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Shuman JHB, Lin AS, Westland MD, Bryant KN, Fortier GE, Piazuelo MB, Reyzer ML, Judd AM, Tsui T, McDonald WH, McClain MS, Schey KL, Algood HM, Cover TL. Helicobacter pylori CagA and Cag type IV secretion system activity have key roles in triggering gastric transcriptional and proteomic alterations. Infect Immun 2025; 93:e0059524. [PMID: 40047510 PMCID: PMC11977315 DOI: 10.1128/iai.00595-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 01/24/2025] [Indexed: 04/09/2025] Open
Abstract
Colonization of the human stomach with cag pathogenicity island (PAI)-positive Helicobacter pylori strains is associated with increased gastric cancer risk compared to colonization with cag PAI-negative strains. To evaluate the contributions of the Cag type IV secretion system (T4SS) and CagA (a secreted bacterial oncoprotein) to gastric molecular alterations relevant for carcinogenesis, we infected Mongolian gerbils with a Cag T4SS-positive wild-type (WT) H. pylori strain, one of two Cag T4SS mutant strains (∆cagT or ∆cagY), or a ∆cagA mutant for 12 weeks. Histologic staining revealed a biphasic distribution of gastric inflammation severity in WT-infected animals and minimal inflammation in animals infected with mutant strains. Atrophic gastritis (a premalignant condition), dysplasia, and gastric adenocarcinoma were only detected in WT-infected animals with high inflammation scores. Transcriptional profiling, liquid chromatography-tandem mass spectrometry analysis of micro-extracted tryptic peptides, and imaging mass spectrometry revealed more than a thousand molecular alterations in gastric tissues from WT-infected animals with high inflammation scores compared to uninfected tissues and few alterations in tissues from other groups of infected animals. Proteins with altered abundance in animals with severe Cag T4SS-induced inflammation mapped to multiple pathways, including the complement/coagulation cascade and proteasome pathway. Proteins exhibiting markedly increased abundance in tissues from H. pylori-infected animals with severe inflammation included calprotectin components, proteins involved in proteasome activation, polymeric immunoglobulin receptor (PIGR), interferon-inducible guanylate-binding protein (GBP2), lactoferrin, lysozyme, superoxide dismutase, and eosinophil peroxidase. These results demonstrate key roles for CagA and Cag T4SS activity in promoting gastric mucosal inflammation, transcriptional alterations, and proteomic alterations relevant to gastric carcinogenesis.IMPORTANCEHelicobacter pylori colonizes the stomachs of about half of humans worldwide, and its presence is the primary risk factor for the development of stomach cancer. H. pylori strains isolated from humans can be broadly classified into two groups based on whether they contain a chromosomal cag pathogenicity island, which encodes a secreted effector protein (CagA) and components of a type IV secretion system (T4SS). In experiments using a Mongolian gerbil model, we found that severe gastric inflammation and gastric transcriptional and proteomic alterations related to gastric cancer development were detected only in animals infected with a wild-type H. pylori strain containing CagA and an intact Cag T4SS. Mutant strains lacking CagA or Cag T4SS activity successfully colonized the stomach without inducing detectable pathologic host responses. These findings illustrate two different patterns of H. pylori-host interaction.
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Affiliation(s)
- Jennifer H. B. Shuman
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Aung Soe Lin
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Mandy D. Westland
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kaeli N. Bryant
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Gabrielle E. Fortier
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M. Blanca Piazuelo
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Michelle L. Reyzer
- Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Audra M. Judd
- Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Tina Tsui
- Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - W. Hayes McDonald
- Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Mark S. McClain
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kevin L. Schey
- Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Holly M. Algood
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| | - Timothy L. Cover
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
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Almutairy B, Alzahrani MS, Waggas DS, Alsaab HO. Particular exosomal micro-RNAs and gastrointestinal (GI) cancer cells' roles: Current theories. Exp Cell Res 2024; 442:114278. [PMID: 39383930 DOI: 10.1016/j.yexcr.2024.114278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/24/2024] [Accepted: 10/06/2024] [Indexed: 10/11/2024]
Abstract
A diverse range of gastrointestinal tract disorders are called gastrointestinal (GI) malignancies. The transformation of normal cells into precursor cells, precursor cells into premalignant cells, and premalignant cells into cancerous cells is facilitated by the interaction of many modifiable and non-modifiable risk factors. Developing relevant therapy alternatives based on a better knowledge of the illness's aetiology is essential to enhance patient outcomes. The exosome is crucial in regulating intercellular interaction because it may send molecular signals to nearby or distant cells. Exosomes produced from cancer can introduce a variety of chemicals and vast concentrations of microRNA (miRNA) into the tumour microenvironment. These miRNAs significantly impact immunological evasion, metastasis, apoptosis resistance, and cell growth. Exosomal miRNAs, or exosomal miRNAs, are essential for controlling cancer resistance to apoptosis, according to mounting data. Exosomal miRNAs function as an interaction hub between cancerous cells and the milieu around them, regulating gene expression and various signalling pathways. Our research examines the regulatory function of exosomal miRNAs in mediating interactions between cancer cells and the stromal and immunological cells that make up the surrounding milieu.
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Affiliation(s)
- Bandar Almutairy
- Department of Pharmacology, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia.
| | - Mohammad S Alzahrani
- Department of Clinical Pharmacy, College of Pharmacy, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia.
| | - Dania S Waggas
- Pathological Sciences Department, Fakeeh College for Medical Sciences, Jeddah University, Saudi Arabia.
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
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3
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Liao H, Zhang C, Wang F, Jin F, Zhao Q, Wang X, Wang S, Gao J. Tumor-derived extracellular vesicle proteins as new biomarkers and targets in precision oncology. J Mol Med (Berl) 2024; 102:961-971. [PMID: 38814362 PMCID: PMC11269371 DOI: 10.1007/s00109-024-02452-6] [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: 11/15/2023] [Revised: 04/09/2024] [Accepted: 04/25/2024] [Indexed: 05/31/2024]
Abstract
Extracellular vesicles (EVs) are important carriers of signaling molecules, such as nucleic acids, proteins, and lipids, and have become a focus of increasing interest due to their numerous physiological and pathological functions. For a long time, most studies on EV components focused on noncoding RNAs; however, in recent years, extracellular vesicle proteins (EVPs) have been found to play important roles in diagnosis, treatment, and drug resistance and thus have been considered favorable biomarkers and therapeutic targets for various tumors. In this review, we describe the general protocols of research on EVPs and summarize their multifaceted roles in precision medicine applications, including cancer diagnosis, dynamic monitoring of therapeutic efficacy, drug resistance research, tumor microenvironment interaction research, and anticancer drug delivery.
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Affiliation(s)
- Haiyan Liao
- Department of Oncology, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Cheng Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Fen Wang
- Department of Oncology, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Feng Jin
- Department of Oncology, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Qiqi Zhao
- Chi Biotech Co., Ltd., Shenzhen, China
| | | | - Shubin Wang
- Department of Oncology, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, China.
| | - Jing Gao
- Department of Oncology, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, China.
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4
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Liu M, Wen Z, Zhang T, Zhang L, Liu X, Wang M. The role of exosomal molecular cargo in exosome biogenesis and disease diagnosis. Front Immunol 2024; 15:1417758. [PMID: 38983854 PMCID: PMC11231912 DOI: 10.3389/fimmu.2024.1417758] [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: 04/15/2024] [Accepted: 06/12/2024] [Indexed: 07/11/2024] Open
Abstract
Exosomes represent a type of extracellular vesicles derived from the endosomal pathway that transport diverse molecular cargoes such as proteins, lipids, and nucleic acids. These cargoes have emerged as crucial elements impacting disease diagnosis, treatment, and prognosis, and are integral to the process of exosome formation. This review delves into the essential molecular cargoes implicated in the phases of exosome production and release. Emphasis is placed on their significance as cancer biomarkers and potential therapeutic targets, accompanied by an exploration of the obstacles and feasible applications linked to these developments.
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Affiliation(s)
- Meijin Liu
- Laboratory Medicine, People's Hospital of Ganzhou Economic Development Zone, Ganzhou, China
| | - Zhenzhen Wen
- Laboratory Medicine, People's Hospital of Ganzhou Economic Development Zone, Ganzhou, China
| | - Tingting Zhang
- Laboratory Medicine, People's Hospital of Ganzhou Economic Development Zone, Ganzhou, China
| | - Linghan Zhang
- Laboratory Medicine, People's Hospital of Ganzhou Economic Development Zone, Ganzhou, China
| | - Xiaoyan Liu
- Laboratory Medicine, People's Hospital of Ganzhou Economic Development Zone, Ganzhou, China
| | - Maoyuan Wang
- Laboratory Medicine, People's Hospital of Ganzhou Economic Development Zone, Ganzhou, China
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Gannan Medical University, GanZhou, China
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Guan XL, Guan XY, Zhang ZY. Roles and application of exosomes in the development, diagnosis and treatment of gastric cancer. World J Gastrointest Oncol 2024; 16:630-642. [PMID: 38577463 PMCID: PMC10989387 DOI: 10.4251/wjgo.v16.i3.630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 12/18/2023] [Accepted: 01/15/2024] [Indexed: 03/12/2024] Open
Abstract
As important messengers of intercellular communication, exosomes can regulate local and distant cellular communication by transporting specific exosomal contents and can also promote or suppress the development and progression of gastric cancer (GC) by regulating the growth and proliferation of tumor cells, the tumor-related immune response and tumor angiogenesis. Exosomes transport bioactive molecules including DNA, proteins, and RNA (coding and noncoding) from donor cells to recipient cells, causing reprogramming of the target cells. In this review, we will describe how exosomes regulate the cellular immune response, tumor angiogenesis, proliferation and metastasis of GC cells, and the role and mechanism of exosome-based therapy in human cancer. We will also discuss the potential application value of exosomes as biomarkers in the diagnosis and treatment of GC and their relationship with drug resistance.
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Affiliation(s)
- Xiao-Li Guan
- Department of General Medicine, The Second Hospital of Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Xiao-Ying Guan
- Department of Pathology, The Second Hospital of Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Zheng-Yi Zhang
- Department of General Medicine, The Second Hospital of Lanzhou University, Lanzhou 730030, Gansu Province, China
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Lei Y, Cai S, Zhang CD, Li YS. The biological role of extracellular vesicles in gastric cancer metastasis. Front Cell Dev Biol 2024; 12:1323348. [PMID: 38333593 PMCID: PMC10850573 DOI: 10.3389/fcell.2024.1323348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 01/15/2024] [Indexed: 02/10/2024] Open
Abstract
Gastric cancer (GC) is a tumor characterized by high incidence and mortality, with metastasis being the primary cause of poor prognosis. Extracellular vesicles (EVs) are an important intercellular communication medium. They contain bioactive substances such as proteins, nucleic acids, and lipids. EVs play a crucial biological role in the process of GC metastasis. Through mechanisms such as remodeling the tumor microenvironment (TME), immune suppression, promoting angiogenesis, and facilitating epithelial-mesenchymal transition (EMT) and mesothelial-mesenchymal transition (MMT), EVs promote invasion and metastasis in GC. Further exploration of the biological roles of EVs will contribute to our understanding of the mechanisms underlying GC metastasis and may provide novel targets and strategies for the diagnosis and treatment of GC. In this review, we summarize the mechanisms by which EVs influence GC metastasis from four aspects: remodeling the TME, modulating the immune system, influencing angiogenesis, and modulating the processes of EMT and MMT. Finally, we briefly summarized the organotropism of GC metastasis as well as the potential and limitations of EVs in GC.
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Affiliation(s)
- Yun Lei
- Department of Surgical Oncology and 8th General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Shuang Cai
- Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chun-Dong Zhang
- Department of Surgical Oncology and 8th General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yong-Shuang Li
- Department of Surgical Oncology and 8th General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Hánělová K, Raudenská M, Masařík M, Balvan J. Protein cargo in extracellular vesicles as the key mediator in the progression of cancer. Cell Commun Signal 2024; 22:25. [PMID: 38200509 PMCID: PMC10777590 DOI: 10.1186/s12964-023-01408-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 11/24/2023] [Indexed: 01/12/2024] Open
Abstract
Exosomes are small vesicles of endosomal origin that are released by almost all cell types, even those that are pathologically altered. Exosomes widely participate in cell-to-cell communication via transferring cargo, including nucleic acids, proteins, and other metabolites, into recipient cells. Tumour-derived exosomes (TDEs) participate in many important molecular pathways and affect various hallmarks of cancer, including fibroblasts activation, modification of the tumour microenvironment (TME), modulation of immune responses, angiogenesis promotion, setting the pre-metastatic niche, enhancing metastatic potential, and affecting therapy sensitivity and resistance. The unique exosome biogenesis, composition, nontoxicity, and ability to target specific tumour cells bring up their use as promising drug carriers and cancer biomarkers. In this review, we focus on the role of exosomes, with an emphasis on their protein cargo, in the key mechanisms promoting cancer progression. We also briefly summarise the mechanism of exosome biogenesis, its structure, protein composition, and potential as a signalling hub in both normal and pathological conditions. Video Abstract.
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Affiliation(s)
- Klára Hánělová
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
| | - Martina Raudenská
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
| | - Michal Masařík
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, Vestec, CZ-252 50, Czech Republic
| | - Jan Balvan
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic.
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Repetto O, Vettori R, Steffan A, Cannizzaro R, De Re V. Circulating Proteins as Diagnostic Markers in Gastric Cancer. Int J Mol Sci 2023; 24:16931. [PMID: 38069253 PMCID: PMC10706891 DOI: 10.3390/ijms242316931] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/22/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
Gastric cancer (GC) is a highly malignant disease affecting humans worldwide and has a poor prognosis. Most GC cases are detected at advanced stages due to the cancer lacking early detectable symptoms. Therefore, there is great interest in improving early diagnosis by implementing targeted prevention strategies. Markers are necessary for early detection and to guide clinicians to the best personalized treatment. The current semi-invasive endoscopic methods to detect GC are invasive, costly, and time-consuming. Recent advances in proteomics technologies have enabled the screening of many samples and the detection of novel biomarkers and disease-related signature signaling networks. These biomarkers include circulating proteins from different fluids (e.g., plasma, serum, urine, and saliva) and extracellular vesicles. We review relevant published studies on circulating protein biomarkers in GC and detail their application as potential biomarkers for GC diagnosis. Identifying highly sensitive and highly specific diagnostic markers for GC may improve patient survival rates and contribute to advancing precision/personalized medicine.
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Affiliation(s)
- Ombretta Repetto
- Facility of Bio-Proteomics, Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy
| | - Roberto Vettori
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy; (R.V.); (A.S.)
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy; (R.V.); (A.S.)
| | - Renato Cannizzaro
- Oncological Gastroenterology, Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy;
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy
| | - Valli De Re
- Facility of Bio-Proteomics, Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy
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Wang X, Xia J, Yang L, Dai J, He L. Recent progress in exosome research: isolation, characterization and clinical applications. Cancer Gene Ther 2023; 30:1051-1065. [PMID: 37106070 DOI: 10.1038/s41417-023-00617-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 03/22/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023]
Abstract
Exosomes, a kind of nano-vesicles released by various cell types, carry a variety of "cargos" including proteins, RNAs, DNAs and lipids. There is substantial evidence that exosomes are involved in intercellular communication by exchanging "cargos" among cells and play important roles in cancer development. Because of the different expressions of "cargos" carried by exosomes in biological fluids under physiological and pathological conditions, exosomes have the potential as a minimally invasive method of liquid biopsy for cancer diagnosis and prognosis. In addition, due to their good biocompatibility, safety, biodistribution and low immunogenicity, exosomes also have potential applications in the development of promising cancer treatment methods. In this review, we summarize the recent progress in the isolation and characterization techniques of exosomes. Moreover, we review the biological functions of exosomes in regulating tumor metastasis, drug resistance and immune regulation during cancer development and outline the applications of exosomes in cancer therapy.
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Affiliation(s)
- Xi Wang
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Jingyi Xia
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Lei Yang
- Department of Pharmacy, The people's hospital of jianyang city, Jianyang, 641400, China
| | - Jingying Dai
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Lin He
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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Shinozuka T, Kanda M, Kodera Y. Site-specific protein biomarkers in gastric cancer: a comprehensive review of novel biomarkers and clinical applications. Expert Rev Mol Diagn 2023; 23:701-712. [PMID: 37395000 DOI: 10.1080/14737159.2023.2232298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 06/29/2023] [Indexed: 07/04/2023]
Abstract
INTRODUCTION Gastric cancer (GC) is the fifth most common cancer and the fourth leading cause of cancer-related death worldwide, thus representing a significant global health burden. Early detection and monitoring of GC are essential to improve patient outcomes. While traditional cancer biomarkers such as carcinoembryonic antigen, carbohydrate antigen (CA) 19-9, and CA 72-4 are widely used, their limited sensitivity and specificity necessitate the exploration of alternative biomarkers. AREAS COVERED This review comprehensively analyzes the landscape of GC protein biomarkers identified from 2019 to 2022, with a focus on tissue, blood, urine, saliva, gastric juice, ascites, and exhaled breath as sample sources. We address the potential clinical applications of these biomarkers in early diagnosis, monitoring recurrence, and predicting survival and therapeutic response of GC patients. EXPERT OPINION The discovery of novel protein biomarkers holds great promise for improving the clinical management of GC. However, further validation in large, diverse cohorts is needed to establish the clinical utility of these biomarkers. Integrating these biomarkers with existing diagnostic and monitoring approaches will likely lead to improved personalized treatment plans and patient outcomes.
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Affiliation(s)
- Takahiro Shinozuka
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Logozzi M, Orefice NS, Di Raimo R, Mizzoni D, Fais S. The Importance of Detecting, Quantifying, and Characterizing Exosomes as a New Diagnostic/Prognostic Approach for Tumor Patients. Cancers (Basel) 2023; 15:cancers15112878. [PMID: 37296842 DOI: 10.3390/cancers15112878] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/11/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
Exosomes are extracellular vesicles (EVs) of nanometric size studied for their role in tumor pathogenesis and progression and as a new source of tumor biomarkers. The clinical studies have provided encouraging but probably unexpected results, including the exosome plasmatic levels' clinical relevance and well-known biomarkers' overexpression on the circulating EVs. The technical approach to obtaining EVs includes methods to physically purify EVs and characterize EVs, such as Nanosight Tracking Analysis (NTA), immunocapture-based ELISA, and nano-scale flow cytometry. Based on the above approaches, some clinical investigations have been performed on patients with different tumors, providing exciting and promising results. Here we emphasize data showing that exosome plasmatic levels are consistently higher in tumor patients than in controls and that plasmatic exosomes express well-known tumor markers (e.g., PSA and CEA), proteins with enzymatic activity, and nucleic acids. However, we also know that tumor microenvironment acidity is a key factor in influencing both the amount and the characteristics of the exosome released by tumor cells. In fact, acidity significantly increases exosome release by tumor cells, which correlates with the number of exosomes that circulate through the body of a tumor patient.
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Affiliation(s)
- Mariantonia Logozzi
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Nicola Salvatore Orefice
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | | | - Davide Mizzoni
- ExoLab Italia, Tecnopolo d'Abruzzo, 67100 L'Aquila, Italy
| | - Stefano Fais
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy
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Lin M, Hu S, Zhang T, Li J, Gao F, Zhang Z, Zheng K, Li G, Ren C, Chen X, Guo F, Zhang S. Effects of Co-Culture EBV-miR-BART1-3p on Proliferation and Invasion of Gastric Cancer Cells Based on Exosomes. Cancers (Basel) 2023; 15:2841. [PMID: 37345178 DOI: 10.3390/cancers15102841] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 05/05/2023] [Accepted: 05/12/2023] [Indexed: 06/23/2023] Open
Abstract
AIM EBV encodes at least 44 miRNAs involved in immune regulation and disease progression. Exosomes can be used as carriers of EBV-miRNA-BART intercellular transmission and affect the biological behavior of cells. We characterized exosomes and established a co-culture experiment of exosomes to explore the mechanism of miR-BART1-3p transmission through the exosome pathway and its influence on tumor cell proliferation and invasion. MATERIALS AND METHODS Exosomes of EBV-positive and EBV-negative gastric cancer cells were characterized by transmission electron microscopy. NanoSight and Western blotting, and miRNA expression profiles in exosomes were sequenced with high throughput. Exosomes with high or low expression of miR-BART1-3p were co-cultured with AGS cells to study the effects on proliferation, invasion, and migration of gastric cancer cells. The target genes of EBV-miR-BART1-3p were screened and predicted by PITA, miRanda, RNAhybrid, virBase, and DIANA-TarBase v.8 databases, and the expression of the target genes after co-culture was detected by qPCR. RESULTS The exosomes secreted by EBV-positive and negative gastric cancer cells range in diameter from 30 nm to 150 nm and express the exosomal signature proteins CD9 and CD63. Small RNA sequencing showed that exosomes expressed some human miRNAs, among which hsa-miR-23b-3p, hsa-miR-320a-3p, and hsa-miR-4521 were highly expressed in AGS-exo; hsa-miR-21-5p, hsa-miR-148a-3p, and hsa-miR-7-5p were highly expressed in SNU-719-exo. All EBV miRNAs were expressed in SNU-719 cells and their exosomes, among which EBV-miR-BART1-5p, EBV-miR-BART22, and EBV-miR-BART16 were the highest in SNU-719 cells; EBV-miR-BART1-5p, EBV-miR-BART10-3p, and EBV-miR-BART16 were the highest in SNU-719-exo. After miR-BART1-3p silencing in gastric cancer cells, the proliferation, healing, migration, and invasion of tumor cells were significantly improved. Laser confocal microscopy showed that exosomes could carry miRNA into recipient cells. After co-culture with miR-BART1-3p silenced exosomes, the proliferation, healing, migration, and invasion of gastric cancer cells were significantly improved. The target gene of miR-BART1-3p was FAM168A, MACC1, CPEB3, ANKRD28, and USP37 after screening by a targeted database. CPEB3 was not expressed in all exosome co-cultured cells, while ANKRD28, USP37, MACC1, and FAM168A were all expressed to varying degrees. USP37 and MACC1 were down-regulated after up-regulation of miR-BART1-3p, which may be the key target genes for miR-BART1-3p to regulate the proliferation of gastric cancer cells through exosomes. CONCLUSIONS miR-BART1-3p can affect the growth of tumor cells through the exosome pathway. The proliferation, healing, migration, and invasion of gastric cancer cells were significantly improved after co-culture with exosomes of miR-BART1-3p silenced expression. USP37 and MACC1 may be potential target genes of miR-BART1-3p in regulating cell proliferation.
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Affiliation(s)
- Mengyao Lin
- Department of Pathology, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou 350005, China
- Department of Pathology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, 999 Huashan Road, Fuzhou 350212, China
| | - Shun Hu
- Department of Pathology, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou 350005, China
- Department of Pathology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, 999 Huashan Road, Fuzhou 350212, China
| | - Tianyi Zhang
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Jiezhen Li
- Department of Pathology, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou 350005, China
| | - Feng Gao
- Department of Pathology, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou 350005, China
- Department of Pathology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, 999 Huashan Road, Fuzhou 350212, China
| | - Zhenzhen Zhang
- Department of Pathology, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou 350005, China
- Department of Pathology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, 999 Huashan Road, Fuzhou 350212, China
| | - Ke Zheng
- Department of Pathology, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou 350005, China
- Department of Pathology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, 999 Huashan Road, Fuzhou 350212, China
| | - Guoping Li
- Department of Pathology, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou 350005, China
- Department of Pathology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, 999 Huashan Road, Fuzhou 350212, China
| | - Caihong Ren
- Department of Pathology, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou 350005, China
- Department of Pathology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, 999 Huashan Road, Fuzhou 350212, China
| | - Xiangna Chen
- Department of Pathology, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou 350005, China
- Department of Pathology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, 999 Huashan Road, Fuzhou 350212, China
| | - Fang Guo
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Sheng Zhang
- Department of Pathology, The First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou 350005, China
- Department of Pathology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, 999 Huashan Road, Fuzhou 350212, China
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13
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Eun JW, Yoon JH, Ahn HR, Kim S, Kim YB, Lim SB, Park W, Kang TW, Baek GO, Yoon MG, Son JA, Weon JH, Kim SS, Cho HJ, Cheong JY. Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib. Cancer Commun (Lond) 2023; 43:455-479. [PMID: 36919193 PMCID: PMC10091107 DOI: 10.1002/cac2.12414] [Citation(s) in RCA: 69] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 12/13/2022] [Accepted: 03/06/2023] [Indexed: 03/16/2023] Open
Abstract
BACKGROUND Cancer-associated fibroblasts (CAFs) play an important role in the induction of chemo-resistance. This study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma (HCC). METHODS We performed a systematic integrative analysis of publicly available gene expression datasets and whole-transcriptome sequencing data from 9 pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues, respectively, to identify key molecules that might induce resistance to TKIs. We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms. The associations of plasma secreted phosphoprotein 1 (SPP1) expression levels before sorafenib/lenvatinib treatment with progression-free survival (PFS) and overall survival (OS) of 54 patients with advanced HCC were evaluated using Kaplan-Meier and Cox regression analysis. RESULTS Bioinformatic analysis identified CAF-derived SPP1 as a candidate molecule driving TKI resistance. SPP1 inhibitors reversed CAF-induced TKI resistance in vitro and in vivo. CAF-derived SPP1 activated rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) through the integrin-protein kinase C-alpha (PKCα) signaling pathway and promoted epithelial-to-mesenchymal transition (EMT). A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS (P = 0.026) and OS (P = 0.047) in patients with advanced HCC after TKI treatment. CONCLUSIONS CAF-derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion. Its inhibition represents a promising therapeutic strategy against TKI resistance in HCC. Moreover, plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction.
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Affiliation(s)
- Jung Woo Eun
- Department of GastroenterologyAjou University School of MedicineSuwonSouth Korea
| | - Jung Hwan Yoon
- Department of PathologyCollege of MedicineThe Catholic University of KoreaSeoulSouth Korea
| | - Hye Ri Ahn
- Department of GastroenterologyAjou University School of MedicineSuwonSouth Korea
- Department of Biomedical SciencesAjou University Graduate School of MedicineSuwonSouth Korea
| | - Seokhwi Kim
- Department of PathologyAjou University School of MedicineSuwonSouth Korea
| | - Young Bae Kim
- Department of PathologyAjou University School of MedicineSuwonSouth Korea
| | - Su Bin Lim
- Department of Biochemistry & Molecular BiologyAjou University School of MedicineSuwonSouth Korea
| | - Won Park
- The Moagen, IncDaejeonSouth Korea
| | | | - Geum Ok Baek
- Department of GastroenterologyAjou University School of MedicineSuwonSouth Korea
| | - Moon Gyeong Yoon
- Department of GastroenterologyAjou University School of MedicineSuwonSouth Korea
| | - Ju A Son
- Department of GastroenterologyAjou University School of MedicineSuwonSouth Korea
- Department of Biomedical SciencesAjou University Graduate School of MedicineSuwonSouth Korea
| | - Ji Hyang Weon
- Department of GastroenterologyAjou University School of MedicineSuwonSouth Korea
- Department of Biomedical SciencesAjou University Graduate School of MedicineSuwonSouth Korea
| | - Soon Sun Kim
- Department of GastroenterologyAjou University School of MedicineSuwonSouth Korea
| | - Hyo Jung Cho
- Department of GastroenterologyAjou University School of MedicineSuwonSouth Korea
| | - Jae Youn Cheong
- Department of GastroenterologyAjou University School of MedicineSuwonSouth Korea
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14
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Hosseinikhah SM, Gheybi F, Moosavian SA, Shahbazi MA, Jaafari MR, Sillanpää M, Kesharwani P, Alavizadeh SH, Sahebkar A. Role of exosomes in tumour growth, chemoresistance and immunity: state-of-the-art. J Drug Target 2023; 31:32-50. [PMID: 35971773 DOI: 10.1080/1061186x.2022.2114000] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Cancer is one of the most lethal diseases, and limited available treatment options contribute to its high mortality rate. Exosomes are considered membrane-bound nanovesicles that include different molecules such as lipids, proteins, and nucleic acids. Virtually most cells could release exosomes via exocytosis in physiological and pathological conditions. Tumour-derived exosomes (TDEs) play essential roles in tumorigenesis, proliferation, progression, metastasis, immune escape, and chemoresistance by transferring functional biological cargos, triggering different autocrine, and paracrine signalling cascades. Due to their antigen-presenting properties, exosomes are widely used as biomarkers and drug carriers and have a prominent role in cancer immunotherapy. They offer various advantages in carrier systems (e.g. in chemotherapy, siRNA, and miRNA), delivery of diagnostic agents owing to their stability, loading of hydrophobic and hydrophilic agents, and drug targeting. Novel exosomes-based carriers can be generated as intelligent systems using various sources and crosslinking chemistry extracellular vesicles (EVs). Exosomes studded with targeting ligands, including peptides, can impart in targeted delivery of cargos to tumour cells. In this review, we comprehensively summarised the important role of tumour-derived exosomes in dictating cancer pathogenesis and resistance to therapy. We have therefore, investigated in further detail the pivotal role of tumour-derived exosomes in targeting various cancer cells and their applications, and prospects in cancer therapy and diagnosis. Additionally, we have implicated the potential utility and significance of tumour exosomes-based nanoparticles as an efficient and novel therapeutic carrier and their applications in treating advanced cancers.
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Affiliation(s)
- Seyedeh Maryam Hosseinikhah
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Gheybi
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Alia Moosavian
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad-Ali Shahbazi
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.,Zanjan Pharmaceutical Nanotechnology Research Center (ZPNRC), Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mahmoud Reza Jaafari
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mika Sillanpää
- Environmental Engineering and Management Research Group, Ton Duc Thang University, Ho Chi Minh City, Vietnam.,Faculty of Environment and Labour Safety, Ton Duc Thang University, Ho Chi Minh City, Vietnam
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, New Delhi, India
| | - Seyedeh Hoda Alavizadeh
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Medicine, The University of Western Australia, Perth, Australia.,Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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15
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The updated role of exosomal proteins in the diagnosis, prognosis, and treatment of cancer. EXPERIMENTAL & MOLECULAR MEDICINE 2022; 54:1390-1400. [PMID: 36138197 PMCID: PMC9535014 DOI: 10.1038/s12276-022-00855-4] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/29/2022] [Accepted: 07/21/2022] [Indexed: 11/08/2022]
Abstract
Exosomes are vesicles encompassed by a lipid bilayer that are released by various living cells. Exosomal proteins are encapsulated within the membrane or embedded on the surface. As an important type of exosome cargo, exosomal proteins can reflect the physiological status of the parent cell and play an essential role in cell-cell communication. Exosomal proteins can regulate tumor development, including tumor-related immune regulation, microenvironment reconstruction, angiogenesis, epithelial-mesenchymal transition, metastasis, etc. The features of exosomal proteins can provide insight into exosome generation, targeting, and biological function and are potential sources of markers for cancer diagnosis, prognosis, and treatment. Here, we summarize the effects of exosomal proteins on cancer biology, the latest progress in the application of exosomal proteins in cancer diagnosis and prognosis, and the potential contribution of exosomal proteins in cancer therapeutics and vaccines.
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16
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Yi X, Chen J, Huang D, Feng S, Yang T, Li Z, Wang X, Zhao M, Wu J, Zhong T. Current perspectives on clinical use of exosomes as novel biomarkers for cancer diagnosis. Front Oncol 2022; 12:966981. [PMID: 36119470 PMCID: PMC9472136 DOI: 10.3389/fonc.2022.966981] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 08/01/2022] [Indexed: 12/11/2022] Open
Abstract
Exosomes are a heterogeneous subset of extracellular vesicles (EVs) that biogenesis from endosomes. Besides, exosomes contain a variety of molecular cargoes including proteins, lipids and nucleic acids, which play a key role in the mechanism of exosome formation. Meanwhile, exosomes are involved with physiological and pathological conditions. The molecular profile of exosomes reflects the type and pathophysiological status of the originating cells so could potentially be exploited for diagnostic of cancer. This review aims to describe important molecular cargoes involved in exosome biogenesis. In addition, we highlight exogenous factors, especially autophagy, hypoxia and pharmacology, that regulate the release of exosomes and their corresponding cargoes. Particularly, we also emphasize exosome molecular cargoes as potential biomarkers in liquid biopsy for diagnosis of cancer.
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Affiliation(s)
- Xiaomei Yi
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Jie Chen
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Defa Huang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Shuo Feng
- English Teaching and Research Section, Gannan Healthcare Vocational College, Ganzhou, China
| | - Tong Yang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Zhengzhe Li
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xiaoxing Wang
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Minghong Zhao
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Jiyang Wu
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Tianyu Zhong
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- *Correspondence: Tianyu Zhong,
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17
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Mishra LC, Pandey U, Gupta A, Gupta J, Sharma M, Mishra G. Alternating exosomes and their mimetics as an emergent strategy for targeted cancer therapy. Front Mol Biosci 2022; 9:939050. [PMID: 36032679 PMCID: PMC9399404 DOI: 10.3389/fmolb.2022.939050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 07/15/2022] [Indexed: 11/18/2022] Open
Abstract
Exosomes, a subtype of the class of extracellular vesicles and nano-sized particles, have a specific membrane structure that makes them an alternative proposition to combat with cancer through slight modification. As constituents of all most all the primary body fluids, exosomes establish the status of intercellular communication. Exosomes have specific proteins/mRNAs and miRNAs which serve as biomarkers, imparting a prognostic tool in clinical and disease pathologies. They have efficient intrinsic targeting potential and efficacy. Engineered exosomes are employed to deliver therapeutic cargos to the targeted tumor cell or the recipient. Exosomes from cancer cells bring about changes in fibroblast via TGFβ/Smad pathway, augmenting the tumor growth. These extracellular vesicles are multidimensional in terms of the functions that they perform. We herein discuss the uptake and biogenesis of exosomes, their role in various facets of cancer studies, cell-to-cell communication and modification for therapeutic and diagnostic use.
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Affiliation(s)
| | - Utkarsh Pandey
- Department of Zoology, Swami Shraddhanand College, University of Delhi, New Delhi, India
| | - Abhikarsh Gupta
- Department of Microbiology, Swami Shraddhanand College, University of Delhi, New Delhi, India
| | - Jyotsna Gupta
- Department of Microbiology, Swami Shraddhanand College, University of Delhi, New Delhi, India
| | - Monal Sharma
- Betterhumans Inc., Gainesville, FL, United States
| | - Gauri Mishra
- Department of Zoology, Swami Shraddhanand College, University of Delhi, New Delhi, India
- Division Radiopharmaceuticals and Radiation Biology, Institute of Nuclear Medicine and Allied Sciences, New Delhi, India
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18
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Proteomic Analysis Reveals Molecular Differences in the Development of Gastric Cancer. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:8266544. [PMID: 35958927 PMCID: PMC9357686 DOI: 10.1155/2022/8266544] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 06/18/2022] [Accepted: 06/23/2022] [Indexed: 02/08/2023]
Abstract
Gastric cancer (GC) is the 3rd leading cause of death from cancer and the 5th most common cancer worldwide. The detection rate of GC among Tibetans is significantly higher than that in Han Chinese, probably due to differences in their living habits, dietary structure, and environment. Despite such a high disease burden, the epidemiology of gastric cancer has not been studied in this population. Molecular markers are required to aid the diagnosis and treatment of GC. In this study, we collected gastric tissue samples from patients in Tibet with chronic nonatrophic gastritis (CNAG) (n = 6), chronic atrophic gastritis (CAG) (n = 7), gastric intraepithelial neoplasia (GIN) (n = 4), and GC (n = 5). The proteins in each group were analyzed using coupled label-free mass spectrometry. In addition, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein interaction networks were used to analyze the differentially expressed proteins (DEPs) among groups. DEPs were quantified in comparisons of GC versus CNAG (223), GC versus GIN (100), and GIN versus CNAG (341). GO and KEGG analyses showed that the DEPs were mainly associated with immunity (GC versus CNAG) and cancer proliferation and metastasis (GC versus GIN, and GIN versus CNAG). Furthermore, the expression levels of cell proliferation and cytoskeleton-related proteins increased consistently during cancer development, such as ITGA4, DDC, and CPT1A; thus, they are potential diagnostic markers. These results obtained by proteomics analysis could improve our understanding of cancer biology in GC and provide a rich resource for data mining and discovering potential immunotherapy targets.
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19
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Molecular and Circulating Biomarkers of Gastric Cancer. Int J Mol Sci 2022; 23:ijms23147588. [PMID: 35886934 PMCID: PMC9322632 DOI: 10.3390/ijms23147588] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/07/2022] [Accepted: 07/07/2022] [Indexed: 01/27/2023] Open
Abstract
Gastric cancer (GC)—a common tumor that affects humans worldwide—is highly malignant with a poor prognosis. GC is frequently not diagnosed until a relatively advanced stage. Early detection and efficient monitoring of tumor dynamics are prerequisites for reducing disease burden and mortality. Minimally invasive methods are needed to establish a diagnosis or monitoring the response to treatment of gastric cancer. Blood-based biomarker assays for the detection of early-stage GC could be of great relevance both for the risk group or for population-wide based screening programs, The currently used tumor marker assays for detecting GC are simple and rapid, but their use is limited by their low sensitivity and specificity. In recent years, several markers have been identified and tested for their clinical relevance in the management of gastric cancer. Here we review the available literature on plasma classical tumor markers, circulating free microRNAs (cfmiRNAs), circulating cell-free DNA (cfDNA), circulating tumor cells (CTCs), autoantibodies against tumor associated antigens (TAAs), and circulating extracellular vesicles (EVs) for diagnosis and monitoring of gastric cancer. This review summarizes the present status and approaches for these biomarkers, which could be potentially used for early diagnosis and accurate prediction of therapeutic approaches. We also discuss the future perspective and challenges in the search for new biomarkers of gastric cancer.
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20
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Skryabin GO, Vinokurova SV, Galetsky SA, Elkin DS, Senkovenko AM, Denisova DA, Komelkov AV, Stilidi IS, Peregorodiev IN, Malikhova OA, Imaraliev OT, Enikeev AD, Tchevkina EM. Isolation and Characterization of Extracellular Vesicles from Gastric Juice. Cancers (Basel) 2022; 14:cancers14143314. [PMID: 35884376 PMCID: PMC9318556 DOI: 10.3390/cancers14143314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/24/2022] [Accepted: 07/02/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Gastric cancer (GC) is one of the most common cancers and the fifth leading cause of cancer-related deaths worldwide. The steadily growing interest in secreted extracellular vesicles (EVs) is related to their ability to carry a variety of biologically active molecules, which can be used as markers for liquid noninvasive diagnosis of malignant neoplasms. For these applications, blood is the most widely used source of EVs. However, this body fluid contains an extremely heterogeneous mixture of EVs originating from different types of normal cells and tissues. The aim of this study was to assess the possibility of using gastric juice (GJ) as an alternative source of EVs since it is expected to be enriched in vesicles of tumor origin. We validated the presence of EVs in GJ using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western-blot analysis of exosomal markers, showed for the first time the feasibility of their isolation by ultracentrifugation and demonstrated the prospect of using GJ-derived EVs as a source of GC miRNA markers. Abstract EVs are involved in local and distant intercellular communication and play a vital role in cancer development. Since EVs have been found in almost all body fluids, there are currently active attempts for their application in liquid diagnostics. Blood is the most commonly used source of EVs for the screening of cancer markers, although the percentage of tumor-derived EVs in the blood is extremely low. In contrast, GJ, as a local biofluid, is expected to be enriched with GC-associated EVs. However, EVs from GJ have never been applied for the screening and are underinvestigated overall. Here we show that EVs can be isolated from GJ by ultracentrifugation. TEM analysis showed high heterogeneity of GJ-derived EVs, including those with exosome-like size and morphology. In addition to morphological diversity, EVs from individual GJ samples differed in the composition of exosomal markers. We also show the presence of stomatin within GJ-derived EVs for the first time. The first conducted comparison of miRNA content in EVs from GC patients and healthy donors performed using a pilot sampling revealed the significant differences in several miRNAs (-135b-3p, -199a-3p, -451a). These results demonstrate the feasibility of the application of GJ-derived EVs for screening for miRNA GC markers.
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Affiliation(s)
- Gleb O. Skryabin
- Institute of Carcinogenesis, N. N. Blokhin National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115478 Moscow, Russia; (G.O.S.); (S.V.V.); (S.A.G.); (D.S.E.); (D.A.D.); (A.D.E.)
| | - Svetlana V. Vinokurova
- Institute of Carcinogenesis, N. N. Blokhin National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115478 Moscow, Russia; (G.O.S.); (S.V.V.); (S.A.G.); (D.S.E.); (D.A.D.); (A.D.E.)
| | - Sergey A. Galetsky
- Institute of Carcinogenesis, N. N. Blokhin National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115478 Moscow, Russia; (G.O.S.); (S.V.V.); (S.A.G.); (D.S.E.); (D.A.D.); (A.D.E.)
| | - Danila S. Elkin
- Institute of Carcinogenesis, N. N. Blokhin National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115478 Moscow, Russia; (G.O.S.); (S.V.V.); (S.A.G.); (D.S.E.); (D.A.D.); (A.D.E.)
| | - Alexey M. Senkovenko
- Department of Bioengineering, Faculty of Biology, M.V. Lomonosov Moscow State University, Leninskie Gory, 1/12, 111234 Moscow, Russia;
| | - Darya A. Denisova
- Institute of Carcinogenesis, N. N. Blokhin National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115478 Moscow, Russia; (G.O.S.); (S.V.V.); (S.A.G.); (D.S.E.); (D.A.D.); (A.D.E.)
| | - Andrey V. Komelkov
- Institute of Carcinogenesis, N. N. Blokhin National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115478 Moscow, Russia; (G.O.S.); (S.V.V.); (S.A.G.); (D.S.E.); (D.A.D.); (A.D.E.)
- Correspondence: (A.V.K.); (E.M.T.)
| | - Ivan S. Stilidi
- Research Institute of Clinical Oncology, N. N. Blokhin National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115478 Moscow, Russia; (I.S.S.); (I.N.P.); (O.A.M.); (O.T.I.)
| | - Ivan N. Peregorodiev
- Research Institute of Clinical Oncology, N. N. Blokhin National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115478 Moscow, Russia; (I.S.S.); (I.N.P.); (O.A.M.); (O.T.I.)
| | - Olga A. Malikhova
- Research Institute of Clinical Oncology, N. N. Blokhin National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115478 Moscow, Russia; (I.S.S.); (I.N.P.); (O.A.M.); (O.T.I.)
| | - Oiatiddin T. Imaraliev
- Research Institute of Clinical Oncology, N. N. Blokhin National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115478 Moscow, Russia; (I.S.S.); (I.N.P.); (O.A.M.); (O.T.I.)
| | - Adel D. Enikeev
- Institute of Carcinogenesis, N. N. Blokhin National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115478 Moscow, Russia; (G.O.S.); (S.V.V.); (S.A.G.); (D.S.E.); (D.A.D.); (A.D.E.)
| | - Elena M. Tchevkina
- Institute of Carcinogenesis, N. N. Blokhin National Medical Research Center of Oncology, Kashirskoye Sh. 24, 115478 Moscow, Russia; (G.O.S.); (S.V.V.); (S.A.G.); (D.S.E.); (D.A.D.); (A.D.E.)
- Correspondence: (A.V.K.); (E.M.T.)
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21
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Removal of small extracellular vesicles inhibits the progression of peritoneal dissemination in gastric cancer. Gastric Cancer 2022; 25:712-725. [PMID: 35368210 DOI: 10.1007/s10120-022-01293-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 03/19/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND The prognosis of gastric cancer patients with peritoneal dissemination is extremely poor and effective treatment for peritoneal dissemination has not been established. Gastric cancer-derived small extracellular vesicles play an important role in the development of a favorable microenvironment for peritoneal metastasis and progression of peritoneal dissemination. Here, we aimed to investigate the transformation of gastric cancer cells by removing gastric cancer-derived small extracellular vesicles and to develop a novel therapy for inhibiting peritoneal dissemination. METHODS Gastric cancer cells were cultured in medium containing gastric cancer- and peritoneal mesothelium-derived small extracellular vesicles and in medium from which small extracellular vesicles were removed by ultracentrifugation. Cell function assays were performed in vitro, and the alternations in gene expression in gastric cancer cells were analyzed. The inhibitory effect of intraperitoneal lavage on peritoneal dissemination was investigated in vivo as a method to remove gastric cancer-derived small extracellular vesicles. RESULTS Removal of gastric cancer-derived small extracellular vesicles suppressed the proliferative and migrative abilities of gastric cancer cells and the adhesion of gastric cancer cells to peritoneal mesothelial cells. It altered the expression of several genes related to the cell cycle and epithelial-mesenchymal transition pathways of gastric cancer cells, leading to the inhibition of gastric cancer cell growth and peritoneal dissemination in vivo. CONCLUSIONS Our study provides novel insights into a novel therapy for inhibiting the peritoneal dissemination of gastric cancer by targeting gastric cancer-derived small extracellular vesicles to improve the prognosis of gastric cancer patients with peritoneal metastasis.
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Yoon JH, Choi BJ, Nam SW, Park WS. Gastric cancer exosomes contribute to the field cancerization of gastric epithelial cells surrounding gastric cancer. Gastric Cancer 2022; 25:490-502. [PMID: 34993738 DOI: 10.1007/s10120-021-01269-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 11/14/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND A dynamic molecular interaction between cancer and the surrounding normal cells is mediated through exosomes. We investigated whether exosomes derived from gastric cancer cells affected the fate of the surrounding gastric epithelial cells. METHODS We analyzed the cell viability and immortalization of primary normal stomach epithelial cells (PNSECs) after treatment with exosomes derived from AGS gastric cancer cells and/or H. pylori CagA. Cell proliferation and apoptosis were analyzed by BrdU incorporation, flow-cytometry, and colony formation assays. We examined telomere length, expression and activity of telomerase, and expression of telomere-related genes in PNSECs treated with cancer exosomes, and in 60 gastric cancer and corresponding mucosal tissues. The differentially expressed genes and transcriptional regulation of telomere-related genes were verified using real-time qPCR and ChIP analyses, respectively. RESULTS Gastric cancer exosomes increased cell viability and the population-doubling levels but inhibited the cellular senescence and apoptosis of PNSECs. The internalization of cancer exosomes in PNSECs dramatically increased the number of surviving colonies and induced a multilayer growth and invasion into the scaffold. Treatment of PNSECs with cancer exosomes markedly increased the expression and activity of telomerase and the T/S ratio and regulated the expression of the telomere-associated genes, heat-shock genes, and hedgehog genes. Compared to gastric mucosae, gastric cancer showed increased hTERT expression, which was positively correlated with telomere length. Interestingly, seven (46.7%) of 15 non-cancerous gastric mucosae demonstrated strong telomerase activity. CONCLUSION These results suggest that gastric cancer exosomes induced the transformation and field cancerization of the surrounding non-cancerous gastric epithelial cells.
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Affiliation(s)
- Jung Hwan Yoon
- Department of Pathology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea
- Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea
| | - Byung Joon Choi
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea
| | - Suk Woo Nam
- Department of Pathology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea
- Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea
| | - Won Sang Park
- Department of Pathology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.
- Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.
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23
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Li C, Zhang Z, Peng E, Peng J. Role of an Exosomes-Related lncRNAs Signature in Tumor Immune Microenvironment of Gastric Cancer. Front Cell Dev Biol 2022; 10:873319. [PMID: 35465325 PMCID: PMC9019506 DOI: 10.3389/fcell.2022.873319] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 03/21/2022] [Indexed: 12/25/2022] Open
Abstract
Background: Exosomes plays a crucial role in intercellular communication of gastric cancer (GC), while long non-coding RNAs (lncRNAs) contributes to the tumorigenesis and progression of GC. This study aims to explore the prognostic exosomes-related lncRNAs of GC patients. Methods: Data of 375 GC patients were obtained from the TCGA database. The entire cohort was randomly divided into a training cohort and a validation cohort in a 2:1 ratio. Exosomes-related lncRNAs were identified by the Pearson correlation analysis with reported exosomes-related genes. LASSO Cox regression was used to construct the signature. Results: A prognostic signature consisting of 11 exosomes-related lncRNAs was identified, and patients with lower risk scores had a better prognosis than those with higher risk scores. ROC curves and multivariate Cox regression analysis showed that the signature was an independent risk factor for prognosis in both the training (HR: 3.254, 95% CI: 2.310–4.583) and validation cohorts (HR: 1.974, 95% CI: 1.108–3.517). Gene set enrichment analysis (GSEA) suggested associations between the signature and several immune-related pathways. The identified signature was shown to be associated with GC tumor microenvironment. The expression of two immune checkpoints was also increased in the high-risk group, including B7-H3 and VSIR, indicating the potential role of the identified signature in GC immunotherapies. Conclusion: A novel exosomes-related lncRNA signature, which may be associated with tumor immune microenvironment and potentially serve as an indicator for immunotherapy, has been identified to precisely predict the prognosis of GC patients.
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Affiliation(s)
- Chan Li
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Zeyu Zhang
- Department of Thyroid Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Emin Peng
- Xiangya International Medical Center, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Emin Peng, ; Jinwu Peng,
| | - Jinwu Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- Department of Pathology, Xiangya Changde Hospital, Changde, China
- *Correspondence: Emin Peng, ; Jinwu Peng,
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24
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Araujo-Abad S, Saceda M, de Juan Romero C. Biomedical application of small extracellular vesicles in cancer treatment. Adv Drug Deliv Rev 2022; 182:114117. [PMID: 35065142 DOI: 10.1016/j.addr.2022.114117] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 12/09/2021] [Accepted: 01/15/2022] [Indexed: 12/17/2022]
Abstract
Extracellular vesicles (EVs) are produced by almost all cell types in vivo or in vitro. Among them, exosomes are small nanovesicles with a lipid bilayer, proteins and RNAs actively involved in cellular communication, suggesting that they may be used both as biomarkers and for therapeutic purposes in diseases such as cancer. Moreover, the idea of using them as drug delivery vehicle arises as a promising field of study. Here, we reviewed recent findings showing the importance of EVs, with special focus in exosomes as biomarkers including the most relevant proteins found in different cancer types and it is discussed the FDA approved tests which use exosomes in clinical practice. Finally, we present an overview of the different chimeric EVs developed in the last few years, demonstrating that they can be conjugate to nanoparticles, biomolecules, cancer drugs, etc., and can be developed for a specific cancer treatment. Additionally, we summarized the clinical trials where EVs are used in the treatment of several cancer types aiming to improve the prognosis of these deadly diseases.
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Affiliation(s)
- Salome Araujo-Abad
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain; Centro de Biotecnología, Universidad Nacional de Loja, Avda. Pio Jaramillo Alvarado s/n, Loja, 110111 Loja, Ecuador
| | - Miguel Saceda
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, 03203 Alicante, Spain; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain
| | - Camino de Juan Romero
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, 03203 Alicante, Spain; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain
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25
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Cappello F, Fais S. Extracellular vesicles in cancer pros and cons: the importance of the evidence-based medicine. Semin Cancer Biol 2022; 86:4-12. [DOI: 10.1016/j.semcancer.2022.01.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 01/18/2022] [Accepted: 01/28/2022] [Indexed: 12/17/2022]
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26
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Deng Y, Sun Z, Wang L, Wang M, Yang J, Li G. Biosensor-based assay of exosome biomarker for early diagnosis of cancer. Front Med 2021; 16:157-175. [PMID: 34570311 DOI: 10.1007/s11684-021-0884-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 07/30/2021] [Indexed: 12/18/2022]
Abstract
Cancer imposes a severe threat to people's health and lives, thus pressing a huge medical and economic burden on individuals and communities. Therefore, early diagnosis of cancer is indispensable in the timely prevention and effective treatment for patients. Exosome has recently become an attractive cancer biomarker in noninvasive early diagnosis because of the unique physiology and pathology functions, which reflects remarkable information regarding the cancer microenvironment, and plays an important role in the occurrence and evolution of cancer. Meanwhile, biosensors have gained great attention for the detection of exosomes due to their superior properties, such as convenient operation, real-time readout, high sensitivity, and remarkable specificity, suggesting promising biomedical applications in the early diagnosis of cancer. In this review, the latest advances of biosensors regarding the assay of exosomes were summarized, and the superiorities of exosomes as markers for the early diagnosis of cancer were evaluated. Moreover, the recent challenges and further opportunities of developing effective biosensors for the early diagnosis of cancer were discussed.
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Affiliation(s)
- Ying Deng
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Zhaowei Sun
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Lei Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Minghui Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Jie Yang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Genxi Li
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
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27
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Heydari R, Abdollahpour-Alitappeh M, Shekari F, Meyfour A. Emerging Role of Extracellular Vesicles in Biomarking the Gastrointestinal Diseases. Expert Rev Mol Diagn 2021; 21:939-962. [PMID: 34308738 DOI: 10.1080/14737159.2021.1954909] [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] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Extracellular vesicles (EVs) play an important role in cell-cell communication and regulation of various cellular functions under physiological and pathophysiological conditions through transferring their cargo to recipient cells. Molecular constituents of EVs are a fingerprinting profile of secreting cells which can be used as promising prognostic, diagnostic, and drug-response biomarkers in clinical settings. AREAS COVERED The present study provides a brief introduction about the biology of EVs and reviews methodologies used for EV isolation and characterization as well as high-throughput strategies to analyze EV contents. Furthermore, this review highlights the importance and unique role of EVs in the development and progression of gastrointestinal (GI) diseases, especially GI cancers, and then discusses their potential use, particularly those isolated from body fluids, in diagnosis and prognosis of GI diseases. EXPERT OPINION In-depth analysis of EV content can lead to the identification of new potential biomarkers for early diagnosis and prognosis prediction of GI diseases. The use of a more targeted approach by establishing more reproducible and standardized methods to decrease variations and obtain desired EV population as well as revisiting large pools of identified biomarkers and their evaluation in larger patient cohorts can result in the introduction of more reliable biomarkers in clinic.
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Affiliation(s)
- Raheleh Heydari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Advanced Therapy Medicinal Product Technology Development Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Anna Meyfour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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28
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Gao J, Li S, Xu Q, Zhang X, Huang M, Dai X, Liu L. Exosomes Promote Pre-Metastatic Niche Formation in Gastric Cancer. Front Oncol 2021; 11:652378. [PMID: 34109113 PMCID: PMC8180914 DOI: 10.3389/fonc.2021.652378] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 05/05/2021] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer has a high rate of metastasis, during which pre-metastatic niches (PMN) provide a supportive environment for the upcoming tumor cells. Exosomes are bilayer vesicles secreted by cells containing biological information that mediates communication between cells. Using exosomes, gastric cancer cells establish PMN remotely in multifarious perspectives, including immunosuppression, stroma remodeling, angiogenesis, mesothelial mesenchymal transformation, and organotropism. In turn, the cell components in PMN secrete exosomes that interact with each other and provide onco-promoting signals. In this review, we highlight the role of exosomes in PMN formation in gastric cancer and discuss their potential values in gastric cancer metastasis diagnosis, prevention, and treatment.
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Affiliation(s)
- Jing Gao
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Song Li
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qian Xu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xue Zhang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Miao Huang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xin Dai
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lian Liu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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29
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Wu H, Fu M, Liu J, Chong W, Fang Z, Du F, Liu Y, Shang L, Li L. The role and application of small extracellular vesicles in gastric cancer. Mol Cancer 2021; 20:71. [PMID: 33926452 PMCID: PMC8081769 DOI: 10.1186/s12943-021-01365-z] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 04/19/2021] [Indexed: 12/15/2022] Open
Abstract
Gastric cancer (GC) is a common tumour that affects humans worldwide, is highly malignant and has a poor prognosis. Small extracellular vesicles (sEVs), especially exosomes, are nanoscale vesicles released by various cells that deliver bioactive molecules to recipient cells, affecting their biological characteristics, changing the tumour microenvironment and producing long-distance effects. In recent years, many studies have clarified the mechanisms by which sEVs function with regard to the initiation, progression, angiogenesis, metastasis and chemoresistance of GC. These molecules can function as mediators of cell-cell communication in the tumour microenvironment and might affect the efficacy of immunotherapy. Due to their unique physiochemical characteristics, sEVs show potential as effective antitumour vaccines as well as drug carriers. In this review, we summarize the roles of sEVs in GC and highlight the clinical application prospects in the future.
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Affiliation(s)
- Hao Wu
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China
| | - Mengdi Fu
- Department of Clinical Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China
| | - Jin Liu
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China
| | - Wei Chong
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Department of Gastroenterological Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.,Department of Digestive Tumor Translational Medicine, Engineering Laboratory of Shandong Province, Shandong Provincial Hospital, Jinan, 250021, Shandong, China
| | - Zhen Fang
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,Department of Gastroenterological Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.,Department of Digestive Tumor Translational Medicine, Engineering Laboratory of Shandong Province, Shandong Provincial Hospital, Jinan, 250021, Shandong, China
| | - Fengying Du
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China
| | - Yang Liu
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China
| | - Liang Shang
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China. .,Department of Gastroenterological Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. .,Department of Digestive Tumor Translational Medicine, Engineering Laboratory of Shandong Province, Shandong Provincial Hospital, Jinan, 250021, Shandong, China.
| | - Leping Li
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China. .,Department of Gastroenterological Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. .,Department of Digestive Tumor Translational Medicine, Engineering Laboratory of Shandong Province, Shandong Provincial Hospital, Jinan, 250021, Shandong, China.
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30
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Naseer M, Hadi S, Syed A, Safdari A, Tahan V. Exosomes: A new frontier under the spotlight for diagnosis and treatment of gastrointestinal diseases. World J Meta-Anal 2021; 9:12-28. [DOI: 10.13105/wjma.v9.i1.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/15/2020] [Accepted: 02/22/2021] [Indexed: 02/06/2023] Open
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31
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Molecular targeted treatment and drug delivery system for gastric cancer. J Cancer Res Clin Oncol 2021; 147:973-986. [PMID: 33550445 DOI: 10.1007/s00432-021-03520-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 01/10/2021] [Indexed: 12/24/2022]
Abstract
Gastric cancer is still a major cancer worldwide. The early diagnosis rate of gastric cancer in most high incidence countries is low. At present, the overall treatment effect of gastric cancer is poor, and the median overall survival remains low. Most of the patients with gastric cancer are in an advanced stage when diagnosed, and drug treatment has become the main means. Thus, new targeted drugs and therapeutic strategies are the hope of improving the therapeutic effect of gastric cancer. In this review, we summarize the new methods and advances of targeted therapy for gastric cancer, including novel molecular targeted therapeutic agents and drug delivery systems, with a major focus on the development of drug delivery systems (drug carriers and targeting peptides). Elaborating these new methods and advances will contribute to the management of gastric cancer.
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32
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Abe S, Matsuzaki J, Sudo K, Oda I, Katai H, Kato K, Takizawa S, Sakamoto H, Takeshita F, Niida S, Saito Y, Ochiya T. A novel combination of serum microRNAs for the detection of early gastric cancer. Gastric Cancer 2021; 24:835-843. [PMID: 33743111 PMCID: PMC8205917 DOI: 10.1007/s10120-021-01161-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 01/18/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND The aim of this study was to identify serum miRNAs that discriminate early gastric cancer (EGC) samples from non-cancer controls using a large cohort. METHODS This retrospective case-control study included 1417 serum samples from patients with EGC (seen at the National Cancer Center Hospital in Tokyo between 2008 and 2012) and 1417 age- and gender-matched non-cancer controls. The samples were randomly assigned to discovery and validation sets and the miRNA expression profiles of whole serum samples were comprehensively evaluated using a highly sensitive DNA chip (3D-Gene®) designed to detect 2565 miRNA sequences. Diagnostic models were constructed using the levels of several miRNAs in the discovery set, and the diagnostic performance of the model was evaluated in the validation set. RESULTS The discovery set consisted of 708 samples from EGC patients and 709 samples from non-cancer controls, and the validation set consisted of 709 samples from EGC patients and 708 samples from non-cancer controls. The diagnostic EGC index was constructed using four miRNAs (miR-4257, miR-6785-5p, miR-187-5p, and miR-5739). In the discovery set, a receiver operating characteristic curve analysis of the EGC index revealed that the area under the curve (AUC) was 0.996 with a sensitivity of 0.983 and a specificity of 0.977. In the validation set, the AUC for the EGC index was 0.998 with a sensitivity of 0.996 and a specificity of 0.953. CONCLUSIONS A novel combination of four serum miRNAs could be a useful non-invasive diagnostic biomarker to detect EGC with high accuracy. A multicenter prospective study is ongoing to confirm the present observations.
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Affiliation(s)
- Seiichiro Abe
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Juntaro Matsuzaki
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Kazuki Sudo
- Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Ichiro Oda
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Hitoshi Katai
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Ken Kato
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Satoko Takizawa
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
- Toray Industries, Inc., Kanagawa, Japan
| | - Hiromi Sakamoto
- Department of Biobank and Tissue Resources, Fundamental Innovative Oncology Core, National Cancer Center Research Institute, Tokyo, Japan
| | - Fumitaka Takeshita
- Department of Translational Oncology, Fundamental Innovative Oncology Core, National Cancer Center Research Institute, Tokyo, Japan
| | - Shumpei Niida
- National Center for Geriatrics and Gerontology, Research Institute, Aichi, Japan
| | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
- Department of Molecular and Cellular Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.
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Fattahi S, Nikbakhsh N, Taheri H, Ranaee M, Akhavan-Niaki H. RNA Sequencing of Early-Stage Gastric Adenocarcinoma Reveals Multiple Activated Pathways and Novel Long Non-Coding RNAs in Patient Tissue Samples. Rep Biochem Mol Biol 2021; 9:478-489. [PMID: 33969142 PMCID: PMC8068441 DOI: 10.52547/rbmb.9.4.478] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 09/24/2020] [Indexed: 01/13/2023]
Abstract
BACKGROUND Gastric cancer is among the most common cancers worldwide that currently lacks effective diagnostic biomarkers and therapeutic targets. Next-generation RNA sequencing is a powerful tool that allows rapid and accurate transcriptome-wide profiling to detect differentially expressed transcripts involved in normal biological and pathological processes. Given the function of this technique, it has the potential to identify new molecular targets for the early diagnosis of disease, particularly in gastric adenocarcinoma. METHODS In this study, whole-transcriptome analysis was performed with RNA sequencing on tumoral and non-tumoral tissue samples from patients with early-stage gastric cancer. Gene ontology and pathway enrichment analysis were used to determine the main function of the specific genes and pathways present in tissue samples. RESULTS Analysis of the differentially expressed genes revealed 5 upregulated and 234 downregulated genes in gastric cancer tissues. Pathway enrichment analysis revealed significantly dysregulated signalling pathways, including those involved in gastric acid secretion, drug metabolism and transporters, molecular toxicology, O-linked glycosylation of mucins, immunotoxicity, metabolism of xenobiotics by cytochrome P450, and glycosylation. We also found novel downregulated non-coding RNAs present in gastric cancer tissues, including GATA6 antisense RNA 1, antisense to LYZ, antisense P4HB, overlapping ACER2, long intergenic non-protein coding RNA 2688 (LINC02688) and uncharacterized LOC25845 (PP7080). CONCLUSION The transcriptomic data found in this study illustrates the power of RNA-sequencing in discovering novel genes and tumorigenic pathways involved in human carcinogenesis. The anomalies present in these genes may serve as promising tools for the development of accurate diagnostic biomarkers for the detection of early-stage gastric cancer.
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Affiliation(s)
- Sadegh Fattahi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran.
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
- North Research Center of Pasteur Institute, Amol, Iran.
| | - Novin Nikbakhsh
- Department of Surgery, Rouhani hospital Babol University of Medical Sciences, Babol, Iran.
| | - Hassan Taheri
- Department of Internal Medicine, Rouhani hospital Babol University of Medical Sciences, Babol, Iran.
| | - Mohammad Ranaee
- Department of Pathology, Rouhani hospital, Babol University of Medical Sciences, Babol, Iran.
| | - Haleh Akhavan-Niaki
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.
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Zhu L, Sun HT, Wang S, Huang SL, Zheng Y, Wang CQ, Hu BY, Qin W, Zou TT, Fu Y, Shen XT, Zhu WW, Geng Y, Lu L, Jia HL, Qin LX, Dong QZ. Isolation and characterization of exosomes for cancer research. J Hematol Oncol 2020; 13:152. [PMID: 33168028 PMCID: PMC7652679 DOI: 10.1186/s13045-020-00987-y] [Citation(s) in RCA: 298] [Impact Index Per Article: 59.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023] Open
Abstract
Exosomes are a subset of extracellular vesicles that carry specific combinations of proteins, nucleic acids, metabolites, and lipids. Mounting evidence suggests that exosomes participate in intercellular communication and act as important molecular vehicles in the regulation of numerous physiological and pathological processes, including cancer development. Exosomes are released by various cell types under both normal and pathological conditions, and they can be found in multiple bodily fluids. Moreover, exosomes carrying a wide variety of important macromolecules provide a window into altered cellular or tissue states. Their presence in biological fluids renders them an attractive, minimally invasive approach for liquid biopsies with potential biomarkers for cancer diagnosis, prediction, and surveillance. Due to their biocompatibility and low immunogenicity and cytotoxicity, exosomes have potential clinical applications in the development of innovative therapeutic approaches. Here, we summarize recent advances in various technologies for exosome isolation for cancer research. We outline the functions of exosomes in regulating tumor metastasis, drug resistance, and immune modulation in the context of cancer development. Finally, we discuss prospects and challenges for the clinical development of exosome-based liquid biopsies and therapeutics.
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Affiliation(s)
- Le Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Hao-Ting Sun
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Shun Wang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Sheng-Lin Huang
- Institutes of Biomedical Sciences, Fudan University, 131 Dong An Road, Shanghai, 200032, China
- Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yan Zheng
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Chao-Qun Wang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Bei-Yuan Hu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Wei Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Tian-Tian Zou
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Yan Fu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Xiao-Tian Shen
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Wen-Wei Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Yan Geng
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Lu Lu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Hu-Liang Jia
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
- Institutes of Biomedical Sciences, Fudan University, 131 Dong An Road, Shanghai, 200032, China.
| | - Qiong-Zhu Dong
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
- Institutes of Biomedical Sciences, Fudan University, 131 Dong An Road, Shanghai, 200032, China.
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Logozzi M, Mizzoni D, Di Raimo R, Fais S. Exosomes: A Source for New and Old Biomarkers in Cancer. Cancers (Basel) 2020; 12:E2566. [PMID: 32916840 PMCID: PMC7565506 DOI: 10.3390/cancers12092566] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 09/04/2020] [Accepted: 09/07/2020] [Indexed: 02/06/2023] Open
Abstract
Clinical oncology needs reliable tumor biomarkers to allow a follow-up of tumor patients who do not necessarily need invasive approaches. To date, the existing biomarkers are not sufficiently reliable, and many of them have generated more problems than facilitating the commitment of clinical oncologists. Over the last decades, a broad family of extracellular vesicles, with size ranging between micro to nano, has been raised as a new hope for potential sources of new tumor biomarkers. However, while knowledge in the field is increasing, we do not currently have definitive information allowing a clinical use of extracellular vesicles in cancer clinics. Recent evidence provides new perspective in clinical oncology, based on data showing that circulating nanovesicles called exosomes may represent a valuable source of tumor biomarkers. In this review, we discuss the existing clinical data supporting a key role of exosomes as a source of tumor biomarkers, including proteins and miRNAs, but also discuss the importance of the expression of known tumor biomarkers when expressed on exosomes.
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Affiliation(s)
| | | | | | - Stefano Fais
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; (M.L.); (D.M.); (R.D.R.)
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Yoon JH, Ashktorab H, Smoot DT, Nam SW, Hur H, Park WS. Uptake and tumor-suppressive pathways of exosome-associated GKN1 protein in gastric epithelial cells. Gastric Cancer 2020; 23:848-862. [PMID: 32291710 DOI: 10.1007/s10120-020-01068-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 03/26/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastrokine 1 (GKN1) is a stomach-specific tumor suppressor that is secreted into extracellular space as an exosomal cargo protein. The objective of this study was to investigate the uptake and tumor-suppressive pathways of exosome-associated GKN1 protein in gastric epithelial cells. METHODS Immunofluorescent and Western blot analysis were used to investigate gastric-specific uptake of HFE-145-derived exosomes. Binding affinity of HFE-145 derived exosomes with integrin proteins was examined using protein microarray chip. Tumor suppressor activities of exosome-carrying GKN1 protein were analyzed using transwell co-culture, MTT assay, BrdU incorporation, immunoprecipitation, and Western blot analysis. RESULTS HFE-145-derived exosomes were internalized only into HFE-145 gastric epithelial cells and gastric cancer cells. Gastric-specific uptake of stomach-derived exosomes required integrin α6 and αX proteins. Clathrin and macropinocytosis increased the uptake of exosomes into gastric epithelial cells, whereas caveolin inhibited the uptake of exosomes. Transwell co-culture of AGS cells with HFE-145 cells markedly inhibited viability and proliferation of AGS cells. Following uptake of HFE-145-derived exosomes in recipient cells, GKN1 protein bound to HRas and inhibited the binding of HRas to b-Raf and c-Raf which subsequently downregulated HRas/Raf/MEK/ERK signaling pathways in AGS, MKN1 cells, and MKN1-derived xenograft tumor tissues. In addition, exosomal GKN1 protein suppressed both migration and invasion of gastric cancer cells by inhibiting epithelial-mesenchymal transition. CONCLUSIONS Gastric-specific uptake of exosomes derived from gastric epithelial cells requires integrin α6 and αX proteins in both gastric epithelial cells and exosomes. Exosomal GKN1 protein inhibits gastric carcinogenesis by downregulating HRas/Raf/MEK/ERK signaling pathways.
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Affiliation(s)
- Jung Hwan Yoon
- Department of Pathology, Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea
| | - Hassan Ashktorab
- Department of Medicine, Howard University, District of Columbia, Washington, 20060, USA
| | - Duane T Smoot
- Department of Medicine, Meharry Medical Center, Nashville, TN, 37208, USA
| | - Suk Woo Nam
- Department of Pathology, Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea
| | - Hoon Hur
- Department of Surgery, Brain Korea 21 Plus Research Center for Biomedical Science, Ajou University School of Medicine, Suwon, 16499, South Korea
| | - Won Sang Park
- Department of Pathology, Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, South Korea.
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Wu Q, Li N, Wang Y, Xu Y, Wu J, Jia G, Ji F, Fang X, Chen F, Cui X. Ultrasensitive and Selective Determination of Carcinoembryonic Antigen Using Multifunctional Ultrathin Amino-Functionalized Ti3C2-MXene Nanosheets. Anal Chem 2020; 92:3354-3360. [DOI: 10.1021/acs.analchem.9b05372] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Qiong Wu
- State Key Laboratory of Automotive Simulation, School of Materials Science and Engineering, and Control and Key Laboratory of Automobile Materials of MOE, Jilin University, 2699 Qianjin Street, Changchun 130012, Jilin, China
- Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital of Jilin University, 126 Sendai Street, Changchun 130033, Jilin, China
| | - Ningbo Li
- State Key Laboratory of Automotive Simulation, School of Materials Science and Engineering, and Control and Key Laboratory of Automobile Materials of MOE, Jilin University, 2699 Qianjin Street, Changchun 130012, Jilin, China
| | - Ying Wang
- State Key Laboratory of Automotive Simulation, School of Materials Science and Engineering, and Control and Key Laboratory of Automobile Materials of MOE, Jilin University, 2699 Qianjin Street, Changchun 130012, Jilin, China
| | - Yanchao Xu
- State Key Laboratory of Automotive Simulation, School of Materials Science and Engineering, and Control and Key Laboratory of Automobile Materials of MOE, Jilin University, 2699 Qianjin Street, Changchun 130012, Jilin, China
| | - Jiandong Wu
- State Key Laboratory of Automotive Simulation, School of Materials Science and Engineering, and Control and Key Laboratory of Automobile Materials of MOE, Jilin University, 2699 Qianjin Street, Changchun 130012, Jilin, China
| | - Guangri Jia
- State Key Laboratory of Automotive Simulation, School of Materials Science and Engineering, and Control and Key Laboratory of Automobile Materials of MOE, Jilin University, 2699 Qianjin Street, Changchun 130012, Jilin, China
| | - Fujian Ji
- Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital of Jilin University, 126 Sendai Street, Changchun 130033, Jilin, China
| | - Xuedong Fang
- Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital of Jilin University, 126 Sendai Street, Changchun 130033, Jilin, China
| | - Fangfang Chen
- Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital of Jilin University, 126 Sendai Street, Changchun 130033, Jilin, China
| | - Xiaoqiang Cui
- State Key Laboratory of Automotive Simulation, School of Materials Science and Engineering, and Control and Key Laboratory of Automobile Materials of MOE, Jilin University, 2699 Qianjin Street, Changchun 130012, Jilin, China
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Wang X, Qian C, Yang Y, Liu MY, Ke Y, Qian ZM. Phosphorylated Rasal2 facilitates breast cancer progression. EBioMedicine 2019; 50:144-155. [PMID: 31759919 PMCID: PMC6921363 DOI: 10.1016/j.ebiom.2019.11.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 10/24/2019] [Accepted: 11/11/2019] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Rasal2 has diametric effects on progression of oestrogen receptor-positive (ER+) and -negative (ER-) breast cancers. The relevant causes are unknown. It is also unknown whether the effects of Rasal2 are mediated by an exosome-transport process. METHODS Exosomes were purified from breast cancer cells and identified by transmission electron microscopy and flow cytometry analysis. In vivo and in vitro experiments were conducted to investigate the role of Rasal2 in exosome-mediated breast cancer progression. Western blot analysis was performed to detect Rasal2 and p-Rasal2 (phosphorylated Rasal2) expression in ER+/ER- breast cancer cells and in exosomes, cancer tissues and blood of patients with ER+ or ER- breast cancer. FINDINGS Phosphorylation of Rasal2 at Serine 237 promoted tumour growth in both ER+ and ER- tumour cells and tissues. The functions of both p-Rasal2 and non-p-Rasal2 (non-phosphorylated-Rasal2) in the modulation of breast cancer progression are exosome-mediated. p-Rasal2 expression in ER+ breast cancer cells and exosomes, cancer tissues and blood was significantly lower than in ER- tumour cells and patients. INTERPRETATION p-Rasal2 facilitates tumour progression in both ER+ and ER- breast cancers. The ratio of p-Rasal2/non-p-Rasal2 in ER+ and ER- breast cancers is one of the factors deciding the role of Rasal2 (or total Rasal2) as a suppressor in ER+ breast cancers or as a promoter in ER- breast cancers. Targeting the phosphorylation of Rasal2 machinery may therefore be useful as a therapy to restrain breast cancer progression by reducing p-Rasal2/non-p-Rasal2 ratio, especially in ER- breast cancers. FUND: NSFC and Hong Kong Research Grants Council.
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Affiliation(s)
- Xuan Wang
- Department of Pharmacology and Biochemistry, Fudan University School of Pharmacy, 826 Zhangheng Road, Pu Dong, Shanghai 201203, China
| | - Christopher Qian
- School of Biomedical Sciences and Gerald Choa Neuroscience Centre, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
| | - Yinlong Yang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200000, China
| | - Meng-Yue Liu
- Institute of Translational & Precision Medicine, Nantong University, Nantong, JS 226019, China
| | - Ya Ke
- School of Biomedical Sciences and Gerald Choa Neuroscience Centre, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
| | - Zhong-Ming Qian
- Department of Pharmacology and Biochemistry, Fudan University School of Pharmacy, 826 Zhangheng Road, Pu Dong, Shanghai 201203, China; Institute of Translational & Precision Medicine, Nantong University, Nantong, JS 226019, China.
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Yoon JH, Park YG, Nam SW, Park WS. The diagnostic value of serum gastrokine 1 (GKN1) protein in gastric cancer. Cancer Med 2019; 8:5507-5514. [PMID: 31376239 PMCID: PMC6745860 DOI: 10.1002/cam4.2457] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 07/16/2019] [Accepted: 07/16/2019] [Indexed: 12/16/2022] Open
Abstract
Early detection of cancer provides effective treatment and saves lives. The objective of this study was to determine whether serum gastrokine 1 (GKN1) protein is a gastric cancer-specific diagnostic biomarker. The serum concentration of GKN1 in healthy individuals (median: 6.34 ng/μL, interquartile range (IQR): 5.66-7.54 ng/μL) was significantly higher compared with the levels in gastric cancer patients (median: 3.48 ng/μL, IQR: 2.90-4.11 ng/μL; P < .0001). At the optimum cutoff (4.94 ng/μL) of serum GKN1 protein, the sensitivity and specificity were 91.2% and 96.0%, respectively, for gastric cancer. Using serum GKN1 protein as the diagnostic reference, the ROC curve showed a satisfactory diagnostic efficacy with an AUC value of 0.9954 (95% CI 0.9919-0.9988) and Youden index of 0.8740. In addition, the diagnostic accuracy of the serum GKN1 protein at the optimum cutoff was 0.9675. Interestingly, serum GKN1 concentrations in patients with advanced gastric cancer (AGC; median: 3.11 ng/μL, IQR: 2.72-3.72 ng/μL) were lower than in patients with early gastric cancer (EGC; median: 4.31 ng/μL, IQR: 3.88-4.88 ng/μL). The diagnostic accuracies at the optimum serum GKN1 cutoff were 0.8912 and 0.9589 for EGC and AGC, respectively. Furthermore, the serum GKN1 concentrations robustly discriminated the patients with gastric cancer from the patients with colorectal, liver, lung, breast, pancreatic, ovary, and prostatic cancers with AUC values greater than 0.94. These data suggest that serum GKN1 is a promising and highly specific diagnostic biomarker for the prompt detection of early and advanced gastric cancers.
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Affiliation(s)
- Jung Hwan Yoon
- Department of Pathology, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
- Functional RNomics Research Center, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
| | - Yong Gyu Park
- Department of Biostatistics, College of MedicineThe Catholic University of KoreaSeoulRepublic of Korea
| | - Suk Woo Nam
- Department of Pathology, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
- Functional RNomics Research Center, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
| | - Won Sang Park
- Department of Pathology, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
- Functional RNomics Research Center, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
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Nakamura S, Kanda M, Kodera Y. Incorporating molecular biomarkers into clinical practice for gastric cancer. Expert Rev Anticancer Ther 2019; 19:757-771. [PMID: 31437076 DOI: 10.1080/14737140.2019.1659136] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Gastric cancer is one of the most common causes of cancer-related mortality worldwide. To improve clinical outcomes, it is critical to develop appropriate approaches to diagnosis and treatment. Biomarkers have numerous potential clinical applications, including screening, assessing risk, determining prognosis, monitoring recurrence, and predicting response to treatment. Furthermore, biomarkers may contribute to the development of effective therapies. Areas covered: Here we review recent progress in exploiting GC-specific biomarkers such as protein-coding genes, microRNAs, long noncoding RNAs, and methylated gene promoters. Expert opinion: The development of biomarkers for diagnosing and monitoring gastric cancer and for individualizing therapeutic targets shows great promise for improving gastric cancer management.
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Affiliation(s)
- Shunsuke Nakamura
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine , Nagoya , Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine , Nagoya , Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine , Nagoya , Japan
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Alarcón-Millán J, Martínez-Carrillo DN, Peralta-Zaragoza O, Fernández-Tilapa G. Regulation of GKN1 expression in gastric carcinogenesis: A problem to resolve (Review). Int J Oncol 2019; 55:555-569. [PMID: 31322194 DOI: 10.3892/ijo.2019.4843] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 07/04/2019] [Indexed: 11/05/2022] Open
Abstract
Gastrokine 1 (GKN1) is a protein expressed on the surface mucosa cells of the gastric antrum and fundus, which contributes to maintaining gastric homeostasis, inhibits inflammation and is a tumor suppressor. The expression of GKN1 decreases in mucosa that are either inflamed or infected by Helicobacter pylori, and is absent in gastric cancer. The measurement of circulating GKN1 concentration, the protein itself, or the mRNA in gastric tissue may be of use for the early diagnosis of cancer. The mechanisms that modulate the deregulation or silencing of GKN1 expression have not been completely described. The modification of histones, methylation of the GKN1 promoter, or proteasomal degradation of the protein have been detected in some patients; however, these mechanisms do not completely explain the absence of GKN1 or the reduction in GKN1 levels. Only NKX6.3 transcription factor has been shown to be a positive modulator of GKN1 transcription, although others also have an affinity with sequences in the promoter of this gene. While microRNAs (miRNAs) are able to directly or indirectly regulate the expression of genes at the post‑transcriptional level, the involvement of miRNAs in the regulation of GKN1 has not been reported. The present review analyzes the information reported on the determination of GKN1 expression and the regulation of its expression at the transcriptional, post‑transcriptional and post‑translational levels; it proposes an integrated model that incorporates the regulation of GKN1 expression via transcription factors and miRNAs in H. pylori infection.
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Affiliation(s)
- Judit Alarcón-Millán
- Clinical Research Laboratory, Faculty of Biological Chemical Sciences, Guerrero Autonomous University, Chilpancingo, Guerrero 39070, México
| | - Dinorah Nashely Martínez-Carrillo
- Clinical Research Laboratory, Faculty of Biological Chemical Sciences, Guerrero Autonomous University, Chilpancingo, Guerrero 39070, México
| | - Oscar Peralta-Zaragoza
- Direction of Chronic Infections and Cancer, Research Center in Infection Diseases, National Institute of Public Health, Cuernavaca, Morelos 62100, México
| | - Gloria Fernández-Tilapa
- Clinical Research Laboratory, Faculty of Biological Chemical Sciences, Guerrero Autonomous University, Chilpancingo, Guerrero 39070, México
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Kahroba H, Hejazi MS, Samadi N. Exosomes: from carcinogenesis and metastasis to diagnosis and treatment of gastric cancer. Cell Mol Life Sci 2019; 76:1747-1758. [PMID: 30734835 PMCID: PMC11105779 DOI: 10.1007/s00018-019-03035-2] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 01/24/2019] [Accepted: 01/29/2019] [Indexed: 02/07/2023]
Abstract
Exosomes represent an important group of extracellular vesicles with a defined size between 40 and 150 nm and cup-shaped construction which have a pivotal role in elimination of intracellular debris and intercellular signaling networks. A line of evidence revealed the impact of different types of exosomes in initiation, progression, and metastasis of gastric cancer (GC). These bioactive vesicles mediate tumor and stromal communication network through modulation of cell signaling for carcinogenesis and pre-metastatic niche formation in distant organs. Exosomes contain various cargos including DNAs (mitochondrial and genomic), proteins, transposable elements, and RNAs (coding and noncoding) with different compositions related to functional status of origin cells. In this review, we summarize the main roles of key exosomal cargos in induction of exosome-mediated signaling in cancer cells. Body fluids are employed frequently as the source of exosomes released by tumor cells with a potential role in early diagnosis of GC and chemoresistance. These vesicles as non-toxic and non-immunogenic carriers are also found to be applied for novel drug delivery systems.
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Affiliation(s)
- Houman Kahroba
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Saeid Hejazi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasser Samadi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Chen Z, Li P, Zhang Z, Zhai X, Liang J, Chen Q, Li K, Lin G, Liu T, Wu Y. Ultrasensitive Sensor Using Quantum Dots-Doped Polystyrene Nanospheres for Clinical Diagnostics of Low-Volume Serum Samples. Anal Chem 2019; 91:5777-5785. [DOI: 10.1021/acs.analchem.9b00010] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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44
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Huang T, Song C, Zheng L, Xia L, Li Y, Zhou Y. The roles of extracellular vesicles in gastric cancer development, microenvironment, anti-cancer drug resistance, and therapy. Mol Cancer 2019; 18:62. [PMID: 30925929 PMCID: PMC6441168 DOI: 10.1186/s12943-019-0967-5] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 02/21/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the leading causes of cancer-related death in both men and women due to delayed diagnosis and high metastatic frequency. Extracellular vesicles (EVs) are membrane-bound nanovesicles which are released by cells into body fluids such as plasma, saliva, breast milk, cerebrospinal fluid, semen, urine, lymphatic fluid, amniotic fluid, sputum and synovial fluid. EVs deliver almost all types of biomolecules such as proteins, nucleic acids, metabolites, and even pharmacological compounds. These bioactive molecules can be delivered to recipient cells to influence their biological properties, modify surrounding microenvironment and distant targets. The extensive exploration of EVs enhances our comprehension of GC biology referring to tumor growth, metastasis, immune response and evasion, chemoresistance and treatment. In this review, we will sum up the effects of GC-derived EVs to the tumor microenvironment. Moreover, we will also summarize the function of microenvironment-derived EVs in GC and discuss how the bidirectional communication between tumor and microenvironment affect GC growth, metastatic behavior, immune response, and drug resistance. At last, we prospect the clinical application viewpoint of EVs in GC.
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Affiliation(s)
- Tingting Huang
- Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Baoan District, Shenzhen, 518020, Guangdong, People's Republic of China.
| | - Chunli Song
- Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Baoan District, Shenzhen, 518020, Guangdong, People's Republic of China
| | - Lei Zheng
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, No.1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Ligang Xia
- Department of Gastrointestinal Surgery, Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, 518020, Guangdong, People's Republic of China
| | - Yang Li
- Department of Gastrointestinal Surgery, Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, 518020, Guangdong, People's Republic of China.
| | - Yiwen Zhou
- Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Baoan District, Shenzhen, 518020, Guangdong, People's Republic of China.
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Fu M, Gu J, Jiang P, Qian H, Xu W, Zhang X. Exosomes in gastric cancer: roles, mechanisms, and applications. Mol Cancer 2019; 18:41. [PMID: 30876419 PMCID: PMC6419325 DOI: 10.1186/s12943-019-1001-7] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 03/11/2019] [Indexed: 12/24/2022] Open
Abstract
Exosomes are nanosized extracellular vesicles that can be released by almost all types of cells. Initially considered as the garbage bins acting to discard unwanted products of cells, exosomes are now recognized as an important way for cellular communication by transmitting bioactive molecules including proteins, DNA, mRNAs, and non-coding RNAs. The recent studies have shown that exosomes are critically involved in human health and diseases including cancer. Exosomes have been suggested to participate in the promotion of tumorigenesis, tumor growth and metastasis, tumor angiogenesis, tumor immune escape, and tumor therapy resistance. Increasing evidence indicate that exosomes play important roles in gastric cancer development and progression. In this review, we summarized the current understanding of exosomes in gastric cancer with an emphasis on the biological roles of exosomes in gastric cancer and their potential as biomarkers for gastric cancer diagnosis as well as potential targets for gastric cancer therapy.
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Affiliation(s)
- Min Fu
- Institute of Digestive Diseases, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China.,Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Jianmei Gu
- Departmemt of Clinical Laboratory Medicine, Nantong Tumor Hospital, 30 Tongyang North Road, Nantong, 226361, Jiangsu, China
| | - Pengcheng Jiang
- Institute of Digestive Diseases, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China
| | - Hui Qian
- Institute of Digestive Diseases, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China.,Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Wenrong Xu
- Institute of Digestive Diseases, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China.,Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China
| | - Xu Zhang
- Institute of Digestive Diseases, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, Jiangsu, China. .,Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China.
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Koper-Lenkiewicz OM, Kamińska J, Gawrońska B, Matowicka-Karna J. The role and diagnostic potential of gastrokine 1 in gastric cancer. Cancer Manag Res 2019; 11:1921-1931. [PMID: 30881118 PMCID: PMC6402446 DOI: 10.2147/cmar.s194949] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Introduction Gene for gastrokine 1 (GKN1) was identified as one of the most significant in gastric cancer and indicated as a potential therapeutic target. Aim The aim was a review of literature reports concerning the role and diagnostic potential of GKN1 in gastric cancer. Materials and methods PubMED database was searched for sources using the following keywords: gastrokine 1/GKN1/AMP-18 and gastric cancer, Helicobacter pylori, aspirin, nonsteroidal anti-inflammatory drugs. Preference was given to the sources which were published within the past 10 years. Conclusion GKN1 is a stomach-specific protein, and its role consists of maintaining mucosal integrity as well as the replenishment of the surface lumen epithelial cells layer. The evaluation of GKN1 expression seems to be a useful indicator of the presence of neoplastic or inflammatory lesions in the gastric mucosa. GKN1 expression is decreased in gastric tumor tissues and derived cell lines and its upregulation in cell lines of gastric cancer induces cells apoptosis. The mechanism by which GKN1 is inactivated in gastric cancer cells is still not fully understood. The future diagnostic capabilities of gastric cancer concern the assessment of serum GKN1 concentration by means of ELISA method. Serum GKN1 concentration is not related to patients’ sex. Moreover, the measurement of GKN1 concentration is possible only after the incubation of samples at 70°C for 10 minutes. Nevertheless, the aspect of quantitative serum GKN1 evaluation is new in the context of available literature and requires further studies.
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Affiliation(s)
- Olga M Koper-Lenkiewicz
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Białystok, Poland,
| | - Joanna Kamińska
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Białystok, Poland,
| | - Beata Gawrońska
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Białystok, Poland,
| | - Joanna Matowicka-Karna
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Białystok, Poland,
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