruka Kuwata
- Department of Medical Technology, School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
| | - Ikumi Niiyama
- Department of Medical Technology, School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
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Chang Y, Yang Y, Li C, Chan M, Lu M, Chen M, Chen C, Hsiao M. RAB31 drives extracellular vesicle fusion and cancer-associated fibroblast formation leading to oxaliplatin resistance in colorectal cancer. JOURNAL OF EXTRACELLULAR BIOLOGY 2024; 3:e141. [PMID: 38939899 PMCID: PMC11080812 DOI: 10.1002/jex2.141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 12/14/2023] [Accepted: 01/06/2024] [Indexed: 06/29/2024]
Abstract
Epithelial-mesenchymal transition (EMT) is associated with tumorigenesis and drug resistance. The Rab superfamily of small G-proteins plays a role in regulating cell cytoskeleton and vesicle transport. However, it is not yet clear how the Rab family contributes to cancer progression by participating in EMT. By analysing various in silico datasets, we identified a statistically significant increase in RAB31 expression in the oxaliplatin-resistant group compared to that in the parental or other chemotherapy drug groups. Our findings highlight RAB31's powerful effect on colorectal cancer cell lines when compared with other family members. In a study that analysed multiple online meta-databases, RAB31 RNA levels were continually detected in colorectal tissue arrays. Additionally, RAB31 protein levels were correlated with various clinical parameters in clinical databases and were associated with negative prognoses for patients. RAB31 expression levels in all three probes were calculated using a computer algorithm and were found to be positively correlated with EMT scores. The expression of the epithelial-type marker CDH1 was suppressed in RAB31 overexpression models, whereas the expression of the mesenchymal-type markers SNAI1 and SNAI2 increased. Notably, RAB31-induced EMT and drug resistance are dependent on extracellular vesicle (EV) secretion. Interactome analysis confirmed that RAB31/AGR2 axis-mediated exocytosis was responsible for maintaining colorectal cell resistance to oxaliplatin. Our study concluded that RAB31 alters the sensitivity of oxaliplatin, a supplementary chemotherapy approach, and is an independent prognostic factor that can be used in the treatment of colorectal cancer.
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Affiliation(s)
- Yu‐Chan Chang
- Department of Biomedical Imaging and Radiological SciencesNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Yi‐Fang Yang
- Department of Medical Education and ResearchKaohsiung Veterans General HospitalKaohsiungTaiwan
| | | | - Ming‐Hsien Chan
- Department of Biomedical Imaging and Radiological SciencesNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Meng‐Lun Lu
- Department of OncologyTaipei Veterans General HospitalTaipeiTaiwan
| | - Ming‐Huang Chen
- Department of OncologyTaipei Veterans General HospitalTaipeiTaiwan
- School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Center of Immuno‐Oncology, Department of OncologyTaipei Veterans General HospitalTaipeiTaiwan
| | - Chi‐Long Chen
- Department of PathologyTaipei Medical University Hospital, Taipei Medical UniversityTaipeiTaiwan
- Department of Pathology, College of MedicineTaipei Medical UniversityTaipeiTaiwan
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Chiba M, Ohsugi Y, Matsumoto K, Tayama C. Analysis of gene expression changes during lipid droplet formation in HepG2 human liver cancer cells. MEDICINE INTERNATIONAL 2024; 4:7. [PMID: 38283130 PMCID: PMC10811445 DOI: 10.3892/mi.2024.131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 12/12/2023] [Indexed: 01/30/2024]
Abstract
Fatty liver is a condition of excessive triglyceride accumulation in hepatocytes. Additionally, hepatocytes exhibit a high degree of fat droplet accumulation during excessive alcohol consumption and metabolic syndrome. However, the molecular mechanisms involved in fat droplet formation remain unknown. The present study used an in vitro fatty liver formation model of the human liver cancer cell line, HepG2, to comprehensively search for fat droplet formation-related genes, and which exhibit changes in expression during fat droplet formation. Microarray analysis with extracted total RNA determined the genes that are involved in fat droplet formation and their expression was confirmed using quantitative polymerase chain reaction following the culture of the HepG2 cells in culture medium containing 0, 50, 200 and 500 µM of oleic acid for 24 h. The results revealed 142 genes demonstrating increased expression levels by >2.0-fold with oleic acid treatment and 426 genes demonstrating decreased expression levels. Perilipin 2 (PLIN2) was estimated as the gene most closely associated with fatty liver. Lipid droplet formation in the HepG2 cells induced by oleic acid led to the upregulation of PLIN2 in a concentration-dependent manner. On the whole, the findings of the present study indicate the involvement of genes in oleic acid-induced lipid droplet formation in HepG2 cells; PLIN2 in particular may play a crucial role in this process.
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Affiliation(s)
- Mitsuru Chiba
- Department of Bioscience and Laboratory Medicine, Graduate School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
- Research Center for Biomedical Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
| | - Yuhei Ohsugi
- Department of Medical Technology, School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
| | - Kana Matsumoto
- Department of Bioscience and Laboratory Medicine, Graduate School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
| | - Chisa Tayama
- Department of Medical Technology, School of Health Sciences, Hirosaki University, Hirosaki, Aomori 036-8564, Japan
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13
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Wang HC, Yin WX, Jiang M, Han JY, Kuai XW, Sun R, Sun YF, Ji JL. Function and biomedical implications of exosomal microRNAs delivered by parenchymal and nonparenchymal cells in hepatocellular carcinoma. World J Gastroenterol 2023; 29:5435-5451. [PMID: 37900996 PMCID: PMC10600808 DOI: 10.3748/wjg.v29.i39.5435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/13/2023] [Accepted: 10/16/2023] [Indexed: 10/19/2023] Open
Abstract
Small extracellular vesicles (exosomes) are important components of the tumor microenvironment. They are small membrane-bound vesicles derived from almost all cell types and play an important role in intercellular communication. Exosomes transmit biological molecules obtained from parent cells, such as proteins, lipids, and nucleic acids, and are involved in cancer development. MicroRNAs (miRNAs), the most abundant contents in exosomes, are selectively packaged into exosomes to carry out their biological functions. Recent studies have revealed that exosome-delivered miRNAs play crucial roles in the tumorigenesis, progression, and drug resistance of hepatocellular carcinoma (HCC). In addition, exosomes have great industrial prospects in the diagnosis, treatment, and prognosis of patients with HCC. This review summarized the composition and function of exosomal miRNAs of different cell origins in HCC and highlighted the association between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC. Finally, we described the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC.
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Affiliation(s)
- Hai-Chen Wang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Wen-Xuan Yin
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Meng Jiang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Jia-Yi Han
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Xing-Wang Kuai
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Rui Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Yu-Feng Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Ju-Ling Ji
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
- Department of Pathology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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Wu L, Xue M, Lai S, Chen J, Lin Y, Ding N, Zhong J, Chen S, Wang L. Hypoxia derived exosomes promote the proliferation and metastasis of colorectal cancer through the regulation of HIF-1α/miR-4299/ZBTB4. Life Sci 2023; 329:121872. [PMID: 37352917 DOI: 10.1016/j.lfs.2023.121872] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 06/14/2023] [Accepted: 06/16/2023] [Indexed: 06/25/2023]
Abstract
AIMS The biological functions of colorectal cancer (CRC) cell derived exosomes responding to hypoxic microenvironment and its underlying mechanisms remain unclear. MAIN METHODS Extracted exosomes were confirmed. CRC cells were incubated with hypoxic and normoxic exosomes and its biological behavior were analyzed. miRNA microarray were conducted. Cells were incubated with miRNAs mimics, inhibitors, or small interfering RNAs; expression of reporter constructs was measured in luciferase assays. Cells were transfected with Lentivirus vectors containing eGFP-miR-4299 overexpression (or ZBTB4 siRNA expression plasmid) and they were injected into BALB/C nude mice subcutaneously or by tail vein and the growth of xenograft tumors or lung metastasis were measured. The clinical significance of ZBTB4 was measured in tumor tissues and adjacent non-tumor tissues. KEY FINDINGS Hypoxic exosomes could tranfer to the recipient normoxic cells and promote the cell proliferation and migration. We found several miRNAs were significantly up-regulated in hypoxic exosomes and the expression levels of miR-4299 increased in both hypoxic cells and hypoxic exosomes. We observed that miR-4299 was upregulated in a HIF-1α dependent way. In addition, ectopic expression of miR-4299 promoted the tumor growth and metastasis in vitro and in vivo. ZBTB4, an identified direct target of miR-4299, could abrogate the effect on tumor growth and distant metastasis. The expression of ZBTB4 were decreased in tumor tissues compared with non-tumor colon tissues from patients. SIGNIFICANCE We demonstrated that in response to hypoxia, CRC cells had an increased production of exosomes. The hypoxia derived exosomes promote the proliferation and metastasis of colorectal cancer by exporting miR-4299 and modulating its target gene ZBTB4.
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Affiliation(s)
- Lunpo Wu
- Department of Gastroenterology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China; Institution of Gastroenterology, Zhejiang University, Hangzhou 310000, China
| | - Meng Xue
- Department of Gastroenterology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China; Institution of Gastroenterology, Zhejiang University, Hangzhou 310000, China
| | - Sanchuan Lai
- Department of Gastroenterology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China; Institution of Gastroenterology, Zhejiang University, Hangzhou 310000, China
| | - Jingyu Chen
- Department of Gastroenterology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China; Institution of Gastroenterology, Zhejiang University, Hangzhou 310000, China
| | - Yifeng Lin
- Department of Gastroenterology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China; Institution of Gastroenterology, Zhejiang University, Hangzhou 310000, China
| | - Ning Ding
- Department of Gastroenterology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China; Institution of Gastroenterology, Zhejiang University, Hangzhou 310000, China
| | - Jing Zhong
- Department of Gastroenterology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China; Institution of Gastroenterology, Zhejiang University, Hangzhou 310000, China
| | - Shujie Chen
- Institution of Gastroenterology, Zhejiang University, Hangzhou 310000, China; Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China.
| | - Liangjing Wang
- Department of Gastroenterology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China; Institution of Gastroenterology, Zhejiang University, Hangzhou 310000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang Province 310058, China.
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15
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Oh S, Lee CM, Kwon SH. Extracellular Vesicle MicroRNA in the Kidney. Compr Physiol 2023; 13:4833-4850. [PMID: 37358511 PMCID: PMC11514415 DOI: 10.1002/cphy.c220023] [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] [Indexed: 06/27/2023]
Abstract
Most cells in our body release membrane-bound, nano-sized particles into the extracellular milieu through cellular metabolic processes. Various types of macromolecules, reflecting the physiological and pathological status of the producing cells, are packaged into such so-called extracellular vesicles (EVs), which can travel over a distance to target cells, thereby transmitting donor cell information. The short, noncoding ribonucleic acid (RNA) called microRNA (miRNA) takes a crucial part in EV-resident macromolecules. Notably, EVs transferring miRNAs can induce alterations in the gene expression profiles of the recipient cells, through genetically instructed, base-pairing interaction between the miRNAs and their target cell messenger RNAs (mRNAs), resulting in either nucleolytic decay or translational halt of the engaged mRNAs. As in other body fluids, EVs released in urine, termed urinary EVs (uEVs), carry specific sets of miRNA molecules, which indicate either normal or diseased states of the kidney, the principal source of uEVs. Studies have therefore been directed to elucidate the contents and biological roles of miRNAs in uEVs and moreover to utilize the gene regulatory properties of miRNA cargos in ameliorating kidney diseases through their delivery via engineered EVs. We here review the fundamental principles of the biology of EVs and miRNA as well as our current understanding of the biological roles and applications of EV-loaded miRNAs in the kidney. We further discuss the limitations of contemporary research approaches, suggesting future directions to overcome the difficulties to advance both the basic biological understanding of miRNAs in EVs and their clinical applications in treating kidney diseases. © 2023 American Physiological Society. Compr Physiol 13:4833-4850, 2023.
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Affiliation(s)
- Sekyung Oh
- Department of Medical Science, Catholic Kwandong University College of Medicine, Incheon 22711, South Korea
| | - Chang Min Lee
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, U.S.A
| | - Sang-Ho Kwon
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, U.S.A
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16
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Afridi W, Strachan S, Kasetsirikul S, Pannu AS, Soda N, Gough D, Nguyen NT, Shiddiky MJA. Potential Avenues for Exosomal Isolation and Detection Methods to Enhance Small-Cell Lung Cancer Analysis. ACS MEASUREMENT SCIENCE AU 2023; 3:143-161. [PMID: 37360040 PMCID: PMC10288614 DOI: 10.1021/acsmeasuresciau.2c00068] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 06/28/2023]
Abstract
Around the world, lung cancer has long been the main factor in cancer-related deaths, with small-cell lung cancer (SCLC) being the deadliest form of lung cancer. Cancer cell-derived exosomes and exosomal miRNAs are considered promising biomarkers for diagnosing and prognosis of various diseases, including SCLC. Due to the rapidity of SCLC metastasis, early detection and diagnosis can offer better diagnosis and prognosis and therefore increase the patient's chances of survival. Over the past several years, many methodologies have been developed for analyzing non-SCLC-derived exosomes. However, minimal advances have been made in SCLC-derived exosome analysis methodologies. This Review discusses the epidemiology and prominent biomarkers of SCLC. Followed by a discussion about the effective strategies for isolating and detecting SCLC-derived exosomes and exosomal miRNA, highlighting the critical challenges and limitations of current methodologies. Finally, an overview is provided detailing future perspectives for exosome-based SCLC research.
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Affiliation(s)
- Waqar
Ahmed Afridi
- School
of Environment and Science, Griffith University, Nathan Campus, Nathan, QLD 4111, Australia
- Queensland
Micro and Nanotechnology Centre, Griffith
University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Simon Strachan
- School
of Environment and Science, Griffith University, Nathan Campus, Nathan, QLD 4111, Australia
- Queensland
Micro and Nanotechnology Centre, Griffith
University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Surasak Kasetsirikul
- Queensland
Micro and Nanotechnology Centre, Griffith
University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Amandeep Singh Pannu
- Queensland
Micro and Nanotechnology Centre, Griffith
University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Narshone Soda
- Queensland
Micro and Nanotechnology Centre, Griffith
University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Daniel Gough
- Centre
for Cancer Research, Hudson Institute of
Medical Research, Clayton, Vic 3168, Australia
- Department
of Molecular and Translational Science, Monash University, Clayton, Vic 3168, Australia
| | - Nam-Trung Nguyen
- Queensland
Micro and Nanotechnology Centre, Griffith
University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Muhammad J. A. Shiddiky
- School
of Environment and Science, Griffith University, Nathan Campus, Nathan, QLD 4111, Australia
- Queensland
Micro and Nanotechnology Centre, Griffith
University, Nathan Campus, Nathan, QLD 4111, Australia
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17
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Kim M, Son IT, Noh GT, Woo SY, Lee RA, Oh BY. Exosomes Derived from Colon Cancer Cells Promote Tumor Progression and Affect the Tumor Microenvironment. J Clin Med 2023; 12:3905. [PMID: 37373600 DOI: 10.3390/jcm12123905] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/01/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Cancer-cell-derived exosomes confer oncogenic properties in their tumor microenvironment and to other cells; however, the exact mechanism underlying this process is unclear. Here, we investigated the roles of cancer-cell-derived exosomes in colon cancer. Exosomes were isolated from colon cancer cell lines, HT-29, SW480, and LoVo, using an ExoQuick-TC kit, identified using Western blotting for exosome markers, and characterized using transmission electron microscopy and nanosight tracking analysis. The isolated exosomes were used to treat HT-29 to evaluate their effect on cancer progression, specifically cell viability and migration. Cancer-associated fibroblasts (CAFs) were obtained from patients with colorectal cancer to analyze the effect of the exosomes on the tumor microenvironment. RNA sequencing was performed to evaluate the effect of the exosomes on the mRNA component of CAFs. The results showed that exosome treatment significantly increased cancer cell proliferation, upregulated N-cadherin, and downregulated E-cadherin. Exosome-treated cells exhibited higher motility than control cells. Compared with control CAFs, exosome-treated CAFs showed more downregulated genes. The exosomes also altered the regulation of different genes involved in CAFs. In conclusion, colon cancer-cell-derived exosomes affect cancer cell proliferation and the epithelial-mesenchymal transition. They promote tumor progression and metastasis and affect the tumor microenvironment.
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Affiliation(s)
- Minsung Kim
- Department of Surgery, Hallym University College of Medicine, Anyang 14068, Republic of Korea
| | - Il Tae Son
- Department of Surgery, Hallym University College of Medicine, Anyang 14068, Republic of Korea
| | - Gyoung Tae Noh
- Department of Surgery, Ewha Womans University College of Medicine, Seoul 07804, Republic of Korea
| | - So-Youn Woo
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul 03760, Republic of Korea
| | - Ryung-Ah Lee
- Department of Surgery, Ewha Womans University College of Medicine, Seoul 07804, Republic of Korea
| | - Bo Young Oh
- Department of Surgery, Hallym University College of Medicine, Anyang 14068, Republic of Korea
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18
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Wang J, Han Y, Huang F, Tang L, Mu J, Liang Y. Diabetic macrophage small extracellular vesicles-associated miR-503/IGF1R axis regulates endothelial cell function and affects wound healing. Front Immunol 2023; 14:1104890. [PMID: 37287964 PMCID: PMC10243549 DOI: 10.3389/fimmu.2023.1104890] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 04/28/2023] [Indexed: 06/09/2023] Open
Abstract
Diabetic foot ulcer (DFU) is a break in the skin of the foot caused by diabetes. It is one of the most serious and debilitating complications of diabetes. The previous study suggested that dominant M1 polarization during DFU could be the leading reason behind impaired wound healing. This study concluded that macrophage M1 polarization predominates in DFU skin tissue. iNOS was increased in HG-induced M1-polarized macrophages; conversely, Arg-1 was decreased. Macrophage pellets after HG stimulation can impair endothelial cell (EC) function by inhibiting cell viability, tube formation and cell migration, indicating M1 macrophage-derived small extracellular vesicles (sEVs) -mediated HUVEC dysfunction. sEVs miR-503 was significantly upregulated in response to HG stimulation, but inhibition of miR-503 in HG-stimulated macrophages attenuated M1 macrophage-induced HUVEC dysfunction. ACO1 interacted with miR-503 and mediated the miR-503 package into sEVs. Under HG stimulation, sEVs miR-503 taken in by HUVECs targeted IGF1R in HUVECs and inhibited IGF1R expression. In HUVECs, miR-503 inhibition improved HG-caused HUVEC dysfunction, whereas IGF1R knockdown aggravated HUVEC dysfunction; IGF1R knockdown partially attenuated miR-503 inhibition effects on HUVECs. In the skin wound model in control or STZ-induced diabetic mice, miR-503-inhibited sEVs improved, whereas IGF1R knockdown further hindered wound healing. Therefore, it can be inferred from the results that the M1 macrophage-derived sEVs miR-503 targets IGF1R in HUVECs, inhibits IGF1R expression, leads to HUVEC dysfunction, and impedes wound healing in diabetic patients, while packaging miR-503 as an M1 macrophage-derived sEVs may be mediated by ACO1.
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Affiliation(s)
- Jianqiang Wang
- Molecular Nutrition Branch, National Engineering Research Center of Rice and By-Product Deep Processing/College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, Hunan, China
| | - Yuanshan Han
- Scientific Research Department, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Fang Huang
- Molecular Nutrition Branch, National Engineering Research Center of Rice and By-Product Deep Processing/College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, Hunan, China
| | - Liuhuan Tang
- Molecular Nutrition Branch, National Engineering Research Center of Rice and By-Product Deep Processing/College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, Hunan, China
| | - Jianfei Mu
- Molecular Nutrition Branch, National Engineering Research Center of Rice and By-Product Deep Processing/College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, Hunan, China
| | - Ying Liang
- Molecular Nutrition Branch, National Engineering Research Center of Rice and By-Product Deep Processing/College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, Hunan, China
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19
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Mansur S, Habib S, Hawkins M, Brown SR, Weinman ST, Bao Y. Preparation of Nanoparticle-Loaded Extracellular Vesicles Using Direct Flow Filtration. Pharmaceutics 2023; 15:pharmaceutics15051551. [PMID: 37242792 DOI: 10.3390/pharmaceutics15051551] [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: 04/24/2023] [Revised: 05/17/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
Extracellular vesicles (EVs) have shown great potential as cell-free therapeutics and biomimetic nanocarriers for drug delivery. However, the potential of EVs is limited by scalable, reproducible production and in vivo tracking after delivery. Here, we report the preparation of quercetin-iron complex nanoparticle-loaded EVs derived from a breast cancer cell line, MDA-MB-231br, using direct flow filtration. The morphology and size of the nanoparticle-loaded EVs were characterized using transmission electron microscopy and dynamic light scattering. The SDS-PAGE gel electrophoresis of those EVs showed several protein bands in the range of 20-100 kDa. The analysis of EV protein markers by a semi-quantitative antibody array confirmed the presence of several typical EV markers, such as ALIX, TSG101, CD63, and CD81. Our EV yield quantification suggested a significant yield increase in direct flow filtration compared with ultracentrifugation. Subsequently, we compared the cellular uptake behaviors of nanoparticle-loaded EVs with free nanoparticles using MDA-MB-231br cell line. Iron staining studies indicated that free nanoparticles were taken up by cells via endocytosis and localized at a certain area within the cells while uniform iron staining across cells was observed for cells treated with nanoparticle-loaded EVs. Our studies demonstrate the feasibility of using direct flow filtration for the production of nanoparticle-loaded EVs from cancer cells. The cellular uptake studies suggested the possibility of deeper penetration of the nanocarriers because the cancer cells readily took up the quercetin-iron complex nanoparticles, and then released nanoparticle-loaded EVs, which can be further delivered to regional cells.
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Affiliation(s)
- Shomit Mansur
- Chemical & Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA
| | - Shahriar Habib
- Chemical & Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA
| | - Mikayla Hawkins
- Chemical & Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA
| | - Spenser R Brown
- Chemical & Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA
| | - Steven T Weinman
- Chemical & Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA
| | - Yuping Bao
- Chemical & Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA
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20
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Almeida C, Teixeira AL, Dias F, Morais M, Medeiros R. Extracellular Vesicles as Potential Therapeutic Messengers in Cancer Management. BIOLOGY 2023; 12:biology12050665. [PMID: 37237479 DOI: 10.3390/biology12050665] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 04/17/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023]
Abstract
A deeper understanding of the communication mechanisms of tumor cells in a tumor microenvironment can improve the development of new therapeutic solutions, leading to a more personalized approach. Recently, the field of extracellular vesicles (EVs) has drawn attention due to their key role in intercellular communication. EVs are nano-sized lipid bilayer vesicles that are secreted by all types of cells and can function as intermediators of intercellular communication with the ability to transfer different cargo (proteins, nucleic acids, sugar…) types among cells. This role of EVs is essential in a cancer context as it can affect tumor promotion and progression and contribute to the pre-metastatic niche establishment. Therefore, scientists from basic, translational, and clinical research areas are currently researching EVs with great expectations due to their potential to be used as clinical biomarkers, which are useful for disease diagnosis, prognosis, patient follow-up, or even as vehicles for drug delivery due to their natural carrier nature. The application of EVs presents numerous advantages as drug delivery vehicles, namely their capacity to overcome natural barriers, their inherent cell-targeting properties, and their stability in the circulation. In this review, we highlight the distinctive features of EVs, their application as efficient drug delivery systems, and their clinical applications.
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Affiliation(s)
- Cristina Almeida
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal
- Research Department of the Portuguese League Against Cancer Regional Nucleus of the North (LPCC-NRNorte), Estrada da Circunvalação 6657, 4200-177 Porto, Portugal
| | - Ana Luísa Teixeira
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal
| | - Francisca Dias
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal
| | - Mariana Morais
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal
- ICBAS School of Medicine and Biomedical Sciences, University of Porto (UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal
- Research Department of the Portuguese League Against Cancer Regional Nucleus of the North (LPCC-NRNorte), Estrada da Circunvalação 6657, 4200-177 Porto, Portugal
- ICBAS School of Medicine and Biomedical Sciences, University of Porto (UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal
- Fernando Pessoa Research, Innovation and Development Institute (I3ID FFP), Fernando Pessoa University (UFP), Praça 9 de Abril 349, 4249-004 Porto, Portugal
- Faculty of Medicine, University of Porto (FMUP), Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
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21
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Exploring the role of exosomes in rheumatoid arthritis. Inflammopharmacology 2023; 31:119-128. [PMID: 36414831 DOI: 10.1007/s10787-022-01100-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 11/04/2022] [Indexed: 11/23/2022]
Abstract
In prosperous countries, autoimmune illnesses affect minimum 7% of the community. Rheumatoid Arthritis (RA) as an autoimmune illness is thought to be induced through a variety of genomic, physiological, and biological factors. Many experts in the field of nanomedicine have looked to stem cells as a viable strategy to repair human tissue; however, exosomes have demonstrated greater potential in recent years. Exosomes, produced from stem cells in particular, have exhibited a high propensity to give therapeutic effects. To resist local cellular stress, they are secreted in a paracrine manner from cells. As a result, exosomes produced from stem cells can provide enormous health uses. If treatment is not given, autoantibodies produce synovial inflammation and arthritis, which can lead to chronic inflammation, and impairment. Exosomes could be administered for the treatment of RA, by acting as therapeutic vectors. Exosomes are murine extracellular vesicles that influence biological mechanisms and signal transduction by transporting genetic and protein components. Diseases like RA and bone fractures could be treated using cell-free therapeutic strategies if exosomes could be isolated from stem cells efficiently and packaged with specific restorative substances. To get to this position, many breakthroughs must be achieved, and the following review summarises the most recent developments in stem cell-derived exosomes, with a focus on the important literature on exosome dynamics in RA.
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22
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Moirangthem A, Gondaliya P, Yan IK, Sayyed AA, Driscoll J, Patel T. Extracellular vesicle‑mediated miR‑126‑3p transfer contributes to inter‑cellular communication in the liver tumor microenvironment. Int J Oncol 2023; 62:31. [PMID: 36660950 PMCID: PMC9851126 DOI: 10.3892/ijo.2023.5479] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 10/24/2022] [Indexed: 01/18/2023] Open
Abstract
Extracellular vesicles (EVs) and their contents are gaining recognition as important mediators of intercellular communication through the transfer of bioactive molecules, such as non‑coding RNA. The present study comprehensively assessed the microRNA (miRNA/miR) content within EVs released from HepG2 liver cancer (LC) cells and LX2 hepatic stellate cells (HSCs) and determined the contribution of EV miRNA to intercellular communication. Using both transwell and spheroid co‑cultures of LC cells and HSCs, miR‑126‑3p within EV was established as a mediator of HSC to LC cell communication that influenced tumor cell migration and invasion, as well as the growth of multicellular LC/HSC spheroids. Manipulation of miR‑126‑3p either by enforced expression using pre‑miR‑126‑3p or by inhibition using antimiR‑126‑3p did not alter tumor cell viability, proliferation or sensitivity to either sorafenib or regorafenib. By contrast, enforced expression of miR‑126‑3p decreased tumor‑cell migration. Knockdown of miR‑126‑3p in tumor cells increased disintegrin and metalloproteinase domain‑containing protein 9 (ADAM9) expression and in HSCs increased collagen‑1A1 accumulation with an increase in compactness of multicellular spheroids. Within LC/HSC spheroids, ADAM9 and vascular endothelial growth factor expression was increased by silencing of miR‑126‑3p but diminished with the restoration of miR‑126‑3p. These studies implicate miR‑126‑3p in functional effects on migration, invasion and spheroid growth of tumor cells in the presence of HSCs, and thereby demonstrate functional EV‑RNA‑based intercellular signaling between HSCs and LC cells that is directly relevant to tumor‑cell behavior.
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Affiliation(s)
| | | | - Irene K. Yan
- Departments of Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Adil Ali Sayyed
- Departments of Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Julia Driscoll
- Departments of Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Tushar Patel
- Departments of Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
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23
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Zhao S, Pan T, Deng J, Cao L, Vicencio JM, Liu J, Zhou G, Ng T, Zhang J. Exosomal transfer of miR-181b-5p confers senescence-mediated doxorubicin resistance via modulating BCLAF1 in breast cancer. Br J Cancer 2023; 128:665-677. [PMID: 36522479 PMCID: PMC9938221 DOI: 10.1038/s41416-022-02077-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 10/25/2022] [Accepted: 11/16/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Doxorubicin resistance represents a major clinical challenge for treating patients with advanced breast cancer (BC). Exosomes, exchanging genetic cargo between heterogeneous populations of tumour cells, have been proposed to mediate drug resistance and cancer progression in other cancer types. However, their specific role in mediating doxorubicin resistance in BC remains unclear. Here, we demonstrate the important role of exosomal miR-181b-5p (exo-miR-181b-5p) in mediating doxorubicin resistance. METHODS Small-RNA sequencing and bioinformatic analyses were used to screen miRNAs mediating doxorubicin resistance in BC, which were further verified by RT-qPCR. SA-β-gal staining assays allowed us to measure cellular senescence. Exosomes from patients' serum before and after neoadjuvant chemotherapy were isolated for exo-miR-181b-5p quantification. RESULTS Doxorubicin-resistant BC cell lines exhibited upregulated exosomal miR-181b-5p. Addition of exo-miR-181b-5p actively fused with recipient cells and transferred a drug-resistant phenotype. Overexpression of miR-181b-5p downregulated p53/p21 levels and inhibited doxorubicin-induced G1 arrest and senescence by suppressing BCLAF1 expression in vitro. Further, in vivo experiments showed treatment of exo-miR-181b-5p inhibitors exhibited superior tumour control and reversed the doxorubicin-resistance phenotype, accompanied with increased tumoral BCLAF1. CONCLUSION Our data suggests exo-miR-181b-5p as a prognostic biomarker and a therapeutic potential for exo-miR-181b-5p inhibitors in the treatment of doxorubicin-resistant BC patients.
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Affiliation(s)
- Shaorong Zhao
- The 3rd Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Teng Pan
- The 3rd Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Jinhai Deng
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
| | - Lixia Cao
- Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, 300071, Tianjin, China
| | - Jose M Vicencio
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
- Cancer Institute, Paul O'Gorman Building, University College London, London, UK
| | - Jingjing Liu
- The 3rd Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Guanglin Zhou
- The 3rd Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Tony Ng
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK
- Cancer Institute, Paul O'Gorman Building, University College London, London, UK
- Cancer Research UK City of London Centre, London, England
| | - Jin Zhang
- The 3rd Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.
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24
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Extracellular Vesicles: New Classification and Tumor Immunosuppression. BIOLOGY 2023; 12:biology12010110. [PMID: 36671802 PMCID: PMC9856004 DOI: 10.3390/biology12010110] [Citation(s) in RCA: 95] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 01/05/2023] [Accepted: 01/05/2023] [Indexed: 01/13/2023]
Abstract
Extracellular vesicles (EVs) are cell-derived membrane-surrounded vesicles carrying various types of molecules. These EV cargoes are often used as pathophysiological biomarkers and delivered to recipient cells whose fates are often altered in local and distant tissues. Classical EVs are exosomes, microvesicles, and apoptotic bodies, while recent studies discovered autophagic EVs, stressed EVs, and matrix vesicles. Here, we classify classical and new EVs and non-EV nanoparticles. We also review EVs-mediated intercellular communication between cancer cells and various types of tumor-associated cells, such as cancer-associated fibroblasts, adipocytes, blood vessels, lymphatic vessels, and immune cells. Of note, cancer EVs play crucial roles in immunosuppression, immune evasion, and immunotherapy resistance. Thus, cancer EVs change hot tumors into cold ones. Moreover, cancer EVs affect nonimmune cells to promote cellular transformation, including epithelial-to-mesenchymal transition (EMT), chemoresistance, tumor matrix production, destruction of biological barriers, angiogenesis, lymphangiogenesis, and metastatic niche formation.
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25
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Tumor-derived exosomes elicit cancer-associated fibroblasts shaping inflammatory tumor microenvironment in head and neck squamous cell carcinoma. Oral Oncol 2023; 136:106270. [PMID: 36462328 DOI: 10.1016/j.oraloncology.2022.106270] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 11/05/2022] [Accepted: 11/24/2022] [Indexed: 12/05/2022]
Abstract
OBJECTIVES Exosome-mediated reciprocal crosstalk between tumor and stromal cells plays a crucial role in tumor development and progression. This study investigated whether exosomes released from head and neck squamous cell carcinoma (HNSCC) tumor cells can convert normal fibroblasts into cancer-associated fibroblasts (CAF)-like cells and further analyzed the functional characterization of fibroblasts educated by tumor-derived exosomes. MATERIALS AND METHODS Exosomes secreted from HNSCC cell lines were isolated and normal fibroblasts were established from normal oropharyngeal mucosa. The effects of the exosomes on fibroblasts were examined by proliferation and migration assays, and exosome-educated fibroblasts were analyzed for the expression of eight genes (IL1B, IL6, CXCL8, TGFB1, ACTA2, FAP, CD274, and PDCD1LG2) by RT-qPCR. Moreover, T cells or CD14-positive cells were co-cultured with culture supernatants from exosome-educated fibroblasts. T-cell proliferation and macrophage polarization were examined using flow cytometry. Then, RNA sequencing (RNA-seq) of exosome-educated fibroblasts and the corresponding control fibroblasts was performed. RESULTS Tumor-derived exosomes enhanced fibroblast proliferation and migration. Moreover, gene expression analysis revealed upregulation of the gene expression of proinflammatory cytokines and immunoregulatory genes, and activated fibroblast marker genes. The culture supernatants of tumor-derived exosome-educated fibroblasts suppressed T cell proliferation and the induction of protumoral macrophages compared with those of control fibroblasts. Next, comprehensive RNA-seq analysis data revealed the activation of 11 signaling pathways, including IL-6- and IL-17-related signaling. CONCLUSION These results indicate that HNSCC tumor cells induce and/or differentiate into CAFs through exosome-based cell-to-cell communication to create an inflammatory tumor microenvironment.
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26
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Abstract
Exosomes are extracellular vesicles, which have the ability to convey various types of cargo between cells. Lately, a great amount of interest has been paid to exosomal microRNAs (miRNAs), since much evidence has suggested that the sorting of miRNAs into exosomes is not an accidental process. It has been shown that exosomal miRNAs (exo-miRNAs) are implicated in a variety of cellular processes including (but not limited to) cell migration, apoptosis, proliferation, and autophagy. Exosomes can play a role in cardiovascular diseases and can be used as diagnostic biomarkers for several diseases, especially cancer. Tremendous advances in technology have led to the development of various platforms for miRNA profiling. Each platform has its own limitations and strengths that need to be understood in order to use them properly. In the current review, we summarize some exo-miRNAs that are relevant to exo-miRNA profiling studies and describe new methods used for the measurement of miRNA profiles in different human bodily fluids.
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27
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Pallares-Rusiñol A, Bernuz M, Moura SL, Fernández-Senac C, Rossi R, Martí M, Pividori MI. Advances in exosome analysis. Adv Clin Chem 2022; 112:69-117. [PMID: 36642486 DOI: 10.1016/bs.acc.2022.09.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
There is growing demand for novel biomarkers that detect early stage disease as well as monitor clinical management and therapeutic strategies. Exosome analysis could provide the next advance in attaining that goal. Exosomes are membrane encapsulated biologic nanometric-sized particles of endocytic origin which are released by all cell types. Unfortunately, exosomes are exceptionally challenging to characterize with current technologies. Exosomes are between 30 and 200nm in diameter, a size that makes them out of the sensitivity range to most cell-oriented sorting or analysis platforms, i.e., traditional flow cytometers. The most common methods for targeting exosomes to date typically involve purification followed by the characterization and the specific determination of their cargo. The whole procedure is time consuming, requiring thus skilled personnel as well as laboratory facilities and benchtop instrumentation. The most relevant methodology for exosome isolation, characterization and quantification is addressed in this chapter, including the most up-to-date approaches to explore the potential usefulness of exosomes as biomarkers in liquid biopsies and in advanced nanomedicine.
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Affiliation(s)
- Arnau Pallares-Rusiñol
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Mireia Bernuz
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Silio Lima Moura
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Carolina Fernández-Senac
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Rosanna Rossi
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Mercè Martí
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - María Isabel Pividori
- Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Grup de Sensors i Biosensors, Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Spain.
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28
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Wang F, Zhang Y, Li J, Xia H, Zhang D, Yao S. The pathogenesis and therapeutic strategies of heat stroke-induced liver injury. Crit Care 2022; 26:391. [PMID: 36528615 PMCID: PMC9758799 DOI: 10.1186/s13054-022-04273-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Heat stroke (HS) is a life-threatening systemic disease characterized by an elevated core body temperature of more than 40 ℃ and subsequent multiple organ dysfunction syndrome. With the growing frequency of global heatwaves, the incidence rate of HS has increased significantly, which has caused a huge burden on people's lives and health. Liver injury is a well-documented complication of HS and usually constitutes the direct cause of patient death. In recent years, a lot of research has been carried out on the pathogenesis and treatment strategies of HS-induced liver injury. In this review, we summarized the important pathogenesis of HS-induced liver injury that has been confirmed so far. In addition to the comprehensive effect of systemic factors such as heat cytotoxicity, coagulopathy, and systemic inflammatory response syndrome, excessive hepatocyte cell pyroptosis, dysfunction of Kupffer cells, abnormal expression of heat shock protein expression, and other factors are also involved in the pathogenesis of HS-induced liver injury. Furthermore, we have also established the current therapeutic strategies for HS-induced liver injury. Our study is of great significance in promoting the understanding of the pathogenesis and treatment of HS-induced liver injury.
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Affiliation(s)
- Fuquan Wang
- grid.33199.310000 0004 0368 7223Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China ,grid.33199.310000 0004 0368 7223Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022 China
| | - Yan Zhang
- grid.33199.310000 0004 0368 7223Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China ,grid.33199.310000 0004 0368 7223Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022 China
| | - Jianhua Li
- grid.190737.b0000 0001 0154 0904Chongqing university Jiangjin hospital, Chongqing, China
| | - Haifa Xia
- grid.33199.310000 0004 0368 7223Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China ,grid.33199.310000 0004 0368 7223Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022 China
| | - Dingyu Zhang
- grid.33199.310000 0004 0368 7223Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China ,grid.33199.310000 0004 0368 7223Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022 China ,grid.507952.c0000 0004 1764 577XWuhan Jinyintan Hospital, Wuhan, 430023 China
| | - Shanglong Yao
- grid.33199.310000 0004 0368 7223Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China ,grid.33199.310000 0004 0368 7223Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022 China
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29
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Tani Y, Ochiai K, Kaneta T. Optical collection of extracellular vesicles in a culture medium enhanced by interactions with gold nanoparticles. ANAL SCI 2022; 39:643-651. [PMID: 36334243 DOI: 10.1007/s44211-022-00207-2] [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: 07/28/2022] [Accepted: 10/21/2022] [Indexed: 11/07/2022]
Abstract
Extracellular vesicles (EVs) exist in biological fluids such as blood, urine, and cerebrospinal fluid and are promising cancer biomarkers. Attempts to isolate and analyze trace EVs, however, have been a challenge for researchers studying their functions and secretion mechanisms, which has stymied the options for diagnostic application. This study demonstrated a collection of EVs that was enhanced by gold nanoparticles (AuNPs) via the use of optical force. The collection system consists of an inverted microscope equipped with a CCD camera, a square capillary connected with a PTFE tube, and an Nd:YAG laser that generates optical force. The laser beam was focused on a capillary wall in which a cell culture medium containing EVs flowed continuously. Control of the surface charges on both the capillary wall and the AuNPs achieved the collection and retention of EVs on the capillary wall. The positively charged capillary wall retained EVs even after the laser irradiation was halted due to the negative charges inherent on the surface of EVs. Conversely, positively charged AuNPs had a strong electrostatic interaction with EVs and enhanced the optical force acting on them, which made collecting them a much more efficient process.
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Affiliation(s)
- Yumeki Tani
- Department of Chemistry, Okayama University, Okayama, 700-8530, Japan
| | - Kenta Ochiai
- Department of Chemistry, Okayama University, Okayama, 700-8530, Japan
| | - Takashi Kaneta
- Department of Chemistry, Okayama University, Okayama, 700-8530, Japan.
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30
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Yin S, Chen A, Ding Y, Song J, Chen R, Zhang P, Yang C. Recent advances in exosomal RNAs analysis towards diagnostic and therapeutic applications. Trends Analyt Chem 2022. [DOI: 10.1016/j.trac.2022.116840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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31
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Lee Y, Kim JH. The emerging roles of extracellular vesicles as intercellular messengers in liver physiology and pathology. Clin Mol Hepatol 2022; 28:706-724. [PMID: 35232008 PMCID: PMC9597227 DOI: 10.3350/cmh.2021.0390] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 02/25/2022] [Indexed: 01/05/2023] Open
Abstract
Extracellular vesicles (EVs) are membrane-enclosed particles released from almost all cell types. EVs mediate intercellular communication by delivering their surface and luminal cargoes, including nucleic acids, proteins, and lipids, which reflect the pathophysiological conditions of their cellular origins. Hepatocytes and hepatic non-parenchymal cells utilize EVs to regulate a wide spectrum of biological events inside the liver and transfer them to distant organs through systemic circulation. The liver also receives EVs from multiple organs and integrates these extrahepatic signals that participate in pathophysiological processes. EVs have recently attracted growing attention for their crucial roles in maintaining and regulating hepatic homeostasis. This review summarizes the roles of EVs in intrahepatic and interorgan communications under different pathophysiological conditions of the liver, with a focus on chronic liver diseases including nonalcoholic steatohepatitis, alcoholic hepatitis, viral hepatitis, liver fibrosis, and hepatocellular carcinoma. This review also discusses recent progress for potential therapeutic applications of EVs by targeting or enhancing EV-mediated cellular communication for the treatment of liver diseases.
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Affiliation(s)
- Youngseok Lee
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea
| | - Jong-Hoon Kim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea,Corresponding author : Jong-Hoon Kim Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea Tel: +82-2-3290-3007, Fax: +82-2-3290-3040, E-mail:
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32
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Li Y, Bao Q, Yang S, Yang M, Mao C. Bionanoparticles in cancer imaging, diagnosis, and treatment. VIEW 2022. [DOI: 10.1002/viw.20200027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
- Yan Li
- Institute of Applied Bioresource Research College of Animal Science Zhejiang University Hangzhou Zhejiang China
| | - Qing Bao
- School of Materials Science and Engineering Zhejiang University Hangzhou Zhejiang China
| | - Shuxu Yang
- Department of Neurosurgery Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou Zhejiang China
| | - Mingying Yang
- Institute of Applied Bioresource Research College of Animal Science Zhejiang University Hangzhou Zhejiang China
| | - Chuanbin Mao
- School of Materials Science and Engineering Zhejiang University Hangzhou Zhejiang China
- Department of Chemistry and Biochemistry Stephenson Life Science Research Center University of Oklahoma Norman Oklahoma USA
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33
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Ottaviani L, Juni RP, de Abreu RC, Sansonetti M, Sampaio-Pinto V, Halkein J, Hegenbarth JC, Ring N, Knoops K, Kocken JMM, Jesus C, Ernault AC, El Azzouzi H, Rühle F, Olieslagers S, Fernandes H, Ferreira L, Braga L, Stoll M, Nascimento DS, de Windt LJ, da Costa Martins PA. Intercellular transfer of miR-200c-3p impairs the angiogenic capacity of cardiac endothelial cells. Mol Ther 2022; 30:2257-2273. [PMID: 35278675 DOI: 10.1016/j.ymthe.2022.03.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/28/2022] [Accepted: 03/07/2022] [Indexed: 10/18/2022] Open
Abstract
As mediators of intercellular communication, extracellular vesicles containing molecular cargo such as microRNAs, are secreted by cells and taken up by recipient cells to influence their cellular phenotype and function. Here, we report that cardiac stress-induced differential microRNA content, with miR-200c-3p being one of the most enriched, in cardiomyocyte-derived extracellular vesicles mediates functional crosstalk with endothelial cells. Silencing of miR-200c-3p in mice subjected to chronic increased cardiac pressure overload resulted in attenuated hypertrophy, smaller fibrotic areas, higher capillary density and preserved cardiac ejection fraction. Interestingly, we were able to maximal rescue microvascular and cardiac function with very low doses of antagomir, which specifically silences miR-200c-3p expression in the non-myocyte cells. Our results reveal vesicle transfer of miR-200c-3p from cardiomyocytes to cardiac endothelial cells, underlining the importance of cardiac intercellular communication in the pathophysiology of heart failure.
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Affiliation(s)
- L Ottaviani
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands; Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University, Maastricht, The Netherlands
| | - R P Juni
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands; Department of Physiology, Amsterdam University Medical Centers, Amsterdam Cardiovascular Science, Amsterdam, The Netherlands
| | - R C de Abreu
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands; Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University, Maastricht, The Netherlands; CNC - Center for Neuroscience and Cell Biology,CIBB - Centre for Innovative Biomedicine and Biotechnology, University Coimbra, Portugal
| | - M Sansonetti
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands; Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University, Maastricht, The Netherlands
| | - V Sampaio-Pinto
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands; Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University, Maastricht, The Netherlands; i3S - Instituto de Investigação e Inovação em Saude, Universidade do Porto, Porto, Portugal; INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal; ICBAS - Instituto de Ciências Biomêdicas de Abel Salazar, Universidade do Porto, Porto, Portugal
| | - J Halkein
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - J C Hegenbarth
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands; Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University, Maastricht, The Netherlands
| | - N Ring
- Cardiovascular Biology Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - K Knoops
- Microscope CORE lab, The Maastricht Multimodal Molecular Imaging Institute (M4I), Maastricht University, Maastricht, The Netherlands
| | - J M M Kocken
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands; Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University, Maastricht, The Netherlands
| | - C Jesus
- CNC - Center for Neuroscience and Cell Biology,CIBB - Centre for Innovative Biomedicine and Biotechnology, University Coimbra, Portugal; Faculty of Medicine University of Coimbra, Coimbra, Portugal
| | - A C Ernault
- Departments of Experimental Cardiology, Biostatistics and Bioinformatics, Amsterdam UMC, location AMC, Amsterdam, The Netherlands
| | - H El Azzouzi
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - F Rühle
- Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany
| | - S Olieslagers
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands; Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University, Maastricht, The Netherlands
| | - H Fernandes
- CNC - Center for Neuroscience and Cell Biology,CIBB - Centre for Innovative Biomedicine and Biotechnology, University Coimbra, Portugal; Faculty of Medicine University of Coimbra, Coimbra, Portugal
| | - L Ferreira
- CNC - Center for Neuroscience and Cell Biology,CIBB - Centre for Innovative Biomedicine and Biotechnology, University Coimbra, Portugal; Faculty of Medicine University of Coimbra, Coimbra, Portugal
| | - L Braga
- Functional Cell Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - M Stoll
- Cardiovascular Biology Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy; Department of Biochemistry, Genetic Epidemiology and Statistical Genetics, CARIM School for Cardiovascular Diseases, Maastricht Center for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands
| | - D S Nascimento
- i3S - Instituto de Investigação e Inovação em Saude, Universidade do Porto, Porto, Portugal; INEB - Instituto Nacional de Engenharia Biomédica, Universidade do Porto, Porto, Portugal; ICBAS - Instituto de Ciências Biomêdicas de Abel Salazar, Universidade do Porto, Porto, Portugal
| | - L J de Windt
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands; Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University, Maastricht, The Netherlands
| | - P A da Costa Martins
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands; Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University, Maastricht, The Netherlands; Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal.
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Almeida C, Teixeira AL, Dias F, Machado V, Morais M, Martins G, Palmeira C, Sousa ME, Godinho I, Batista S, Costa-Silva B, Medeiros R. Extracellular Vesicles Derived-LAT1 mRNA as a Powerful Inducer of Colorectal Cancer Aggressive Phenotype. BIOLOGY 2022; 11:biology11010145. [PMID: 35053143 PMCID: PMC8773288 DOI: 10.3390/biology11010145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 12/31/2021] [Accepted: 01/07/2022] [Indexed: 11/16/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world and represents the third most deadly tumor worldwide. About 15–25% of patients present metastasis in the moment of diagnosis, the liver being the most common site of metastization. Therefore, the development of new therapeutic agents is needed, to improve the patients’ prognosis. Amino acids transporters, LAT1 and ASCT2, are described as upregulated in CRC, being associated with a poor prognosis. Extracellular vesicles have emerged as key players in cell-to-cell communication due to their ability to transfer biomolecules between cells, with a phenotypic impact on the recipient cells. Thus, this study analyzes the presence of LAT1 and ASCT2 mRNAs in CRC-EVs and evaluates their role in phenotype modulation in a panel of four recipient cell lines (HCA-7, HEPG-2, SK-HEP-1, HKC-8). We found that HCT 116-EVs carry LAT1, ASCT2 and other oncogenic mRNAs being taken up by recipient cells. Moreover, the HCT 116-EVs’ internalization was associated with the increase of LAT1 mRNA in SK-HEP-1 cells. We also observed that HCT 116-EVs induce a higher cell migration capacity and proliferation of SK-HEP-1 and HKC-8 cells. The present study supports the LAT1-EVs’ mRNA involvement in cell phenotype modulation, conferring advantages in cell migration and proliferation.
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Affiliation(s)
- Cristina Almeida
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; (C.A.); (F.D.); (V.M.); (M.M.); (R.M.)
- Research Department of the Portuguese League against Cancer Regional Nucleus of the North (LPCC-NRN), Estrada da Circunvalação 6657, 4200-177 Porto, Portugal
| | - Ana Luísa Teixeira
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; (C.A.); (F.D.); (V.M.); (M.M.); (R.M.)
- ICBAS School of Medicine and Biomedical Sciences, University of Porto (UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal
- Correspondence: ; Tel.: +351-225-084-000 (ext. 5410)
| | - Francisca Dias
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; (C.A.); (F.D.); (V.M.); (M.M.); (R.M.)
| | - Vera Machado
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; (C.A.); (F.D.); (V.M.); (M.M.); (R.M.)
| | - Mariana Morais
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; (C.A.); (F.D.); (V.M.); (M.M.); (R.M.)
| | - Gabriela Martins
- Immunology Department, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; (G.M.); (C.P.); (M.E.S.); (I.G.)
| | - Carlos Palmeira
- Immunology Department, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; (G.M.); (C.P.); (M.E.S.); (I.G.)
- Pathology and Experimental Therapeutic Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
- Fernando Pessoa Research, Innovation and Development Institute (I3ID FFP), Fernando Pessoa University (UFP), Praça 9 de Abril 349, 4249-004 Porto, Portugal
| | - Maria Emília Sousa
- Immunology Department, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; (G.M.); (C.P.); (M.E.S.); (I.G.)
| | - Inês Godinho
- Immunology Department, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; (G.M.); (C.P.); (M.E.S.); (I.G.)
| | - Sílvia Batista
- Systems Oncology Group, Champalimaud Research, Champalimaud Centre for the Unknown, Av. Brasília, 1400-038 Lisbon, Portugal; (S.B.); (B.C.-S.)
| | - Bruno Costa-Silva
- Systems Oncology Group, Champalimaud Research, Champalimaud Centre for the Unknown, Av. Brasília, 1400-038 Lisbon, Portugal; (S.B.); (B.C.-S.)
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; (C.A.); (F.D.); (V.M.); (M.M.); (R.M.)
- Research Department of the Portuguese League against Cancer Regional Nucleus of the North (LPCC-NRN), Estrada da Circunvalação 6657, 4200-177 Porto, Portugal
- ICBAS School of Medicine and Biomedical Sciences, University of Porto (UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal
- Fernando Pessoa Research, Innovation and Development Institute (I3ID FFP), Fernando Pessoa University (UFP), Praça 9 de Abril 349, 4249-004 Porto, Portugal
- Faculty of Medicine, University of Porto (FMUP), Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
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Chen H, Hou K, Wu Y, Liu Z. Use of Adipose Stem Cells Against Hypertrophic Scarring or Keloid. Front Cell Dev Biol 2022; 9:823694. [PMID: 35071247 PMCID: PMC8770320 DOI: 10.3389/fcell.2021.823694] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 12/17/2021] [Indexed: 12/26/2022] Open
Abstract
Hypertrophic scars or keloid form as part of the wound healing reaction process, and its formation mechanism is complex and diverse, involving multi-stage synergistic action of multiple cells and factors. Adipose stem cells (ASCs) have become an emerging approach for the treatment of many diseases, including hypertrophic scarring or keloid, owing to their various advantages and potential. Herein, we analyzed the molecular mechanism of hypertrophic scar or keloid formation and explored the role and prospects of stem cell therapy, in the treatment of this condition.
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Affiliation(s)
| | | | | | - Zeming Liu
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Gupta S, Mazumder P. Exosomes as diagnostic tools. Adv Clin Chem 2022; 110:117-144. [DOI: 10.1016/bs.acc.2022.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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The Hidden Link of Exosomes to Head and Neck Cancer. Cancers (Basel) 2021; 13:cancers13225802. [PMID: 34830956 PMCID: PMC8616040 DOI: 10.3390/cancers13225802] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/12/2021] [Accepted: 11/18/2021] [Indexed: 12/24/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) represents an aggressive and heterogenous group of cancers whose pathologies remain largely unresolved. Despite recent advances in HNSCC therapeutic strategies, the overall survival of HNSCC patients remains poor and continues to prompt efforts to develop more effective therapies. Exosomes are a subtype of extracellular vesicles secreted by a variety of cells that have begun to spark significant interest in their roles in cancer. As membranous vesicles, spanning from 30-150 nm in diameter, exosomes mediate the transport of various molecules, such as proteins, nucleic acids, and lipids, intercellularly throughout the body. In doing so, exosomes not only act to deliver materials to cancer cells but also as signals that can confer their progression. Accumulating evidence shows the direct correlation between exosomes and the aggressiveness of HNSCC. However, more research is warranted in this field to further our understanding. In this review, we attempt to highlight the tumor-supporting roles and therapeutic potential of exosomes in HNSCC. We introduce first the biogenesis and component features of exosomes, followed by their involvement in HNSCC proliferation and metastasis. We then move on to discuss HNSCC-derived exosomes' influence on the tumor microenvironment and their function in tumor drug resistance. Finally, we explore the promising potential of exosomes as HNSCC biomarkers and therapeutic targets and drug carriers for HNSCC treatments.
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Titu S, Grapa CM, Mocan T, Balacescu O, Irimie A. Tetraspanins: Physiology, Colorectal Cancer Development, and Nanomediated Applications. Cancers (Basel) 2021; 13:cancers13225662. [PMID: 34830819 PMCID: PMC8616055 DOI: 10.3390/cancers13225662] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/01/2021] [Accepted: 11/09/2021] [Indexed: 01/10/2023] Open
Abstract
Simple Summary Considering the high incidence of colorectal cancer in adults, as well as the need for identifying novel therapies, we hereby explore the role of tetraspanins in the development of colorectal cancer. We have focused on variate aspects starting from the structure and general physiology and ending with the precise mechanisms involved in the dual reported role of tetraspanins (pro–tumoral and tumor suppressor key player element). Moreover, the present review focuses on the potential of tetraspanins as a target for nanotechnology-mediated therapies, also gathering the limited attempts towards this aim and their reported data. Abstract Tetraspanins are transmembrane proteins expressed in a multitude of cells throughout the organism. They contribute to many processes that surround cell–cell interactions and are associated with the progress of some diseases, including cancer. Their crucial role in cell physiology is often understated. Furthermore, recent studies have shown their great potential in being used as targeting molecules. Data have suggested the potential of tetraspanins as a targeting vector for nanomediated distribution and delivery for colorectal cancer applications. Our aim is to provide a review on the important part that tetraspanins play in the human organism and highlight their potential use for drug delivery systems using nanotechnology.
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Affiliation(s)
- Stefan Titu
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Faculty of Medicine, 400126 Cluj-Napoca, Romania; (S.T.); (C.M.G.); (A.I.)
- Department of Surgical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca, 400015 Cluj-Napoca, Romania
| | - Cristiana Maria Grapa
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Faculty of Medicine, 400126 Cluj-Napoca, Romania; (S.T.); (C.M.G.); (A.I.)
- Nanomedicine Department, Regional Institute of Gastroenterology and Hepatology, 400126 Cluj-Napoca, Romania
| | - Teodora Mocan
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Faculty of Medicine, 400126 Cluj-Napoca, Romania; (S.T.); (C.M.G.); (A.I.)
- Nanomedicine Department, Regional Institute of Gastroenterology and Hepatology, 400126 Cluj-Napoca, Romania
- Correspondence:
| | - Ovidiu Balacescu
- Department of Genetics, Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca, 400015 Cluj-Napoca, Romania;
| | - Alexandru Irimie
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Faculty of Medicine, 400126 Cluj-Napoca, Romania; (S.T.); (C.M.G.); (A.I.)
- Department of Surgical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca, 400015 Cluj-Napoca, Romania
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Kuracha MR, Thomas P, Tobi M, McVicker BL. Role of cell-free network communication in alcohol-associated disorders and liver metastasis. World J Gastroenterol 2021; 27:7080-7099. [PMID: 34887629 PMCID: PMC8613644 DOI: 10.3748/wjg.v27.i41.7080] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/02/2021] [Accepted: 09/30/2021] [Indexed: 02/06/2023] Open
Abstract
The aberrant use of alcohol is a major factor in cancer progression and metastasis. Contributing mechanisms include the systemic effects of alcohol and the exchange of bioactive molecules between cancerous and non-cancerous cells along the brain-gut-liver axis. Such interplay leads to changes in molecular, cellular, and biological functions resulting in cancer progression. Recent investigations have examined the role of extracellular vesicles (EVs) in cancer mechanisms in addition to their contribution as diagnostic biomarkers. Also, EVs are emerging as novel cell-free mediators in pathophysiological scenarios including alcohol-mediated gut microbiome dysbiosis and the release of nanosized EVs into the circulatory system. Interestingly, EVs in cancer patients are enriched with oncogenes, miRNA, lipids, and glycoproteins whose delivery into the hepatic microenvironment may be enhanced by the detrimental effects of alcohol. Proof-of-concept studies indicate that alcohol-associated liver disease is impacted by the effects of exosomes, including altered immune responses, reprogramming of stromal cells, and remodeling of the extracellular matrix. Moreover, the culmination of alcohol-related changes in the liver likely contributes to enhanced hepatic metastases and poor outcomes for cancer patients. This review summarizes the numerous aspects of exosome communications between organs with emphasis on the relationship of EVs in alcohol-associated diseases and cancer metastasis. The potential impact of EV cargo and release along a multi-organ axis is highly relevant to the promotion of tumorigenic mechanisms and metastatic disease. It is hypothesized that EVs target recipient tissues to initiate the formation of prometastatic niches and cancer progression. The study of alcohol-associated mechanisms in metastatic cancers is expected to reveal a better understanding of factors involved in the growth of secondary malignancies as well as novel approaches for therapeutic interventions.
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Affiliation(s)
- Murali R Kuracha
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Peter Thomas
- Department of Surgery, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Martin Tobi
- Research and Development Service, Detroit VAMC, Detroit, MI 48201, United States
- Department of Medicine, Central Michigan University College of Medicine, Detroit, MI 48201, United States
| | - Benita L McVicker
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Research Service, Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
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Exosomes Derived from miR-146a-5p-Enriched Mesenchymal Stem Cells Protect the Cardiomyocytes and Myocardial Tissues in the Polymicrobial Sepsis through Regulating MYBL1. Stem Cells Int 2021; 2021:1530445. [PMID: 34691188 PMCID: PMC8536448 DOI: 10.1155/2021/1530445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 09/13/2021] [Indexed: 12/20/2022] Open
Abstract
Background At present, the study has confirmed that the mesenchymal stem cell-derived exosomes (MCSs-Exo) possess cardio-protection in sepsis. Nevertheless, the molecular mechanism of the protection of MSCs-Exo in sepsis remains unknown. Therefore, this research is aimed at studying the molecular mechanism. Methods The effects of MSCs-Exo and miR-146a-5p in LPS-induced cardiomyocytes (H9C2 cells) in vitro were verified by CCK-8, EdU assay, flow cytometry, Western blot assay, and RT-qPCR. The effect of MSCs-Exo in vivo was evaluated by CLP-induced sepsis model. The potential gene in MSCs-Exo was verified by bioinformatics analysis, and the potential target of miR-146a-5p was identified by bioinformatics analysis and luciferase reporter assay. At last, the function of miR-146a-5p and its target genes on LPS-induced cardiomyocytes (H9C2 cells) in vitro was validated by recuse experiment. Results Our findings revealed that MSCs-Exo could effectively protect cardiomyocytes of inflammation model in vitro and myocardial tissues of sepsis model in vivo. Meanwhile, we found that miR-146a-5p was a potential gene in MSCs-Exo, and MYBL1 was the target gene of miR-146a-5p and negatively regulated by miR-146a-5p. In addition, miR-146a-5p overexpression promoted proliferation and inhibited apoptosis of LPS-induced cardiomyocytes. The rescue experiment demonstrated that miR-146a-5p could effectively repress the inflammatory response of cardiomyocytes via decreasing MYBL1 expression. Conclusion This study suggests that miR-146a-5p-bearing MSC-derived exosomes may become an effective treatment for sepsis.
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Sousa D, Lima RT, Lopes-Rodrigues V, Gonzalez E, Royo F, Xavier CPR, Falcón-Pérez JM, Vasconcelos MH. Different Ability of Multidrug-Resistant and -Sensitive Counterpart Cells to Release and Capture Extracellular Vesicles. Cells 2021; 10:cells10112886. [PMID: 34831110 PMCID: PMC8616370 DOI: 10.3390/cells10112886] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer multidrug resistance (MDR) is one of the main challenges for cancer treatment efficacy. MDR is a phenomenon by which tumor cells become resistant to several unrelated drugs. Some studies have previously described the important role of extracellular vesicles (EVs) in the dissemination of a MDR phenotype. EVs’ cargo may include different players of MDR, such as microRNAS and drug-efflux pumps, which may be transferred from donor MDR cells to recipient drug-sensitive counterparts. The present work aimed to: (i) compare the ability of drug-sensitive and their MDR counterpart cells to release and capture EVs and (ii) study and relate those differences with possible distinct fate of the endocytic pathway in these counterpart cells. Our results showed that MDR cells released more EVs than their drug-sensitive counterparts and also that the drug-sensitive cells captured more EVs than their MDR counterparts. This difference in the release and capture of EVs may be associated with differences in the endocytic pathway between drug-sensitive and MDR cells. Importantly, manipulation of the recycling pathway influenced the response of drug-sensitive cells to doxorubicin treatment.
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Affiliation(s)
- Diana Sousa
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (D.S.); (R.T.L.); (V.L.-R.); (C.P.R.X.)
- Cancer Drug Resistance Group, IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Department of Biological Sciences, FFUP—Faculty of Pharmacy of the University of Porto, 4050-313 Porto, Portugal
| | - Raquel T. Lima
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (D.S.); (R.T.L.); (V.L.-R.); (C.P.R.X.)
- Cancer Drug Resistance Group, IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Department of Pathology, FMUP—Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal
- Cancer Signaling & Metabolism Group, IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
| | - Vanessa Lopes-Rodrigues
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (D.S.); (R.T.L.); (V.L.-R.); (C.P.R.X.)
- Cancer Drug Resistance Group, IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- ICBAS-UP—Institute of Biomedical Sciences Abel Salazar of the University of Porto, 4099-003 Porto, Portugal
| | - Esperanza Gonzalez
- Exosomes Lab. & Metabolomics Platform, CIC bioGUNE, CIBERehd, 28160 Derio, Spain; (E.G.); (F.R.); (J.M.F.-P.)
| | - Félix Royo
- Exosomes Lab. & Metabolomics Platform, CIC bioGUNE, CIBERehd, 28160 Derio, Spain; (E.G.); (F.R.); (J.M.F.-P.)
| | - Cristina P. R. Xavier
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (D.S.); (R.T.L.); (V.L.-R.); (C.P.R.X.)
- Cancer Drug Resistance Group, IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
| | - Juan M. Falcón-Pérez
- Exosomes Lab. & Metabolomics Platform, CIC bioGUNE, CIBERehd, 28160 Derio, Spain; (E.G.); (F.R.); (J.M.F.-P.)
- IKERBASQUE Basque Foundation for Science, 48013 Bilbao, Spain
| | - M. Helena Vasconcelos
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (D.S.); (R.T.L.); (V.L.-R.); (C.P.R.X.)
- Cancer Drug Resistance Group, IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
- Department of Biological Sciences, FFUP—Faculty of Pharmacy of the University of Porto, 4050-313 Porto, Portugal
- Correspondence: ; Tel.: +351-225-570-772
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Abstract
The transmission of information between tumor cells and other cell types in the tumor microenvironment plays an important role in tumor metastasis and is critically modulated by exosomes and other mediators. Tumor-derived exosomes can promote epithelial-mesenchymal transition, angiogenesis, immune escape, formation of the pre-metastatic microenvironment, and transmission of drug-resistant molecules, thereby promoting tumor growth, invasion, and metastasis. Integrins are important regulatory molecules on exosomes that can locate metastatic cells at the initial stage of metastasis and show good organotropism. This fact suggests that a clear understanding of the roles of exosomal integrins will be beneficial for future clinical applications. Follow-up studies on exosomes using continuously updated purification techniques and identification methods are extremely important. In addition to their potential as cancer biomarkers, exosomes also provide new research directions for precision medicine. Currently, exosomes have potential value in disease treatment and provide clinicians with more meaningful judgment standards.
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Wang M, Wang Y, Ye F, Yu K, Wei W, Liu M, Wang R, Cui S. Exosome encapsulated ncRNAs in the development of HCC: potential circulatory biomarkers and clinical therapeutic targets. Am J Cancer Res 2021; 11:3794-3812. [PMID: 34522450 PMCID: PMC8414376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 04/13/2021] [Indexed: 06/13/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most deadly malignant cancer in the world and has the third highest mortality rate among cancer-related deaths worldwide. Its poor prognosis can be attributed to late diagnosis, high risk of recurrence and drug resistance. Therefore, finding a new biomarker to help us in the early diagnosis, and exploring the molecular mechanisms involved in recurrence and drug resistance is a reasonable research direction for clinical treatment of HCC. At present, the exosomes related to HCC have been confirmed to carry ncRNAs, transfer them to target cells, and bind corresponding target molecules. Furthermore, they affect the proliferation and metastasis of hepatocellular carcinoma by promoting angiogenesis, epithelial-mesenchymal transition (EMT), and inhibiting the function of the body's immune system. They play an important role in the recurrence and resistance of HCC. Besides, exosomes are stably expressed in body fluids such as sera, are easy to collect and cause little harm to the human body. They are the best candidates for liquid biopsy. Therefore, exosomal ncRNAs have application prospects as biomarkers and targeted molecules for therapy. This article summarizes the current research involving ncRNAs in HCC-related exosomes.
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Affiliation(s)
- Mingyuan Wang
- The First School of Clinical Medicine, Nanjing Medical UniversityNanjing 210029, Jiangsu, China
| | - Yutong Wang
- The First School of Clinical Medicine, Nanjing Medical UniversityNanjing 210029, Jiangsu, China
| | - Fan Ye
- The First School of Clinical Medicine, Nanjing Medical UniversityNanjing 210029, Jiangsu, China
| | - Kai Yu
- The First School of Clinical Medicine, Nanjing Medical UniversityNanjing 210029, Jiangsu, China
| | - Weicheng Wei
- School of Pediatrics, Nanjing Medical UniversityNanjing 210029, Jiangsu, China
| | - Muyue Liu
- The First School of Clinical Medicine, Nanjing Medical UniversityNanjing 210029, Jiangsu, China
| | - Rui Wang
- Department of Medical Oncology, Jinling Hospital of PLANanjing 210002, Jiangsu, China
| | - Shiyun Cui
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, Jiangsu, China
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Exosomal miR-1260b derived from non-small cell lung cancer promotes tumor metastasis through the inhibition of HIPK2. Cell Death Dis 2021; 12:747. [PMID: 34321461 PMCID: PMC8319168 DOI: 10.1038/s41419-021-04024-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/30/2021] [Accepted: 07/13/2021] [Indexed: 01/03/2023]
Abstract
Tumor-derived exosomes (TEXs) contain enriched miRNAs, and exosomal miRNAs can affect tumor growth, including cell proliferation, metastasis, and drug resistance through cell-to-cell communication. We investigated the role of exosomal miR-1260b derived from non-small cell lung cancer (NSCLC) in tumor progression. Exosomal miR-1260b induced angiogenesis by targeting homeodomain-interacting protein kinase-2 (HIPK2) in human umbilical vein endothelial cells (HUVECs). Furthermore, exosomal miR-1260b or suppression of HIPK2 led to enhanced cellular mobility and cisplatin resistance in NSCLC cells. In patients with NSCLC, the level of HIPK2 was significantly lower in tumor tissues than in normal lung tissues, while that of miR-1260b was higher in tumor tissues. HIPK2 and miR-1260b expression showed an inverse correlation, and this correlation was strong in distant metastasis. Finally, the expression level of exosomal miR-1260b in plasma was higher in patients with NSCLC than in healthy individuals, and higher levels of exosomal miR-1260b were associated with high-grade disease, metastasis, and poor survival. In conclusion, exosomal miR-1260b can promote angiogenesis in HUVECs and metastasis of NSCLC by regulating HIPK2 and may serve as a prognostic marker for lung cancers.
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Bahrami A, Moradi Binabaj M, A Ferns G. Exosomes: Emerging modulators of signal transduction in colorectal cancer from molecular understanding to clinical application. Biomed Pharmacother 2021; 141:111882. [PMID: 34218003 DOI: 10.1016/j.biopha.2021.111882] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/10/2021] [Accepted: 06/28/2021] [Indexed: 12/15/2022] Open
Abstract
Exosomes are small cell derived membrane nano-vesicles that carry various components including lipids, proteins and nucleic acids. There is accumulating evidence that exosomes have a role in tumorigenesis, tumor invasiveness and metastasis. Furthermore, oncogene mutation may influence exosome release from tumor cells. Exosomes may induce colorectal cancer by altering signaling cascades such as the Wnt/β-catenin and KRAS pathways that are involved in cell proliferation, apoptosis, dissemination, angiogenesis, and drug resistance. The aim of this review was to overview recent findings evaluating the association between tumor cells-derived exosomes and their content in modulating signaling pathways in colorectal cancer.
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Affiliation(s)
- Afsane Bahrami
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.
| | - Maryam Moradi Binabaj
- Non-Communicable Diseases Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran.
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
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Alteration of payload in extracellular vesicles by crosstalk with mesenchymal stem cells from different origin. J Nanobiotechnology 2021; 19:148. [PMID: 34016123 PMCID: PMC8139033 DOI: 10.1186/s12951-021-00890-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 05/08/2021] [Indexed: 02/07/2023] Open
Abstract
Background The application of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) requires customized materials to target disease or cell damage. We hypothesized that EVs exert different inflammatory effects on one recipient cell, although stem cells of different origins in humans have similar payloads. Results Here, the payload of EVs released by crosstalk between MSCs and human middle ear epithelial cells (HMEECs) extracted from adipose tissue, bone marrow and tonsils significantly increased the level of anti-inflammatory factors. EVs derived from the co-culture medium decreased TNF-, COX-2, IL-1, and IL-6 levels to approximately zero within 3h in HMEECs. Expression of miR-638 and amyloid- A4 precursor protein-binding family A member 2 was analyzed using microarrays and gene ontology analysis, respectively. Conclusions In conclusion, stem cells of different origins have different payloads through crosstalk with recipient-specific cells. Inducing specific factors in EVs by co-culture with MSCs could be valuable in regenerative medicine. Graphical abstract ![]()
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Handa T, Kuroha M, Nagai H, Shimoyama Y, Naito T, Moroi R, Kanazawa Y, Shiga H, Kakuta Y, Kinouchi Y, Masamune A. Liquid Biopsy for Colorectal Adenoma: Is the Exosomal miRNA Derived From Organoid a Potential Diagnostic Biomarker? Clin Transl Gastroenterol 2021; 12:e00356. [PMID: 33979310 PMCID: PMC8116025 DOI: 10.14309/ctg.0000000000000356] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 04/05/2021] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION MicroRNAs (miRNAs) can serve as tumor biomarkers; however, their role in evaluating colorectal adenoma (CRA) is unclear. Recently, the organoid culture system enabled long-term expansion of human colon epithelium. This study aimed to examine the potential of exosomal miRNAs extracted from CRA organoids as biomarkers in the clinical liquid biopsy CRA test. METHODS We established organoid cultures from normal colon and CRA using resected specimens. Exosomes were isolated from the conditioned medium organoids. MiRNAs were isolated from the exosomes, and their expression profiles were compared using microarray analysis. To identify miRNA candidates for liquid biopsy, we prospectively compared changes in their expression in serum and exosomes before and after endoscopic resection in 26 patients with CRA. RESULTS Seven exosomal miRNAs were overexpressed in CRA organoids: miR-4323, miR-4284, miR-1268a, miR-1290, miR-6766-3p, miR-21-5p, and miR-1246. The expression levels of 4 exosomal miRNAs (miR-4323, miR-4284, miR-1290, and miR-1246) and 2 serum miRNAs (miR-1290 and miR-1246) were significantly lower in posttreatment sera. The combined expression of 4 exosomal miRNAs could identify both CRA and large-size (>12.6 cm2) CRA with respective areas under the curve of 0.698 (95% confidence interval [CI] = 0.536-0.823) and 0.834 (95% CI = 0.660-0.929). Combinations of 2-serum miRNA expression values could identify both CRA and large-size CRA with respective area under the curves of 0.691 (95% CI = 0.528-0.817) and 0.834 (95% CI = 0.628-0.938). DISCUSSION We found that exosomal miRNAs derived from the CRA organoid culture could be potential diagnostic biomarkers for CRA.
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Affiliation(s)
- Tomoyuki Handa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masatake Kuroha
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroshi Nagai
- Department of Gastroenterology, Shirakawa Kosei General Hospital, Fukushima, Japan
| | - Yusuke Shimoyama
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takeo Naito
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Rintaro Moroi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshitake Kanazawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hisashi Shiga
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoichi Kakuta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshitaka Kinouchi
- Health Administration Center, Center for the Advancement of Higher Education, Tohoku University, Sendai, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Sorop A, Constantinescu D, Cojocaru F, Dinischiotu A, Cucu D, Dima SO. Exosomal microRNAs as Biomarkers and Therapeutic Targets for Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms22094997. [PMID: 34066780 PMCID: PMC8125948 DOI: 10.3390/ijms22094997] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/28/2021] [Accepted: 05/04/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second most common cause of cancer-related death globally. This type of liver cancer is frequently detected at a late stage by current biomarkers because of the high clinical and biological heterogeneity of HCC tumours. From a plethora of molecules and cellular compounds, small nanoparticles with an endosomal origin are valuable cancer biomarkers or cargos for novel treatments. Despite their small sizes, in the range of 40–150 nm, these particles are delimited by a lipid bilayer membrane with a specific lipid composition and carry functional information—RNA, proteins, miRNAs, long non-coding RNAs (lncRNAs), or DNA fragments. This review summarizes the role of exosomal microRNA (miRNA) species as biomarkers in HCC therapy. After we briefly introduce the exosome biogenesis and the methods of isolation and characterization, we discuss miRNA’s correlation with the diagnosis and prognosis of HCC, either as single miRNA species, or as specific panels with greater clinical impact. We also review the role of exosomal miRNAs in the tumourigenic process and in the cell communication pathways through the delivery of cargos, including proteins or specific drugs.
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Affiliation(s)
- Andrei Sorop
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania; (A.S.); (D.C.); (S.O.D.)
- Department DAFAB, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania; (F.C.); (A.D.)
| | - Diana Constantinescu
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania; (A.S.); (D.C.); (S.O.D.)
| | - Florentina Cojocaru
- Department DAFAB, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania; (F.C.); (A.D.)
| | - Anca Dinischiotu
- Department DAFAB, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania; (F.C.); (A.D.)
| | - Dana Cucu
- Department DAFAB, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania; (F.C.); (A.D.)
- Correspondence: ; Tel.: +40-728-257-607
| | - Simona Olimpia Dima
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania; (A.S.); (D.C.); (S.O.D.)
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, 022238 Bucharest, Romania
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Danac JMC, Uy AGG, Garcia RL. Exosomal microRNAs in colorectal cancer: Overcoming barriers of the metastatic cascade (Review). Int J Mol Med 2021; 47:112. [PMID: 33907829 PMCID: PMC8075282 DOI: 10.3892/ijmm.2021.4945] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/07/2021] [Indexed: 12/15/2022] Open
Abstract
The journey of cancer cells from a primary tumor to distant sites is a multi-step process that involves cellular reprogramming, the breaking or breaching of physical barriers and the preparation of a pre-metastatic niche for colonization. The loss of adhesion between cells, cytoskeletal remodeling, the reduction in size and change in cell shape, the destruction of the extracellular matrix, and the modification of the tumor microenvironment facilitate migration and invasion into surrounding tissues. The promotion of vascular leakiness enables intra- and extravasation, while angiogenesis and immune suppression help metastasizing cells become established in the new site. Tumor-derived exosomes have long been known to harbor microRNAs (miRNAs or miRs) that help prepare secondary sites for metastasis; however, their roles in the early and intermediate steps of the metastatic cascade are only beginning to be characterized. The present review article presents a summary and discussion of the miRNAs that form part of colorectal cancer (CRC)-derived exosomal cargoes and which play distinct roles in epithelial to mesenchymal plasticity and metastatic organotropism. First, an overview of epithelial-to-mesenchymal transition (EMT), metastatic organotropism, as well as exosome biogenesis, cargo sorting and uptake by recipient cells is presented. Lastly, the potential of these exosomal miRNAs as prognostic biomarkers for metastatic CRC, and the blocking of these as a possible therapeutic intervention is discussed.
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Affiliation(s)
- Joshua Miguel C Danac
- Disease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular Biology and Biotechnology, National Science Complex, University of the Philippines Diliman, Quezon City 1101, Philippines
| | - Aileen Geobee G Uy
- Disease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular Biology and Biotechnology, National Science Complex, University of the Philippines Diliman, Quezon City 1101, Philippines
| | - Reynaldo L Garcia
- Disease Molecular Biology and Epigenetics Laboratory, National Institute of Molecular Biology and Biotechnology, National Science Complex, University of the Philippines Diliman, Quezon City 1101, Philippines
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Naseer M, Hadi S, Syed A, Safdari A, Tahan V. Exosomes: A new frontier under the spotlight for diagnosis and treatment of gastrointestinal diseases. World J Meta-Anal 2021; 9:12-28. [DOI: 10.13105/wjma.v9.i1.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/15/2020] [Accepted: 02/22/2021] [Indexed: 02/06/2023] Open
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