|
1
|
Chideriotis S, Anastasiadi AT, Tzounakas VL, Fortis SP, Kriebardis AG, Valsami S. Morphogens and Cell-Derived Structures (Exosomes and Cytonemes) as Components of the Communication Between Cells. Int J Mol Sci 2025; 26:881. [PMID: 39940651 PMCID: PMC11816454 DOI: 10.3390/ijms26030881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/16/2025] [Accepted: 01/18/2025] [Indexed: 02/16/2025] Open
Abstract
Morphogens, which are non-classical transcription factors, according to several studies, display a crucial role in tissue patterning, organ architecture establishment, and human disease pathogenesis. Recent advances have expanded the morphogen participation to a wide range of human diseases. There are many genetic syndromes caused by mutations of components of morphogen signaling pathways. The aberrant morphogen pathways also promote cancer cell maintenance, renewal, proliferation, and migration. On the other hand, exosomes and their application in the biomedical field are of evolving significance. The evidence that membrane structures participate in the creation of morphogenic gradience and biodistribution of morphogen components renders them attractive as new therapeutic tools. This intercellular morphogen transport is performed by cell-derived structures, mainly exosomes and cytonemes, and extracellular substances like heparan sulphate proteoglycans and lipoproteins. The interaction between morphogens and Extracellular Vesicles has been observed at first in the most studied insect, Drosophila, and afterwards analogous findings have been proved in vertebrates. This review presents the protagonists and mechanisms of lipid-modified morphogens (Hedgehog and Wnt/β-catenin) biodistribution.
Collapse
Affiliation(s)
| | - Alkmini T. Anastasiadi
- Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece; (A.T.A.); (V.L.T.)
| | - Vassilis L. Tzounakas
- Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece; (A.T.A.); (V.L.T.)
| | - Sotirios P. Fortis
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, School of Health & Caring Sciences, University of West Attica (UniWA), 12243 Egaleo, Greece; (S.P.F.); (A.G.K.)
| | - Anastasios G. Kriebardis
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, School of Health & Caring Sciences, University of West Attica (UniWA), 12243 Egaleo, Greece; (S.P.F.); (A.G.K.)
| | - Serena Valsami
- Hematology Laboratory, Blood Bank, Aretaieion Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece
| |
Collapse
|
|
2
|
Batista IA, Machado JC, Melo SA. Advances in exosomes utilization for clinical applications in cancer. Trends Cancer 2024; 10:947-968. [PMID: 39168775 DOI: 10.1016/j.trecan.2024.07.010] [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: 03/28/2024] [Revised: 07/04/2024] [Accepted: 07/25/2024] [Indexed: 08/23/2024]
Abstract
Exosomes are regarded as having transformative potential for clinical applications. Exosome-based liquid biopsies offer a noninvasive method for early cancer detection and real-time disease monitoring. Clinical trials are underway to validate the efficacy of exosomal biomarkers for enhancing diagnostic accuracy and predicting treatment responses. Additionally, engineered exosomes are being developed as targeted drug delivery systems that can navigate the bloodstream to deliver therapeutic agents to tumor sites, thus enhancing treatment efficacy while minimizing systemic toxicity. Exosomes also exhibit immunomodulatory properties, which are being harnessed to boost antitumor immune responses. In this review, we detail the latest advances in clinical trials and research studies, underscoring the potential of exosomes to revolutionize cancer care.
Collapse
Affiliation(s)
- Inês A Batista
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal
| | - José C Machado
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Departamento de Patologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal; P.CCC Porto Comprehensive Cancer Centre, Raquel Seruca, Portugal
| | - Sonia A Melo
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Departamento de Patologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal; P.CCC Porto Comprehensive Cancer Centre, Raquel Seruca, Portugal.
| |
Collapse
|
|
3
|
Cerrotti G, Buratta S, Latella R, Calzoni E, Cusumano G, Bertoldi A, Porcellati S, Emiliani C, Urbanelli L. Hitting the target: cell signaling pathways modulation by extracellular vesicles. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2024; 5:527-552. [PMID: 39697631 PMCID: PMC11648414 DOI: 10.20517/evcna.2024.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 07/10/2024] [Accepted: 09/18/2024] [Indexed: 12/20/2024]
Abstract
Extracellular vesicles (EVs) are lipid bilayer-enclosed nanoparticles released outside the cell. EVs have drawn attention not only for their role in cell waste disposal, but also as additional tools for cell-to-cell communication. Their complex contents include not only lipids, but also proteins, nucleic acids (RNA, DNA), and metabolites. A large part of these molecules are involved in mediating or influencing signal transduction in target cells. In multicellular organisms, EVs have been suggested to modulate signals in cells localized either in the neighboring tissue or in distant regions of the body by interacting with the cell surface or by entering the cells via endocytosis or membrane fusion. Most of the EV-modulated cell signaling pathways have drawn considerable attention because they affect morphogenetic signaling pathways, as well as pathways activated by cytokines and growth factors. Therefore, they are implicated in relevant biological processes, such as embryonic development, cancer initiation and spreading, tissue differentiation and repair, and immune response. Furthermore, it has recently emerged that multicellular organisms interact with and receive signals through EVs released by their microbiota as well as by edible plants. This review reports studies investigating EV-mediated signaling in target mammalian cells, with a focus on key pathways for organism development, organ homeostasis, cell differentiation and immune response.
Collapse
Affiliation(s)
- Giada Cerrotti
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia 06123, Italy
| | - Sandra Buratta
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia 06123, Italy
| | - Raffaella Latella
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia 06123, Italy
| | - Eleonora Calzoni
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia 06123, Italy
| | - Gaia Cusumano
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia 06123, Italy
| | - Agnese Bertoldi
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia 06123, Italy
| | - Serena Porcellati
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia 06123, Italy
| | - Carla Emiliani
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia 06123, Italy
- Centro di Eccellenza sui Materiali Innovativi Nanostrutturati (CEMIN), University of Perugia, Perugia 06123, Italy
| | - Lorena Urbanelli
- Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia 06123, Italy
- Centro di Eccellenza sui Materiali Innovativi Nanostrutturati (CEMIN), University of Perugia, Perugia 06123, Italy
| |
Collapse
|
|
4
|
Liu X, Wu F, Pan W, Liu G, Zhang H, Yan D, Zheng S, Ma Z, Ren X. Tumor-associated exosomes in cancer progression and therapeutic targets. MedComm (Beijing) 2024; 5:e709. [PMID: 39247621 PMCID: PMC11380050 DOI: 10.1002/mco2.709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 08/05/2024] [Accepted: 08/06/2024] [Indexed: 09/10/2024] Open
Abstract
Exosomes are small membrane vesicles that are released by cells into the extracellular environment. Tumor-associated exosomes (TAEs) are extracellular vesicles that play a significant role in cancer progression by mediating intercellular communication and contributing to various hallmarks of cancer. These vesicles carry a cargo of proteins, lipids, nucleic acids, and other biomolecules that can be transferred to recipient cells, modifying their behavior and promoting tumor growth, angiogenesis, immune modulation, and drug resistance. Several potential therapeutic targets within the TAEs cargo have been identified, including oncogenic proteins, miRNAs, tumor-associated antigens, immune checkpoint proteins, drug resistance proteins, and tissue factor. In this review, we will systematically summarize the biogenesis, composition, and function of TAEs in cancer progression and highlight potential therapeutic targets. Considering the complexity of exosome-mediated signaling and the pleiotropic effects of exosome cargoes has challenge in developing effective therapeutic strategies. Further research is needed to fully understand the role of TAEs in cancer and to develop effective therapies that target them. In particular, the development of strategies to block TAEs release, target TAEs cargo, inhibit TAEs uptake, and modulate TAEs content could provide novel approaches to cancer treatment.
Collapse
Affiliation(s)
- Xiaomin Liu
- Lab for Noncoding RNA & Cancer School of Life Sciences Shanghai University Shanghai China
- Shanghai New Tobacco Product Research Institute Co., Ltd. Shanghai China
| | - Fan Wu
- Lab for Noncoding RNA & Cancer School of Life Sciences Shanghai University Shanghai China
| | - Wei Pan
- Lab for Noncoding RNA & Cancer School of Life Sciences Shanghai University Shanghai China
| | - Guangchao Liu
- Shanghai New Tobacco Product Research Institute Co., Ltd. Shanghai China
| | - Hui Zhang
- Shanghai New Tobacco Product Research Institute Co., Ltd. Shanghai China
| | - Dawei Yan
- Shanghai New Tobacco Product Research Institute Co., Ltd. Shanghai China
| | - Saijing Zheng
- Shanghai New Tobacco Product Research Institute Co., Ltd. Shanghai China
| | - Zhongliang Ma
- Lab for Noncoding RNA & Cancer School of Life Sciences Shanghai University Shanghai China
| | - Xiaojun Ren
- Department of Chemistry College of Chemistry and Life Sciences Beijing University of Technology Beijing China
| |
Collapse
|
|
5
|
Hong Y, Yang J, Liu X, Huang S, Liang T, Bai X. Deciphering extracellular vesicles protein cargo in pancreatic cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189142. [PMID: 38914240 DOI: 10.1016/j.bbcan.2024.189142] [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: 01/13/2024] [Revised: 06/12/2024] [Accepted: 06/19/2024] [Indexed: 06/26/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) presents a significant therapeutic challenge as it is frequently diagnosed at advanced inoperable stages. Therefore, the development of a reliable screening tool for PDAC is crucial for effective prevention and treatment. Extracellular vesicles (EVs), characterized by their cup-shaped lipid bilayer structure and ubiquitous release from various cell types, offer notable advantages as an emerging liquid biopsy technique that is rapid, minimally invasive, easily sampled, and cost-effective. While EVs play a substantial role in cancer progression, EV proteins serve as direct mediators of diverse cellular behaviors and have immense potential as biomarkers for PDAC diagnosis and prognostication. This review provides an overview of EV proteins regarding PDAC diagnosis and prognostic implications as well as disease progression.
Collapse
Affiliation(s)
- Yifan Hong
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Jiaqi Yang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
| | - Xinyuan Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Sicong Huang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China.
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, China.
| |
Collapse
|
|
6
|
Yamauchi N, Otsuka M, Ishikawa T, Kakeji Y, Kikuchi A, Masuda A, Kodama Y, Minami Y, Kamizaki K. Role of Wnt5b-Ror1 signaling in the proliferation of pancreatic ductal adenocarcinoma cells. Genes Cells 2024; 29:503-511. [PMID: 38531660 DOI: 10.1111/gtc.13115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 03/20/2024] [Accepted: 03/21/2024] [Indexed: 03/28/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most refractory cancers with the worst prognosis. Although several molecules are known to be associated with the progression of PDAC, the molecular mechanisms underlying the progression of PDAC remain largely elusive. The Ror-family receptors, Ror1 and Ror2, which act as a receptor(s) for Wnt-family ligands, particularly Wnt5a, are involved in the progression of various types of cancers. Here, we show that higher expression of Ror1 and Wnt5b, but not Ror2, are associated with poorer prognosis of PDAC patients, and that Ror1 and Wnt5b are expressed highly in a type of PDAC cell lines, PANC-1 cells. Knockdown of either Ror1 or Wnt5b in PANC-1 cells inhibited their proliferation significantly in vitro, and knockout of Ror1 in PANC-1 cells resulted in a significant inhibition of tumor growth in vivo. Furthermore, we show that Wnt5b-Ror1 signaling in PANC-1 cells promotes their proliferation in a cell-autonomous manner by modulating our experimental setting in vitro. Collectively, these findings indicate that Wnt5b-Ror1 signaling might play an important role in the progression of some if not all of PDAC by promoting proliferation.
Collapse
Affiliation(s)
- Natsuko Yamauchi
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan
- Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Mako Otsuka
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Tomohiro Ishikawa
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Yoshihiro Kakeji
- Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Akira Kikuchi
- Center for Infectious Disease Education and Research, Osaka University, Suita, Japan
| | - Atsuhiro Masuda
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yuzo Kodama
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yasuhiro Minami
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Koki Kamizaki
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan
| |
Collapse
|
|
7
|
Rahmati S, Moeinafshar A, Rezaei N. The multifaceted role of extracellular vesicles (EVs) in colorectal cancer: metastasis, immune suppression, therapy resistance, and autophagy crosstalk. J Transl Med 2024; 22:452. [PMID: 38741166 DOI: 10.1186/s12967-024-05267-8] [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: 03/19/2024] [Accepted: 04/29/2024] [Indexed: 05/16/2024] Open
Abstract
Extracellular vesicles (EVs) are lipid bilayer structures released by all cells and widely distributed in all biological fluids. EVs are implicated in diverse physiopathological processes by orchestrating cell-cell communication. Colorectal cancer (CRC) is one of the most common cancers worldwide, with metastasis being the leading cause of mortality in CRC patients. EVs contribute significantly to the advancement and spread of CRC by transferring their cargo, which includes lipids, proteins, RNAs, and DNAs, to neighboring or distant cells. Besides, they can serve as non-invasive diagnostic and prognostic biomarkers for early detection of CRC or be harnessed as effective carriers for delivering therapeutic agents. Autophagy is an essential cellular process that serves to remove damaged proteins and organelles by lysosomal degradation to maintain cellular homeostasis. Autophagy and EV release are coordinately activated in tumor cells and share common factors and regulatory mechanisms. Although the significance of autophagy and EVs in cancer is well established, the exact mechanism of their interplay in tumor development is obscure. This review focuses on examining the specific functions of EVs in various aspects of CRC, including progression, metastasis, immune regulation, and therapy resistance. Further, we overview emerging discoveries relevant to autophagy and EVs crosstalk in CRC.
Collapse
Affiliation(s)
- Soheil Rahmati
- Student Research Committee, Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran
- Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Aysan Moeinafshar
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran.
- Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
8
|
Zhang C, Brunt L, Ono Y, Rogers S, Scholpp S. Cytoneme-mediated transport of active Wnt5b-Ror2 complexes in zebrafish. Nature 2024; 625:126-133. [PMID: 38123680 PMCID: PMC10764289 DOI: 10.1038/s41586-023-06850-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 11/08/2023] [Indexed: 12/23/2023]
Abstract
Chemical signalling is the primary means by which cells communicate in the embryo. The underlying principle refers to a group of ligand-producing cells and a group of cells that respond to this signal because they express the appropriate receptors1,2. In the zebrafish embryo, Wnt5b binds to the receptor Ror2 to trigger the Wnt-planar cell polarity (PCP) signalling pathway to regulate tissue polarity and cell migration3,4. However, it remains unclear how this lipophilic ligand is transported from the source cells through the aqueous extracellular space to the target tissue. In this study, we provide evidence that Wnt5b, together with Ror2, is loaded on long protrusions called cytonemes. Our data further suggest that the active Wnt5b-Ror2 complexes form in the producing cell and are handed over from these cytonemes to the receiving cell. Then, the receiving cell has the capacity to initiate Wnt-PCP signalling, irrespective of its functional Ror2 receptor status. On the tissue level, we further show that cytoneme-dependent spreading of active Wnt5b-Ror2 affects convergence and extension in the zebrafish gastrula. We suggest that cytoneme-mediated transfer of ligand-receptor complexes is a vital mechanism for paracrine signalling. This may prompt a reevaluation of the conventional concept of characterizing responsive and non-responsive tissues solely on the basis of the expression of receptors.
Collapse
Affiliation(s)
- Chengting Zhang
- Living Systems Institute, School of Biosciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK
| | - Lucy Brunt
- Living Systems Institute, School of Biosciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK
| | - Yosuke Ono
- Living Systems Institute, School of Biosciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK
| | - Sally Rogers
- Living Systems Institute, School of Biosciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK
| | - Steffen Scholpp
- Living Systems Institute, School of Biosciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
| |
Collapse
|
|
9
|
Xue W, Cai L, Li S, Hou Y, Wang YD, Yang D, Xia Y, Nie X. WNT ligands in non-small cell lung cancer: from pathogenesis to clinical practice. Discov Oncol 2023; 14:136. [PMID: 37486552 PMCID: PMC10366069 DOI: 10.1007/s12672-023-00739-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/26/2023] [Indexed: 07/25/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is the malignant tumor with the highest morbidity and leading cause of death worldwide, whereas its pathogenesis has not been fully elucidated. Although mutations in some crucial genes in WNT pathways such as β-catenin and APC are not common in NSCLC, the abnormal signal transduction of WNT pathways is still closely related to the occurrence and progression of NSCLC. WNT ligands (WNTs) are a class of secreted glycoproteins that activate WNT pathways through binding to their receptors and play important regulatory roles in embryonic development, cell differentiation, and tissue regeneration. Therefore, the abnormal expression or dysfunction of WNTs undoubtedly affects WNT pathways and thus participates in the pathogenesis of diseases. There are 19 members of human WNTs, WNT1, WNT2, WNT2b, WNT3, WNT3a, WNT4, WNT5a, WNT5b, WNT6, WNT7a, WNT7b, WNT8a, WNT8b, WNT9a, WNT9b, WNT10a, WNT10b, WNT11 and WNT16. The expression levels of WNTs, binding receptors, and activated WNT pathways are diverse in different tissue types, which endows the complexity of WNT pathways and multifarious biological effects. Although abundant studies have reported the role of WNTs in the pathogenesis of NSCLC, it still needs further study as therapeutic targets for lung cancer. This review will systematically summarize current research on human WNTs in NSCLC, from molecular pathogenesis to potential clinical practice.
Collapse
Affiliation(s)
- Wanting Xue
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Hebi Key Laboratory of Liver Disease, People's Hospital of Hebi, Henan University, Kaifeng, Hebi, China
| | - Lihong Cai
- Kaifeng Key Laboratory of Radiation Oncology, Kaifeng Cancer Hospital, Kaifeng University, Kaifeng, 475003, China
| | - Su Li
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Hebi Key Laboratory of Liver Disease, People's Hospital of Hebi, Henan University, Kaifeng, Hebi, China
| | - Yujia Hou
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Hebi Key Laboratory of Liver Disease, People's Hospital of Hebi, Henan University, Kaifeng, Hebi, China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Dongbin Yang
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Hebi Key Laboratory of Liver Disease, People's Hospital of Hebi, Henan University, Kaifeng, Hebi, China.
- Hebi Key Laboratory of Liver Disease, People's Hospital of Hebi, Henan University, Hebi, 458030, China.
| | - Yubing Xia
- Kaifeng Key Laboratory of Radiation Oncology, Kaifeng Cancer Hospital, Kaifeng University, Kaifeng, 475003, China.
| | - Xiaobo Nie
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Hebi Key Laboratory of Liver Disease, People's Hospital of Hebi, Henan University, Kaifeng, Hebi, China.
- School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China.
| |
Collapse
|
|
10
|
Tufail M, Wu C. WNT5A: a double-edged sword in colorectal cancer progression. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2023; 792:108465. [PMID: 37495091 DOI: 10.1016/j.mrrev.2023.108465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 07/12/2023] [Accepted: 07/17/2023] [Indexed: 07/28/2023]
Abstract
The Wnt signaling pathway is known to play a crucial role in cancer, and WNT5A is a member of this pathway that binds to the Frizzled (FZD) and Receptor Tyrosine Kinase-Like Orphan Receptor (ROR) family members to activate non-canonical Wnt signaling pathways. The WNT5A pathway is involved in various cellular processes, such as proliferation, differentiation, migration, adhesion, and polarization. In the case of colorectal cancer (CRC), abnormal activation or inhibition of WNT5A signaling can lead to both oncogenic and antitumor effects. Moreover, WNT5A is associated with inflammation, metastasis, and altered metabolism in cancer cells. This article aims to discuss the molecular mechanisms and dual roles of WNT5A in CRC.
Collapse
Affiliation(s)
- Muhammad Tufail
- Institute of Biomedical Sciences, Shanxi University, Taiyuan 030006, China.
| | - Changxin Wu
- Institute of Biomedical Sciences, Shanxi University, Taiyuan 030006, China
| |
Collapse
|
|
11
|
Kim M, Son IT, Noh GT, Woo SY, Lee RA, Oh BY. Exosomes Derived from Colon Cancer Cells Promote Tumor Progression and Affect the Tumor Microenvironment. J Clin Med 2023; 12:3905. [PMID: 37373600 DOI: 10.3390/jcm12123905] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/01/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Cancer-cell-derived exosomes confer oncogenic properties in their tumor microenvironment and to other cells; however, the exact mechanism underlying this process is unclear. Here, we investigated the roles of cancer-cell-derived exosomes in colon cancer. Exosomes were isolated from colon cancer cell lines, HT-29, SW480, and LoVo, using an ExoQuick-TC kit, identified using Western blotting for exosome markers, and characterized using transmission electron microscopy and nanosight tracking analysis. The isolated exosomes were used to treat HT-29 to evaluate their effect on cancer progression, specifically cell viability and migration. Cancer-associated fibroblasts (CAFs) were obtained from patients with colorectal cancer to analyze the effect of the exosomes on the tumor microenvironment. RNA sequencing was performed to evaluate the effect of the exosomes on the mRNA component of CAFs. The results showed that exosome treatment significantly increased cancer cell proliferation, upregulated N-cadherin, and downregulated E-cadherin. Exosome-treated cells exhibited higher motility than control cells. Compared with control CAFs, exosome-treated CAFs showed more downregulated genes. The exosomes also altered the regulation of different genes involved in CAFs. In conclusion, colon cancer-cell-derived exosomes affect cancer cell proliferation and the epithelial-mesenchymal transition. They promote tumor progression and metastasis and affect the tumor microenvironment.
Collapse
Affiliation(s)
- Minsung Kim
- Department of Surgery, Hallym University College of Medicine, Anyang 14068, Republic of Korea
| | - Il Tae Son
- Department of Surgery, Hallym University College of Medicine, Anyang 14068, Republic of Korea
| | - Gyoung Tae Noh
- Department of Surgery, Ewha Womans University College of Medicine, Seoul 07804, Republic of Korea
| | - So-Youn Woo
- Department of Microbiology, Ewha Womans University College of Medicine, Seoul 03760, Republic of Korea
| | - Ryung-Ah Lee
- Department of Surgery, Ewha Womans University College of Medicine, Seoul 07804, Republic of Korea
| | - Bo Young Oh
- Department of Surgery, Hallym University College of Medicine, Anyang 14068, Republic of Korea
| |
Collapse
|
|
12
|
Jo H, Shim K, Jeoung D. Exosomes: Diagnostic and Therapeutic Implications in Cancer. Pharmaceutics 2023; 15:pharmaceutics15051465. [PMID: 37242707 DOI: 10.3390/pharmaceutics15051465] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/25/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
Exosomes are a subset of extracellular vesicles produced by all cells, and they are present in various body fluids. Exosomes play crucial roles in tumor initiation/progression, immune suppression, immune surveillance, metabolic reprogramming, angiogenesis, and the polarization of macrophages. In this work, we summarize the mechanisms of exosome biogenesis and secretion. Since exosomes may be increased in the cancer cells and body fluids of cancer patients, exosomes and exosomal contents can be used as cancer diagnostic and prognostic markers. Exosomes contain proteins, lipids, and nucleic acids. These exosomal contents can be transferred into recipient cells. Therefore, this work details the roles of exosomes and exosomal contents in intercellular communications. Since exosomes mediate cellular interactions, exosomes can be targeted for developing anticancer therapy. This review summarizes current studies on the effects of exosomal inhibitors on cancer initiation and progression. Since exosomal contents can be transferred, exosomes can be modified to deliver molecular cargo such as anticancer drugs, small interfering RNAs (siRNAs), and micro RNAs (miRNAs). Thus, we also summarize recent advances in developing exosomes as drug delivery platforms. Exosomes display low toxicity, biodegradability, and efficient tissue targeting, which make them reliable delivery vehicles. We discuss the applications and challenges of exosomes as delivery vehicles in tumors, along with the clinical values of exosomes. In this review, we aim to highlight the biogenesis, functions, and diagnostic and therapeutic implications of exosomes in cancer.
Collapse
Affiliation(s)
- Hyein Jo
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Kyeonghee Shim
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Dooil Jeoung
- Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 24341, Republic of Korea
| |
Collapse
|
|
13
|
Wu Y, Terekhanova NV, Caravan W, Naser Al Deen N, Lal P, Chen S, Mo CK, Cao S, Li Y, Karpova A, Liu R, Zhao Y, Shinkle A, Strunilin I, Weimholt C, Sato K, Yao L, Serasanambati M, Yang X, Wyczalkowski M, Zhu H, Zhou DC, Jayasinghe RG, Mendez D, Wendl MC, Clark D, Newton C, Ruan Y, Reimers MA, Pachynski RK, Kinsinger C, Jewell S, Chan DW, Zhang H, Chaudhuri AA, Chheda MG, Humphreys BD, Mesri M, Rodriguez H, Hsieh JJ, Ding L, Chen F. Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma. Nat Commun 2023; 14:1681. [PMID: 36973268 PMCID: PMC10042888 DOI: 10.1038/s41467-023-37211-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 03/07/2023] [Indexed: 03/29/2023] Open
Abstract
Identifying tumor-cell-specific markers and elucidating their epigenetic regulation and spatial heterogeneity provides mechanistic insights into cancer etiology. Here, we perform snRNA-seq and snATAC-seq in 34 and 28 human clear cell renal cell carcinoma (ccRCC) specimens, respectively, with matched bulk proteogenomics data. By identifying 20 tumor-specific markers through a multi-omics tiered approach, we reveal an association between higher ceruloplasmin (CP) expression and reduced survival. CP knockdown, combined with spatial transcriptomics, suggests a role for CP in regulating hyalinized stroma and tumor-stroma interactions in ccRCC. Intratumoral heterogeneity analysis portrays tumor cell-intrinsic inflammation and epithelial-mesenchymal transition (EMT) as two distinguishing features of tumor subpopulations. Finally, BAP1 mutations are associated with widespread reduction of chromatin accessibility, while PBRM1 mutations generally increase accessibility, with the former affecting five times more accessible peaks than the latter. These integrated analyses reveal the cellular architecture of ccRCC, providing insights into key markers and pathways in ccRCC tumorigenesis.
Collapse
Affiliation(s)
- Yige Wu
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Nadezhda V Terekhanova
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Wagma Caravan
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Nataly Naser Al Deen
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Preet Lal
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Siqi Chen
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Chia-Kuei Mo
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Song Cao
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Yize Li
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Alla Karpova
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Ruiyang Liu
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Yanyan Zhao
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Andrew Shinkle
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Ilya Strunilin
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Cody Weimholt
- Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Kazuhito Sato
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Lijun Yao
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Mamatha Serasanambati
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Xiaolu Yang
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Matthew Wyczalkowski
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Houxiang Zhu
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Daniel Cui Zhou
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Reyka G Jayasinghe
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
| | - Daniel Mendez
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Michael C Wendl
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA
- Department of Genetics, Washington University in St. Louis, St. Louis, MO, 63110, USA
- Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO, 63130, USA
| | - David Clark
- Department of Pathology, Johns Hopkins University, Baltimore, MD, 21231, USA
| | | | - Yijun Ruan
- The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT, 06032, USA
| | - Melissa A Reimers
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Russell K Pachynski
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Chris Kinsinger
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Scott Jewell
- Van Andel Institutes, Grand Rapids, MI, 49503, USA
| | - Daniel W Chan
- Department of Pathology, Johns Hopkins University, Baltimore, MD, 21231, USA
| | - Hui Zhang
- Department of Pathology, Johns Hopkins University, Baltimore, MD, 21231, USA
| | - Aadel A Chaudhuri
- Department of Genetics, Washington University in St. Louis, St. Louis, MO, 63110, USA
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, 63110, USA
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Milan G Chheda
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Benjamin D Humphreys
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Mehdi Mesri
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Henry Rodriguez
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - James J Hsieh
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Li Ding
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA.
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, 63108, USA.
- Department of Genetics, Washington University in St. Louis, St. Louis, MO, 63110, USA.
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, 63110, USA.
| | - Feng Chen
- Oncology Division, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA.
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, 63110, USA.
| |
Collapse
|
|
14
|
Dwivedi M, Ghosh D, Saha A, Hasan S, Jindal D, Yadav H, Yadava A, Dwivedi M. Biochemistry of exosomes and their theranostic potential in human diseases. Life Sci 2023; 315:121369. [PMID: 36639052 DOI: 10.1016/j.lfs.2023.121369] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/22/2022] [Accepted: 01/01/2023] [Indexed: 01/11/2023]
Abstract
Exosomes are classified as special extracellular vesicles in the eukaryotic system having diameters ranging from 30 to 120 nm. These vesicles carry various endogenous molecules including DNA, mRNA, microRNA, circular RNA, and proteins, crucial for numerous metabolic reactions and can be proposed as therapeutic or diagnostic targets for several disorders. The donor exosomes release their content to recipient cells and further establish the significant intercellular communication showing biological effects by triggering environmental alterations. Exosomes derived from mesenchymal and dendritic cells have demonstrated their therapeutic potential against organ injury. Yet, various intricacies are involved in exosomal transport and its inclusion in cancer and other disease pathogenesis needs to be explored. The exosomes represent profound potential as diagnostic biomarkers and therapeutic carriers in various pathophysiological conditions such as neurodegenerative diseases, chronic cancers, infectious diseases, female reproductive diseases and cardiovascular diseases. In the current study, we demonstrate the advancements in the implication of exosomes as one of the irrefutable prognostic biological targets in human health and diseases.
Collapse
Affiliation(s)
- Manish Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India.
| | - Diya Ghosh
- Department of Biotechnology, Heritage Institute of Technology, Kolkata, West Bengal, India
| | - Anwesha Saha
- Department of Biotechnology, Heritage Institute of Technology, Kolkata, West Bengal, India
| | - Saba Hasan
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India
| | - Divya Jindal
- Center for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, India
| | - Hitendra Yadav
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India
| | - Anuradha Yadava
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India
| | - Medha Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India
| |
Collapse
|
|
15
|
He J, Yang L, Zhou N, Zu L, Xu S. The role and underlying mechanisms of tumour-derived exosomes in lung cancer metastasis. Curr Opin Oncol 2023; 35:46-53. [PMID: 36321569 DOI: 10.1097/cco.0000000000000913] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Lung cancer is one of the most common malignant tumours worldwide. Metastasis is a serious influencing factor for poor treatment effect and shortened survival in lung cancer. But the complicated underlying molecular mechanisms of tumour metastasis remain unclear. In this review, we aim to further summarize and explore the underlying mechanisms of tumour-derived exosomes (TDEs) in lung cancer metastasis. RECENT FINDINGS TDEs are actively produced and released by tumour cells and carry messages from tumour cells to normal or abnormal cells residing at close or distant sites. Many studies have shown that TDEs promote lung cancer metastasis and development through multiple mechanisms, including epithelial-mesenchymal transition, immunosuppression and the formation of a premetastatic niche. TDEs regulate these mechanisms to promote metastasis by carrying DNA, proteins, miRNA, mRNA, lncRNA and ceRNA. Further exploring TDEs related to metastasis may be a promising treatment strategy and deserve further investigation. SUMMARY Overall, TDEs play a critical role in metastatic of lung cancer. Further studies are needed to explore the underlying mechanisms of TDEs in lung cancer metastasis.
Collapse
Affiliation(s)
- Jinling He
- Department of Lung Cancer Surgery
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Lingqi Yang
- Department of Lung Cancer Surgery
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Ning Zhou
- Department of Lung Cancer Surgery
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Lingling Zu
- Department of Lung Cancer Surgery
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Song Xu
- Department of Lung Cancer Surgery
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| |
Collapse
|
|
16
|
The exosome: a review of current therapeutic roles and capabilities in human reproduction. Drug Deliv Transl Res 2023; 13:473-502. [PMID: 35980542 PMCID: PMC9794547 DOI: 10.1007/s13346-022-01225-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/03/2022] [Indexed: 12/31/2022]
Abstract
Exosomes are nano-vesicles (30-150 nm) which may be useful as therapeutic delivery vehicles and as diagnostic biomarkers. Exosomes are produced naturally within the human body and therefore are not prone to immunogenicity effects which would otherwise destroy unelicited foreign bodies. Clinically, they have been regarded as ideal candidates for applications relating to biomarker developments for the early detection of different diseases. Furthermore, exosomes may be of interest as potential drug delivery vehicles, which may improve factors such as bioavailability of loaded molecular cargo, side effect profiles, off-target effects, and pharmacokinetics of drug molecules. In this review, the therapeutic potential of exosomes and their use as clinical biomarkers for early diagnostics will be explored, alongside exosomes as therapeutic delivery vehicles. This review will evaluate techniques for cargo loading, and the capacity of loaded exosomes to improve various reproductive disease states. It becomes important, therefore, to consider factors such as loading efficiency, loading methods, cell viability, exosomal sources, exosome isolation, and the potential therapeutic benefits of exosomes. Issues related to targeted drug delivery will also be discussed. Finally, the variety of therapeutic cargo and the application of appropriate loading methods is explored, in the context of establishing clinical utility. Exosomes have more recently been widely accpeted as potential tools for disease diagnostics and the targeted delivery of certain therapeutic molecules-and in due time exosomes will be utilised more commonly within the clinical setting. Specifically, exosomal biomarkers can be identified and related to various detrimental conditions which occur during pregnancy. Considering, this review will explore the potential future of exosomes as both diagnostic tools and therapeutic delivery vehicles to treat related conditions, including the challenges which exist towards incorporating exosomes within the clinical environment to benefit patients.
Collapse
|
|
17
|
Functional regulation of Wnt protein through post-translational modifications. Biochem Soc Trans 2022; 50:1797-1808. [DOI: 10.1042/bst20220735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/10/2022] [Accepted: 11/21/2022] [Indexed: 12/13/2022]
Abstract
Wnts are lipid-modified signaling glycoproteins present in all metazoans that play key roles in development and homeostasis. Post-translational modifications of Wnts regulate their function. Wnts have a unique post-translational modification, O-linked palmitoleation, that is absolutely required for their function. This Wnt-specific modification occurs during Wnt biosynthesis in the endoplasmic reticulum (ER), catalyzed by the O-acyltransferase Porcupine (PORCN). Palmitoleation is required for Wnt to bind to its transporter Wntless (WLS/Evi) as well as to its receptor Frizzled (FZD). Recent structural studies have illustrated how PORCN recognizes its substrates, and how drugs inhibit this. The abundance of WLS is tightly regulated by intracellular recycling and ubiquitylation-mediated degradation in the ER. The function of Wnt glycosylation is less well understood, and the sites and types of glycosylation are not largely conserved among different Wnts. In polarized tissues, the type of glycans can determine whether the route of trafficking is apical or basolateral. In addition, pairing of the 24 highly conserved cysteines in Wnts to form disulfide bonds is critical in maintaining proper structure and activities. Extracellularly, the amino terminus of a subset of Wnts can be cleaved by a dedicated glycosylphosphatidylinositol (GPI)-anchored metalloprotease TIKI, resulting in the inactivation of these Wnt proteins. Additionally, NOTUM is a secreted extracellular carboxylesterase that removes the palmitoleate moiety from Wnt, antagonizing its activity. In summary, Wnt signaling activity is controlled at multiple layers by post-translational modifications.
Collapse
|
|
18
|
Konkimalla A, Konishi S, Kobayashi Y, Kadur Lakshminarasimha Murthy P, Macadlo L, Mukherjee A, Elmore Z, Kim SJ, Pendergast AM, Lee PJ, Asokan A, Knudsen L, Bravo-Cordero JJ, Tata A, Tata PR. Multi-apical polarity of alveolar stem cells and their dynamics during lung development and regeneration. iScience 2022; 25:105114. [PMID: 36185377 PMCID: PMC9519774 DOI: 10.1016/j.isci.2022.105114] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 08/25/2022] [Accepted: 09/08/2022] [Indexed: 11/24/2022] Open
Abstract
Epithelial cells of diverse tissues are characterized by the presence of a single apical domain. In the lung, electron microscopy studies have suggested that alveolar type-2 epithelial cells (AT2s) en face multiple alveolar sacs. However, apical and basolateral organization of the AT2s and their establishment during development and remodeling after injury repair remain unknown. Thick tissue imaging and electron microscopy revealed that a single AT2 can have multiple apical domains that enface multiple alveoli. AT2s gradually establish multi-apical domains post-natally, and they are maintained throughout life. Lineage tracing, live imaging, and selective cell ablation revealed that AT2s dynamically reorganize multi-apical domains during injury repair. Single-cell transcriptome signatures of residual AT2s revealed changes in cytoskeleton and cell migration. Significantly, cigarette smoke and oncogene activation lead to dysregulation of multi-apical domains. We propose that the multi-apical domains of AT2s enable them to be poised to support the regeneration of a large array of alveolar sacs.
Collapse
Affiliation(s)
- Arvind Konkimalla
- Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
- Medical Scientist Training Program, Duke University School of Medicine, Durham, NC 27710, USA
| | - Satoshi Konishi
- Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Yoshihiko Kobayashi
- Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
| | | | - Lauren Macadlo
- Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Ananya Mukherjee
- Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Zachary Elmore
- Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA
| | - So-Jin Kim
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine and the Durham Veterans Administration Medical Center, Durham, NC 27710, USA
| | - Ann Marie Pendergast
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA
| | - Patty J. Lee
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine and the Durham Veterans Administration Medical Center, Durham, NC 27710, USA
| | - Aravind Asokan
- Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Biomedical Engineering, Regeneration Next, Duke University, Durham, NC 27710, USA
- Center for Advanced Genomic Technologies, Duke University, Durham, NC 27710, USA
| | - Lars Knudsen
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover 30625, Germany
| | - Jose Javier Bravo-Cordero
- Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Aleksandra Tata
- Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Purushothama Rao Tata
- Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine and the Durham Veterans Administration Medical Center, Durham, NC 27710, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA
- Center for Advanced Genomic Technologies, Duke University, Durham, NC 27710, USA
- Duke Regeneration Center, Duke University, Durham, NC 27710, USA
| |
Collapse
|
|
19
|
Shao X, Hua S, Feng T, Ocansey DKW, Yin L. Hypoxia-Regulated Tumor-Derived Exosomes and Tumor Progression: A Focus on Immune Evasion. Int J Mol Sci 2022; 23:ijms231911789. [PMID: 36233088 PMCID: PMC9570495 DOI: 10.3390/ijms231911789] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/24/2022] [Accepted: 09/29/2022] [Indexed: 11/16/2022] Open
Abstract
Tumor cells express a high quantity of exosomes packaged with unique cargos under hypoxia, an important characteristic feature in solid tumors. These hypoxic tumor-derived exosomes are, crucially, involved in the interaction of cancer cells with their microenvironment, facilitating not only immune evasion, but increased cell growth and survival, enhanced angiogenesis, epithelial–mesenchymal transition (EMT), therapeutic resistance, autophagy, pre-metastasis, and metastasis. This paper explores the tumor microenvironment (TME) remodeling effects of hypoxic tumor-derived exosome towards facilitating the tumor progression process, particularly, the modulatory role of these factors on tumor cell immune evasion through suppression of immune cells, expression of surface recognition molecules, and secretion of antitumor soluble factor. Tumor-expressed exosomes educate immune effector cells, including macrophages, monocytes, T cells, natural killer (NK) cells, dendritic cells (DCs), γδ T lymphocytes, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), mast cells, and B cells, within the hypoxic TME through the release of factors that regulate their recruitment, phenotype, and function. Thus, both hypoxia and tumor-derived exosomes modulate immune cells, growth factors, cytokines, receptor molecules, and other soluble factors, which, together, collaborate to form the immune-suppressive milieu of the tumor environment. Exploring the contribution of exosomal cargos, such as RNAs and proteins, as indispensable players in the cross-talk within the hypoxic tumor microenvironmental provides a potential target for antitumor immunity or subverting immune evasion and enhancing tumor therapies.
Collapse
|
|
20
|
Lucotti S, Kenific CM, Zhang H, Lyden D. Extracellular vesicles and particles impact the systemic landscape of cancer. EMBO J 2022; 41:e109288. [PMID: 36052513 PMCID: PMC9475536 DOI: 10.15252/embj.2021109288] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 02/16/2022] [Accepted: 03/23/2022] [Indexed: 11/09/2022] Open
Abstract
Intercellular cross talk between cancer cells and stromal and immune cells is essential for tumor progression and metastasis. Extracellular vesicles and particles (EVPs) are a heterogeneous class of secreted messengers that carry bioactive molecules and that have been shown to be crucial for this cell-cell communication. Here, we highlight the multifaceted roles of EVPs in cancer. Functionally, transfer of EVP cargo between cells influences tumor cell growth and invasion, alters immune cell composition and function, and contributes to stromal cell activation. These EVP-mediated changes impact local tumor progression, foster cultivation of pre-metastatic niches at distant organ-specific sites, and mediate systemic effects of cancer. Furthermore, we discuss how exploiting the highly selective enrichment of molecules within EVPs has profound implications for advancing diagnostic and prognostic biomarker development and for improving therapy delivery in cancer patients. Altogether, these investigations into the role of EVPs in cancer have led to discoveries that hold great promise for improving cancer patient care and outcome.
Collapse
Affiliation(s)
- Serena Lucotti
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Candia M Kenific
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Haiying Zhang
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - David Lyden
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| |
Collapse
|
|
21
|
Fang Z, Ding Y, Xue Z, Li P, Li J, Li F. Roles of exosomes as drug delivery systems in cancer immunotherapy: a mini-review. Discov Oncol 2022; 13:74. [PMID: 35962862 PMCID: PMC9375799 DOI: 10.1007/s12672-022-00539-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/08/2022] [Indexed: 11/04/2022] Open
Abstract
Exosomes can be released by a variety of cells and participate in intercellular communication in many physiological processes in the body. They can be used as carriers of cancer therapeutic drugs and have natural delivery capabilities. Some biologically active substances on exosomes, such as major histocompatibility complex (MHC), have been shown to be involved in exosome-mediated anticancer immune responses and have important regulatory effects on the immune system. Exosome-based drug delivery systems hold great promise in future cancer immunotherapy. However, there are still substantial challenges to be overcome in the clinical application of exosomes as drug carriers. This article reviews the biological characteristics of exosome drug delivery systems and their potential applications and challenges in cancer immunotherapy.
Collapse
Affiliation(s)
- Zhen Fang
- Department of General Surgery, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China
| | - Yixuan Ding
- Department of General Surgery, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China
| | - Zhigang Xue
- Department of General Surgery, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China
| | - Peijuan Li
- Dalian Medical University, Dalian, Liaoning, China.
| | - Jia Li
- Department of General Surgery, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China.
| | - Fei Li
- Department of General Surgery, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China.
| |
Collapse
|
|
22
|
Zhao L, Corvigno S, Ma S, Celestino J, Fleming ND, Hajek RA, Lankenau Ahumada A, Jennings NB, Thompson EJ, Tang H, Westin SN, Jazaeri AA, Zhang J, Futreal PA, Sood AK, Lee S. Molecular Profiles of Serum-Derived Extracellular Vesicles in High-Grade Serous Ovarian Cancer. Cancers (Basel) 2022; 14:cancers14153589. [PMID: 35892848 PMCID: PMC9330879 DOI: 10.3390/cancers14153589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/18/2022] [Accepted: 07/20/2022] [Indexed: 02/04/2023] Open
Abstract
Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (R0) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have a response enabling interval cytoreductive surgery. Clinically useful biomarkers for predicting these outcomes are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. In this study, we performed extensive molecular characterization of serum-derived EVs and correlated the findings with therapeutic outcomes in patients with HGSC. Using EV-DNA whole-genome sequencing and EV-RNA sequencing, we identified distinct somatic EV-DNA alterations in cancer-hallmark genes and in ovarian cancer genes, as well as significantly altered oncogenic pathways between the R0 group and NACT groups. We also found significantly altered EV-RNA transcriptomic variations and enriched pathways between the groups. Taken together, our data suggest that the molecular characteristics of EVs could enable prediction of patients with HGSC who could undergo R0 surgery or respond to chemotherapy.
Collapse
Affiliation(s)
- Li Zhao
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (L.Z.); (J.Z.); (P.A.F.)
| | - Sara Corvigno
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Shaolin Ma
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Joseph Celestino
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Nicole D. Fleming
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Richard A. Hajek
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Adrian Lankenau Ahumada
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Nicholas B. Jennings
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Erika J. Thompson
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (E.J.T.); (H.T.)
| | - Hongli Tang
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (E.J.T.); (H.T.)
| | - Shannon N. Westin
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Amir A. Jazaeri
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
| | - Jianhua Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (L.Z.); (J.Z.); (P.A.F.)
| | - P. Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (L.Z.); (J.Z.); (P.A.F.)
| | - Anil K. Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
- Correspondence: (A.K.S.); (S.L.)
| | - Sanghoon Lee
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.C.); (S.M.); (J.C.); (N.D.F.); (R.A.H.); (A.L.A.); (N.B.J.); (S.N.W.); (A.A.J.)
- Correspondence: (A.K.S.); (S.L.)
| |
Collapse
|
|
23
|
Paskeh MDA, Entezari M, Mirzaei S, Zabolian A, Saleki H, Naghdi MJ, Sabet S, Khoshbakht MA, Hashemi M, Hushmandi K, Sethi G, Zarrabi A, Kumar AP, Tan SC, Papadakis M, Alexiou A, Islam MA, Mostafavi E, Ashrafizadeh M. Emerging role of exosomes in cancer progression and tumor microenvironment remodeling. J Hematol Oncol 2022; 15:83. [PMID: 35765040 PMCID: PMC9238168 DOI: 10.1186/s13045-022-01305-4] [Citation(s) in RCA: 284] [Impact Index Per Article: 94.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 06/13/2022] [Indexed: 12/14/2022] Open
Abstract
Cancer is one of the leading causes of death worldwide, and the factors responsible for its progression need to be elucidated. Exosomes are structures with an average size of 100 nm that can transport proteins, lipids, and nucleic acids. This review focuses on the role of exosomes in cancer progression and therapy. We discuss how exosomes are able to modulate components of the tumor microenvironment and influence proliferation and migration rates of cancer cells. We also highlight that, depending on their cargo, exosomes can suppress or promote tumor cell progression and can enhance or reduce cancer cell response to radio- and chemo-therapies. In addition, we describe how exosomes can trigger chronic inflammation and lead to immune evasion and tumor progression by focusing on their ability to transfer non-coding RNAs between cells and modulate other molecular signaling pathways such as PTEN and PI3K/Akt in cancer. Subsequently, we discuss the use of exosomes as carriers of anti-tumor agents and genetic tools to control cancer progression. We then discuss the role of tumor-derived exosomes in carcinogenesis. Finally, we devote a section to the study of exosomes as diagnostic and prognostic tools in clinical courses that is important for the treatment of cancer patients. This review provides a comprehensive understanding of the role of exosomes in cancer therapy, focusing on their therapeutic value in cancer progression and remodeling of the tumor microenvironment.
Collapse
Affiliation(s)
- Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.,Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.,Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hossein Saleki
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohamad Javad Naghdi
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sina Sabet
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Amin Khoshbakht
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.,Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Division of Epidemiology, Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.,NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, 34396, Istanbul, Turkey
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.,NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany.
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, Australia.,AFNP Med Austria, Vienna, Austria
| | - Md Asiful Islam
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.,Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA.,Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, Turkey.
| |
Collapse
|
|
24
|
Martín-Medina A, Cerón-Pisa N, Martinez-Font E, Shafiek H, Obrador-Hevia A, Sauleda J, Iglesias A. TLR/WNT: A Novel Relationship in Immunomodulation of Lung Cancer. Int J Mol Sci 2022; 23:6539. [PMID: 35742983 PMCID: PMC9224119 DOI: 10.3390/ijms23126539] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/01/2022] [Accepted: 06/07/2022] [Indexed: 02/07/2023] Open
Abstract
The most frequent cause of death by cancer worldwide is lung cancer, and the 5-year survival rate is still very poor for patients with advanced stage. Understanding the crosstalk between the signaling pathways that are involved in disease, especially in metastasis, is crucial to developing new targeted therapies. Toll-like receptors (TLRs) are master regulators of the immune responses, and their dysregulation in lung cancer is linked to immune escape and promotes tumor malignancy by facilitating angiogenesis and proliferation. On the other hand, over-activation of the WNT signaling pathway has been reported in lung cancer and is also associated with tumor metastasis via induction of Epithelial-to-mesenchymal-transition (EMT)-like processes. An interaction between both TLRs and the WNT pathway was discovered recently as it was found that the TLR pathway can be activated by WNT ligands in the tumor microenvironment; however, the implications of such interactions in the context of lung cancer have not been discussed yet. Here, we offer an overview of the interaction of TLR-WNT in the lung and its potential implications and role in the oncogenic process.
Collapse
Affiliation(s)
- Aina Martín-Medina
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
| | - Noemi Cerón-Pisa
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
| | - Esther Martinez-Font
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Medical Oncology Department, Hospital Universitario Son Espases, 07120 Palma, Spain
| | - Hanaa Shafiek
- Chest Diseases Department, Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt
| | - Antònia Obrador-Hevia
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Molecular Diagnosis Unit, Hospital Universitario Son Espases, 07120 Palma, Spain
| | - Jaume Sauleda
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Department of Respiratory Medicine, Hospital Universitario Son Espases, 07120 Palma, Spain
- Centro de Investigación Biomédica en Red in Respiratory Diseases (CIBERES), 28029 Madrid, Spain
| | - Amanda Iglesias
- Instituto de Investigación Sanitaria de les Illes Balears (IdISBa), 07120 Palma, Spain
- Centro de Investigación Biomédica en Red in Respiratory Diseases (CIBERES), 28029 Madrid, Spain
| |
Collapse
|
|
25
|
Galindo A, Javier-Reyna R, García-Rivera G, Bañuelos C, Chávez-Munguía B, Salazar-Villatoro L, Orozco E. EhVps23, an ESCRT-I Member, Is a Key Factor in Secretion, Motility, Phagocytosis and Tissue Invasion by Entamoeba histolytica. Front Cell Infect Microbiol 2022; 12:835654. [PMID: 35360117 PMCID: PMC8964110 DOI: 10.3389/fcimb.2022.835654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 02/17/2022] [Indexed: 11/25/2022] Open
Abstract
The EhVps23 protein, an orthologue of the yeast Vps23 and the mammalian TSG101 proteins, is the single member of the ESCRT-I complex of Entamoeba histolytica identified and characterized until now. EhVps23 actively participates in vesicular trafficking and phagocytosis, which influence several cellular events. In this paper, we investigated the role of EhVps23 in virulence-related functions, including the invasive capacity of trophozoites, using transfected trophozoites. Trophozoites overexpressing the EhVps23 protein (Neo-EhVps23) presented helical arrangements in the cytoplasm, similar to the ones formed by EhVps32 for scission of vesicles. By confocal and transmission electron microscopy, EhVps23 was detected in multivesicular bodies, vesicles, and the extracellular space. It was secreted in vesicles together with other proteins, including the EhADH adhesin. Probably, these vesicles carry molecules that participate in the prey capture or in cell-cell communication. Mass spectrometry of precipitates obtained using α-EhVps23 antibodies, evidenced the presence of proteins involved in motility, phagocytosis, vesicular trafficking and secretion. The study of cellular functions, revealed that Neo-EhVps23 trophozoites exhibit characteristics similar to those described for mammalian transformed cells: they grew 50% faster than the control; presented a significant higher rate of phagocytosis, and migrated five-fold faster than the control, in concordance with the low rate of migration exhibited by Ehvps23-knocked down trophozoites. In addition, Neo-EhVps23 trophozoites produced dramatic liver abscesses in experimental animals. In conclusion, our results showed that EhVps23 overexpression gave to the trophozoites characteristics that resemble cancer cells, such as increased cell proliferation, migration, and invasion. The mutant that overexpresses EhVps23 can be a good study model to explore different events related to the transformation of malignant cells.
Collapse
Affiliation(s)
- Ausencio Galindo
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (IPN), Ciudad de México, Mexico
| | - Rosario Javier-Reyna
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (IPN), Ciudad de México, Mexico
| | - Guillermina García-Rivera
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (IPN), Ciudad de México, Mexico
| | - Cecilia Bañuelos
- Programa Transdisciplinario en Desarrollo Científico y Tecnológico para la Sociedad, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (IPN), Ciudad de México, Mexico
| | - Bibiana Chávez-Munguía
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (IPN), Ciudad de México, Mexico
| | - Lizbeth Salazar-Villatoro
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (IPN), Ciudad de México, Mexico
| | - Esther Orozco
- Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (IPN), Ciudad de México, Mexico
- *Correspondence: Esther Orozco,
| |
Collapse
|
|
26
|
Kong X, Chen X, Ou S, Wang W, Li R. Derivation of human triploid trophoblast stem cells. J Assist Reprod Genet 2022; 39:1183-1193. [PMID: 35243570 PMCID: PMC9107551 DOI: 10.1007/s10815-022-02436-w] [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: 10/18/2022] Open
Abstract
PURPOSE Human trophoblast stem cells (hTSCs) are counterparts of the precursor cells of the placenta and are valuable cell models for the study of placental development and the pathogenesis of placental diseases. The aim of this work was to establish a triploid human TSC (hTSC3PN) derived from the tripronuclear embryos, which are clinically discarded but readily available, for potential applications in basic placental research and disease modeling. METHODS Eighteen tripronuclear human zygotes from IVF were collected and cultured for 5-6 days. Five high-quality blastocysts were harvested and were individually cultured in hTSC medium. Finally, two hTSC lines were established after 10 days and could be passaged stably. RESULTS The karyotyping analysis showed that hTSC3PN contained three sets of chromosomes. And the hTSC3PN exhibited typical features of hTSCs, with the ability to differentiate into two trophoblast lineages: extravillous cytotrophoblasts (EVTs) and syncytiotrophoblasts (STs). In addition, the hTSC3PN can mimic some vital features of trophoblast, including hormone secretion and invasion. Further studies showed that the proliferation and differentiation of hTSC3PN were reduced compared with normal hTSCs, which may be related to the disturbed metabolic signaling in hTSC3PN. CONCLUSIONS We established the triploid hTSC lines derived from tripronuclear embryos, which provides a potentially useful research model in vitro to study human placental biology and diseases.
Collapse
Affiliation(s)
- Xuhui Kong
- Department of Histology and Embryology, Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xin Chen
- Department of Histology and Embryology, Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Songbang Ou
- Reproductive Medicine Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Wenjun Wang
- Reproductive Medicine Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. .,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Guangzhou, China.
| | - Ruiqi Li
- Reproductive Medicine Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. .,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Guangzhou, China. .,Reproductive Medicine Center, The First People's Hospital of Kashgar, Kashgar, China.
| |
Collapse
|
|
27
|
Abedi E, Karimi M, Yaghobi R, Mohammadi H, Haghpanah S, Moghadam M, Bayat E, Rezvani A, Ramzi M. Oncogenic and tumor suppressor genes expression in myeloproliferative neoplasms: The hidden side of a complex pathology. J Clin Lab Anal 2022; 36:e24289. [PMID: 35176183 PMCID: PMC8993601 DOI: 10.1002/jcla.24289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 11/22/2021] [Accepted: 12/21/2021] [Indexed: 11/30/2022] Open
Abstract
Background The present study aimed to explore the changes in the expressions of six tumor‐related genes in myeloproliferative neoplasms (MPNs). The study population included 130 patients with MPNs (52 with chronic myeloid leukemia (CML), 49 with essential thrombocythemia (ET), 20 with polycythemia vera (PV), and 9 with primary myelofibrosis (PMF)) and 51 healthy individuals. Methods The expression profiling of six genes (ADAMTS18, CMTM5, CDKN2B, DCC, FHIT, and WNT5B) in the peripheral blood granulocyte cells was explored by real‐time quantitative reverse transcription polymerase chain reaction. Results The patients with MPNs showed significant downregulation of CMTM5 (EFC = 0.66) and DCC (EFC = 0.65) genes in contrast to a non‐significant upregulation of ADAMTS18, CDKN2B, FHIT, and WNT5B genes. Downregulation of DCC was consistent in all subtypes of MPN (EFC range: 0.591–0.860). However, CMTM5 had a 1.22‐fold upregulation in PMF in contrast to downregulation in other MPN subtypes (EFC range: 0.599–0.775). The results revealed a significant downregulation in CMTM5 and DCC at below 60‐years of age. Furthermore, female patients showed a clear‐cut downregulation in both CMTM5 and DCC (EFC DCC: 0.436 and CMTM5: 0.570), while male patients presented a less prominent downregulation with a borderline p‐value only in DCC (EFC: 0.69; p = 0.05). Conclusions Chronic myeloid leukemia cases showed a significant upregulation of WNT5B, as a known oncogenesis gene. Two tumor suppressor genes, namely DCC and CMTM5, were downregulated in the patients with MPNs, especially in females and patients below 60 years of age.
Collapse
Affiliation(s)
- Elham Abedi
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehran Karimi
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ramin Yaghobi
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamid Mohammadi
- Department of Pediatrics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sezaneh Haghpanah
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohamad Moghadam
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elahe Bayat
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Rezvani
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mani Ramzi
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| |
Collapse
|
|
28
|
Jahan S, Mukherjee S, Ali S, Bhardwaj U, Choudhary RK, Balakrishnan S, Naseem A, Mir SA, Banawas S, Alaidarous M, Alyenbaawi H, Iqbal D, Siddiqui AJ. Pioneer Role of Extracellular Vesicles as Modulators of Cancer Initiation in Progression, Drug Therapy, and Vaccine Prospects. Cells 2022; 11:490. [PMID: 35159299 PMCID: PMC8833976 DOI: 10.3390/cells11030490] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/25/2022] [Accepted: 01/28/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer is one of the leading diseases, causing deaths worldwide. Nearly 10 million deaths were reported in 2020 due to cancer alone. Several factors are involved in cancer progressions, such as lifestyle and genetic characteristics. According to a recent report, extracellular vesicles (EVs) are involved in cancer initiation, progression, and therapy failure. EVs can play a major role in intracellular communication, the maintenance of tissue homeostasis, and pathogenesis in several types of diseases. In a healthy person, EVs carry different cargoes, such as miRNA, lncRNA etc., to help other body functions. On the other hand, the same EV in a tumor microenvironment carries cargoes such as miRNA, lncRNA, etc., to initiate or help cancer progression at various stages. These stages may include the proliferation of cells and escape from apoptosis, angiogenesis, cell invasion, and metastasis, reprogramming energy metabolism, evasion of the immune response, and transfer of mutations. Tumor-derived EVs manipulate by altering normal functions of the body and affect the epigenetics of normal cells by limiting the genetic makeup through transferring mutations, histone modifications, etc. Tumor-derived EVs also pose therapy resistance through transferring drug efflux pumps and posing multiple drug resistances. Such EVs can also help as biomarkers for different cancer types and stages, which ultimately help with cancer diagnosis at early stages. In this review, we will shed light on EVs' role in performing normal functions of the body and their position in different hallmarks of cancer, in altering the genetics of a normal cell in a tumor microenvironment, and their role in therapy resistance, as well as the importance of EVs as diagnostic tools.
Collapse
Affiliation(s)
- Sadaf Jahan
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Shouvik Mukherjee
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Shaheen Ali
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Urvashi Bhardwaj
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Ranjay Kumar Choudhary
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Santhanaraj Balakrishnan
- Medical Equipment Technology, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Asma Naseem
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Shabir Ahmad Mir
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Saeed Banawas
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
- Department of Biomedical Sciences, Oregon State University, Corvallis, OR 97331, USA
| | - Mohammed Alaidarous
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Hadeel Alyenbaawi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Danish Iqbal
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Arif Jamal Siddiqui
- Department of Biology, College of Science, University of Hail, Hail 81451, Saudi Arabia
| |
Collapse
|
|
29
|
Izutsu R, Osaki M, Nemoto H, Jingu M, Sasaki R, Yoshioka Y, Ochiya T, Okada F. AMIGO2 contained in cancer cell-derived extracellular vesicles enhances the adhesion of liver endothelial cells to cancer cells. Sci Rep 2022; 12:792. [PMID: 35039535 PMCID: PMC8763894 DOI: 10.1038/s41598-021-04662-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 12/29/2021] [Indexed: 01/02/2023] Open
Abstract
Adhesion of cancer cells to vascular endothelial cells in target organs is an initial step in cancer metastasis. Our previous studies revealed that amphoterin-induced gene and open reading frame 2 (AMIGO2) promotes the adhesion of tumor cells to liver endothelial cells, followed by the formation of liver metastasis in a mouse model. However, the precise mechanism underlying AMIGO2-promoted the adhesion of tumor cells and liver endothelial cells remains unknown. This study was conducted to explore the role of cancer cell-derived AMIGO2-containing extracellular vesicles (EVs) in the adhesion of cancer cells to human hepatic sinusoidal endothelial cells (HHSECs). Western blotting indicated that AMIGO2 was present in EVs from AMIGO2-overexpressing MKN-28 gastric cancer cells. The efficiency of EV incorporation into HHSECs was independent of the AMIGO2 content in EVs. When EV-derived AMIGO2 was internalized in HHSECs, it significantly enhanced the adhesion of HHSECs to gastric (MKN-28 and MKN-74) and colorectal cancer cells (SW480), all of which lacked AMIGO2 expression. Thus, we identified a novel mechanism by which EV-derived AMIGO2 released from AMIGO2-expressing cancer cells stimulates endothelial cell adhesion to different cancer cells for the initiate step of liver metastasis.
Collapse
Affiliation(s)
- Runa Izutsu
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Mitsuhiko Osaki
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan.
- Chromosomal Engineering Research Center, Tottori University, Yonago, Tottori, Japan.
| | - Hideyuki Nemoto
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Maho Jingu
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Ryo Sasaki
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
| | - Yusuke Yoshioka
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
| | - Futoshi Okada
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan
- Chromosomal Engineering Research Center, Tottori University, Yonago, Tottori, Japan
| |
Collapse
|
|
30
|
Eftekhari A, Maleki Dizaj S, Sharifi S, Salatin S, Khalilov R, Samiei M, Zununi Vahed S, Ahmadian E. Salivary biomarkers in cancer. Adv Clin Chem 2022; 110:171-192. [PMID: 36210075 DOI: 10.1016/bs.acc.2022.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
31
|
Soltész B, Buglyó G, Németh N, Szilágyi M, Pös O, Szemes T, Balogh I, Nagy B. The Role of Exosomes in Cancer Progression. Int J Mol Sci 2021; 23:ijms23010008. [PMID: 35008434 PMCID: PMC8744561 DOI: 10.3390/ijms23010008] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/05/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Early detection, characterization and monitoring of cancer are possible by using extracellular vesicles (EVs) isolated from non-invasively obtained liquid biopsy samples. They play a role in intercellular communication contributing to cell growth, differentiation and survival, thereby affecting the formation of tumor microenvironments and causing metastases. EVs were discovered more than seventy years ago. They have been tested recently as tools of drug delivery to treat cancer. Here we give a brief review on extracellular vesicles, exosomes, microvesicles and apoptotic bodies. Exosomes play an important role by carrying extracellular nucleic acids (DNA, RNA) in cell-to-cell communication causing tumor and metastasis development. We discuss the role of extracellular vesicles in the pathogenesis of cancer and their practical application in the early diagnosis, follow up, and next-generation treatment of cancer patients.
Collapse
Affiliation(s)
- Beáta Soltész
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary; (G.B.); (N.N.); (M.S.); (I.B.); (B.N.)
- Correspondence: ; Tel.: +36-52416531
| | - Gergely Buglyó
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary; (G.B.); (N.N.); (M.S.); (I.B.); (B.N.)
| | - Nikolett Németh
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary; (G.B.); (N.N.); (M.S.); (I.B.); (B.N.)
| | - Melinda Szilágyi
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary; (G.B.); (N.N.); (M.S.); (I.B.); (B.N.)
| | - Ondrej Pös
- Geneton Ltd., 841 04 Bratislava, Slovakia; (O.P.); (T.S.)
- Comenius University Science Park, Comenius University, 841 04 Bratislava, Slovakia
| | - Tomas Szemes
- Geneton Ltd., 841 04 Bratislava, Slovakia; (O.P.); (T.S.)
- Comenius University Science Park, Comenius University, 841 04 Bratislava, Slovakia
| | - István Balogh
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary; (G.B.); (N.N.); (M.S.); (I.B.); (B.N.)
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - Bálint Nagy
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary; (G.B.); (N.N.); (M.S.); (I.B.); (B.N.)
| |
Collapse
|
|
32
|
Mammes A, Pasquier J, Mammes O, Conti M, Douard R, Loric S. Extracellular vesicles: General features and usefulness in diagnosis and therapeutic management of colorectal cancer. World J Gastrointest Oncol 2021; 13:1561-1598. [PMID: 34853637 PMCID: PMC8603448 DOI: 10.4251/wjgo.v13.i11.1561] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/29/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
In the world, among all type of cancers, colorectal cancer (CRC) is the third most commonly diagnosed in males and the second in females. In most of cases, (RP1) patients’ prognosis limitation with malignant tumors can be attributed to delayed diagnosis of the disease. Identification of patients with early-stage disease leads to more effective therapeutic interventions. Therefore, new screening methods and further innovative treatment approaches are mandatory as they may lead to an increase in progression-free and overall survival rates. For the last decade, the interest in extracellular vesicles (EVs) research has exponentially increased as EVs generation appears to be a universal feature of every cell that is strongly involved in many mechanisms of cell-cell communication either in physiological or pathological situations. EVs can cargo biomolecules, such as lipids, proteins, nucleic acids and generate transmission signal through the intercellular transfer of their content. By this mechanism, tumor cells can recruit and modify the adjacent and systemic microenvironment to support further invasion and dissemination. This review intends to cover the most recent literature on the role of EVs production in colorectal normal and cancer tissues. Specific attention is paid to the use of EVs for early CRC diagnosis, follow-up, and prognosis as EVs have come into the spotlight of research as a high potential source of ‘liquid biopsies’. The use of EVs as new targets or nanovectors as drug delivery systems for CRC therapy is also summarized.
Collapse
Affiliation(s)
- Aurelien Mammes
- INSERM UMR-938, Cancer Biology and Therapeutics Unit, Saint-Antoine Research Center, Saint Antoine University Hospital, Paris 75012, France
| | - Jennifer Pasquier
- INSERM UMR-938, Cancer Biology and Therapeutics Unit, Saint-Antoine Research Center, Saint Antoine University Hospital, Paris 75012, France
| | | | - Marc Conti
- INSERM UMR-938, Cancer Biology and Therapeutics Unit, Saint-Antoine Research Center, Saint Antoine University Hospital, Paris 75012, France
- Metabolism Research Unit, Integracell SAS, Longjumeau 91160, France
| | - Richard Douard
- UCBM, Necker University Hospital, Paris 75015, France
- Gastrointestinal Surgery Department, Clinique Bizet, Paris 75016, France
| | - Sylvain Loric
- INSERM UMR-938, Cancer Biology and Therapeutics Unit, Saint-Antoine Research Center, Saint Antoine University Hospital, Paris 75012, France
| |
Collapse
|
|
33
|
Gao X, Zhou J, Wang J, Dong X, Chang Y, Jin Y. Mechanism of exosomal miR-155 derived from bone marrow mesenchymal stem cells on stemness maintenance and drug resistance in myeloma cells. J Orthop Surg Res 2021; 16:637. [PMID: 34689803 PMCID: PMC8543846 DOI: 10.1186/s13018-021-02793-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 10/12/2021] [Indexed: 02/04/2023] Open
Abstract
Objective This study was to explore the effect of exosomal miR-155 derived from bone marrow mesenchymal stem cells (BMSCs) on stemness maintenance and drug resistance in MPC-11 multiple myeloma cells. Methods MPC-11 cells were transfected with mimics or inhibitors of miR-155. miR-155 expression was detected by qRT-PCR, cell condition was observed, and the expression of stemness maintenance markers OCT-4 and Nanog was observed by immunofluorescence. The expression of proteins associated with the Hedgehog signaling pathway and drug resistance was evaluated by western blot. To investigate whether exosomes affect cell behavior by horizontal delivery of miR-155, MPC-11 cells were co-cultured with exosomes isolated from BMSCs that were transfected with mimics or inhibitors of miR-155. Cell proliferation and the expression of proteins related to stemness maintenance protein and drug resistance were examined. Results In function assays, after miR-155-mimics transfection, the expression levels of proteins related to stemness maintenance marker, Hedgehog signaling, and drug resistance were increased in MPC-11 cells. BMSC-derived exosomes carrying miR-155 inhibited apoptosis, promoted cell division, and upregulated the expression of protein associated with stemness maintenance, Hedgehog signaling, and drug resistance. Conclusion Therefore, our findings indicate that exosomal delivery of miR-155 exerted the same effect as transfection did on the stemness maintenance and drug resistance of multiple myeloma cells. Supplementary Information The online version contains supplementary material available at 10.1186/s13018-021-02793-9.
Collapse
Affiliation(s)
- Xinyu Gao
- Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.,Department of Hematology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jin Zhou
- Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
| | - Jinghua Wang
- Department of Hematology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Xiushuai Dong
- Department of Hematology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yuying Chang
- Department of Hematology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yinglan Jin
- Department of Hematology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| |
Collapse
|
|
34
|
Perkins RS, Suthon S, Miranda-Carboni GA, Krum SA. WNT5B in cellular signaling pathways. Semin Cell Dev Biol 2021; 125:11-16. [PMID: 34635443 DOI: 10.1016/j.semcdb.2021.09.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 12/31/2022]
Abstract
The Wnt signaling ligand WNT5B is implicated in various developmental pathways, both in normal and pathological physiology. Most of the research on WNT5B has been associated with expression analysis and disease states, leaving the signaling pathways underexplored. Here, we review the current understandings of WNT5B's regulation of signal transduction, from receptors to downstream mediators and transcription factors. We also describe its roles in β-catenin-dependent and β-catenin-independent (Planar Cell Polarity and Wnt/Ca2+) Wnt signaling.
Collapse
Affiliation(s)
- Rachel S Perkins
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Sarocha Suthon
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Gustavo A Miranda-Carboni
- Department of Medicine, Division of Hematology and Oncology, University of Tennessee Health Science Center, Memphis, TN, USA; Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Susan A Krum
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, USA; Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
| |
Collapse
|
|
35
|
Khalid M, Hodjat M, Abdollahi M. Environmental Exposure to Heavy Metals Contributes to Diseases Via Deregulated Wnt Signaling Pathways. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2021; 20:370-382. [PMID: 34567167 PMCID: PMC8457726 DOI: 10.22037/ijpr.2021.114897.15089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Wnt signaling plays a critical role during embryogenesis and is responsible for regulating the homeostasis of the adult stem cells and cells fate via a multitude of signaling pathways and associated transcription factors, receptors, effectors, and inhibitors. For this review, published articles were searched from PubMed Central, Embase, Medline, and Google Scholar. The search terms were Wnt, canonical, noncanonical, signaling pathway, β-catenin, environment, and heavy metals. Published articles on Wnt signaling pathways and heavy metals as contributing factors for causing diseases via influencing Wnt signaling pathways were included. Wnt canonical or noncanonical signaling pathways are the key regulators of stem cell homeostasis that control many mechanisms. There is an adequate balance between β-catenin dependent and independent Wnt signaling pathways and remain highly conserved throughout different development stages. Environmental heavy metal exposure may cause either inhibition or overexpression of any component of Wnt signaling pathways such as Wnt protein, transcription factors, receptors, ligands, or transducers to impede normal cellular function via negatively affecting Wnt signaling pathways. Environmental exposure to heavy metals potentially contributes to diseases via deregulated Wnt signaling pathways.
Collapse
Affiliation(s)
- Madiha Khalid
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mahshid Hodjat
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences (TUMS), Tehran, Iran.,Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences (TUMS), Tehran, Iran.,Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
36
|
Exosomes as A Next-Generation Diagnostic and Therapeutic Tool in Prostate Cancer. Int J Mol Sci 2021; 22:ijms221810131. [PMID: 34576294 PMCID: PMC8465219 DOI: 10.3390/ijms221810131] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/15/2021] [Accepted: 09/16/2021] [Indexed: 12/03/2022] Open
Abstract
Extracellular vesicles (EVs) have brought great momentum to the non-invasive liquid biopsy procedure for the detection, characterization, and monitoring of cancer. Despite the common use of PSA (prostate-specific antigen) as a biomarker for prostate cancer, there is an unmet need for a more specific diagnostic tool to detect tumor progression and recurrence. Exosomes, which are EVs that are released from all cells, play a large role in physiology and pathology, including cancer. They are involved in intercellular communication, immune function, and they are present in every bodily fluid studied—making them an excellent window into how cells are operating. With liquid biopsy, EVs can be isolated and analyzed, enabling an insight into a potential therapeutic value, serving as a vehicle for drugs or nucleic acids that have anti-neoplastic effects. The current application of advanced technology also points to higher-sensitivity detection methods that are minimally invasive. In this review, we discuss the current understanding of the significance of exosomes in prostate cancer and the potential diagnostic value of these EVs in disease progression.
Collapse
|
|
37
|
Master Regulators of Epithelial-Mesenchymal Transition and WNT Signaling Pathways in Juvenile Nasopharyngeal Angiofibromas. Biomedicines 2021; 9:biomedicines9091258. [PMID: 34572445 PMCID: PMC8469518 DOI: 10.3390/biomedicines9091258] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/31/2021] [Accepted: 09/06/2021] [Indexed: 02/08/2023] Open
Abstract
Juvenile nasopharyngeal angiofibroma (JNA) is a rare fibrovascular benign tumor showing an invasive growth pattern and affecting mainly male adolescents. We investigated the role of epithelial–mesenchymal transition (EMT) and WNT signaling pathways in JNA. Gene expression profiles using nine JNA paired with four inferior nasal turbinate samples were interrogated using a customized 2.3K microarray platform containing genes mainly involved in EMT and WNT/PI3K pathways. The expression of selected genes (BCL2, CAV1, CD74, COL4A2, FZD7, ING1, LAMB1, and RAC2) and proteins (BCL2, CAV1, CD74, FZD7, RAF1, WNT5A, and WNT5B) was investigated by RT-qPCR (28 cases) and immunohistochemistry (40 cases), respectively. Among 104 differentially expressed genes, we found a significantly increased expression of COL4A2 and LAMB1 and a decreased expression of BCL2 and RAC2 by RT-qPCR. The immunohistochemistry analysis revealed a low expression of BCL2 and a negative to moderate expression of FZD7 in most samples, while increased CAV1 and RAF1 expression were detected. Moderate to strong CD74 protein expression was observed in endothelial and inflammatory cells. A significant number of JNAs (78%) presented reduced WNT5A and increased WNT5B expression. Overall, the transcript and protein profile indicated the involvement of EMT and WNT pathways in JNA. These candidates are promising druggable targets for treating JNA.
Collapse
|
|
38
|
Jiang C, Zhang N, Hu X, Wang H. Tumor-associated exosomes promote lung cancer metastasis through multiple mechanisms. Mol Cancer 2021; 20:117. [PMID: 34511114 PMCID: PMC8436438 DOI: 10.1186/s12943-021-01411-w] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 08/19/2021] [Indexed: 02/06/2023] Open
Abstract
As an important medium of intercellular communication, exosomes play an important role in information transmission between tumor cells and their microenvironment. Tumor metastasis is a serious influencing factor for poor treatment effect and shortened survival. Lung cancer is a major malignant tumor that seriously threatens human health. The study of the underlying mechanisms of exosomes in tumor genesis and development may provide new ideas for early and effective diagnosis and treatment of lung cancer metastasis. Many studies have shown that tumor-derived exosomes promote lung cancer development through a number of processes. By promoting epithelial-mesenchymal transition of tumor cells, they induce angiogenesis, establishment of the pretransfer microenvironment, and immune escape. This understanding enables researchers to better understand the mechanism of lung cancer metastasis and explore new treatments for clinical application. In this article, we systematically review current research progress of tumor-derived exosomes in metastasis of lung cancer. Although positive progress has been made toward understanding the mechanism of exosomes in lung cancer metastasis, systematic basic research and clinical translational research remains lacking and are needed to translate our scientific understanding toward applications in the clinical diagnosis and treatment of lung cancer metastasis in the near future.
Collapse
Affiliation(s)
- Chunyang Jiang
- Department of Thoracic Surgery, Tianjin Union Medical Center, Nankai University, 190 Jieyuan Road, Hongqiao District, Tianjin, 300121, China.
| | - Na Zhang
- Department of Respiratory Medicine, Tianjin Union Medical Center, Nankai University, 190 Jieyuan Road, Hongqiao District, Tianjin, 300121, China
| | - Xiaoli Hu
- Department of Respiratory Medicine, The Second People's Hospital of Linhai City, 198 Dubei Road, Linhai, 317016, Zhejiang Province, China
| | - Hongyan Wang
- Department of Thoracic Surgery, The 4th Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, Hebei Province, China.
| |
Collapse
|
|
39
|
Exosomes: Emerging Therapy Delivery Tools and Biomarkers for Kidney Diseases. Stem Cells Int 2021; 2021:7844455. [PMID: 34471412 PMCID: PMC8405320 DOI: 10.1155/2021/7844455] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/25/2021] [Accepted: 08/01/2021] [Indexed: 02/06/2023] Open
Abstract
Exosomes are nanometer-sized small EVs coated with bilayer structure, which are released by prokaryotic and eukaryotic cells. Exosomes are rich in a variety of biologically active substances, such as proteins, nucleotides, and lipids. Exosomes are widely present in various body fluids and cell culture supernatants, and it mediates the physiological and pathological processes of the body through the shuttle of these active ingredients to target cells. In recent years, studies have shown that exosomes from a variety of cell sources can play a beneficial role in acute and chronic kidney disease. In particular, exosomes derived from mesenchymal stem cells have significant curative effects on the prevention and treatment of kidney disease in preclinical trials. Besides, some encapsulated substances are demonstrated to exert beneficial effects on various diseases, so they have attracted much attention. In addition, exosomes have extensive sources, stable biological activity, and good biocompatibility and are easy to store and transport; these advantages endow exosomes with superior diagnostic value. With the rapid development of liquid biopsy technology related to exosomes, the application of exosomes in the rapid diagnosis of kidney disease has become more prominent. In this review, the latest development of exosomes, including the biosynthesis process, the isolation and identification methods of exosomes are systematically summarized. The utilization of exosomes in diagnosis and their positive effects in the repair of kidney dysfunction are discussed, along with the specific mechanisms. This review is expected to be helpful for relevant studies and to provide insight into future applications in clinical practice.
Collapse
|
|
40
|
Catoni C, Di Paolo V, Rossi E, Quintieri L, Zamarchi R. Cell-Secreted Vesicles: Novel Opportunities in Cancer Diagnosis, Monitoring and Treatment. Diagnostics (Basel) 2021; 11:1118. [PMID: 34205256 PMCID: PMC8233857 DOI: 10.3390/diagnostics11061118] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/12/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) are important mediators of intercellular communication playing a pivotal role in the regulation of physiological and pathological processes, including cancer. In particular, there is significant evidence suggesting that tumor-derived EVs exert an immunosuppressive activity during cancer progression, as well as stimulate tumor cell migration, angiogenesis, invasion and metastasis. The use of EVs as a liquid biopsy is currently a fast-growing area of research in medicine, with the potential to provide a step-change in the diagnosis and treatment of cancer, allowing the prediction of both therapy response and prognosis. EVs could be useful not only as biomarkers but also as drug delivery systems, and may represent a target for anticancer therapy. In this review, we attempted to summarize the current knowledge about the techniques used for the isolation of EVs and their roles in cancer biology, as liquid biopsy biomarkers and as therapeutic tools and targets.
Collapse
Affiliation(s)
- Cristina Catoni
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; (C.C.); (R.Z.)
| | - Veronica Di Paolo
- Laboratory of Drug Metabolism, Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy;
| | - Elisabetta Rossi
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; (C.C.); (R.Z.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Luigi Quintieri
- Laboratory of Drug Metabolism, Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy;
| | - Rita Zamarchi
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; (C.C.); (R.Z.)
| |
Collapse
|
|
41
|
Hosseini R, Asef-Kabiri L, Yousefi H, Sarvnaz H, Salehi M, Akbari ME, Eskandari N. The roles of tumor-derived exosomes in altered differentiation, maturation and function of dendritic cells. Mol Cancer 2021; 20:83. [PMID: 34078376 PMCID: PMC8170799 DOI: 10.1186/s12943-021-01376-w] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
Tumor-derived exosomes (TDEs) have been shown to impede anti-tumor immune responses via their immunosuppressive cargo. Since dendritic cells (DCs) are the key mediators of priming and maintenance of T cell-mediated responses; thus it is logical that the exosomes released by tumor cells can exert a dominant influence on DCs biology. This paper intends to provide a mechanistic insight into the TDEs-mediated DCs abnormalities in the tumor context. More importantly, we discuss extensively how tumor exosomes induce subversion of DCs differentiation, maturation and function in separate sections. We also briefly describe the importance of TDEs at therapeutic level to help guide future treatment options, in particular DC-based vaccination strategy, and review advances in the design and discovery of exosome inhibitors. Understanding the exosomal content and the pathways by which TDEs are responsible for immune evasion may help to revise treatment rationales and devise novel therapeutic approaches to overcome the hurdles in cancer treatment.
Collapse
Affiliation(s)
- Reza Hosseini
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Leila Asef-Kabiri
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Yousefi
- Department of Biochemistry and Molecular Biology, LSUHSC School of Medicine, New Orleans, USA
| | - Hamzeh Sarvnaz
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Majid Salehi
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | | | - Nahid Eskandari
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
| |
Collapse
|
|
42
|
Paclíková P, Radaszkiewicz TW, Potěšil D, Harnoš J, Zdráhal Z, Bryja V. Roles of individual human Dishevelled paralogs in the Wnt signalling pathways. Cell Signal 2021; 85:110058. [PMID: 34082011 DOI: 10.1016/j.cellsig.2021.110058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/26/2021] [Accepted: 05/27/2021] [Indexed: 12/21/2022]
Abstract
Dishevelled (DVL) proteins are key mediators of most Wnt pathways. In all vertebrates, three DVL paralogs are present (DVL1, DVL2 and DVL3) but it is poorly defined to what extent they are functionally redundant. Here, we generated T-REx HEK 293 cells with only one DVL paralog (i.e., DVL1-only, DVL2-only, and DVL3-only) and compared their response to Wnt-3a and Wnt-5a ligands with wild type and DVL triple knockout cells. We show that DVL is essential, in addition to the previously shown Wnt-3a-induced phosphorylation of LRP6 and transcriptional activation of TCF/LEF-dependent reporter, also for Wnt-3a-induced degradation of AXIN1 and Wnt-5a-induced phosphorylation of ROR1. We have quantified the molar ratios of DVL1:DVL2:DVL3 in our model to be approximately 4:80:16. Interestingly, DVL-only cells do not compensate for the lack of other paralogs and are still fully functional in all analyzed readouts with the exception of Wnt-3a-induced transcription assessed by TopFlash assay. In this assay, the DVL1-only cell line was the most potent; on the contrary, the DVL3-only cell line exhibited only the negligible capacity to mediate Wnt signals. Using a novel model system - complementation assays in T-REx HEK 293 with amplified Wnt signal response (RNF43/ZNRF3/DVL1/DVL2/DVL3 penta KO cells) we demonstrate that it is not the total amount of DVL but ratio of individual paralogs what decides the signal strength. In sum, this study contributes to our better understanding of the role of individual human DVL paralogs in the Wnt pathway.
Collapse
Affiliation(s)
- Petra Paclíková
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | | | - David Potěšil
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Jakub Harnoš
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Zbyněk Zdráhal
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Vítězslav Bryja
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; Institute of Biophysics, Academy of Sciences of Czech Republic, Brno, Czech Republic.
| |
Collapse
|
|
43
|
Suthon S, Perkins RS, Bryja V, Miranda-Carboni GA, Krum SA. WNT5B in Physiology and Disease. Front Cell Dev Biol 2021; 9:667581. [PMID: 34017835 PMCID: PMC8129536 DOI: 10.3389/fcell.2021.667581] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 04/09/2021] [Indexed: 12/20/2022] Open
Abstract
WNT5B, a member of the WNT family of proteins that is closely related to WNT5A, is required for cell migration, cell proliferation, or cell differentiation in many cell types. WNT5B signals through the non-canonical β-catenin-independent signaling pathway and often functions as an antagonist of canonical WNT signaling. Although WNT5B has a high amino acid identity with WNT5A and is often assumed to have similar activities, WNT5B often exhibits unique expression patterns and functions. Here, we describe the distinct effects and mechanisms of WNT5B on development, bone, adipose tissue, cardiac tissue, the nervous system, the mammary gland, the lung and hematopoietic cells, compared to WNT5A. We also highlight aberrances in non-canonical WNT5B signaling contributing to diseases such as osteoarthritis, osteoporosis, obesity, type 2 diabetes mellitus, neuropathology, and chronic diseases associated with aging, as well as various cancers.
Collapse
Affiliation(s)
- Sarocha Suthon
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Rachel S Perkins
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Vitezslav Bryja
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia
- Department of Cytokinetics, Institute of Biophysics, Czech Academy of Sciences, Brno, Czechia
| | - Gustavo A Miranda-Carboni
- Division of Hematology and Oncology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
- Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Susan A Krum
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, United States
- Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, United States
| |
Collapse
|
|
44
|
Smolarz M, Widlak P. Serum Exosomes and Their miRNA Load-A Potential Biomarker of Lung Cancer. Cancers (Basel) 2021; 13:cancers13061373. [PMID: 33803617 PMCID: PMC8002857 DOI: 10.3390/cancers13061373] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/14/2021] [Accepted: 03/15/2021] [Indexed: 12/19/2022] Open
Abstract
Early detection of lung cancer in screening programs is a rational way to reduce mortality associated with this malignancy. Low-dose computed tomography, a diagnostic tool used in lung cancer screening, generates a relatively large number of false-positive results, and its complementation with molecular biomarkers would greatly improve the effectiveness of such programs. Several biomarkers of lung cancer based on different components of blood, including miRNA signatures, were proposed. However, only a few of them have been positively validated in the context of early cancer detection yet, which imposes a constant need for new biomarker candidates. An emerging source of cancer biomarkers are exosomes and other types of extracellular vesicles circulating in body fluids. Hence, different molecular components of serum/plasma-derived exosomes were tested and showed different levels in lung cancer patients and healthy individuals. Several studies focused on the miRNA component of these vesicles. Proposed signatures of exosome miRNA had promising diagnostic value, though none of them have yet been clinically validated. These signatures involved a few dozen miRNA species overall, including a few species that recurred in different signatures. It is worth noting that all these miRNA species have cancer-related functions and have been associated with lung cancer progression. Moreover, a few of them, including known oncomirs miR-17, miR-19, miR-21, and miR-221, appeared in multiple miRNA signatures of lung cancer based on both the whole serum/plasma and serum/plasma-derived exosomes.
Collapse
|
|
45
|
Fu D, Liu B, Jiang H, Li Z, Fan C, Zang L. Bone marrow mesenchymal stem cells-derived exosomal microRNA-19b-1-5p reduces proliferation and raises apoptosis of bladder cancer cells via targeting ABL2. Genomics 2021; 113:1338-1348. [PMID: 33722655 DOI: 10.1016/j.ygeno.2021.03.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 02/06/2021] [Accepted: 03/05/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Exosomes are involved in intercellular communication via specialized molecular cargo, such as microRNAs (miRNAs). However, the mechanisms underlying exosomal miR-19b-1-5p in bladder cancer remain largely unknown, thus, we aim to investigate the effect of exosomal miR-19b-1-5p on bladder cancer with the involvement of non-receptor protein tyrosine kinase Arg (ABL2). METHODS miR-19b-1-5p and ABL2 expression were tested in bladder cancer. miR-19b-1-5p inhibition/elevation assays were conducted to determine its role in bladder cancer. Exosomes were extracted from bone marrow mesenchymal stem cells (BMSCs). Exosomes and T24 cells were co-cultured to verify their function in biological characteristics of bladder cancer cells. RESULTS miR-19b-1-5p was down-regulated while ABL2 was upregulated in bladder cancer. Exosomal miR-19b-1-5p suppressed malignant behaviors of bladder cancer cells, and also inhibited tumor growth in vivo. Up-regulated ABL2 mitigated the effects of miR-19b-1-5p up-regulation on bladder cancer cells. CONCLUSION BMSCs-derived exosomal miR-19b-1-5p suppresses bladder cancer growth via decreasing ABL2.
Collapse
Affiliation(s)
- Dewang Fu
- The Department of Urology Sugery, The First Affiliate Hospital of Jinzhou Medical University, Jinzhou 121000, Liaoning, China
| | - Ben Liu
- The Department of Urology Sugery, The First Affiliate Hospital of Jinzhou Medical University, Jinzhou 121000, Liaoning, China
| | - Huamao Jiang
- The Department of Urology Sugery, The First Affiliate Hospital of Jinzhou Medical University, Jinzhou 121000, Liaoning, China
| | - Zhaowei Li
- The Department of Urology Sugery, The First Affiliate Hospital of Jinzhou Medical University, Jinzhou 121000, Liaoning, China
| | - Chenghui Fan
- The Department of Urology Sugery, The First Affiliate Hospital of Jinzhou Medical University, Jinzhou 121000, Liaoning, China
| | - Li'e Zang
- The Department of Neurology, The First Affiliate Hospital of Jinzhou Medical University, Jinzhou 121000, Liaoning, China.
| |
Collapse
|
|
46
|
Diaz-Garrido N, Cordero C, Olivo-Martinez Y, Badia J, Baldomà L. Cell-to-Cell Communication by Host-Released Extracellular Vesicles in the Gut: Implications in Health and Disease. Int J Mol Sci 2021; 22:ijms22042213. [PMID: 33672304 PMCID: PMC7927122 DOI: 10.3390/ijms22042213] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/17/2021] [Accepted: 02/19/2021] [Indexed: 12/12/2022] Open
Abstract
Communication between cells is crucial to preserve body homeostasis and health. Tightly controlled intercellular dialog is particularly relevant in the gut, where cells of the intestinal mucosa are constantly exposed to millions of microbes that have great impact on intestinal homeostasis by controlling barrier and immune functions. Recent knowledge involves extracellular vesicles (EVs) as mediators of such communication by transferring messenger bioactive molecules including proteins, lipids, and miRNAs between cells and tissues. The specific functions of EVs principally depend on the internal cargo, which upon delivery to target cells trigger signal events that modulate cellular functions. The vesicular cargo is greatly influenced by genetic, pathological, and environmental factors. This finding provides the basis for investigating potential clinical applications of EVs as therapeutic targets or diagnostic biomarkers. Here, we review current knowledge on the biogenesis and cargo composition of EVs in general terms. We then focus the attention to EVs released by cells of the intestinal mucosa and their impact on intestinal homeostasis in health and disease. We specifically highlight their role on epithelial barrier integrity, wound healing of epithelial cells, immunity, and microbiota shaping. Microbiota-derived EVs are not reviewed here.
Collapse
Affiliation(s)
- Natalia Diaz-Garrido
- Secció de Bioquímica i Biología Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (N.D.-G.); (C.C.); (Y.O.-M.); (J.B.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
| | - Cecilia Cordero
- Secció de Bioquímica i Biología Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (N.D.-G.); (C.C.); (Y.O.-M.); (J.B.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
| | - Yenifer Olivo-Martinez
- Secció de Bioquímica i Biología Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (N.D.-G.); (C.C.); (Y.O.-M.); (J.B.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
| | - Josefa Badia
- Secció de Bioquímica i Biología Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (N.D.-G.); (C.C.); (Y.O.-M.); (J.B.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
| | - Laura Baldomà
- Secció de Bioquímica i Biología Molecular, Departament de Bioquímica i Fisiologia, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain; (N.D.-G.); (C.C.); (Y.O.-M.); (J.B.)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Barcelona, Spain
- Correspondence: ; Tel.: +34-93-403-44-96
| |
Collapse
|
|
47
|
Ramai D, Tai W, Rivera M, Facciorusso A, Tartaglia N, Pacilli M, Ambrosi A, Cotsoglou C, Sacco R. Natural Progression of Non-Alcoholic Steatohepatitis to Hepatocellular Carcinoma. Biomedicines 2021; 9:biomedicines9020184. [PMID: 33673113 PMCID: PMC7918599 DOI: 10.3390/biomedicines9020184] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 02/01/2021] [Accepted: 02/09/2021] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a chronic and progressive form of non-alcoholic fatty liver disease (NAFLD). Its global incidence is increasing which makes NASH an epidemic and a public health threat. Due to repeated insults to the liver, patients are at risk for developing hepatocellular carcinoma (HCC). The progression of NASH to HCC was initially defined according to a two-hit model which involved the development of steatosis, followed by lipid peroxidation and inflammation. However, current research defines a “multi-hit” or “multi-parallel hit” model which synthesizes several contributing pathways involved in progressive fibrosis and oncogenesis. This perspective considers the effects of cellular, genetic, immunologic, metabolic, and endocrine pathways leading up to HCC which underscores the complexity of this condition. This article will provide an updated review of the pathogenic mechanisms leading from NASH to HCC as well as an exploration of the role of biomarkers and screening.
Collapse
Affiliation(s)
- Daryl Ramai
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, NY 11201, USA; (D.R.); (W.T.); (M.R.)
| | - Waqqas Tai
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, NY 11201, USA; (D.R.); (W.T.); (M.R.)
| | - Michelle Rivera
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, NY 11201, USA; (D.R.); (W.T.); (M.R.)
| | - Antonio Facciorusso
- Section of Gastroenterology, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
| | - Nicola Tartaglia
- General Surgery Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (N.T.); (M.P.); (A.A.)
| | - Mario Pacilli
- General Surgery Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (N.T.); (M.P.); (A.A.)
| | - Antonio Ambrosi
- General Surgery Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (N.T.); (M.P.); (A.A.)
| | - Christian Cotsoglou
- General Surgey Unit, Department of Surgery, ASST-Vimercate, 20871 Vimercate, Italy;
| | - Rodolfo Sacco
- Section of Gastroenterology, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
- Correspondence:
| |
Collapse
|
|
48
|
Sinha D, Roy S, Saha P, Chatterjee N, Bishayee A. Trends in Research on Exosomes in Cancer Progression and Anticancer Therapy. Cancers (Basel) 2021; 13:cancers13020326. [PMID: 33477340 PMCID: PMC7829710 DOI: 10.3390/cancers13020326] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/09/2021] [Accepted: 01/14/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Intensive research in the field of cancer biology has discovered a unique mode of interplay between cells via extracellular bioactive vesicles called exosomes. Exosomes serve as intermediators among cells via their cargoes that, in turn, contribute in the progression of cancer. They are ubiquitously present in all body fluids as they are secreted from both normal and tumor cells. These minuscules exhibit multiple unique properties that facilitate their migration to distant locations and modulate the microenvironment for progression of cancer. This review summarizes the multifarious role of exosomes in various aspects of cancer research with its pros and cons. It discusses biogenesis of exosomes, their functional role in cancer metastasis, both protumorigenic and antitumorigenic, and also their applications in anticancer therapy. Abstract Exosomes, the endosome-derived bilayered extracellular nanovesicles with their contribution in many aspects of cancer biology, have become one of the prime foci of research. Exosomes derived from various cells carry cargoes similar to their originator cells and their mode of generation is different compared to other extracellular vesicles. This review has tried to cover all aspects of exosome biogenesis, including cargo, Rab-dependent and Rab-independent secretion of endosomes and exosomal internalization. The bioactive molecules of the tumor-derived exosomes, by virtue of their ubiquitous presence and small size, can migrate to distal parts and propagate oncogenic signaling and epigenetic regulation, modulate tumor microenvironment and facilitate immune escape, tumor progression and drug resistance responsible for cancer progression. Strategies improvised against tumor-derived exosomes include suppression of exosome uptake, modulation of exosomal cargo and removal of exosomes. Apart from the protumorigenic role, exosomal cargoes have been selectively manipulated for diagnosis, immune therapy, vaccine development, RNA therapy, stem cell therapy, drug delivery and reversal of chemoresistance against cancer. However, several challenges, including in-depth knowledge of exosome biogenesis and protein sorting, perfect and pure isolation of exosomes, large-scale production, better loading efficiency, and targeted delivery of exosomes, have to be confronted before the successful implementation of exosomes becomes possible for the diagnosis and therapy of cancer.
Collapse
Affiliation(s)
- Dona Sinha
- Department of Receptor Biology and Tumour Metastasis, Chittaranjan National Cancer Institute, Kolkata 700 026, India; (S.R.); (P.S.); (N.C.)
- Correspondence: or (D.S.); or (A.B.)
| | - Sraddhya Roy
- Department of Receptor Biology and Tumour Metastasis, Chittaranjan National Cancer Institute, Kolkata 700 026, India; (S.R.); (P.S.); (N.C.)
| | - Priyanka Saha
- Department of Receptor Biology and Tumour Metastasis, Chittaranjan National Cancer Institute, Kolkata 700 026, India; (S.R.); (P.S.); (N.C.)
| | - Nabanita Chatterjee
- Department of Receptor Biology and Tumour Metastasis, Chittaranjan National Cancer Institute, Kolkata 700 026, India; (S.R.); (P.S.); (N.C.)
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
- Correspondence: or (D.S.); or (A.B.)
| |
Collapse
|
|
49
|
Zheng D, Huo M, Li B, Wang W, Piao H, Wang Y, Zhu Z, Li D, Wang T, Liu K. The Role of Exosomes and Exosomal MicroRNA in Cardiovascular Disease. Front Cell Dev Biol 2021; 8:616161. [PMID: 33511124 PMCID: PMC7835482 DOI: 10.3389/fcell.2020.616161] [Citation(s) in RCA: 123] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 12/17/2020] [Indexed: 12/12/2022] Open
Abstract
Exosomes are small vesicles (30–150 nm in diameter) enclosed by a lipid membrane bilayer, secreted by most cells in the body. They carry various molecules, including proteins, lipids, mRNA, and other RNA species, such as long non-coding RNA, circular RNA, and microRNA (miRNA). miRNAs are the most numerous cargo molecules in the exosome. They are endogenous non-coding RNA molecules, approximately 19–22-nt-long, and important regulators of protein biosynthesis. Exosomes can be taken up by neighboring or distant cells, where they play a role in post-transcriptional regulation of gene expression by targeting mRNA. Exosomal miRNAs have diverse functions, such as participation in inflammatory reactions, cell migration, proliferation, apoptosis, autophagy, and epithelial–mesenchymal transition. There is increasing evidence that exosomal miRNAs play an important role in cardiovascular health. Exosomal miRNAs are widely involved in the occurrence and development of cardiovascular diseases, such as atherosclerosis, acute coronary syndrome, heart failure (HF), myocardial ischemia reperfusion injury, and pulmonary hypertension. In this review, we present a systematic overview of the research progress into the role of exosomal miRNAs in cardiovascular diseases, and present new ideas for the diagnosis and treatment of cardiovascular diseases.
Collapse
Affiliation(s)
- Dongdong Zheng
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Ming Huo
- Department of Day Operating Room, The Second Hospital of Jilin University, Changchun, China
| | - Bo Li
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Weitie Wang
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Hulin Piao
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Yong Wang
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Zhicheng Zhu
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Dan Li
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Tiance Wang
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Kexiang Liu
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
50
|
Schubert A, Boutros M. Extracellular vesicles and oncogenic signaling. Mol Oncol 2021; 15:3-26. [PMID: 33207034 PMCID: PMC7782092 DOI: 10.1002/1878-0261.12855] [Citation(s) in RCA: 21] [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: 08/19/2020] [Revised: 10/17/2020] [Accepted: 10/30/2020] [Indexed: 12/19/2022] Open
Abstract
In recent years, extracellular vesicles (EVs) emerged as potential diagnostic and prognostic markers for cancer therapy. While the field of EV research is rapidly developing and their application as vehicles for therapeutic cargo is being tested, little is still known about the exact mechanisms of signaling specificity and cargo transfer by EVs, especially in vivo. Several signaling cascades have been found to use EVs for signaling in the tumor-stroma interaction. These include potentially oncogenic, verbatim transforming, signaling cascades such as Wnt and TGF-β signaling, and other signaling cascades that have been tightly associated with tumor progression and metastasis, such as PD-L1 and VEGF signaling. Multiple mechanisms of how these signaling cascades and EVs interplay to mediate these complex processes have been described, such as direct signal activation through pathway components on or in EVs or indirectly by influencing vesicle biogenesis, cargo sorting, or uptake dynamics. In this review, we summarize the current knowledge of EVs, their biogenesis, and our understanding of EV interactions with recipient cells with a focus on selected oncogenic and cancer-associated signaling pathways. After an in-depth look at how EVs mediate and influence signaling, we discuss potentially translatable EV functions and existing knowledge gaps.
Collapse
Affiliation(s)
- Antonia Schubert
- Division Signaling and Functional GenomicsGerman Cancer Research Center (DKFZ) and Heidelberg UniversityGermany
- Clinic for Hematology and Medical OncologyUniversity Medical Center GöttingenGermany
| | - Michael Boutros
- Division Signaling and Functional GenomicsGerman Cancer Research Center (DKFZ) and Heidelberg UniversityGermany
| |
Collapse
|