|
1
|
Surman M, Wilczak M, Bzowska M, Tylko G, Przybyło M. The Proangiogenic Effects of Melanoma-Derived Ectosomes Are Mediated by αvβ5 Integrin Rather than αvβ3 Integrin. Cells 2024; 13:1336. [PMID: 39195226 PMCID: PMC11352487 DOI: 10.3390/cells13161336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 07/28/2024] [Accepted: 08/10/2024] [Indexed: 08/29/2024] Open
Abstract
Ectosomes are carriers of proangiogenic factors during cancer progression. This study investigated whether the proangiogenic effect exerted by melanoma-derived ectosomes on recipient endothelial cells is mediated by ectosomal αvβ3 and αvβ5 integrins. Ectosomes were isolated from the conditioned culture media of four melanoma cell lines and melanocytes. Changes in gene and protein expression of αvβ3 and αvβ5 integrins, as well as VEGF and TNF-α were assessed in ectosome-treated endothelial cells. To confirm the functional involvement of ectosomal integrins in functional tests (Alamar Blue, wound healing and tube formation assays), ectosomes were also pretreated with anti-integrin antibodies and integrin-blocking peptides echistatin and cilengitide. Melanoma-derived ectosomes induced changes in the expression of αvβ3 and αvβ5 integrins in recipient endothelial cells, leading to increased viability, migratory properties, and tube formation potential. The extent of proangiogenic stimulation varied depending on the types of cells releasing ectosomes and the recipient cells. The use of anti-integrin antibodies and integrin-blocking peptides revealed a more significant role for the αvβ5 integrin/VEGF than the αvβ3 integrin/TNF-α pathway in the interactions between ectosomes and endothelial cells. The study demonstrated the functional role of ectosomal αvβ3 and αvβ5 integrins. It also provided a baseline understanding of ectosome-mediated αvβ3 integrin/TNF-α and αvβ5 integrin/VEGF signaling in angiogenesis.
Collapse
Affiliation(s)
- Magdalena Surman
- Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland; (M.S.); (M.W.)
| | - Magdalena Wilczak
- Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland; (M.S.); (M.W.)
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, 30-348 Krakow, Poland
| | - Małgorzata Bzowska
- Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland;
| | - Grzegorz Tylko
- Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland;
| | - Małgorzata Przybyło
- Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland; (M.S.); (M.W.)
| |
Collapse
|
|
2
|
Ren J, Jin Z, Huang Y. Exosomal miR-106a-5p derived from intermittently hypoxic non-small-cell lung cancer increases tumor malignancy. Physiol Rep 2024; 12:e16157. [PMID: 39085755 PMCID: PMC11291016 DOI: 10.14814/phy2.16157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 06/24/2024] [Accepted: 07/09/2024] [Indexed: 08/02/2024] Open
Abstract
Intermittent hypoxia (IH) is a hallmark of obstructive sleep apnea (OSA), which is related to tumorigenesis and progression. We explored the possible mechanisms by which OSA may promote the development of non-small cell lung cancer (NSCLC). In this study, NSCLC cells with and without miR-106a-5p inhibition were exposed to IH or room air (RA), and subsequently, exosomes were extracted and identified. Macrophages were incubated with these exosomes to detect the expression of the STAT3 signaling pathway and M2-type macrophage markers, as well as the effect of the macrophages on the malignancy of NSCLC cells. A nude mouse tumorigenesis model was constructed to detect the effects of exosomal miR-106a-5p on M2 macrophage polarization and NSCLC cell malignancy. Our results showed that IH exosomes promoted the polarization of M2 macrophages, thereby promoting the proliferation, invasion, and metastasis of NSCLC cells. Further, Based on microarray analysis of RA and IH exosomes, we discovered that miR-106a-5p, transferred to the macrophages through exosomes, participated in this mechanism by promoting M2 macrophage polarization via down-regulating PTEN and activating the STAT3 signaling pathway in vitro and in vivo. For patients with NSCLC and OSA, exosomal miR-106a-5p levels showed a positive relation to AHI. Exosomal miR-106a-5p represents a potential therapeutic target among patients with concomitant cancer and NSCLC.
Collapse
Affiliation(s)
- Jie Ren
- Department of Respiratory MedicineThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Zhuan Jin
- Department of Respiratory MedicineThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Yongjie Huang
- Department of Respiratory MedicineThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| |
Collapse
|
|
3
|
Aalami AH, Shahriari A, Mazaheri M, Aalami F, Sahebkar A. Advancing gastrointestinal cancer diagnostics: a systematic review and meta-analysis of circulating microRNA-1246 as a non-invasive biomarker. Biomarkers 2024; 29:233-243. [PMID: 38696280 DOI: 10.1080/1354750x.2024.2350714] [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: 03/31/2024] [Accepted: 04/19/2024] [Indexed: 05/04/2024]
Abstract
BACKGROUND Despite numerous reports on the alterations of microRNA-1246 (miR-1246) expression level in digestive system cancers, its role in gastrointestinal cancers (GICs) remains unclear. This meta-analysis aimed to assess the diagnostic potential of circulating miR-1246 in GICs. METHODS Meta-disc version 1.4 and Comprehensive Meta-Analysis (CMA) version 3.7 software were used to calculate pooled sensitivity, specificity, likelihood ratios, diagnostic odds ratio (DOR), area under the curve (AUC), Q*index and summary receiver-operating characteristic (SROC). Subgroup analyses were conducted for cancer type, sample type and geographical region. Publication bias was assessed using Begg's and Egger's tests. RESULTS A total of 14 articles involving 18 studies and 1526 participants (972 cases and 554 controls) were included. The diagnostic accuracy of miRNA-1246 in GICs was as follows: pooled sensitivity: 0.81 (95% CI: 0.79 - 0.83), specificity: 0.74 (95% CI: 0.71 - 0.77), PLR: 3.315 (95% CI: 2.33 - 4.72), NLR: 0.221 (95% CI: 0.153 - 0.319), DOR: 16.87 (95% CI: 9.45 - 30.09), AUC: 0.891, and Q*-index: 0.807. No publication bias was found based on Begg's (p = 0.172) and Egger's (p = 0.113) tests. CONCLUSION Circulating miR-1246 shows promise as a non-invasive biomarker for early detection of GICs.
Collapse
Affiliation(s)
- Amir Hossein Aalami
- Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT, USA
- Division of Nephrology and Hypertension, Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT, USA
| | - Ali Shahriari
- Department of Internal Medicine, Mashhad Medical Sciences Branch, Islamic Azad University, Mashhad, Iran
| | - Mohammad Mazaheri
- Department of Molecular, Cell and Systems Biology, College of Natural and Agricultural Sciences, University of California Riverside, Riverside, CA, USA
| | - Farnoosh Aalami
- Student Research Committee, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
4
|
Berkholz J, Karle W. Unravelling the molecular interplay: SUMOylation, PML nuclear bodies and vascular cell activity in health and disease. Cell Signal 2024; 119:111156. [PMID: 38574938 DOI: 10.1016/j.cellsig.2024.111156] [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: 01/01/2024] [Revised: 03/23/2024] [Accepted: 04/01/2024] [Indexed: 04/06/2024]
Abstract
In the seemingly well-researched field of vascular research, there are still many underestimated factors and molecular mechanisms. In recent years, SUMOylation has become increasingly important. SUMOylation is a post-translational modification in which small ubiquitin-related modifiers (SUMO) are covalently attached to target proteins. Sites where these SUMO modification processes take place in the cell nucleus are PML nuclear bodies (PML-NBs) - multiprotein complexes with their essential main component and organizer, the PML protein. PML and SUMO, either alone or as partners, influence a variety of cellular processes, including regulation of transcription, senescence, DNA damage response and defence against microorganisms, and are involved in innate immunity and inflammatory responses. They also play an important role in maintaining homeostasis in the vascular system and in pathological processes leading to the development and progression of cardiovascular diseases. This review summarizes information about the function of SUMO(ylation) and PML(-NBs) in the human vasculature from angiogenesis to disease and highlights their clinical potential as drug targets.
Collapse
Affiliation(s)
- Janine Berkholz
- Institute of Physiology, Charité - Universitätsmedizin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.
| | - Weronika Karle
- Institute of Physiology, Charité - Universitätsmedizin, Berlin, Germany
| |
Collapse
|
|
5
|
Saadh MJ, Allela OQB, Sattay ZJ, Al Zuhairi RAH, Ahmad H, Eldesoky GE, Adil M, Ali MS. Deciphering the functional landscape and therapeutic implications of noncoding RNAs in the TGF-β signaling pathway in colorectal cancer: A comprehensive review. Pathol Res Pract 2024; 255:155158. [PMID: 38320438 DOI: 10.1016/j.prp.2024.155158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/18/2024] [Accepted: 01/18/2024] [Indexed: 02/08/2024]
Abstract
Colorectal cancer (CRC) remains a major global health concern, necessitating an in-depth exploration of the intricate molecular mechanisms underlying its progression and potential therapeutic interventions. Transforming Growth Factor-β (TGF-β) signaling, a pivotal pathway implicated in CRC plays a dual role as a tumor suppressor in the early stages and a promoter of tumor progression in later stages. Recent research has shed light on the critical involvement of noncoding RNAs (ncRNAs) in modulating the TGF-β signaling pathway, introducing a new layer of complexity to our understanding of CRC pathogenesis. This comprehensive review synthesizes the current state of knowledge regarding the function and therapeutic potential of various classes of ncRNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), in the context of TGF-β signaling in CRC. The intricate interplay between these ncRNAs and key components of the TGF-β pathway is dissected, revealing regulatory networks that contribute to the dynamic balance between tumor suppression and promotion. Emphasis is placed on how dysregulation of specific ncRNAs can disrupt this delicate equilibrium, fostering CRC initiation, progression, and metastasis. Moreover, the review provides a critical appraisal of the emerging therapeutic strategies targeting ncRNAs associated with TGF-β signaling in CRC. The potential of these ncRNAs as diagnostic and prognostic biomarkers is discussed, highlighting their clinical relevance. Additionally, the challenges and prospects of developing RNA-based therapeutics, such as RNA interference and CRISPR/Cas-based approaches, are explored in the context of modulating TGF-β signaling for CRC treatment. In conclusion, this review offers a comprehensive overview of the intricate interplay between ncRNAs and the TGF-β signaling pathway in CRC. By unraveling the functional significance of these regulatory elements, we gain valuable insights into the molecular landscape of CRC, paving the way for the development of novel and targeted therapeutic interventions aimed at modulating the TGF-β signaling cascade through the manipulation of ncRNAs.
Collapse
Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan
| | | | - Zahraa Jasim Sattay
- Department of Medical Laboratory Technology l, University of imam Jaafar Al-Sadiq, Iraq
| | | | - Hijaz Ahmad
- Section of Mathematics, International Telematic University Uninettuno, Corso Vittorio Emanuele II, 39, Rome 00186, Italy; Center for Applied Mathematics and Bioinformatics, Gulf University for Science and Technology, Kuwait; Department of Computer Science and Mathematics, Lebanese American University, Beirut, Lebanon
| | - Gaber E Eldesoky
- Chemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | | | | |
Collapse
|
|
6
|
Lukosevicius R, Alzbutas G, Varkalaite G, Salteniene V, Tilinde D, Juzenas S, Kulokiene U, Janciauskas D, Poskiene L, Adamonis K, Kiudelis G, Kupcinskas J, Skieceviciene J. 5'-Isoforms of miR-1246 Have Distinct Targets and Stronger Functional Impact Compared with Canonical miR-1246 in Colorectal Cancer Cells In Vitro. Int J Mol Sci 2024; 25:2808. [PMID: 38474054 DOI: 10.3390/ijms25052808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/05/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
Colorectal cancer (CRC) is a multifactorial disease involving genetic and epigenetic factors, such as miRNAs. Sequencing-based studies have revealed that miRNAs have many isoforms (isomiRs) with modifications at the 3'- and 5'-ends or in the middle, resulting in distinct targetomes and, consequently, functions. In the present study, we aimed to evaluate the putative targets and functional role of miR-1246 and its two 5'-isoforms (ISO-miR-1246_a and ISO-miR-1246_G) in vitro. Commercial Caco-2 cells of CRC origin were analyzed for the expression of WT-miR-1246 and its 5'-isoforms using small RNA sequencing data, and the overabundance of the two miR-1246 isoforms was determined in cells. The transcriptome analysis of Caco-2 cells transfected with WT-miR-1246, ISO-miR-1246_G, and ISO-miR-1246_a indicated the minor overlap of the targetomes between the studied miRNA isoforms. Consequently, an enrichment analysis showed the involvement of the potential targets of the miR-1246 isoforms in distinct signaling pathways. Cancer-related pathways were predominantly more enriched in dysregulated genes in ISO-miR-1246_G and ISO-miR-1246_a, whereas cell cycle pathways were more enriched in WT-miR-1246. The functional analysis of WT-miR-1246 and its two 5'-isoforms revealed that the inhibition of any of these molecules had a tumor-suppressive role (reduced cell viability and migration and promotion of early cell apoptosis) in CRC cells. However, the 5'-isoforms had a stronger effect on viability compared with WT-miR-1246. To conclude, this research shows that WT-miR-1246 and its two 5'-isoforms have different targetomes and are involved in distinct signaling pathways but collectively play an important role in CRC pathogenesis.
Collapse
Affiliation(s)
- Rokas Lukosevicius
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Gediminas Alzbutas
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Greta Varkalaite
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Violeta Salteniene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Deimante Tilinde
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Simonas Juzenas
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
- Institute of Biotechnology, Life Science Centre, Vilnius University, LT-10257 Vilnius, Lithuania
| | - Ugne Kulokiene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Dainius Janciauskas
- Department of Pathology, Medical Academy, Hospital of Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Lina Poskiene
- Department of Pathology, Medical Academy, Hospital of Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Kestutis Adamonis
- Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Gediminas Kiudelis
- Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Juozas Kupcinskas
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
- Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| |
Collapse
|
|
7
|
Liu Y, Wu H, Sang Y, Chong W, Shang L, Li L. Research progress of exosomes in the angiogenesis of digestive system tumour. Discov Oncol 2024; 15:33. [PMID: 38341827 PMCID: PMC10859358 DOI: 10.1007/s12672-024-00879-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 01/30/2024] [Indexed: 02/13/2024] Open
Abstract
Malignant tumours of the digestive system cover a wide range of diseases that affect the health of people to a large extent. Angiogenesis is indispensable in the development, and metastasis of tumours, mainly in two ways: occupation or formation. Vessels can provide nutrients, oxygen, and growth factors for tumours to encourage growth and metastasis, so cancer progression depends on simultaneous angiogenesis. Recently, exosomes have been proven to participate in the angiogenesis of tumours. They influence angiogenesis by binding to tyrosine kinase receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 with different affinities, regulating Yap-VEGF pathway, Akt pathway or other signaling pathway. Additionally, exosomes are potential therapeutic vectors that can deliver many types of cargoes to different cells. In this review, we summarize the roles of exosomes in the angiogenesis of digestive system tumours and highlight the clinical application prospects, directly used as targers or delivery vehicles, in antiangiogenic therapy.
Collapse
Affiliation(s)
- Yuan Liu
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
- Department of Gastrointestinal Surgery, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital, Jinan, 250021, China
- Department of Gastrointestinal Surgery, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - Hao Wu
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yaodong Sang
- Department of Gastrointestinal Surgery, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital, Jinan, 250021, China
- Department of Gastrointestinal Surgery, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - Wei Chong
- Department of Gastrointestinal Surgery, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital, Jinan, 250021, China.
- Department of Gastrointestinal Surgery, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China.
| | - Liang Shang
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
- Department of Gastrointestinal Surgery, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital, Jinan, 250021, China.
- Department of Gastrointestinal Surgery, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China.
| | - Leping Li
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
- Department of Gastrointestinal Surgery, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital, Jinan, 250021, China.
- Department of Gastrointestinal Surgery, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China.
| |
Collapse
|
|
8
|
Yu L, Zeng X, Hu X, Wen Q, Chen P. Advances and challenges in clinical applications of tumor cell-derived extracellular vesicles. Colloids Surf B Biointerfaces 2024; 234:113704. [PMID: 38113751 DOI: 10.1016/j.colsurfb.2023.113704] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/05/2023] [Accepted: 12/07/2023] [Indexed: 12/21/2023]
Abstract
Extracellular vesicles (EVs) are a class of substances that feature vesicle-like structures. Initially deemed to be "biological waste", recent studies have highlighted the crucial role of EVs in mediating information communication between cells by transporting bioactive components. Specifically, tumor cell-derived extracellular vesicles (TEVs) contain components that can be utilized for disease diagnosis and as vaccines to activate the immune system. Moreover, since TEVs have a phospholipid bilayer shell and can transport exogenous substances, they are being increasingly explored as drug delivery vehicles in anti-tumor therapy. TEVs have proven highly compatible with their corresponding tumor cells, allowing for efficient drug delivery and exerting killing effects on tumor cells through various mechanisms such as domino effects, lysosomal pathways, and inhibition of drug efflux from tumor tissues. Despite these promising developments, challenges remain in the clinical applications of EVs derived from tumor cells. This paper outlines the current advances and limitations in this field, highlighting the potential of TEVs as a powerful tool for combating cancer.
Collapse
Affiliation(s)
- Li Yu
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Oncology, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, China
| | - Xiaonan Zeng
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Xiao Hu
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Oncology, the Second Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Qinglian Wen
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Ping Chen
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
| |
Collapse
|
|
9
|
Silonov SA, Smirnov EY, Kuznetsova IM, Turoverov KK, Fonin AV. PML Body Biogenesis: A Delicate Balance of Interactions. Int J Mol Sci 2023; 24:16702. [PMID: 38069029 PMCID: PMC10705990 DOI: 10.3390/ijms242316702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 11/21/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
PML bodies are subnuclear protein complexes that play a crucial role in various physiological and pathological cellular processes. One of the general structural proteins of PML bodies is a member of the tripartite motif (TRIM) family-promyelocytic leukemia protein (PML). It is known that PML interacts with over a hundred partners, and the protein itself is represented by several major isoforms, differing in their variable and disordered C-terminal end due to alternative splicing. Despite nearly 30 years of research, the mechanisms underlying PML body formation and the role of PML proteins in this process remain largely unclear. In this review, we examine the literature and highlight recent progress in this field, with a particular focus on understanding the role of individual domains of the PML protein, its post-translational modifications, and polyvalent nonspecific interactions in the formation of PML bodies. Additionally, based on the available literature, we propose a new hypothetical model of PML body formation.
Collapse
Affiliation(s)
- Sergey A. Silonov
- Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia; (E.Y.S.); (I.M.K.); (K.K.T.)
| | | | | | | | - Alexander V. Fonin
- Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia; (E.Y.S.); (I.M.K.); (K.K.T.)
| |
Collapse
|
|
10
|
Osei GY, Adu-Amankwaah J, Koomson S, Beletaa S, Asiamah EA, Smith-Togobo C, Razak SRA. MicroRNAs and colorectal cancer: clinical potential and regulatory networks. Mol Biol Rep 2023; 50:9575-9585. [PMID: 37776413 DOI: 10.1007/s11033-023-08810-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 09/08/2023] [Indexed: 10/02/2023]
Abstract
Colorectal cancer (CRC) is a serious global health concern, with a high incidence and mortality rate. Although there have been advancements in the early detection and treatment of CRC, therapy resistance is common. MicroRNAs (miRNAs), a type of small non-coding RNA that regulates gene expression, are key players in the initiation and progression of CRC. Recently, there has been growing attention to the complex interplay of miRNAs in cancer development. miRNAs are powerful RNA molecules that regulate gene expression and have been implicated in various physiological and pathological processes, including carcinogenesis. By identifying current challenges and limitations of treatment strategies and suggesting future research directions, this review aims to contribute to ongoing efforts to enhance CRC diagnosis and treatment. It also provides a comprehensive overview of the role miRNAs play in CRC carcinogenesis and explores the potential of miRNA-based therapies as a treatment option. Importantly, this review highlights the exciting potential of targeted modulation of miRNA function as a therapeutic approach for CRC.
Collapse
Affiliation(s)
- George Yiadom Osei
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Pulau Pinang, 13200, Malaysia
- Department of Medical Laboratory Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Joseph Adu-Amankwaah
- Department of Physiology, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Selina Koomson
- Department of Medical Laboratory Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Solomon Beletaa
- Department of Medical Laboratory Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Emmanuel Akomanin Asiamah
- Department of Medical Laboratory Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
- Discipline of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, 4001, South Africa
- Cancer and Infectious Diseases Epidemiology Research Unit (CIDERU), College of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa
| | - Cecilia Smith-Togobo
- Department of Medical Laboratory Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Siti Razila Abdul Razak
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Pulau Pinang, 13200, Malaysia.
| |
Collapse
|
|
11
|
Hosseini R, Hosseinzadeh N, Asef-Kabiri L, Akbari A, Ghezelbash B, Sarvnaz H, Akbari ME. Small extracellular vesicle TGF-β in cancer progression and immune evasion. Cancer Gene Ther 2023; 30:1309-1322. [PMID: 37344681 DOI: 10.1038/s41417-023-00638-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/24/2023] [Accepted: 06/12/2023] [Indexed: 06/23/2023]
Abstract
Transforming growth factor-β (TGF-β) is a well-known cytokine that controls various processes in normal physiology and disease context. Strong preclinical and clinical literature supports the crucial roles of the TGF-β in several aspects of cancer biology. Recently emerging evidence reveals that the release of TGF-β from tumor/immune/stromal cells in small extracellular vesicles (sEVs) plays an important part in tumor development and immune evasion. Hence, this review aims to address the packaging, release, and signaling pathways of TGF-β carried in sEVs (sEV-TGF-β) in cancer, and to explore its underpinning roles in tumor development, growth, progression, metastasis, etc. We also highlight key progresses in deciphering the roles of sEV-TGF-β in subverting anti-tumor immune responses. The paper ends with a focus on the clinical significance of TGF-β carried in sEVs and draws attention to its diagnostic, therapeutic, and prognostic importance.
Collapse
Affiliation(s)
- Reza Hosseini
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Nashmin Hosseinzadeh
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Leila Asef-Kabiri
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Akbari
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behrooz Ghezelbash
- Laboratory Hematology and Blood Banking, School of Allied Medical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamzeh Sarvnaz
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | | |
Collapse
|
|
12
|
Pourali G, Zafari N, Fiuji H, Batra J, Nazari E, Khazaei M, Hassanian SM, Vahabi M, Kiani M, Ghayour-Mobarhan M, Peters GJ, Ferns GA, Lam AKY, Giovannetti E, Avan A. Extracellular vesicles: Emerging mediators of cell communication in gastrointestinal cancers exhibiting metabolic abnormalities. Cytokine Growth Factor Rev 2023; 73:101-113. [PMID: 37573251 DOI: 10.1016/j.cytogfr.2023.08.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 08/03/2023] [Accepted: 08/03/2023] [Indexed: 08/14/2023]
Abstract
There is a complex interaction between pro-tumoural and anti-tumoural networks in the tumour microenvironment (TME). Throughout tumourigenesis, communication between malignant cells and various cells of the TME contributes to metabolic reprogramming. Tumour Dysregulation of metabolic pathways offer an evolutional advantage in the TME and enhance the tumour progression, invasiveness, and metastasis. Therefore, understanding these interactions within the TME is crucial for the development of innovative cancer treatments. Extracellular vesicles (EVs) serve as carriers of various materials that include microRNAs, proteins, and lipids that play a vital role in the communication between tumour cells and non-tumour cells. EVs are actively involved in the metabolic reprogramming process. This review summarized recent findings regarding the involvement of EVs in the metabolic reprogramming of various cells in the TME of gastrointestinal cancers. Additionally, we highlight identified microRNAs involved in the reprogramming process in this group of cancers and explained the abnormal tumour metabolism targeted by exosomal cargos as well as the novel potential therapeutic approaches.
Collapse
Affiliation(s)
- Ghazaleh Pourali
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nima Zafari
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Fiuji
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam U.M.C., VU. University Medical Center (VUMC), Amsterdam, the Netherlands
| | - Jyotsna Batra
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia; Translational Research Institute, Queensland University of Technology, Brisbane, Australia; Center for genomics and Personalised Health, Queensland University of Technology, Brisbane, Australia
| | - Elham Nazari
- Department of Health Information Technology and Management, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahrou Vahabi
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam U.M.C., VU. University Medical Center (VUMC), Amsterdam, the Netherlands
| | - MohammadAli Kiani
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Godefridus J Peters
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam U.M.C., VU. University Medical Center (VUMC), Amsterdam, the Netherlands; Professor In Biochemistry, Medical University of Gdansk, Gdansk, Poland
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Alfred King-Yin Lam
- Pathology, School of Medicine and Dentistry, Gold Coast campus, Griffith University, Gold Coast, QLD 4222, Australia
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam U.M.C., VU. University Medical Center (VUMC), Amsterdam, the Netherlands; Cancer Pharmacology Lab, AIRC Start up Unit, Fondazione Pisana per La Scienza, Pisa, Italy
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; College of Medicine, University of Warith Al-Anbiyaa, Karbala, Iraq,; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia.
| |
Collapse
|
|
13
|
Gu Y, Becker MA, Müller L, Reuss K, Umlauf F, Tang T, Menger MD, Laschke MW. MicroRNAs in Tumor Endothelial Cells: Regulation, Function and Therapeutic Applications. Cells 2023; 12:1692. [PMID: 37443725 PMCID: PMC10340284 DOI: 10.3390/cells12131692] [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: 05/18/2023] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Tumor endothelial cells (TECs) are key stromal components of the tumor microenvironment, and are essential for tumor angiogenesis, growth and metastasis. Accumulating evidence has shown that small single-stranded non-coding microRNAs (miRNAs) act as powerful endogenous regulators of TEC function and blood vessel formation. This systematic review provides an up-to-date overview of these endothelial miRNAs. Their expression is mainly regulated by hypoxia, pro-angiogenic factors, gap junctions and extracellular vesicles, as well as long non-coding RNAs and circular RNAs. In preclinical studies, they have been shown to modulate diverse fundamental angiogenesis-related signaling pathways and proteins, including the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway; the rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway; the phosphoinositide 3-kinase (PI3K)/AKT pathway; and the transforming growth factor (TGF)-β/TGF-β receptor (TGFBR) pathway, as well as krüppel-like factors (KLFs), suppressor of cytokine signaling (SOCS) and metalloproteinases (MMPs). Accordingly, endothelial miRNAs represent promising targets for future anti-angiogenic cancer therapy. To achieve this, it will be necessary to further unravel the regulatory and functional networks of endothelial miRNAs and to develop safe and efficient TEC-specific miRNA delivery technologies.
Collapse
Affiliation(s)
- Yuan Gu
- Institute for Clinical & Experimental Surgery, Saarland University, 66421 Saar, Germany; (M.A.B.); (L.M.); (K.R.); (F.U.); (T.T.); (M.D.M.); (M.W.L.)
| | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Salazar A, Chavarria V, Flores I, Ruiz S, Pérez de la Cruz V, Sánchez-García FJ, Pineda B. Abscopal Effect, Extracellular Vesicles and Their Immunotherapeutic Potential in Cancer Treatment. Molecules 2023; 28:molecules28093816. [PMID: 37175226 PMCID: PMC10180522 DOI: 10.3390/molecules28093816] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 04/25/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
The communication between tumor cells and the microenvironment plays a fundamental role in the development, growth and further immune escape of the tumor. This communication is partially regulated by extracellular vesicles which can direct the behavior of surrounding cells. In recent years, it has been proposed that this feature could be applied as a potential treatment against cancer, since several studies have shown that tumors treated with radiotherapy can elicit a strong enough immune response to eliminate distant metastasis; this phenomenon is called the abscopal effect. The mechanism behind this effect may include the release of extracellular vesicles loaded with damage-associated molecular patterns and tumor-derived antigens which activates an antigen-specific immune response. This review will focus on the recent discoveries in cancer cell communications via extracellular vesicles and their implication in tumor development, as well as their potential use as an immunotherapeutic treatment against cancer.
Collapse
Affiliation(s)
- Aleli Salazar
- Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico
| | - Víctor Chavarria
- Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico
- Immunoregulation Lab, Department of Immunology, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Itamar Flores
- Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico
| | - Samanta Ruiz
- Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico
| | - Verónica Pérez de la Cruz
- Neurobiochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico
| | | | - Benjamin Pineda
- Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City 14269, Mexico
| |
Collapse
|
|
15
|
Wadhonkar K, Singh N, Heralde FM, Parihar SP, Hirani N, Baig MS. Exosome-derived miRNAs regulate macrophage-colorectal cancer cell cross-talk during aggressive tumor development. COLORECTAL CANCER 2023. [DOI: 10.2217/crc-2022-0012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2023]
Abstract
Colorectal cancer is one of the leading causes of death worldwide. Its incidence and mortality have significantly increased during the past few years. Colorectal cancer cells cross-talk with other cells through exosomes in their tumor microenvironment. The miRNAs containing exosomes are responsible for tumor growth, invasion, and metastasis. Multiple studies have shown that exosomal miRNAs are key players in the crosstalk between cancerous, immune, and stromal cells during colorectal cancer development. They help in the establishment of the tumorigenic microenvironment by reprogramming macrophages towards a pro-tumorigenic phenotype. In this review, we discussed various exosomal miRNAs derived both from colorectal cancer cells and macrophages that promote or inhibit cancer aggression. We also discussed various miRNA-based therapeutic approaches to inhibit cancer progression.
Collapse
Affiliation(s)
- Khandu Wadhonkar
- Department of Biosciences & Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol-453552, Indore, India
| | - Neha Singh
- Department of Biosciences & Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol-453552, Indore, India
| | - Francisco M Heralde
- Department of Biochemistry & Molecular Biology, College of Medicine, University of the Philippines-Manila, Manila 1000, Philippines
| | - Suraj P Parihar
- Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) & Institute of Infectious Diseases & Molecular Medicine (IDM), Division of Medical Microbiology, Faculty of Health Sciences, University of Cape Town, Cape Town, 7925, South Africa
- Department of Biochemistry, Human Metabolomics, Faculty of Natural & Agricultural Sciences, North-West University, Potchefstroom, 2520, South Africa
| | - Nik Hirani
- MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, UK
| | - Mirza S Baig
- Department of Biosciences & Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol-453552, Indore, India
| |
Collapse
|
|
16
|
Kotelevets L, Chastre E. Extracellular Vesicles in Colorectal Cancer: From Tumor Growth and Metastasis to Biomarkers and Nanomedications. Cancers (Basel) 2023; 15:1107. [PMID: 36831450 PMCID: PMC9953945 DOI: 10.3390/cancers15041107] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Colorectal cancer (CRC) is a leading public health concern due to its incidence and high mortality rates, highlighting the requirement of an early diagnosis. Evaluation of circulating extracellular vesicles (EVs) might constitute a noninvasive and reliable approach for CRC detection and for patient follow-up because EVs display the molecular features of the cells they originate. EVs are released by almost all cell types and are mainly categorized as exosomes originating from exocytosis of intraluminal vesicles from multivesicular bodies, ectosomes resulting from outward budding of the plasma membrane and apoptotic bodies' ensuing cell shrinkage. These vesicles play a critical role in intercellular communications during physiological and pathological processes. They facilitate CRC progression and premetastatic niche formation, and they enable transfer of chemotherapy resistance to sensitive cells through the local or remote delivery of their lipid, nucleic acid and protein content. On another note, their stability in the bloodstream, their permeation in tissues and their sheltering of packaged material make engineered EVs suitable vectors for efficient delivery of tracers and therapeutic agents for tumor imaging or treatment. Here, we focus on the physiopathological role of EVs in CRCs, their value in the diagnosis and prognosis and ongoing investigations into therapeutic approaches.
Collapse
Affiliation(s)
- Larissa Kotelevets
- Sorbonne Université, INSERM, UMR_S938, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France
| | - Eric Chastre
- Sorbonne Université, INSERM, UMR_S938, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France
| |
Collapse
|
|
17
|
Morimoto M, Maishi N, Tsumita T, Alam MT, Kikuchi H, Hida Y, Yoshioka Y, Ochiya T, Annan DA, Takeda R, Kitagawa Y, Hida K. miR-1246 in tumor extracellular vesicles promotes metastasis via increased tumor cell adhesion and endothelial cell barrier destruction. Front Oncol 2023; 13:973871. [PMID: 37124539 PMCID: PMC10130374 DOI: 10.3389/fonc.2023.973871] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 03/29/2023] [Indexed: 05/02/2023] Open
Abstract
Background Tumor blood vessels play a key role in tumor metastasis. We have previously reported that tumor endothelial cells (TECs) exhibit abnormalities compared to normal endothelial cells. However, it is unclear how TECs acquire these abnormalities. Tumor cells secrete extracellular vesicles (EVs) to create a suitable environment for themselves. We have previously identified miR-1246 to be more abundant in high metastatic melanoma EVs than in low metastatic melanoma EVs. In the current study, we focused on miR-1246 as primarily responsible for acquiring abnormalities in TECs and examined whether the alteration of endothelial cell (EC) character by miR-1246 promotes cancer metastasis. Methods We analyzed the effect of miR-1246 in metastatic melanoma, A375SM-EVs, in vivo metastasis. The role of tumor EV-miR-1246 in the adhesion between ECs and tumor cells and the EC barrier was addressed. Changes in the expression of adhesion molecule and endothelial permeability were examined. Results Intravenous administration of A375SM-EVs induced tumor cell colonization in the lung resulting in lung metastasis. In contrast, miR-1246 knockdown in A375SM decreased lung metastasis in vivo. miR-1246 transfection in ECs increased the expression of adhesion molecule ICAM-1 via activation of STAT3, followed by increased tumor cell adhesion to ECs. Furthermore, the expression of VE-Cadherin was downregulated in miR-1246 overexpressed EC. A375SM-EV treatment enhanced endothelial permeability. VE-Cadherin was validated as the potential target gene of miR-1246 via the target gene prediction database and 3' UTR assay. Conclusion miR-1246 in high metastatic tumor EVs promotes lung metastasis by inducing the adhesion of tumor cells to ECs and destroying the EC barrier.
Collapse
Affiliation(s)
- Masahiro Morimoto
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan
- Department of Oral Diagnosis and Medicine, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan
| | - Nako Maishi
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan
| | - Takuya Tsumita
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan
| | - Mohammad Towfik Alam
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan
| | - Hiroshi Kikuchi
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan
- Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Yasuhiro Hida
- Department of Cardiovascular and Thoracic Surgery, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Yusuke Yoshioka
- Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Takahiro Ochiya
- Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Dorcas A. Annan
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan
| | - Ryo Takeda
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan
- Department of Oral Diagnosis and Medicine, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan
| | - Yoshimasa Kitagawa
- Department of Oral Diagnosis and Medicine, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan
| | - Kyoko Hida
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan
- *Correspondence: Kyoko Hida,
| |
Collapse
|
|
18
|
Deng DK, Zhang JJ, Gan D, Zou JK, Wu RX, Tian Y, Yin Y, Li X, Chen FM, He XT. Roles of extracellular vesicles in periodontal homeostasis and their therapeutic potential. J Nanobiotechnology 2022; 20:545. [PMID: 36585740 PMCID: PMC9801622 DOI: 10.1186/s12951-022-01757-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 12/23/2022] [Indexed: 01/01/2023] Open
Abstract
Periodontal tissue is a highly dynamic and frequently stimulated area where homeostasis is easily destroyed, leading to proinflammatory periodontal diseases. Bacteria-bacteria and cell-bacteria interactions play pivotal roles in periodontal homeostasis and disease progression. Several reviews have comprehensively summarized the roles of bacteria and stem cells in periodontal homeostasis. However, they did not describe the roles of extracellular vesicles (EVs) from bacteria and cells. As communication mediators evolutionarily conserved from bacteria to eukaryotic cells, EVs secreted by bacteria or cells can mediate interactions between bacteria and their hosts, thereby offering great promise for the maintenance of periodontal homeostasis. This review offers an overview of EV biogenesis, the effects of EVs on periodontal homeostasis, and recent advances in EV-based periodontal regenerative strategies. Specifically, we document the pathogenic roles of bacteria-derived EVs (BEVs) in periodontal dyshomeostasis, focusing on plaque biofilm formation, immune evasion, inflammatory pathway activation and tissue destruction. Moreover, we summarize recent advancements in cell-derived EVs (CEVs) in periodontal homeostasis, emphasizing the multifunctional biological effects of CEVs on periodontal tissue regeneration. Finally, we discuss future challenges and practical perspectives for the clinical translation of EV-based therapies for periodontitis.
Collapse
Affiliation(s)
- Dao-Kun Deng
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Jiu-Jiu Zhang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Dian Gan
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Jie-Kang Zou
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Rui-Xin Wu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Yi Tian
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Yuan Yin
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Xuan Li
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China.
| | - Fa-Ming Chen
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China.
| | - Xiao-Tao He
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi'an, People's Republic of China.
| |
Collapse
|
|
19
|
Bryant P, Sikavitsas VI. Cancer Exosomes: An Overview and the Applications of Flow. FLUIDS 2022; 8:7. [DOI: 10.3390/fluids8010007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Cancer is one of the most prevalent and disruptive diseases affecting the population, and as such, is the subject of major research efforts. Recently, these efforts have been put towards understanding the role that exosomes can play in the progression of cancer. Exosomes are small extracellular vesicles ranging from 40–150 nm in size that carry bioactive molecules like proteins, DNA, RNA, miRNA, and surface receptors. One of the most important features of exosomes is their ability to easily travel throughout the body, extending the reach of parent cell’s signaling capabilities. Cancer derived exosomes (CDEs) carry dangerous cargo that can aid in the metastasis, and disease progression through angiogenesis, promoting epithelial to mesenchymal transition, and immune suppression. Exosomes can transport these molecules to cells in the tumor environment as well as distant premetastatic locations making them an extremely versatile tool in the toolbelt of cancer. This review aims to compile the present knowledge and understanding of the involvement of exosomes in the progression of cancer as well as current production, isolation, and purification methods, with particular interest on flow perfusion bioreactor and microfluidics systems, which allow for accurate modeling and production of exosomes.
Collapse
Affiliation(s)
- Parker Bryant
- School of Chemical, Biological, and Materials Engineering, University of Oklahoma, Norman, OK 73019, USA
- Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK 73019, USA
| | - Vassilios I. Sikavitsas
- School of Chemical, Biological, and Materials Engineering, University of Oklahoma, Norman, OK 73019, USA
- Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK 73019, USA
| |
Collapse
|
|
20
|
Rafiee R, Razmara E, Motavaf M, Mossahebi-Mohammadi M, Khajehsharifi S, Rouhollah F, Babashah S. Circulating serum miR-1246 and miR-1229 as diagnostic biomarkers in colorectal carcinoma. J Cancer Res Ther 2022; 18:S383-S390. [PMID: 36510992 DOI: 10.4103/jcrt.jcrt_752_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Background Colorectal cancer (CRC) is one of the most common cancers worldwide. Although colonoscopy is considered as the "Gold Standard" technique to detect CRC, its application is invasive and cost incurred. Thus, noninvasive or minimally invasive approaches are of utmost importance. The aberrant expression of some microRNAs (miRNAs, miRs) has been suggested in association with CRC pathogenesis. This study aimed to validate if circulating serum miR-1229 and miR-1246 are diagnostic biomarkers for CRC. Materials and Methods Serum samples were isolated from 45 CRC patients and also 45 healthy controls (HC). The expression levels of circulating serum-derived miR-1229 and miR-1246 were evaluated by quantitative real-time polymerase chain reaction. Receiver operating characteristic (ROC) curves were constructed to evaluate the CRC diagnostic accuracy of selected miRNAs. Furthermore, the association of candidate miRNAs and clinicopathological characteristics were evaluated. Functional enrichment of the candidate miRNAs was applied using in silico tools. Results The expression of miR-1229 and miR-1246 was significantly higher in CRC patients than HC (P < 0.0001) and also was found in association with lymph node metastasis (P < 0.05). We demonstrated a significant up-regulation of serum-derived miR-1246 in advanced tumor-node-metastasis stage III of CRC patients (P < 0.05). Areas under the ROC curve of miR-1229 and miR-1246 were 0.81 and 0.84, respectively (P < 0.0001). Conclusion We confirmed the capability of circulating serum miR-1229 and miR-1246 as novel diagnostic biomarkers for CRC.
Collapse
Affiliation(s)
- Reihaneh Rafiee
- Department of Cellular and Molecular Sciences, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ehsan Razmara
- Department of Medical Genetics, Faculty of Medical Sciences, TarbiatModares University, Tehran, Iran
| | - Mahsa Motavaf
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Majid Mossahebi-Mohammadi
- International Collaborative Center on Growth Factor Research, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | | | - Fatemeh Rouhollah
- Department of Cellular and Molecular Sciences, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sadegh Babashah
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| |
Collapse
|
|
21
|
Kugeratski FG, Santi A, Zanivan S. Extracellular vesicles as central regulators of blood vessel function in cancer. Sci Signal 2022; 15:eaaz4742. [PMID: 36166511 DOI: 10.1126/scisignal.aaz4742] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Blood vessels deliver oxygen and nutrients that sustain tumor growth and enable the dissemination of cancer cells to distant sites and the recruitment of intratumoral immune cells. In addition, the structural and functional abnormalities of the tumor vasculature foster the development of an aggressive tumor microenvironment and impair the efficacy of existing cancer therapies. Extracellular vesicles (EVs) have emerged as major players of tumor progression, and a growing body of evidence has demonstrated that EVs derived from cancer cells trigger multiple responses in endothelial cells that alter blood vessel function in tumors. EV-mediated signaling in endothelial cells can occur through the transfer of functional cargos such as miRNAs, lncRNAs, cirRNAs, and proteins. Moreover, membrane-bound proteins in EVs can elicit receptor-mediated signaling in endothelial cells. Together, these mechanisms reprogram endothelial cells and contribute to the sustained exacerbated angiogenic signaling typical of tumors, which, in turn, influences cancer progression. Targeting these angiogenesis-promoting EV-dependent mechanisms may offer additional strategies to normalize tumor vasculature. Here, we discuss the current knowledge pertaining to the contribution of cancer cell-derived EVs in mechanisms regulating blood vessel functions in tumors. Moreover, we discuss the translational opportunities in targeting the dysfunctional tumor vasculature using EVs and highlight the open questions in the field of EV biology that can be addressed using mass spectrometry-based proteomics analysis.
Collapse
Affiliation(s)
- Fernanda G Kugeratski
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Alice Santi
- Department of Experimental and Clinical Biomedical Sciences, Università degli Studi di Firenze, 50134 Firenze, Italy
| | - Sara Zanivan
- CRUK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK
- School of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1QH, UK
| |
Collapse
|
|
22
|
Li X, Du L, Liu Q, Lu Z. MicroRNAs: Novel players in the diagnosis and treatment of cancer cachexia (Review). Exp Ther Med 2022; 24:446. [PMID: 35720622 PMCID: PMC9199081 DOI: 10.3892/etm.2022.11373] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 05/03/2022] [Indexed: 12/02/2022] Open
Abstract
Cachexia denotes a complex metabolic syndrome featuring severe loss of weight, fatigue and anorexia. In total, 50-80% of patients suffering from advanced cancer are diagnosed with cancer cachexia, which contributes to 40% of cancer-associated mortalities. MicroRNAs (miRNAs) are non-coding RNAs capable of regulating gene expression. Dysregulated miRNA expression has been observed in muscle tissue, adipose tissue and blood samples from patients with cancer cachexia compared with that of samples from patients with cancer without cachexia or healthy controls. In addition, miRNAs promote and maintain the malignant state of systemic inflammation, while inflammation contributes to cancer cachexia. The present review discusses the role of miRNAs in the progression of cancer cachexia, and assess their diagnostic value and potential therapeutic value.
Collapse
Affiliation(s)
- Xin Li
- Department of Oncology, Affiliated Hospital of Weifang Medical College, Weifang, Shandong 261000, P.R. China
| | - Lidong Du
- Graduate School, Weifang Medical College, Weifang, Shandong 261000, P.R. China
| | - Qiang Liu
- Graduate School, Weifang Medical College, Weifang, Shandong 261000, P.R. China
| | - Zhong Lu
- Department of Oncology, Affiliated Hospital of Weifang Medical College, Weifang, Shandong 261000, P.R. China
| |
Collapse
|
|
23
|
Bouzari B, Mohammadi S, Bokov DO, Krasnyuk II, Hosseini-Fard SR, Hajibaba M, Mirzaei R, Karampoor S. Angioregulatory role of miRNAs and exosomal miRNAs in glioblastoma pathogenesis. Biomed Pharmacother 2022; 148:112760. [PMID: 35228062 DOI: 10.1016/j.biopha.2022.112760] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 02/23/2022] [Accepted: 02/23/2022] [Indexed: 11/19/2022] Open
Abstract
Glioblastoma (GB) is a highly aggressive cancer of the central nervous system, occurring in the brain or spinal cord. Many factors such as angiogenesis are associated with GB development. Angiogenesis is a procedure by which the pre-existing blood vessels create new vessels that play an essential role in health and disease, including tumors. Also, angiogenesis is one of the significant factors thought to be responsible for treatment resistance in many tumors, including GB. Hence, an improved understanding of the molecular processes underlying GB angiogenesis will pave the way for developing potential new treatments. Recently, it has been found that microRNAs (miRNAs) and exosomal miRNAs have a crucial role in inducing or inhibiting the angiogenesis process in GB development. A better knowledge of the miRNA's regulation pathway in the angiogenesis process in cancer offers unique mechanistic insight into the mechanism of tumor-associated neovascularization. Because of advancements in miRNA characterization and delivery methods, miRNAs can also be employed in clinical settings as potential biomarkers for anti-angiogenic treatment response as well as therapies targeting tumor angiogenesis. The recent finding and insights about miRNAs' angioregulatory role and exosomal miRNAs in GB are provided throughout the review. Also, we discuss the new concept of miRNAs-based therapies for GB in the future.
Collapse
Affiliation(s)
- Behnaz Bouzari
- Department of Pathology, Firouzgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Shabahang Mohammadi
- ENT and Head and Neck Research Center and Department, Firoozgar General Hospital, The Five Senses Health Institute, Iran
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow 119991, Russian Federation; Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, 2/14 Ustyinsky pr., Moscow 109240, Russian Federation
| | - Ivan Ivanovich Krasnyuk
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow 119991, Russian Federation
| | - Seyed Reza Hosseini-Fard
- Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Marzieh Hajibaba
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
24
|
Liu P, Zhang Q, Mi J, Wang S, Xu Q, Zhuang D, Chen W, Liu C, Zhang L, Guo J, Wu X. Exosomes derived from stem cells of human deciduous exfoliated teeth inhibit angiogenesis in vivo and in vitro via the transfer of miR-100-5p and miR-1246. Stem Cell Res Ther 2022; 13:89. [PMID: 35241153 PMCID: PMC8895508 DOI: 10.1186/s13287-022-02764-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/29/2021] [Indexed: 12/14/2022] Open
Abstract
Background Anti-angiogenic therapy has been shown to be a promising strategy for anti-tumor treatment. Increasing evidence indicates that tumor angiogenesis is affected by exosomes that are secreted by mesenchymal stem cells (MSCs), but whether exosomes derived from MSCs suppress or promote angiogenesis remain paradoxical. The purpose of this study focused on understanding the potential role of exosomes derived from stem cells of human deciduous exfoliated teeth (SHED-Exos) in regulating angiogenesis and the underlying molecular mechanism. Methods Exosomes were isolated from supernatants of SHED cells using an exosome purification kit and were characterized by transmission electron microscopy, nanoparticle tracking analysis and western blot analysis. Cell Counting Kit-8, flow cytometric assays, western blots, wound healing and transwell migration assays were performed to characterize the roles of SHED-Exos on cell proliferation, apoptosis and migration of human umbilical vein endothelial cells (HUVECs). The anti-angiogenic activity of SHED-Exos was assessed via a tube formation assay of endothelial cells and angiogenesis-related factors were analyzed by western blotting. In vivo, we used the chick chorioallantoic membrane (CAM) assay and an oral squamous cell carcinoma (OSCC) xenograft transplantation model with nude mice that received multi-point injections at three-day intervals to evaluate the effects on angiogenesis. Furthermore, the sequencing of microRNAs (miRNAs) in SHED-Exos was performed to investigate the underlying anti-angiogenic mechanism. Results The results showed that SHED-Exos inhibit cell proliferation and migration and induce apoptosis in HUVECs. SHED-Exos suppress the tube-like structure formation of HUVECs in vitro. SHED-Exos downregulate several angiogenesis-related factors, including VEGFA, MMP-9 and ANGPT1. In vivo, the chick CAM assay verified that treatment with SHED-Exos inhibits micro-vascular formation, and importantly, significantly reduces the micro-vascular formation of tumors generated from xenografted OSCC cells, which was associated with the inhibition of tumor growth in vivo. Mechanistically, our data suggested that SHED-Exos are enriched with miR-100-5p and miR-1246 and are transferred to endothelial cells, which results in decreased tube formation via the down-regulation of VEGFA expression. Conclusions These results demonstrate that SHED-Exos inhibit angiogenesis in vitro and in vivo, which suggests that SHED-Exos could potentially serve as a novel and effective therapeutic approach for anti-angiogenic treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02764-9.
Collapse
Affiliation(s)
- Panpan Liu
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China.,Department of Pediatrics Dentistry and Preventive Dentistry, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China
| | - Qun Zhang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China
| | - Jun Mi
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China
| | - Shuangshuang Wang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China
| | - Qiuping Xu
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China.,Savaid Stomatology School of Hangzhou Medical College, Ningbo Stomatology Hospital, Ningbo, China
| | - Dexuan Zhuang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China
| | - Wenqian Chen
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China.,Savaid Stomatology School of Hangzhou Medical College, Ningbo Stomatology Hospital, Ningbo, China
| | - Chang Liu
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China.,Savaid Stomatology School of Hangzhou Medical College, Ningbo Stomatology Hospital, Ningbo, China
| | - Liwei Zhang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China.,Savaid Stomatology School of Hangzhou Medical College, Ningbo Stomatology Hospital, Ningbo, China
| | - Jing Guo
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China. .,Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China. .,Savaid Stomatology School of Hangzhou Medical College, Ningbo Stomatology Hospital, Ningbo, China.
| | - Xunwei Wu
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No.44-1 Wenhua Road West, Jinan, Shandong, China. .,Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. .,Savaid Stomatology School of Hangzhou Medical College, Ningbo Stomatology Hospital, Ningbo, China.
| |
Collapse
|
|
25
|
Kumar VS, Anjali K. Tumour generated exosomal miRNAs: A major player in tumour angiogenesis. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166383. [DOI: 10.1016/j.bbadis.2022.166383] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 02/18/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022]
|
|
26
|
Lukosevicius R, Juzenas S, Salteniene V, Kulokiene U, Arstikyte J, Hemmrich-Stanisak G, Franke A, Link A, Ruzgys P, Satkauskas S, Pauzas H, Latkauskas T, Kiudelis G, Balaguer F, Kupcinskas J, Skieceviciene J. miRNome Profiling and Functional Analysis Reveal Involvement of hsa-miR-1246 in Colon Adenoma-Carcinoma Transition by Targeting AXIN2 and CFTR. Int J Mol Sci 2022; 23:2107. [PMID: 35216222 PMCID: PMC8876010 DOI: 10.3390/ijms23042107] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/26/2022] [Accepted: 02/10/2022] [Indexed: 12/24/2022] Open
Abstract
Regulatory changes occurring early in colorectal cancer development remain poorly investigated. Since the majority of cases develop from polyps in the adenoma-carcinoma transition, a search of early molecular features, such as aberrations in miRNA expression occurring prior to cancer development, would enable identification of potentially causal, rather than consequential, candidates in the progression of polyp to cancer. In the current study, by employing small RNA-seq profiling of colon biopsy samples, we described differentially expressed miRNAs and their isoforms in the adenoma-carcinoma transition. Analysis of healthy-adenoma-carcinoma sequence in an independent validation group enabled us to identify early deregulated miRNAs including hsa-miR-1246 and hsa-miR-215-5p, the expressions of which are, respectively, gradually increasing and decreasing. Loss-of-function experiments revealed that inhibition of hsa-miR-1246 lead to reduced cell viability, colony formation, and migration rate, thereby indicating an oncogenic effect of this miRNA in vitro. Subsequent western blot and luciferase reporter assay provided evidence of hsa-miR-1246 being involved in the regulation of target AXIN2 and CFTR genes' expression. To conclude, the present study revealed possible involvement of hsa-miR-1246 in early colorectal cancer development and regulation of tumor suppressors AXIN2 and CFTR.
Collapse
Affiliation(s)
- Rokas Lukosevicius
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (R.L.); (S.J.); (V.S.); (U.K.); (J.A.)
| | - Simonas Juzenas
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (R.L.); (S.J.); (V.S.); (U.K.); (J.A.)
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany; (G.H.-S.); (A.F.)
| | - Violeta Salteniene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (R.L.); (S.J.); (V.S.); (U.K.); (J.A.)
| | - Ugne Kulokiene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (R.L.); (S.J.); (V.S.); (U.K.); (J.A.)
| | - Justina Arstikyte
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (R.L.); (S.J.); (V.S.); (U.K.); (J.A.)
| | - Georg Hemmrich-Stanisak
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany; (G.H.-S.); (A.F.)
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany; (G.H.-S.); (A.F.)
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, 39106 Magdeburg, Germany;
| | - Paulius Ruzgys
- Biophysical Research Group, Faculty of Natural Sciences, Vytautas Magnus University, 44248 Kaunas, Lithuania; (P.R.); (S.S.)
| | - Saulius Satkauskas
- Biophysical Research Group, Faculty of Natural Sciences, Vytautas Magnus University, 44248 Kaunas, Lithuania; (P.R.); (S.S.)
| | - Henrikas Pauzas
- Department of Surgery, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (H.P.); (T.L.)
| | - Tadas Latkauskas
- Department of Surgery, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (H.P.); (T.L.)
| | - Gediminas Kiudelis
- Department of Gastroenterology, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania;
| | - Francesc Balaguer
- Department of Gastroenterology, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), University of Barcelona, 08036 Barcelona, Spain;
| | - Juozas Kupcinskas
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (R.L.); (S.J.); (V.S.); (U.K.); (J.A.)
- Department of Gastroenterology, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania;
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (R.L.); (S.J.); (V.S.); (U.K.); (J.A.)
| |
Collapse
|
|
27
|
Zhu S, Li S, Yi M, Li N, Wu K. Roles of Microvesicles in Tumor Progression and Clinical Applications. Int J Nanomedicine 2021; 16:7071-7090. [PMID: 34703228 PMCID: PMC8536885 DOI: 10.2147/ijn.s325448] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 10/08/2021] [Indexed: 12/20/2022] Open
Abstract
Microvesicles are extracellular vesicles with diameter ranging from 100 to 1000 nm that are secreted by tumor cells or other cells in the tumor microenvironment. A growing number of studies demonstrate that tumor-derived microvesicles are involved in tumor initiation and progression, as well as drug resistance. In addition, tumor-derived microvesicles carry a variety of immunogenic molecules and inhibit tumor response to immunotherapy; therefore, they can be exploited for use in tumor vaccines. Moreover, because of their high stability, tumor-derived microvesicles extracted from body fluids can be used as biomarkers for cancer diagnosis or assessment of prognosis. Tumor-derived microvesicles can also be deployed to reverse drug resistance of tumor regenerative cells, or to deliver chemotherapeutic drugs and oncolytic adenovirus for the treatment of cancer patients. This review summarizes the general characteristics of tumor-derived microvesicles, focusing on their biological characteristics, their involvement in tumor progression, and their clinical applications.
Collapse
Affiliation(s)
- Shuangli Zhu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Shiyu Li
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Ning Li
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, People's Republic of China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.,Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, People's Republic of China
| |
Collapse
|
|
28
|
Torii C, Maishi N, Kawamoto T, Morimoto M, Akiyama K, Yoshioka Y, Minami T, Tsumita T, Alam MT, Ochiya T, Hida Y, Hida K. miRNA-1246 in extracellular vesicles secreted from metastatic tumor induces drug resistance in tumor endothelial cells. Sci Rep 2021; 11:13502. [PMID: 34226586 PMCID: PMC8257582 DOI: 10.1038/s41598-021-92879-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
Tumor endothelial cells (TECs) reportedly exhibit altered phenotypes. We have demonstrated that TECs acquire drug resistance with the upregulation of P-glycoprotein (P-gp, ABCB1), contrary to traditional assumptions. Furthermore, P-gp expression was higher in TECs of highly metastatic tumors than in those of low metastatic tumors. However, the detailed mechanism of differential P-gp expression in TECs remains unclear. miRNA was identified in highly metastatic tumor extracellular vesicles (EVs) and the roles of miRNA in endothelial cell resistance were analyzed in vitro and in vivo. In the present study, we found that treatment of highly metastatic tumor-conditioned medium induced resistance to 5-fluorouracil (5-FU) with interleukin-6 (IL-6) upregulation in endothelial cells (ECs). Among the soluble factors secreted from highly metastatic tumors, we focused on EVs and determined that miR-1246 was contained at a higher level in highly metastatic tumor EVs than in low metastatic tumor EVs. Furthermore, miR-1246 was transported via the EVs into ECs and induced IL-6 expression. Upregulated IL-6 induced resistance to 5-FU with STAT3 and Akt activation in ECs in an autocrine manner. These results suggested that highly metastatic tumors induce drug resistance in ECs by transporting miR-1246 through EVs.
Collapse
Affiliation(s)
- Chisaho Torii
- Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan
- Department of Oral and Maxillofacial Surgery, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
| | - Nako Maishi
- Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
| | - Taisuke Kawamoto
- Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
| | - Masahiro Morimoto
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
- Department of Oral Diagnosis and Medicine, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
| | - Kosuke Akiyama
- Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
| | - Yusuke Yoshioka
- Institute of Medical Science, Tokyo Medical University, Tokyo, 160-0023, Japan
| | - Takashi Minami
- Division of Molecular and Vascular Biology, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, 860-0811, Japan
| | - Takuya Tsumita
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
| | - Mohammad Towfik Alam
- Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan
| | - Takahiro Ochiya
- Institute of Medical Science, Tokyo Medical University, Tokyo, 160-0023, Japan
| | - Yasuhiro Hida
- Department of Cardiovascular and Thoracic Surgery, Hokkaido University Faculty of Medicine, Sapporo, 060-8638, Japan
| | - Kyoko Hida
- Department of Vascular Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan.
- Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan.
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, 060-8586, Japan.
| |
Collapse
|
|
29
|
Umwali Y, Yue CB, Gabriel ANA, Zhang Y, Zhang X. Roles of exosomes in diagnosis and treatment of colorectal cancer. World J Clin Cases 2021; 9:4467-4479. [PMID: 34222415 PMCID: PMC8223826 DOI: 10.12998/wjcc.v9.i18.4467] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/15/2021] [Accepted: 05/06/2021] [Indexed: 02/06/2023] Open
Abstract
Exosomes are extracellular vesicles that mediate intercellular communication. They contain different molecules, such as DNA, RNA, lipid, and protein, playing essential roles in the pathogenesis of colorectal cancer (CRC). Exosomes derived from CRC are implicated in tumorigenesis, chemotherapy resistance, and metastasis. Besides, they can enhance CRC progression by increasing tumor cell proliferation, reducing apoptosis mechanistically through altering particular essential regulatory genes, or controlling several signaling pathways. Therefore, exosomes derived from CRC are essential biomarkers and can be used in the diagnosis. Indeed, it is crucial to understand the role of exosomes in CRC, which is necessary to develop diagnostic and therapeutic strategies for early detection and treatment. In the present review, we discuss the roles of exosomes in the diagnosis and treatment of CRC.
Collapse
Affiliation(s)
- Yvette Umwali
- Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Cong-Bo Yue
- Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Abakundana Nsenga Ariston Gabriel
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Yi Zhang
- Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Xin Zhang
- Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| |
Collapse
|
|
30
|
Dos Santos ES, Wagner VP, Cabral Ramos J, Lambert DW, Castilho RM, Paes Leme AF. Epigenetic modulation of the tumor microenvironment in head and neck cancer: Challenges and opportunities. Crit Rev Oncol Hematol 2021; 164:103397. [PMID: 34146679 DOI: 10.1016/j.critrevonc.2021.103397] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/31/2021] [Accepted: 06/07/2021] [Indexed: 12/22/2022] Open
Abstract
Head and neck cancer is globally challenging due to the resistance to therapy and aggressive behavior leading to high rates of mortality. Recent findings show that the tumor microenvironment plays a role in the maintenance and progression of many solid tumors, including head and neck cancer. The mechanisms involved in the modulation and regulation of the tumor microenvironment remain poorly understood. Increasing evidence suggests that epigenetic events can modulate the crosstalk between neoplastic and non-neoplastic cells during tumor progression. In this review, we explore the current understanding of the involvement of epigenetic events in the modulation of the tumor microenvironment and its impact on head and neck cancer behavior. We also explore the latest therapeutic strategies that use epigenetic-modulating drugs to manage tumor growth and progression.
Collapse
Affiliation(s)
| | - Vivian Petersen Wagner
- The University of Sheffield Faculty of Medicine Dentistry and Health, 152607, Sheffield, United Kingdom of Great Britain and Northern Ireland
| | - Joab Cabral Ramos
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
| | - Daniel W Lambert
- The University of Sheffield Faculty of Medicine Dentistry and Health, 152607, Sheffield, United Kingdom of Great Britain and Northern Ireland
| | - Rogerio Moraes Castilho
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, Division of Oral Pathology, Radiology and Medicine, University of Michigan School of Dentistry. Ann Arbor, 48109-1078, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Adriana Franco Paes Leme
- The Brazilian Bioscience National Laboratory, Center for Research in Energy and Materials, Campinas, Brazil
| |
Collapse
|
|
31
|
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.
Collapse
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
| |
Collapse
|
|
32
|
Tang Y, Zong S, Zeng H, Ruan X, Yao L, Han S, Hou F. MicroRNAs and angiogenesis: a new era for the management of colorectal cancer. Cancer Cell Int 2021; 21:221. [PMID: 33865381 PMCID: PMC8052662 DOI: 10.1186/s12935-021-01920-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 04/07/2021] [Indexed: 02/08/2023] Open
Abstract
MicroRNAs (miRNAs) are a class of small noncoding RNA molecules containing only 20–22 nucleotides. MiRNAs play a role in gene silencing and translation suppression by targeting and binding to mRNA. Proper control of miRNA expression is very important for maintaining a normal physiological environment because miRNAs can affect most cellular pathways, including cell cycle checkpoint, cell proliferation, and apoptosis pathways, and have a wide range of target genes. With these properties, miRNAs can modulate multiple signalling pathways involved in cancer development, such as cell proliferation, apoptosis, and migration pathways. MiRNAs that activate or inhibit the molecular pathway related to tumour angiogenesis are common topics of research. Angiogenesis promotes tumorigenesis and metastasis by providing oxygen and diffusible nutrients and releasing proangiogenic factors and is one of the hallmarks of tumour progression. CRC is one of the most common tumours, and metastasis has always been a difficult issue in its treatment. Although comprehensive treatments, such as surgery, radiotherapy, chemotherapy, and targeted therapy, have prolonged the survival of CRC patients, the overall response is not optimistic. Therefore, there is an urgent need to find new therapeutic targets to improve CRC treatment. In a series of recent reports, miRNAs have been shown to bidirectionally regulate angiogenesis in colorectal cancer. Many miRNAs can directly act on VEGF or inhibit angiogenesis through other pathways (HIF-1a, PI3K/AKT, etc.), while some miRNAs, specifically many exosomal miRNAs, are capable of promoting CRC angiogenesis. Understanding the mechanism of action of miRNAs in angiogenesis is of great significance for finding new targets for the treatment of tumour angiogenesis. Deciphering the exact role of specific miRNAs in angiogenesis is a challenge due to the high complexity of their actions. Here, we describe the latest advances in the understanding of miRNAs and their corresponding targets that play a role in CRC angiogenesis and discuss possible miRNA-based therapeutic strategies.
Collapse
Affiliation(s)
- Yufei Tang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Shaoqi Zong
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.,Graduate School of Shanghai, University of Traditional Chinese Medicine, Shanghai, China
| | - Hailun Zeng
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Xiaofeng Ruan
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Liting Yao
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Susu Han
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Fenggang Hou
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
| |
Collapse
|
|
33
|
Moloudizargari M, Hekmatirad S, Mofarahe ZS, Asghari MH. Exosomal microRNA panels as biomarkers for hematological malignancies. Curr Probl Cancer 2021; 45:100726. [PMID: 33752898 DOI: 10.1016/j.currproblcancer.2021.100726] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 02/11/2021] [Indexed: 02/07/2023]
Abstract
Hematological malignancies are classified as a heterogeneous category of cancers with various degrees of incidence and prognosis and different etiologies. Due to their aggressive essence they should be diagnosed as early as possible to improve prognosis, treatment outcome and survival. Bases on the limitations of previously identified biomarkers in terms of sensitivity, specificity and predictability, it is necessary to develop new diagnostic tools and biomarkers for the early diagnosis of hematological malignancies. Exosomes are nanovesicles secreted by almost all cell types in both physiological and pathological conditions. They play major roles in intercellular communication and are recently being considered as disease biomarkers. These nanovesicles carry proteins, lipids and nucleic acids like microRNAs (miRNAs). miRNAs are small noncoding RNAs, which act as translational suppressors via regulating protein-coding genes. The aberrant expression of miRNAs has been shown in various conditions including hematological malignancies. Moreover, it is now known that tumor cells secrete higher amounts of exosomes compared to normal cells. The idea of using exosomal miRNAs in serum as biomarkers is based on their surprisingly high stability and specificity. In the present paper, we reviewed and recommended exosomal miRNA panels including (miR-150, miR-155 and miR-1246), (miR-17-5p, miR-20a-5p, miR-16-5p and miR-5a-5p), (miR-18a, Let-7b) and (miR192-5p, miR21-5p, miR320b and Let-7d), for their potential to be used as non-invasive biomarkers in different hematological malignancies such as multiple myeloma, leukemia, and lymphoma.
Collapse
Affiliation(s)
- Milad Moloudizargari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shirin Hekmatirad
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Zahra Shams Mofarahe
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Asghari
- Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Sciences, Babol, Iran.
| |
Collapse
|
|
34
|
Yamada NO, Senda T. Circulating microRNA-92a-3p in colorectal cancer: a review. Med Mol Morphol 2021; 54:193-202. [PMID: 33620640 DOI: 10.1007/s00795-021-00282-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 02/05/2021] [Indexed: 12/11/2022]
Abstract
Recent studies have found that microRNAs (miRNAs) are present in body fluids, including blood, cerebrospinal fluid, tears, saliva, breast milk, and urine in a stable form, and are called circulating miRNAs. Although their biological roles remain to be determined, circulating miRNAs are considered as mediators of intercellular communication like hormones and cytokines. Because circulating miRNAs can be collected in a non-invasive manner called as "liquid biopsy", they have also been studied as potential biomarkers for early detection, evaluation of therapeutic effects, and prediction of prognosis in various diseases, including cancers. In this review, we focus on the studies on circulating microRNA-92a-3p (miR-92a-3p) in colorectal cancer (CRC), considering their existence form, isolation methods, potential as biomarkers, and roles in CRC development and progression.
Collapse
Affiliation(s)
- Nami O Yamada
- Department of Anatomy, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan.
| | - Takao Senda
- Department of Anatomy, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan
| |
Collapse
|
|
35
|
González-González A, García-Sánchez D, Dotta M, Rodríguez-Rey JC, Pérez-Campo FM. Mesenchymal stem cells secretome: The cornerstone of cell-free regenerative medicine. World J Stem Cells 2020; 12:1529-1552. [PMID: 33505599 PMCID: PMC7789121 DOI: 10.4252/wjsc.v12.i12.1529] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 10/07/2020] [Accepted: 11/11/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are the most frequently used stem cells in clinical trials due to their easy isolation from various adult tissues, their ability of homing to injury sites and their potential to differentiate into multiple cell types. However, the realization that the beneficial effect of MSCs relies mainly on their paracrine action, rather than on their engraftment in the recipient tissue and subsequent differentiation, has opened the way to cell-free therapeutic strategies in regenerative medicine. All the soluble factors and vesicles secreted by MSCs are commonly known as secretome. MSCs secretome has a key role in cell-to-cell communication and has been proven to be an active mediator of immune-modulation and regeneration both in vitro and in vivo. Moreover, the use of secretome has key advantages over cell-based therapies, such as a lower immunogenicity and easy production, handling and storage. Importantly, MSCs can be modulated to alter their secretome composition to better suit specific therapeutic goals, thus, opening a large number of possibilities. Altogether these advantages now place MSCs secretome at the center of an important number of investigations in different clinical contexts, enabling rapid scientific progress in this field.
Collapse
Affiliation(s)
- Alberto González-González
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Daniel García-Sánchez
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Monica Dotta
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - José C Rodríguez-Rey
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Flor M Pérez-Campo
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain.
| |
Collapse
|
|
36
|
Guo S, Chen J, Chen F, Zeng Q, Liu WL, Zhang G. Exosomes derived from Fusobacterium nucleatum-infected colorectal cancer cells facilitate tumour metastasis by selectively carrying miR-1246/92b-3p/27a-3p and CXCL16. Gut 2020; 70:gutjnl-2020-321187. [PMID: 33172926 DOI: 10.1136/gutjnl-2020-321187] [Citation(s) in RCA: 126] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 10/20/2020] [Accepted: 10/25/2020] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Exosomes released from tumour cells are packed with unique RNA and protein cargo, and they are emerging as an important mediator in the communication network that promotes tumour progression. The facultative intracellular bacterium Fusobacterium nucleatum (Fn) is an important colorectal cancer (CRC)-associated bacterium. To date, the function of exosomes from Fn-infected CRC cells has not been explored. DESIGN Exosomes were isolated by sequential differential centrifugation and verified by transmission electron microscopy, NanoSight analysis and Western blotting. Given that exosomes have been shown to transport miRNAs and proteins to alter cellular functions, we performed miRNA sequencing and proteome analysis of exosomes from Fn-infected and non-infected cells. The biological role and mechanism of exosomes from Fn-infected cells in CRC tumour growth and liver metastasis were determined in vitro and in vivo. RESULTS We demonstrated that exosomes delivered miR-1246/92b-3p/27a-3p and CXCL16/RhoA/IL-8 from Fn-infected cells into non-infected cells to increase cell migration ability in vitro and promote tumour metastasis in vivo. Finally, both circulating exosomal miR-1246/92b-3p/27a-3p and CXCL16 levels were closely associated with Fn abundance and tumour stage in patients with CRC. CONCLUSION This study suggests that Fn infection may stimulate tumour cells to generate miR-1246/92b-3p/27a-3p-rich and CXCL16/RhoA/IL-8 exosomes that are delivered to uninfected cells to promote prometastatic behaviours.
Collapse
Affiliation(s)
- Songhe Guo
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Jun Chen
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Fangfang Chen
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Qiuyao Zeng
- Department of Clinical Laboratory Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Wan-Li Liu
- Department of Clinical Laboratory Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Ge Zhang
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
37
|
Vu LT, Gong J, Pham TT, Kim Y, Le MTN. microRNA exchange via extracellular vesicles in cancer. Cell Prolif 2020; 53:e12877. [PMID: 33169503 PMCID: PMC7653238 DOI: 10.1111/cpr.12877] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/20/2020] [Accepted: 06/23/2020] [Indexed: 12/23/2022] Open
Abstract
Cells utilize different means of inter-cellular communication to function properly. Here, we review the crosstalk between cancer cells and their surrounding environment through microRNA (miRNA)-containing extracellular vesicles (EVs). The current findings suggest that the export of miRNAs and uptake of miRNA-containing EVs might be an active process. As post-transcriptional regulators of gene expression, cancer-derived miRNAs that are taken up by normal cells can change the translational profile of the recipient cell towards a transformed proteome. Stromal cells can also deliver miRNAs via EVs to cancer cells to support tumour growth and cancer progression. Therefore, gaining a better understanding of EV-mediated inter-cellular communication in the tumour microenvironment might lead to the development of novel diagnostic and therapeutic strategies.
Collapse
Affiliation(s)
- Luyen Tien Vu
- Department of PharmacologyYong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of Biomedical SciencesCollege of Veterinary Medicine and Life SciencesCity University of Hong KongKowloonHong Kong
| | - Jinhua Gong
- Department of Biomedical SciencesCollege of Veterinary Medicine and Life SciencesCity University of Hong KongKowloonHong Kong
- City University of Hong Kong Shenzhen Research InstituteShenzhenChina
| | - Thach Tuan Pham
- Department of PharmacologyYong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of Biomedical SciencesCollege of Veterinary Medicine and Life SciencesCity University of Hong KongKowloonHong Kong
| | - Yeokyeong Kim
- Department of Biomedical SciencesCollege of Veterinary Medicine and Life SciencesCity University of Hong KongKowloonHong Kong
| | - Minh T. N. Le
- Department of PharmacologyYong Loo Lin School of MedicineNational University of SingaporeSingapore
- Department of Biomedical SciencesCollege of Veterinary Medicine and Life SciencesCity University of Hong KongKowloonHong Kong
- City University of Hong Kong Shenzhen Research InstituteShenzhenChina
| |
Collapse
|
|
38
|
Avisar A, Cohen M, Brenner B, Bronshtein T, Machluf M, Bar-Sela G, Aharon A. Extracellular Vesicles Reflect the Efficacy of Wheatgrass Juice Supplement in Colon Cancer Patients During Adjuvant Chemotherapy. Front Oncol 2020; 10:1659. [PMID: 32984039 PMCID: PMC7479215 DOI: 10.3389/fonc.2020.01659] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 07/28/2020] [Indexed: 12/12/2022] Open
Abstract
Introduction Colorectal cancer (CC) is the third most common type of cancer, accounting for 10% of all cancer cases. Adjuvant chemotherapy is recommended in stages II–III CC. Wheatgrass juice (WGJ) from wheat seeds has high nutritional values, may induce synergistic benefits to chemotherapy and may attenuate chemotherapy-related side effects. Extracellular vesicles (EVs) are subcellular membrane blebs. EVs include exosomes (generated in the endosome, in size <150 nm) and microvesicles (shed from the plasma cell membrane) provide information on their parental cells and play a role in intercellular communication. We aimed to elucidate the effects of chemotherapy administration with supportive treatment of WGJ on CC patients’ EVs characteristics. Methods EVs were isolated from the blood samples of 15 healthy controls (HCs) and 50 CC patients post-surgery, treated by chemotherapy, with or without additional daily WGJ. Blood samples were taken before, during, and at the end of chemotherapy. EVs were characterized by size, concentration, membrane antigens and cytokine content using nanoparticle-tracking analysis, western blot, flow cytometry, and protein array methods. Results EVs were found to be similar by size and concentration with reduced levels of exosome markers (CD81) on samples at the end of combined treatment (chemotherapy and WGJ). Higher levels of endothelial EVs, which may indicate impairment of the vascular endothelial cells during treatment, were found in CC patients treated by chemotherapy only compared to those with chemotherapy and daily WGJ. Also, EVs thrombogenicity was lower in patients added WGJ compared to patients who had only chemotherapy (levels of tissue factor p = 0.029 and endothelial protein C receptor p = 0.005). Following treatments, levels of vascular endothelial growth factor receptors (VEGFR-1) and the majority of growth-factors/pro-inflammatory cytokines were higher in EVs of patients treated by chemotherapy only than in EVs obtained from patients with the combined treatment. Conclusion Daily consumption of WGJ during chemotherapy may reduce vascular damage and chemotherapy-related thrombogenicity, growth factors and cytokines, as reflected by the characteristics of patient’s EVs.
Collapse
Affiliation(s)
- Adva Avisar
- The Graduate Studies Authority, University of Haifa, Haifa, Israel
| | - Miri Cohen
- School of Social Work, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
| | - Benjamin Brenner
- Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.,Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Tomer Bronshtein
- The Lab for Cancer Drug Delivery & Cell Based Technologies, The Faculty of Biotechnology and Food Engineering, Technion - Israel Institute of Technology, Haifa, Israel
| | - Marcelle Machluf
- The Lab for Cancer Drug Delivery & Cell Based Technologies, The Faculty of Biotechnology and Food Engineering, Technion - Israel Institute of Technology, Haifa, Israel
| | - Gil Bar-Sela
- Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.,Cancer Center, Emek Medical Center, Afula, Israel
| | - Anat Aharon
- Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.,Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.,Hematology Research Laboratory, Hematology and Bone Marrow Transplantation, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| |
Collapse
|
|
39
|
Kesidou D, da Costa Martins PA, de Windt LJ, Brittan M, Beqqali A, Baker AH. Extracellular Vesicle miRNAs in the Promotion of Cardiac Neovascularisation. Front Physiol 2020; 11:579892. [PMID: 33101061 PMCID: PMC7546892 DOI: 10.3389/fphys.2020.579892] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 08/25/2020] [Indexed: 12/13/2022] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of mortality worldwide claiming almost 17. 9 million deaths annually. A primary cause is atherosclerosis within the coronary arteries, which restricts blood flow to the heart muscle resulting in myocardial infarction (MI) and cardiac cell death. Despite substantial progress in the management of coronary heart disease (CHD), there is still a significant number of patients developing chronic heart failure post-MI. Recent research has been focused on promoting neovascularisation post-MI with the ultimate goal being to reduce the extent of injury and improve function in the failing myocardium. Cardiac cell transplantation studies in pre-clinical models have shown improvement in cardiac function; nonetheless, poor retention of the cells has indicated a paracrine mechanism for the observed improvement. Cell communication in a paracrine manner is controlled by various mechanisms, including extracellular vesicles (EVs). EVs have emerged as novel regulators of intercellular communication, by transferring molecules able to influence molecular pathways in the recipient cell. Several studies have demonstrated the ability of EVs to stimulate angiogenesis by transferring microRNA (miRNA, miR) molecules to endothelial cells (ECs). In this review, we describe the process of neovascularisation and current developments in modulating neovascularisation in the heart using miRNAs and EV-bound miRNAs. Furthermore, we critically evaluate methods used in cell culture, EV isolation and administration.
Collapse
Affiliation(s)
- Despoina Kesidou
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Paula A. da Costa Martins
- Department of Molecular Genetics, Faculty of Science and Engineering, Maastricht University, Maastricht, Netherlands
- Faculty of Health, Medicine and Life Sciences, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands
| | - Leon J. de Windt
- Department of Molecular Genetics, Faculty of Science and Engineering, Maastricht University, Maastricht, Netherlands
| | - Mairi Brittan
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Abdelaziz Beqqali
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Andrew Howard Baker
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
| |
Collapse
|
|
40
|
Pezzicoli G, Tucci M, Lovero D, Silvestris F, Porta C, Mannavola F. Large Extracellular Vesicles-A New Frontier of Liquid Biopsy in Oncology. Int J Mol Sci 2020; 21:ijms21186543. [PMID: 32906787 PMCID: PMC7555129 DOI: 10.3390/ijms21186543] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/02/2020] [Accepted: 09/04/2020] [Indexed: 12/11/2022] Open
Abstract
Extracellular Vesicles (EVs) are emerging as pivotal elements in cancer. Many studies have focused on the role of Small- (S)-EVs but in recent years Large-(L)-EVs have progressively gained increasing interest due to their peculiar content and functions. Tumor-derived L-EVs carry a lot of oncogenic proteins, nucleic acids and lipids to recipient cells and are involved in the reshaping of the tumor microenvironment as well as in the metabolic rewiring and the promotion of the pro-metastatic attitude of cancer cells. Several techniques have been developed for the isolation of L-EVs and commercial kits are also available for efficient and easy recovery of these vesicles. Also, the improvement in DNA sequencing and “omics sciences” profoundly changed the way to analyze and explore the molecular content of L-EVs, thus providing novel and potentially useful cancer biomarkers. Herein, we review the most recent findings concerning the role of L-EVs in cancer and discuss their possible use in oncology as “liquid biopsy” tools as compared to the other classes of EVs.
Collapse
Affiliation(s)
- Gaetano Pezzicoli
- Department of Biomedical Sciences and Human Oncology, University of Bari ‘Aldo Moro’, 70121 Bari, Italy; (G.P.); (M.T.); (D.L.); (F.S.); (C.P.)
| | - Marco Tucci
- Department of Biomedical Sciences and Human Oncology, University of Bari ‘Aldo Moro’, 70121 Bari, Italy; (G.P.); (M.T.); (D.L.); (F.S.); (C.P.)
- National Cancer Center, Tumori Institute Giovanni Paolo II, 70121 Bari, Italy
| | - Domenica Lovero
- Department of Biomedical Sciences and Human Oncology, University of Bari ‘Aldo Moro’, 70121 Bari, Italy; (G.P.); (M.T.); (D.L.); (F.S.); (C.P.)
| | - Franco Silvestris
- Department of Biomedical Sciences and Human Oncology, University of Bari ‘Aldo Moro’, 70121 Bari, Italy; (G.P.); (M.T.); (D.L.); (F.S.); (C.P.)
| | - Camillo Porta
- Department of Biomedical Sciences and Human Oncology, University of Bari ‘Aldo Moro’, 70121 Bari, Italy; (G.P.); (M.T.); (D.L.); (F.S.); (C.P.)
| | - Francesco Mannavola
- Department of Biomedical Sciences and Human Oncology, University of Bari ‘Aldo Moro’, 70121 Bari, Italy; (G.P.); (M.T.); (D.L.); (F.S.); (C.P.)
- Correspondence:
| |
Collapse
|
|
41
|
Salah M, Shaheen I, El-Shanawany P, Eid Saad N, Saad R, El Guibaly M, Momen N. Detection of miR-1246, miR-23a and miR-451 in sera of colorectal carcinoma patients: a case-control study in Cairo University hospital. Afr Health Sci 2020; 20:1283-1291. [PMID: 33402976 PMCID: PMC7751536 DOI: 10.4314/ahs.v20i3.33] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Background Colorectal cancer (CRC) has high morbidity and mortality rates. Invasive techniques and other laboratory tests with variable sensitivity and specificity are currently used in diagnosis. Micro ribonucleic acids (miRNAs) have bio vital roles in cell proliferation and apoptosis. Dys-regulation of miRNAs is linked to tumour genesis. The objective of this study was to evaluate the specificity and sensitivity of serum non-invasive biomarkers (micro-RNAs), miR-1246, miR-23a, and miR-451in CRC patients. Methods Peripheral expression of three miRNAs (miR-1246, miR-23a and miR-451) was investigated in sera of 37 CRC Egyptian patients and 30 healthy controls, using quantitative real-time polymerase chain reaction trying to reach the optimal non-invasive combination of miRNAs. Results Serum miR-1246 was up-regulated in sera of CRC patients compared to normal controls (fold change = 3.55; P<0.001) and showed 100% sensitivity and 80% specificity in diagnosis of CRC. Serum miR-451 was significantly down-regulated in CRC patients (fold change = -4.86; p= 0.014), whereas, miR-23a was down-regulated but this was not statistically significant. Conclusion Up-regulation of miR-1246 and down-regulation of miR-451 in the sera of primary CRC Egyptian patients were confirmed with high sensitivity and specificity. Large-scale studies on a wider spectrum of miRNAs in Egyptian CRC patients are needed.
Collapse
|
|
42
|
Nazari-Shafti TZ, Neuber S, Garcia Duran A, Xu Z, Beltsios E, Seifert M, Falk V, Stamm C. Human mesenchymal stromal cells and derived extracellular vesicles: Translational strategies to increase their proangiogenic potential for the treatment of cardiovascular disease. Stem Cells Transl Med 2020; 9:1558-1569. [PMID: 32761804 PMCID: PMC7695640 DOI: 10.1002/sctm.19-0432] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 05/14/2020] [Accepted: 05/18/2020] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) offer great potential for the treatment of cardiovascular diseases (CVDs) such as myocardial infarction and heart failure. Studies have revealed that the efficacy of MSCs is mainly attributed to their capacity to secrete numerous trophic factors that promote angiogenesis, inhibit apoptosis, and modulate the immune response. There is growing evidence that MSC‐derived extracellular vesicles (EVs) containing a cargo of lipids, proteins, metabolites, and RNAs play a key role in this paracrine mechanism. In particular, encapsulated microRNAs have been identified as important positive regulators of angiogenesis in pathological settings of insufficient blood supply to the heart, thus opening a new path for the treatment of CVD. In the present review, we discuss the current knowledge related to the proangiogenic potential of MSCs and MSC‐derived EVs as well as methods to enhance their biological activities for improved cardiac tissue repair. Increasing our understanding of mechanisms supporting angiogenesis will help optimize future approaches to CVD intervention.
Collapse
Affiliation(s)
- Timo Z Nazari-Shafti
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany.,German Centre for Cardiovascular Research, Partner Site Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Sebastian Neuber
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany.,German Centre for Cardiovascular Research, Partner Site Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Ana Garcia Duran
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin-Brandenburg School for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Zhiyi Xu
- Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Eleftherios Beltsios
- Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Martina Seifert
- Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt- Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Volkmar Falk
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany.,German Centre for Cardiovascular Research, Partner Site Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Division of Cardiovascular Surgery, University of Zurich, Zurich, Switzerland
| | - Christof Stamm
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany.,German Centre for Cardiovascular Research, Partner Site Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin, Germany
| |
Collapse
|
|
43
|
Mastrogamvraki N, Zaravinos A. Signatures of co-deregulated genes and their transcriptional regulators in colorectal cancer. NPJ Syst Biol Appl 2020; 6:23. [PMID: 32737302 PMCID: PMC7395738 DOI: 10.1038/s41540-020-00144-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 06/19/2020] [Indexed: 02/06/2023] Open
Abstract
The deregulated genes in colorectal cancer (CRC) vary significantly across different studies. Thus, a systems biology approach is needed to identify the co-deregulated genes (co-DEGs), explore their molecular networks, and spot the major hub proteins within these networks. We reanalyzed 19 GEO gene expression profiles to identify and annotate CRC versus normal signatures, single-gene perturbation, and single-drug perturbation signatures. We identified the co-DEGs across different studies, their upstream regulating kinases and transcription factors (TFs). Connectivity Map was used to identify likely repurposing drugs against CRC within each group. The functional changes of the co-upregulated genes in the first category were mainly associated with negative regulation of transforming growth factor β production and glomerular epithelial cell differentiation; whereas the co-downregulated genes were enriched in cotranslational protein targeting to the membrane. We identified 17 hub proteins across the co-upregulated genes and 18 hub proteins across the co-downregulated genes, composed of well-known TFs (MYC, TCF3, PML) and kinases (CSNK2A1, CDK1/4, MAPK14), and validated most of them using GEPIA2 and HPA, but also through two signature gene lists composed of the co-up and co-downregulated genes. We further identified a list of repurposing drugs that can potentially target the co-DEGs in CRC, including camptothecin, neostigmine bromide, emetine, remoxipride, cephaeline, thioridazine, and omeprazole. Similar analyses were performed in the co-DEG signatures in single-gene or drug perturbation experiments in CRC. MYC, PML, CDKs, CSNK2A1, and MAPKs were common hub proteins among all studies. Overall, we identified the critical genes in CRC and we propose repurposing drugs that could be used against them.
Collapse
Affiliation(s)
- Natalia Mastrogamvraki
- Department of Life Sciences, School of Sciences, European University Cyprus, 1516, Nicosia, Cyprus
| | - Apostolos Zaravinos
- Department of Basic Medical Sciences, College of Medicine, Member of QU Health, Qatar University, Doha, Qatar.
| |
Collapse
|
|
44
|
Di Paolo V, Colletti M, Ferruzzi V, Russo I, Galardi A, Alessi I, Milano GM, Di Giannatale A. Circulating Biomarkers for Tumor Angiogenesis: Where Are We? Curr Med Chem 2020; 27:2361-2380. [PMID: 30129403 DOI: 10.2174/0929867325666180821151409] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 07/10/2018] [Accepted: 07/17/2018] [Indexed: 01/26/2023]
Abstract
BACKGROUND In recent years, several anti-angiogenic drugs have been developed and their addition to standard treatment has been associated with clinical benefits. However, the response to anti-angiogenic therapy is characterized by considerable variability. In this context, the development of dynamic non-invasive biomarkers would be helpful to elucidate the emergence of anti-angiogenic resistance as well as to correctly address the treatment. OBJECTIVES The purpose of this review is to describe current reports on circulating diagnostic and prognostic biomarkers related to angiogenesis. We further discuss how this non-invasive strategy could improve the monitoring of tumor treatment and help clinical strategy. RESULTS We discuss the latest evidence in the literature regarding circulating anti-angiogenic markers. Besides growth factor proteins, different circulating miRNAs could exert a pro- or anti-angiogenic activity so as to represent suitable candidates for a non-invasive strategy. Recent reports indicate that tumor-derived exosomes, which are small membrane vesicles abundant in biological fluids, also have an impact on vascular remodeling. CONCLUSION Numerous circulating biomarkers related to angiogenesis have been recently identified. Their use will allow identifying patients who are more likely to benefit from a specific anti-angiogenic treatment, as well as detecting those who will develop resistance and/or adverse effects. Nonetheless, further studies are required to elucidate the role of these biomarkers in clinical settings.
Collapse
Affiliation(s)
- Virginia Di Paolo
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Marta Colletti
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Valentina Ferruzzi
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Ida Russo
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Angela Galardi
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Iside Alessi
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Giuseppe Maria Milano
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| | - Angela Di Giannatale
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
| |
Collapse
|
|
45
|
Gao S, Zhang F, Sun H, Yang X. LncRNA GA-Binding Protein Transcription Factor Subunit Beta-1 Antisense RNA 1 Inhibits Renal Carcinoma Growth Through an MiR-1246/Phosphoenolpyruvate Carboxykinase 1 Pathway. Onco Targets Ther 2020; 13:6827-6836. [PMID: 32764970 PMCID: PMC7367931 DOI: 10.2147/ott.s257275] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 07/01/2020] [Indexed: 12/30/2022] Open
Abstract
Objective To clarify the role and mechanism of GABPB1-AS1 in renal cell carcinoma. Methods We collected 48 pairs of tumor and adjacent normal tissues from patients with clear cell renal cell carcinoma (ccRCC). Both 786-o and caki-1 ccRCC cell lines were transfected with GA-binding protein transcription factor subunit beta-1 antisense RNA 1 (GABPB1-AS1), miR-1246, or small interfering RNA phosphoenolpyruvate carboxykinase 1 (siPCK1) vectors. RNA expression was examined by quantitative reverse transcription-PCR and protein expression by Western blot. Cell proliferation was measured by Cell Counting Kit-8 assays. Cell migration and invasion were measured by transwell assays. Targeting relationships between genes were tested by luciferase reporter gene assays. Results Lower GABPB1-AS1 expression was found in ccRCC cells and tissues. GABPB1-AS1 expression was inversely associated with tumor size, TNM stage, and Furhman stage. High GABPB1-AS1 expression was associated with a better prognosis. GABPB1-AS1 overexpression significantly inhibited proliferation, migration, and invasion by 786-o and caki-1 cells. GABPB1-AS1 overexpression reduced tumor weights in xenograft experiments. Luciferase reporter assays showed that miR-1246 overexpression significantly inhibited the luciferase activity of 786-o and caki-1 cells transfected with wild-type (WT)-GABPB1-AS1 or WT-PCK1. Knockdown of PCK1 weakened the inhibition of proliferation, migration, and invasion induced by GABPB1-AS1 overexpression in 786-o and caki-1 cells. Conclusion GABPB1-AS1 inhibits ccRCC growth and plays a tumor suppressor role through an miR-1246/PCK1 axis.
Collapse
Affiliation(s)
- Shuang Gao
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.,Department of Pathology, People's Hospital of Liaoning Province, Shenyang 110016, People's Republic of China
| | - Feng Zhang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Hanxue Sun
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Xianghong Yang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| |
Collapse
|
|
46
|
Branscome H, Paul S, Yin D, El-Hage N, Agbottah ET, Zadeh MA, Liotta LA, Kashanchi F. Use of Stem Cell Extracellular Vesicles as a "Holistic" Approach to CNS Repair. Front Cell Dev Biol 2020; 8:455. [PMID: 32587858 PMCID: PMC7298153 DOI: 10.3389/fcell.2020.00455] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 05/15/2020] [Indexed: 12/20/2022] Open
Abstract
Neurodegeneration is a hallmark of many diseases and disorders of the central nervous system (CNS). High levels of neuroinflammation are often associated with irreparable damage to CNS cells due to the dysregulation of signaling cascades that are unable to restore a homeostatic balance. Due to the inherent complexity of the CNS, development of CNS-related therapeutics has met limited success. While stem cell therapy has been evaluated in the context of CNS repair, the mechanisms responsible for their functional properties have not been clearly defined. In recent years, there has been growing interest in the use of stem cell extracellular vesicles (EVs) for the treatment of various CNS pathologies as these vesicles are believed to mediate many of the functional effects associated with their donor stem cells. The potency of stem cell EVs is believed to be largely driven by their biological cargo which includes various types of RNAs, proteins, and cytokines. In this review, we describe the characteristic properties of stem cell EVs and summarize their reported neuroprotective and immunomodulatory functions. A special emphasis is placed on the identification of specific biological cargo, including proteins and non-coding RNA molecules, that have been found to be associated with stem cell EVs. Collectively, this review highlights the potential of stem cell EVs as an alternative to traditional stem cell therapy for the repair of cellular damage associated with diverse CNS pathologies.
Collapse
Affiliation(s)
- Heather Branscome
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
- American Type Culture Collection (ATCC), Manassas, VA, United States
| | - Siddhartha Paul
- American Type Culture Collection (ATCC) Cell Systems, Gaithersburg, MD, United States
| | - Dezhong Yin
- American Type Culture Collection (ATCC) Cell Systems, Gaithersburg, MD, United States
| | - Nazira El-Hage
- Department of Immunology and Nano-Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
| | - Emmanuel T. Agbottah
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
| | - Mohammad Asad Zadeh
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
| | - Lance A. Liotta
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, United States
| | - Fatah Kashanchi
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
| |
Collapse
|
|
47
|
Zhang Y, Liu Y, Guo X, Hu Z, Shi H. Interfering Human Papillomavirus E6/E7 Oncogenes in Cervical Cancer Cells Inhibits the Angiogenesis of Vascular Endothelial Cells via Increasing miR-377 in Cervical Cancer Cell-Derived Microvesicles. Onco Targets Ther 2020; 13:4145-4155. [PMID: 32523352 PMCID: PMC7236052 DOI: 10.2147/ott.s239979] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 03/11/2020] [Indexed: 01/06/2023] Open
Abstract
Background The dysregulation of the human papillomavirus 18 E6 and E7 oncogenes plays a critical role in the angiogenesis of cervical cancer (CC), including the proliferation, migration, and tube formation of vascular endothelial cells. Interfering E6/E7 increases the number of CC cell-derived microvesicles (CC-MVs). Additionally, microRNAs (miRNAs) can modulate CC angiogenesis and can be encapsulated in MVs. Objective We aim to investigate whether E6/E7 affects CC angiogenesis via regulating miRNAs in CC-MVs. Methods CC-MVs were isolated from a CC cell line (HeLa) which were transfected with small interfering RNAs (siRNAs) against E6/E7 or co-transfected with miR-377 mimics/inhibitors. The expression of several miRNAs in CC-MVs was detected using quantitative real-time PCR. After co-incubating CC-MVs with human umbilical vein endothelial cells (HUVECs), cell proliferation, migration, and tube formation of HUVECs were determined using cell counting kit-8, transwell, and tube formation assays, respectively. Results MiR-377 was increased in E6/E7-interfering CC-MVs. Overexpressing miR-377 in CC-MVs suppressed HUVEC proliferation, migration, and tube formation. LPAR2, the cell surface G protein-coupled receptor, was the downstream target of miR-377 in HUVECs. The co-transfection of E6/E7 siRNAs and miR-377 inhibitors in CCs negated the effect of E6/E7 siRNAs on the elevation of miR-377 in CC-MVs. In HUVECs, the co-transfection of E6/E7 siRNAs and miR-377 inhibitors restored the LPAR2 expression which was reduced by the E6/E7 siRNA transfection. Meanwhile, miR-377 mimic reduced LPAR2 expression and inhibited HUVEC proliferation, migration, and tube formation, while such response was negated by LPAR2 overexpression. Conclusion Interfering E6/E7 increased miR-377 in CC-MVs, and overexpressing miR-377 in CC-MVs inhibited angiogenesis of HUVECs via reducing LPAR2.
Collapse
Affiliation(s)
- Ying Zhang
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, People's Republic of China
| | - Yao Liu
- Department of Gynaecology, Hami Central Hospital, Hami, Xinjiang 839000, People's Republic of China
| | - Xingrong Guo
- Department of Gynaecology, Hami Central Hospital, Hami, Xinjiang 839000, People's Republic of China
| | - Zhenhua Hu
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, People's Republic of China
| | - Huirong Shi
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, People's Republic of China
| |
Collapse
|
|
48
|
Ozaki Tan SJ, Floriano JF, Nicastro L, Emanueli C, Catapano F. Novel Applications of Mesenchymal Stem Cell-derived Exosomes for Myocardial Infarction Therapeutics. Biomolecules 2020; 10:E707. [PMID: 32370160 PMCID: PMC7277090 DOI: 10.3390/biom10050707] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/22/2020] [Accepted: 04/27/2020] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity globally, representing approximately a third of all deaths every year. The greater part of these cases is represented by myocardial infarction (MI), or heart attack as it is better known, which occurs when declining blood flow to the heart causes injury to cardiac tissue. Mesenchymal stem cells (MSCs) are multipotent stem cells that represent a promising vector for cell therapies that aim to treat MI due to their potent regenerative effects. However, it remains unclear the extent to which MSC-based therapies are able to induce regeneration in the heart and even less clear the degree to which clinical outcomes could be improved. Exosomes, which are small extracellular vesicles (EVs) known to have implications in intracellular communication, derived from MSCs (MSC-Exos), have recently emerged as a novel cell-free vector that is capable of conferring cardio-protection and regeneration in target cardiac cells. In this review, we assess the current state of research of MSC-Exos in the context of MI. In particular, we place emphasis on the mechanisms of action by which MSC-Exos accomplish their therapeutic effects, along with commentary on the current difficulties faced with exosome research and the ongoing clinical applications of stem-cell derived exosomes in different medical contexts.
Collapse
Affiliation(s)
- Sho Joseph Ozaki Tan
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
| | - Juliana Ferreria Floriano
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
- Botucatu Medical School, Sao Paulo State University, Botucatu 18618687, Brazil
| | - Laura Nicastro
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
| | - Costanza Emanueli
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
| | - Francesco Catapano
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
| |
Collapse
|
|
49
|
Yoshikawa R, Heishima K, Ueno Y, Kawade M, Maeda Y, Yoshida K, Murakami M, Sakai H, Akao Y, Mori T. Development of synthetic microRNA-214 showing enhanced cytotoxicity and RNase resistance for treatment of canine hemangiosarcoma. Vet Comp Oncol 2020; 18:570-579. [PMID: 32072720 DOI: 10.1111/vco.12580] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 02/12/2020] [Accepted: 02/12/2020] [Indexed: 02/06/2023]
Abstract
MicroRNA-214 (miR-214), a pivotal tumour-suppressive miRNA, is downregulated in canine hemangiosarcoma (HSA) cells. Although these tumour-suppressive miRNAs are potential therapeutic agents, their clinical efficacy may be limited because of their vulnerability to RNase-rich microenvironments and low in vivo transfection rates. We developed synthetic miR-214s with enhanced cytotoxicity, RNase resistance and quantity of miR-214 in/on cells. These synthetic miR-214s were synthesized by various chemical modifications (such as 4'-aminoethyl-2'-fluoro, 2'-fluoro, 2'-O-methyl, phosphorothioate and oligospermine modifications) of the wild-type mature miR-214 sequences. Transfection of HSA cells with synthetic miR-214 (miR-214 5AE) demonstrated significant growth suppressive effect and induced the strongest apoptotic response. Synthetic miR-214s (miR-214 5AE, miR-214 10AE and miR-214 OS) were much more stable than mature miR-214s in foetal bovine serum. Similar to mature miR-214, 5AE and OS suppressed the expression level of COP1 in HSA cells. The quantity of synthetic miR-214s in/on cells was higher than that of mature miR-214. In conclusion, we developed a clinically applicable, synthetic miR-214 5AE that regulates the COP1 protein expression similar to that mediated by mature miR-214. Additionally, miR-214 5AE confers better cytotoxicity, nuclease resistance and transfection rate than mature miR-214. Thus, miR-214 5AE could potentially be a novel miRNA-based chemotherapeutic agent that could improve the prognosis of HSA. Its in vivo effects on canine HSA need to be examined in future.
Collapse
Affiliation(s)
- Ryutaro Yoshikawa
- Laboratory of Veterinary Clinical Oncology, Joint Department of Veterinary Medicine, Gifu University, Gifu, Japan
| | - Kazuki Heishima
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
| | - Yoshihito Ueno
- Course of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan.,United Graduate School of Agricultural Science, Gifu University, Gifu, Japan.,Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, Gifu, Japan
| | - Miwa Kawade
- Course of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Yusuke Maeda
- Course of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Kyoko Yoshida
- Laboratory of Veterinary Clinical Oncology, Joint Department of Veterinary Medicine, Gifu University, Gifu, Japan
| | - Mami Murakami
- Laboratory of Veterinary Clinical Oncology, Joint Department of Veterinary Medicine, Gifu University, Gifu, Japan
| | - Hiroki Sakai
- Department of Veterinary Pathology, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Yukihiro Akao
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
| | - Takashi Mori
- Laboratory of Veterinary Clinical Oncology, Joint Department of Veterinary Medicine, Gifu University, Gifu, Japan.,Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, Gifu, Japan
| |
Collapse
|
|
50
|
Surman M, Drożdż A, Stępień E, Przybyło M. Extracellular Vesicles as Drug Delivery Systems - Methods of Production and Potential Therapeutic Applications. Curr Pharm Des 2020; 25:132-154. [PMID: 30848183 DOI: 10.2174/1381612825666190306153318] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 03/01/2019] [Indexed: 01/08/2023]
Abstract
Drug delivery systems are created to achieve the desired therapeutic effect of a specific pharmaceutical compound. Numerous drawbacks and side effects such as unfavorable pharmacokinetics, lack of tissue selectivity, immunogenicity, increased systemic clearance and toxicity, have been observed for currently available drug delivery systems (DDSs). The use of natural and artificial extracellular vesicles (EVs) in drug delivery may help to solve the aforementioned problems faced by different DDSs. Due to their self-origin, small size, flexibility, the presence of multiple adhesive molecules on their surfaces as well as their function as biomolecules carriers, EVs are the perfect candidates for DDSs. Currently, several drug delivery systems based on EVs have been proposed. While the great potential of these particles in targeted drug delivery has been recognized in cancer, hepatitis C, neurodegenerative diseases, inflammatory states etc., this field is still in the early stage of development. Unfortunately, the use of EVs from natural sources (cell cultures, body fluids) results in numerous problems in terms of the heterogeneity of isolated vesicle population as well as the method of isolation thereof, which may influence vesicle composition and properties. Therefore, there is a significant need for the synthesis of artificial EV-based DDSs under strictly controlled laboratory conditions and from well-defined biomolecules (proteins and lipids). Vesicle-mimetic delivery systems, characterized by properties similar to natural EVs, will bring new opportunities to study the mechanisms of DDS internalization and their biological activity after delivering their cargo to a target cell.
Collapse
Affiliation(s)
- Magdalena Surman
- Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland
| | - Anna Drożdż
- Department of Medical Physics, M. Smoluchowski Institute of Physics, Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, Krakow, Poland
| | - Ewa Stępień
- Department of Medical Physics, M. Smoluchowski Institute of Physics, Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, Krakow, Poland
| | - Małgorzata Przybyło
- Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland
| |
Collapse
|