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1
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Esmaili M, Jafari N, Ahmadzadeh F, Toosi SMV, Abediankenari S. Effect of conditioned medium from miRNA-34a transfected gastric cancer-associated fibroblast on peripheral blood mononuclear cells. BMC Immunol 2025; 26:9. [PMID: 40000950 PMCID: PMC11854116 DOI: 10.1186/s12865-025-00688-6] [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: 11/16/2024] [Accepted: 02/12/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Cancer-associated fibroblast (CAF) cells play an important role in gastric malignancy. MiRNA dysregulation has been detected in CAF cells, which is related to the tumor progression ability of these cells. Therefore, this study aimed to evaluate the function of miRNA34a in CAF cells in gastric carcinoma. METHOD We transiently transfected miRNA-34a mimic in CAF cells and examined the effect of the overexpressed miRNA on PD-L1 expression using real-time PCR. Next, we evaluated the role of transfected CAF-conditioned medium (CM) on the immune response and viability of gastric cancer cell lines. RESULTS We have shown that miRNA-34a significantly reduced PD-L1 expression in CAF cells (p < 0.05). However, the conditioned medium of transfected cells had no significant effect on the immune response. We also found that CM of miRNA-34a transfected CAF cells significantly suppressed gastric cancer cell line viability relative to the control group (P < 0.05). CONCLUSION We indicated that CM of miRNA-34a transfected CAF can reduce gastric cancer cell line proliferation. Additionally, miRNA-34a in these cells may improve immune response via PD-L1 reduction. Thus, miRNA-34a could be a potential therapeutic agent in gastric cancer treatment. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Mozhgan Esmaili
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Narjes Jafari
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Fatemeh Ahmadzadeh
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | | | - Saeid Abediankenari
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
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2
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Liu R, Zhou J, Chen X, Zhang J, Chen Q, Liu X, Yao K. Diagnostic and Therapeutic Advances of RNAs in Precision Medicine of Gastrointestinal Tumors. Biomedicines 2024; 13:47. [PMID: 39857631 PMCID: PMC11762367 DOI: 10.3390/biomedicines13010047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/01/2024] [Accepted: 12/10/2024] [Indexed: 01/27/2025] Open
Abstract
Gastrointestinal tumors present a significant challenge for precision medicine due to their complexity, necessitating the development of more specific diagnostic tools and therapeutic agents. Recent advances have positioned coding and non-coding RNAs as emerging biomarkers for these malignancies, detectable by liquid biopsies, and as innovative therapeutic agents. Many RNA-based therapeutics, such as small interfering RNA (siRNA) and antisense oligonucleotides (ASO), have entered clinical trials or are available on the market. This review provides a narrative examination of the diagnostic and therapeutic potential of RNA in gastrointestinal cancers, with an emphasis on its application in precision medicine. This review discusses the current challenges, such as drug resistance and tumor metastasis, and highlights how RNA molecules can be leveraged for targeted detection and treatment. Additionally, this review categorizes specific diagnostic biomarkers and RNA therapeutic targets based on tissue type, offering a comprehensive analysis of their role in advancing precision medicine for gastrointestinal tumors.
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Affiliation(s)
- Runhan Liu
- Department of Gastrointestinal Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, China
- School of Clinical Medicine, Henan University, Kaifeng 475004, China
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Jiaxin Zhou
- School of Life Sciences, Henan University, Kaifeng 475004, China
- School of Pharmacy, Henan University, Kaifeng 475004, China
| | - Xiaochen Chen
- School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Jie Zhang
- School of Life Sciences, Henan University, Kaifeng 475004, China
- School of Pharmacy, Henan University, Kaifeng 475004, China
| | - Qunzhi Chen
- School of Life Sciences, Henan University, Kaifeng 475004, China
| | - Xiaoming Liu
- Department of Gastrointestinal Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, China
- School of Clinical Medicine, Henan University, Kaifeng 475004, China
| | - Kunhou Yao
- Department of Gastrointestinal Surgery, Huaihe Hospital of Henan University, Kaifeng 475000, China
- School of Clinical Medicine, Henan University, Kaifeng 475004, China
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Su Z, Lu C, Zhang F, Liu H, Li M, Qiao M, Zou X, Luo D, Li H, He M, Se H, Jing J, Wang X, Yang H, Yang H. Cancer-associated fibroblasts-secreted exosomal miR-92a-3p promotes tumor growth and stemness in hepatocellular carcinoma through activation of Wnt/β-catenin signaling pathway by suppressing AXIN1. J Cell Physiol 2024; 239:e31344. [PMID: 38949237 DOI: 10.1002/jcp.31344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 05/29/2024] [Accepted: 06/11/2024] [Indexed: 07/02/2024]
Abstract
Cancer-associated fibroblasts (CAFs) are a major cellular component in the tumor microenvironment and have been shown to exhibit protumorigenic effects in hepatocellular carcinoma (HCC). This study aimed to delve into the mechanisms underlying the tumor-promoting effects of CAFs in HCC. Small RNA sequencing was conducted to screen differential expressed microRNAs in exosomes derived from CAFs and normal fibroblasts (NFs). The miR-92a-3p expression was then measured using reverse transcriptase quantitative real-time PCR in CAFs, NFs, CAFs-derived exosomes (CAFs-Exo), and NF-derived exosomes (NFs-Exo). Compared to NFs or NF-Exo, CAFs and CAFs-Exo significantly promoted HCC cell proliferation, migration, and stemness. Additionally, compared to NFs or NF-Exo, miR-92a-3p level was notably higher in CAFs and CAFs-Exo, respectively. Exosomal miR-92a-3p was found to enhance HCC cell proliferation, migration, and stemness. Meanwhile, AXIN1 was targeted by miR-92a-3p. Exosomal miR-92a-3p could activate β-catenin/CD44 signaling in HCC cells by inhibiting AXIN1 messenger RNA. Furthermore, in vivo studies verified that exosomal miR-92a-3p notably promoted tumor growth and stemness through targeting AXIN1/β-catenin axis. Collectively, CAFs secreted exosomal miR-92a-3p was capable of promoting growth and stemness in HCC through activation of Wnt/β-catenin signaling pathway by suppressing AXIN1. Therefore, targeting CAFs-derived miR-92a-3p may be a potential strategy for treating HCC.
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Affiliation(s)
- Zenong Su
- Department of Oncology, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
- Institute of Cancer, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
- Department of Graduate School, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region, China
| | - Chao Lu
- Department of Oncology, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
- Institute of Cancer, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
- Department of Graduate School, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Feifei Zhang
- Department of Nuclear Medicine, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Huan Liu
- Department of Oncology, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
- Institute of Cancer, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
- Department of Graduate School, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Meiqing Li
- Department of Oncology, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
- Institute of Cancer, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Meng Qiao
- Department of Oncology, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
- Institute of Cancer, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Xiaohong Zou
- Department of Oncology, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
- Institute of Cancer, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Danyang Luo
- Department of Oncology, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
- Institute of Cancer, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Haojing Li
- Department of Oncology, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
- Institute of Cancer, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Min He
- Department of Oncology, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
- Institute of Cancer, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Han Se
- Department of Graduate School, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region, China
| | - Jing Jing
- Department of Graduate School, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Xiangcheng Wang
- Department of Nuclear Medicine, Shenzhen People's Hospital, Shenzhen, Guangzhou, China
| | - Hao Yang
- Department of Radiation Oncology, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Hong Yang
- Department of Oncology, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
- Institute of Cancer, Inner Mongolia People's Hospital, People's Hospital of Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
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Xu H, Huang K, Shi M, Gong H, Han M, Tian W, Wang X, Zhang D. MicroRNAs in Helicobacter pylori-infected gastric cancer: Function and clinical application. Pharmacol Res 2024; 205:107216. [PMID: 38761883 DOI: 10.1016/j.phrs.2024.107216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/10/2024] [Accepted: 05/11/2024] [Indexed: 05/20/2024]
Abstract
Gastric cancer (GC) is the leading cause of cancer-related death worldwide, and it is associated with a combination of genetic, environmental, and microbial risk factors. Helicobacter pylori (H. pylori) is classified as a type I carcinogen, however, the exact regulatory mechanisms underlying H. pylori-induced GC are incompletely defined. MicroRNAs (miRNAs), one of small non-coding RNAs, negatively regulate gene expression through binding to their target genes. Dysregulation of miRNAs is crucial in human cancer. A noteworthy quantity of aberrant miRNAs induced by H. pylori through complex regulatory networks have been identified. These miRNAs substantially affect genetic instability, cell proliferation, apoptosis, invasion, metastasis, autophagy, chemoresistance, and the tumor microenvironment, leading to GC development and progression. Importantly, some H. pylori-associated miRNAs hold promise as therapeutic tools and biomarkers for GC prevention, diagnosis, and prognosis. Nonetheless, clinical application of miRNAs remains in its infancy with multiple issues, including sensitivity and specificity, stability, reliable delivery systems, and off-target effects. Additional research on the specific molecular mechanisms and more clinical data are still required. This review investigated the biogenesis, regulatory mechanisms, and functions of miRNAs in H. pylori-induced GC, offering novel insights into the potential clinical applications of miRNA-based therapeutics and biomarkers.
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Affiliation(s)
- Huimei Xu
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Ke Huang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Dental Maxillofacial Reconstruction and Biological Intelligence Manufacturing, School of Stomatology, Lanzhou University, Lanzhou 730030, China
| | - Mingxuan Shi
- Key Laboratory of Dental Maxillofacial Reconstruction and Biological Intelligence Manufacturing, School of Stomatology, Lanzhou University, Lanzhou 730030, China
| | - Hang Gong
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Mengyu Han
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Wenji Tian
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Xiaoying Wang
- Department of Emergency, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China.
| | - Dekui Zhang
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China.
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Gao W, Zhou J, Morshedi M. MicroRNA-34 and gastrointestinal cancers: a player with big functions. Cancer Cell Int 2024; 24:163. [PMID: 38725047 PMCID: PMC11084024 DOI: 10.1186/s12935-024-03338-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 04/18/2024] [Indexed: 05/12/2024] Open
Abstract
It is commonly assumed that gastrointestinal cancer is the most common form of cancer across the globe and is the leading contributor to cancer-related death. The intricate mechanisms underlying the growth of GI cancers have been identified. It is worth mentioning that both non-coding RNAs (ncRNAs) and certain types of RNA, such as circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs), can have considerable impact on the development of gastrointestinal (GI) cancers. As a tumour suppressor, in the group of short non-coding regulatory RNAs is miR-34a. miR-34a silences multiple proto-oncogenes at the post-transcriptional stage by targeting them, which inhibits all physiologically relevant cell proliferation pathways. However, it has been discovered that deregulation of miR-34a plays important roles in the growth of tumors and the development of cancer, including invasion, metastasis, and the tumor-associated epithelial-mesenchymal transition (EMT). Further understanding of miR-34a's molecular pathways in cancer is also necessary for the development of precise diagnoses and effective treatments. We outlined the most recent research on miR-34a functions in GI cancers in this review. Additionally, we emphasize the significance of exosomal miR-34 in gastrointestinal cancers.
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Affiliation(s)
- Wei Gao
- Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, The First Hospital, China Medical University, Shenyang, 110001, China
| | - Jianping Zhou
- Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, The First Hospital, China Medical University, Shenyang, 110001, China.
| | - Mohammadamin Morshedi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Gou Z, Li J, Liu J, Yang N. The hidden messengers: cancer associated fibroblasts-derived exosomal miRNAs as key regulators of cancer malignancy. Front Cell Dev Biol 2024; 12:1378302. [PMID: 38694824 PMCID: PMC11061421 DOI: 10.3389/fcell.2024.1378302] [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: 01/29/2024] [Accepted: 04/08/2024] [Indexed: 05/04/2024] Open
Abstract
Cancer-associated fibroblasts (CAFs), a class of stromal cells in the tumor microenvironment (TME), play a key role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis, and resistance to chemotherapy. CAFs mediate their activities by secreting soluble chemicals, releasing exosomes, and altering the extracellular matrix (ECM). Exosomes contain various biomolecules, such as nucleic acids, lipids, and proteins. microRNA (miRNA), a 22-26 nucleotide non-coding RNA, can regulate the cellular transcription processes. Studies have shown that miRNA-loaded exosomes secreted by CAFs engage in various regulatory communication networks with other TME constituents. This study focused on the roles of CAF-derived exosomal miRNAs in generating cancer malignant characteristics, including immune modulation, tumor growth, migration and invasion, epithelial-mesenchymal transition (EMT), and treatment resistance. This study thoroughly examines miRNA's dual regulatory roles in promoting and suppressing cancer. Thus, changes in the CAF-derived exosomal miRNAs can be used as biomarkers for the diagnosis and prognosis of patients, and their specificity can be used to develop newer therapies. This review also discusses the pressing problems that require immediate attention, aiming to inspire researchers to explore more novel avenues in this field.
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Affiliation(s)
- Zixuan Gou
- Bethune First Clinical School of Medicine, The First Hospital of Jilin University, Changchun, China
| | - Jiannan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Jianming Liu
- Department of Otolaryngology Head and Neck Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Na Yang
- Department of Clinical Pharmacy, The First Hospital of Jilin University, Changchun, China
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Wu Y, Han W, Dong H, Liu X, Su X. The rising roles of exosomes in the tumor microenvironment reprogramming and cancer immunotherapy. MedComm (Beijing) 2024; 5:e541. [PMID: 38585234 PMCID: PMC10999178 DOI: 10.1002/mco2.541] [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: 09/06/2023] [Revised: 03/12/2024] [Accepted: 03/15/2024] [Indexed: 04/09/2024] Open
Abstract
Exosomes are indispensable for intercellular communications. Tumor microenvironment (TME) is the living environment of tumor cells, which is composed of various components, including immune cells. Based on TME, immunotherapy has been recently developed for eradicating cancer cells by reactivating antitumor effect of immune cells. The communications between tumor cells and TME are crucial for tumor development, metastasis, and drug resistance. Exosomes play an important role in mediating these communications and regulating the reprogramming of TME, which affects the sensitivity of immunotherapy. Therefore, it is imperative to investigate the role of exosomes in TME reprogramming and the impact of exosomes on immunotherapy. Here, we review the communication role of exosomes in regulating TME remodeling and the efficacy of immunotherapy, as well as summarize the underlying mechanisms. Furthermore, we also introduce the potential application of the artificially modified exosomes as the delivery systems of antitumor drugs. Further efforts in this field will provide new insights on the roles of exosomes in intercellular communications of TME and cancer progression, thus helping us to uncover effective strategies for cancer treatment.
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Affiliation(s)
- Yu Wu
- Clinical Medical Research Center of the Affiliated HospitalInner Mongolia Medical UniversityHohhotChina
| | - Wenyan Han
- Clinical Laboratorythe Second Affiliated Hospital of Inner Mongolia Medical UniversityHohhotChina
| | - Hairong Dong
- Clinical LaboratoryHohhot first hospitalHohhotChina
| | - Xiaofeng Liu
- Hepatopancreatobiliary Surgery Department IKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital and InstituteBeijingChina
| | - Xiulan Su
- Clinical Medical Research Center of the Affiliated HospitalInner Mongolia Medical UniversityHohhotChina
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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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Li J, Li X, Zhang Z, Wang S, Huang X, Min L, Li P. Helicobacter pylori promotes gastric fibroblast proliferation and migration by expulsing exosomal miR-124-3p. Microbes Infect 2024; 26:105236. [PMID: 37813158 DOI: 10.1016/j.micinf.2023.105236] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/22/2023] [Accepted: 10/02/2023] [Indexed: 10/11/2023]
Abstract
Gastric fibroblasts (GFs) are direct targets of Helicobacter pylori (H. pylori). GFs infected with H. pylori exhibit marked changes in their morphology and biological behavior. However, the molecular mechanisms by which H. pylori regulates GFs remain unknown. In this study, we cocultured GFs with H. pylori for 48 h. As a result, GFs exhibited an elongated and spindle-shaped morphology. Further, cancer-associated fibroblast (CAF) biomarkers were increased, and related behaviors were significantly enhanced in H. pylori-activated GFs. The number of extracellular vesicles (EVs) secreted by H. pylori-activated GFs remarkably increased. The miR-124-3p level was increased in secreted EVs but decreased in the cytoplasm of H. pylori-activated GFs. Overexpression of miRNA-124-3p in the original GFs significantly suppressed their proliferation and migration. In addition, the migration-promoting effects of H. pylori-activated GFs were suppressed by miR-124-3p and GW4869, which blocked EV generation. Finally, pull-down and luciferase assays revealed that SNAI2 is a target of miR-124-3p. The migration-inhibitory effects of GFs treated with miR-124-3p were eliminated by the overexpression of SNAI2, and the upregulation of SNAI2 in H. pylori-activated GFs was partially alleviated by miR-124-3p or GW4869. Overall, H. pylori infection promotes the proliferation and migration of GFs by accelerating the expulsion of EVs carrying miRNA-124-3p, a SNAI2 inhibitor.
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Affiliation(s)
- Jun Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050 Beijing, PR China; Department of Gastroenterology, Chui Yang Liu Hospital Affiliated to Tsinghua University, 100020 Beijing, PR China
| | - Xiangji Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050 Beijing, PR China
| | - Zheng Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050 Beijing, PR China
| | - Shidong Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050 Beijing, PR China
| | - Xinyuan Huang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050 Beijing, PR China
| | - Li Min
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050 Beijing, PR China.
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, 100050 Beijing, PR China.
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Lu H, Zhou J, Li X, Han X, Ma S, Feng C. MiR-526b-3p enhances sensitivity of head and neck squamous cell carcinoma cells to radiotherapy via suppressing exosomal LAMP3-mediated autophagy. Autoimmunity 2023; 56:2259125. [PMID: 37740656 DOI: 10.1080/08916934.2023.2259125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 09/10/2023] [Indexed: 09/24/2023]
Abstract
Lysosomal associated membrane protein 3 (LAMP3) has been reported to be a tumour promoter in multiple cancer types by modulating tumour cell autophagy. However, the potential mechanism of LAMP3 in radio-resistance of head and neck squamous cell carcinoma (HNSCC) remains unknown. Therefore, our current study aims to detect the impacts of LAMP3 on the resistance of HNSCC cells to radiotherapy and meanwhile explore its functional mechanism. Through RT-Qpcr examination, LAMP3 expression was identified to be expressed at a significantly high level in irradiation-resistant HNSCC cell lines compared with irradiation-sensitive HNSCC cell lines. Functional assays including CCK-8, colony formation and Transwell assays demonstrated that LAMP3 enhanced the radio-resistance through inducing autophagy to promote HNSCC cell growth. Furthermore, irradiation-resistant HNSCC cells could transfer exosomal LAMP3 to elevate LAMP3 expression in irradiation-sensitive HNSCC cells. Mechanistically, microRNA (miRNA) miR-526b-3p could inhibit LAMP3 expression so as to strengthen sensitivity of HNSCC cells to radiotherapy. In a word, exosomal LAMP3 expression promoted radioresistance of HNSCC cells via inducing autophagy, while this effect could be suppressed by miR-526b-3p in a targeted manner.
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Affiliation(s)
- Huixiang Lu
- Heavy Ion Radiotherapy Department, Wuwei Cancer Hospital & Institute, Wuwei Academy of Medical Sciences, Wuwei, Gansu, China
| | - Junnian Zhou
- Head, Neck and Maxillofacial Surgery Department, Wuwei Cancer Hospital, Wuwei, Gansu, China
| | - Xiaojun Li
- Heavy Ion Radiotherapy Department, Wuwei Cancer Hospital & Institute, Wuwei Academy of Medical Sciences, Wuwei, Gansu, China
| | - Xiaoqin Han
- Head, Neck and Maxillofacial Surgery Department, Wuwei Cancer Hospital, Wuwei, Gansu, China
| | - Shuping Ma
- Heavy Ion Radiotherapy Department, Wuwei Cancer Hospital & Institute, Wuwei Academy of Medical Sciences, Wuwei, Gansu, China
| | - Chunlan Feng
- Heavy Ion Radiotherapy Department, Wuwei Cancer Hospital & Institute, Wuwei Academy of Medical Sciences, Wuwei, Gansu, China
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12
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Krzysiek-Maczka G, Brzozowski T, Ptak-Belowska A. Helicobacter pylori-activated fibroblasts as a silent partner in gastric cancer development. Cancer Metastasis Rev 2023; 42:1219-1256. [PMID: 37460910 PMCID: PMC10713772 DOI: 10.1007/s10555-023-10122-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 06/20/2023] [Indexed: 12/18/2023]
Abstract
The discovery of Helicobacter pylori (Hp) infection of gastric mucosa leading to active chronic gastritis, gastroduodenal ulcers, and MALT lymphoma laid the groundwork for understanding of the general relationship between chronic infection, inflammation, and cancer. Nevertheless, this sequence of events is still far from full understanding with new players and mediators being constantly identified. Originally, the Hp virulence factors affecting mainly gastric epithelium were proposed to contribute considerably to gastric inflammation, ulceration, and cancer. Furthermore, it has been shown that Hp possesses the ability to penetrate the mucus layer and directly interact with stroma components including fibroblasts and myofibroblasts. These cells, which are the source of biophysical and biochemical signals providing the proper balance between cell proliferation and differentiation within gastric epithelial stem cell compartment, when exposed to Hp, can convert into cancer-associated fibroblast (CAF) phenotype. The crosstalk between fibroblasts and myofibroblasts with gastric epithelial cells including stem/progenitor cell niche involves several pathways mediated by non-coding RNAs, Wnt, BMP, TGF-β, and Notch signaling ligands. The current review concentrates on the consequences of Hp-induced increase in gastric fibroblast and myofibroblast number, and their activation towards CAFs with the emphasis to the altered communication between mesenchymal and epithelial cell compartment, which may lead to inflammation, epithelial stem cell overproliferation, disturbed differentiation, and gradual gastric cancer development. Thus, Hp-activated fibroblasts may constitute the target for anti-cancer treatment and, importantly, for the pharmacotherapies diminishing their activation particularly at the early stages of Hp infection.
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Affiliation(s)
- Gracjana Krzysiek-Maczka
- Department of Physiology, the Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Kraków, Poland.
| | - Tomasz Brzozowski
- Department of Physiology, the Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Kraków, Poland.
| | - Agata Ptak-Belowska
- Department of Physiology, the Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Kraków, Poland
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13
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Fu J, Imani S, Wu MY, Wu RC. MicroRNA-34 Family in Cancers: Role, Mechanism, and Therapeutic Potential. Cancers (Basel) 2023; 15:4723. [PMID: 37835417 PMCID: PMC10571940 DOI: 10.3390/cancers15194723] [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: 08/04/2023] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 10/15/2023] Open
Abstract
MicroRNA (miRNA) are small noncoding RNAs that play vital roles in post-transcriptional gene regulation by inhibiting mRNA translation or promoting mRNA degradation. The dysregulation of miRNA has been implicated in numerous human diseases, including cancers. miR-34 family members (miR-34s), including miR-34a, miR-34b, and miR-34c, have emerged as the most extensively studied tumor-suppressive miRNAs. In this comprehensive review, we aim to provide an overview of the major signaling pathways and gene networks regulated by miR-34s in various cancers and highlight the critical tumor suppressor role of miR-34s. Furthermore, we will discuss the potential of using miR-34 mimics as a novel therapeutic approach against cancer, while also addressing the challenges associated with their development and delivery. It is anticipated that gaining a deeper understanding of the functions and mechanisms of miR-34s in cancer will greatly contribute to the development of effective miR-34-based cancer therapeutics.
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Affiliation(s)
- Junjiang Fu
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, China
| | - Saber Imani
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310022, China
| | - Mei-Yi Wu
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland Baltimore, Baltimore, MD 21201, USA
| | - Ray-Chang Wu
- Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC 20052, USA
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14
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Kaur S, Nathani A, Singh M. Exosomal delivery of cannabinoids against cancer. Cancer Lett 2023; 566:216243. [PMID: 37257632 PMCID: PMC10426019 DOI: 10.1016/j.canlet.2023.216243] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/11/2023] [Accepted: 05/21/2023] [Indexed: 06/02/2023]
Abstract
Exosomes are extracellular vesicles (EVs) originating from endosomes that play a role in cellular communication. These vesicles which mimic the parental cells that release them are promising candidates for targeted drug delivery and therapeutic applications against cancer because of their favorable biocompatibility, specific targeting, low toxicity, and immunogenicity. Currently, Delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and other cannabinoids (e.g., CBG, THCV, CBC), are being explored for their anticancer and anti-proliferative properties. Several mechanisms, including cell cycle arrest, proliferation inhibition, activation of autophagy and apoptosis, inhibition of adhesion, metastasis, and angiogenesis have been proposed for their anticancer activity. EVs could be engineered as cannabinoid delivery systems for tumor-specificity leading to superior anticancer effects. This review discusses current techniques for EV isolation from various sources, characterization and strategies to load them with cannabinoids. More extensively, we culminate information available on different sources of EVs that have anticancer activity, mechanism of action of cannabinoids against various wild type and resistant tumors and role of CBD in histone modifications and cancer epigenetics. We have also enumerated the role of EVs containing cannabinoids against various tumors and in chemotherapy induced neuropathic pain.
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Affiliation(s)
- Sukhmandeep Kaur
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Aakash Nathani
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Mandip Singh
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, 32307, USA.
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15
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Yang P, Yang W, Wei Z, Li Y, Yang Y, Wang J. Novel targets for gastric cancer: The tumor microenvironment (TME), N6-methyladenosine (m6A), pyroptosis, autophagy, ferroptosis and cuproptosis. Biomed Pharmacother 2023; 163:114883. [PMID: 37196545 DOI: 10.1016/j.biopha.2023.114883] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/07/2023] [Accepted: 05/12/2023] [Indexed: 05/19/2023] Open
Abstract
Gastric cancer (GC) is a fatal illness, and its mortality rate is very high all over the world. At present, it is a serious health problem for any country. It is a multifactorial disease due to the rising drug resistance and the increasing global cancer burden, the treatment of GC still faces many obstacles and problems. In recent years, research on GC is being carried out continuously, and we hope to address the new targets of GC treatment through this review. At the same time, we also hope to discover new ways to fight GC and create more gospel for clinical patients. First, we discuss the descriptive tumor microenvironment (TME), N6-methyladenosine (m6A), pyroptosis, autophagy, ferroptosis, and cuproptosis. Finally, we expounded on the new or potential targets of GC treatment.
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Affiliation(s)
- Peizheng Yang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China
| | - Wanting Yang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China
| | - Zhong Wei
- Gastrointestinal Surgery, Anhui Provincial Hospital, Hefei, China
| | - Yan Li
- Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), Department of Materials Sciences and Chemical Engineering, Dalian University of Technology, Dalian, Liaoning 116024, China
| | - Yinfeng Yang
- School of Medical Informatics Engineering, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China.
| | - Jinghui Wang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China.
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16
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Lu J, Shi Y, Zhang F, Zhang Y, Zhao X, Zheng H, Li L, Zhao S, Zhao L. Mechanism of lnRNA-ICL involved in lung cancer development in COPD patients through modulating microRNA-19-3p/NKRF/NF-κB axis. Cancer Cell Int 2023; 23:58. [PMID: 37013587 PMCID: PMC10071758 DOI: 10.1186/s12935-023-02900-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 03/23/2023] [Indexed: 04/05/2023] Open
Abstract
The incidence of lung cancer (LC) in chronic obstructive pulmonary disease (COPD) patients is dozens of times higher than that in patients without COPD. Elevated activity of nuclear factor-k-gene binding (NF-κB) was found in lung tissue of patients with COPD, and the continuous activation of NF-κB is observed in both malignant transformation and tumor progression of LC, suggesting that NF-κB and its regulators may play a key role in the progression of LC in COPD patients. Here, we report for the first time that a key long non-coding RNA (lncRNA)-ICL involved in the regulation of NF-κB activity in LC tissues of COPD patients. The analyses showed that the expression of ICL significantly decreased in LC tissues of LC patients with COPD than that in LC tissues of LC patients without COPD. Functional experiments in vitro showed that exogenous ICL only significantly inhibited the proliferation, invasion and migration in primary tumor cells of LC patients with COPD compared to LC patients without COPD. Mechanism studies have shown that ICL could suppress the activation of NF-κB by blocking the hsa-miR19-3p/NKRF/NF-κB pathway as a microRNA sponge. Furthermore, In vivo experiments showed that exogenous ICL effectively inhibited the growth of patient-derived subcutaneous tumor xenografts (PDX) of LC patients with COPD and significantly prolonged the survival time of tumor-bearing mice. In a word, our study shows that the decrease of ICL is associated with an increased risk of LC in patients with COPD, ICL is not only expected to be a new therapeutic target for LC in COPD patients, but also has great potential to be used as a new marker for evaluating the occurrence, severity stratification and prognosis of LC in patients with COPD.
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Affiliation(s)
- Jingjing Lu
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, NO. 150 Jimo Road, Shanghai, 200120, China
| | - Yan Shi
- Institute for Clinical Trials of Drug, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Feng Zhang
- Department of Pharmacy, Changzheng Hospital, Naval Medical University, No. 415, Fengyang Road, Shanghai, 200003, China
| | - Ying Zhang
- Department of Emergency Medicine, Shanghai East Hospital, Tongji University School of Medicine, NO. 150 Jimo Road, Shanghai, 200120, China
| | - Xiangwang Zhao
- Department of Emergency Medicine, Shanghai East Hospital, Tongji University School of Medicine, NO. 150 Jimo Road, Shanghai, 200120, China
| | - Haiyan Zheng
- Department of Emergency Medicine, Shanghai East Hospital, Tongji University School of Medicine, NO. 150 Jimo Road, Shanghai, 200120, China
| | - Lingyu Li
- Department of Emergency Medicine, Shanghai East Hospital, Tongji University School of Medicine, NO. 150 Jimo Road, Shanghai, 200120, China
| | - Shiqiao Zhao
- Department of Biostatistics, Yale School of Public Health, New Haven, CT, 06510, USA
| | - Liming Zhao
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, NO. 150 Jimo Road, Shanghai, 200120, China.
- Department of Emergency Medicine, Shanghai East Hospital, Tongji University School of Medicine, NO. 150 Jimo Road, Shanghai, 200120, China.
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17
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Zhou Y, Wang G, Cai J, Du Y, Li H, Duan L, Zhao G, Huang Y. Exosomal transfer of miR-195-5p restrains lung adenocarcinoma progression. Exp Cell Res 2023; 424:113485. [PMID: 36657657 DOI: 10.1016/j.yexcr.2023.113485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 01/11/2023] [Accepted: 01/15/2023] [Indexed: 01/19/2023]
Abstract
Exosome is an important way for tumor cells to communicate with other cells and plays an important role in tumor progression. Previous studies revealed that miR-195-5p acts as a tumor suppressor in lung cancer. However, the role and molecular mechanism of exosomal transferred miR-195-5p in lung adenocarcinoma (LAC) remains unknown. Here, we found that miR-195-5p expression in circulating exosomes of LAC patients was lower than that of healthy controls. Meanwhile, the expression of exosomal miR-195-5p from normal bronchial epithelial cell line BEAS-2B cells was significantly higher than that of lung cancer cell lines. The exosome labeling assay confirmed that BEAS-2B cells-derived exosomes could be captured by lung cancer cells. Furthermore, exosomal miR-195-5p derived from BEAS-2B cells remarkably inhibited the proliferation, migration, invasion of lung cancer cells, and tumor growth in vivo. In addition, exosomal miR-195-5p from BEAS-2B cells also suppressed the tube-forming ability of vascular endothelial cells. Moreover, we verified that miR-195-5p decreased apelin (APLN) expression to inactivate the Wnt signaling pathway, thereby inhibiting tumor invasiveness and angiogenesis. In conclusion, our research shows that exosomal miR-195-5p from normal bronchial epithelial cells hinders the progression of LAC, suggesting that regulation of exosomal miR-195-5p provides a novel strategy for LAC treatment.
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Affiliation(s)
- Yongchun Zhou
- Molecular Diagnostic Center, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, China
| | - Gaowei Wang
- Medical Department, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, China
| | - Jingjing Cai
- Molecular Diagnostic Center, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, China
| | - Yaqian Du
- Molecular Diagnostic Center, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, China
| | - Hongsheng Li
- Molecular Diagnostic Center, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, China
| | - Lincan Duan
- Department of Thoracic Surgery II, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, China
| | - Guangqiang Zhao
- Department of Thoracic Surgery I, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, China
| | - Yunchao Huang
- Department of Thoracic Surgery I, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, China.
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18
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Zhang Q, Wang Y, Liu F. Cancer-associated fibroblasts: Versatile mediators in remodeling the tumor microenvironment. Cell Signal 2023; 103:110567. [PMID: 36538999 DOI: 10.1016/j.cellsig.2022.110567] [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: 11/12/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 12/23/2022]
Abstract
Current cancer therapeutic strategies are generally not sufficient to eradicate malignancy, as cancer stroma cells contribute to tumor evasion and therapeutic resistance. Cancer-associated fibroblasts (CAFs) constitute a largely heterogeneous type of stromal cell population and are important components of the tumor microenvironment (TME). CAFs are the most abundant stromal cell type and are actively involved in tumor progression through complex mechanisms involving effects on other cell types. Research conducted in recent years has emphasized an emerging function of CAFs in the remodeling of the TME that promotes tumor progression with effects on response to treatment by various molecular mechanisms. A comprehensive mechanism of tumor-promoting activities of CAFs could facilitate the development of novel diagnostic and therapeutic approaches. In this review, the biological characterization of CAFs and the mechanisms of their effects on TME remodeling are summarized. Furthermore, we also highlight currently available therapeutic strategies targeting CAF in the context of optimizing the success of immunotherapies and briefly discuss possible future perspectives and challenges related to CAF studies.
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Affiliation(s)
- Qing Zhang
- Department of Neurosurgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Yang Wang
- Department of Neurosurgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
| | - Fusheng Liu
- Brain Tumor Research Center, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing 100070, China; Beijing Laboratory of Biomedical Materials, Beijing 100070, China.
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19
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Wu T, Liu Y, Ali NM, Zhang B, Cui X. Effects of Exosomes on Tumor Bioregulation and Diagnosis. ACS OMEGA 2023; 8:5157-5168. [PMID: 36816660 PMCID: PMC9933233 DOI: 10.1021/acsomega.2c06567] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 12/21/2022] [Indexed: 06/18/2023]
Abstract
Exosomes are lipid bilayer vesicles in biological fluids, which can participate in biological processes by mediating intercellular communication and activating intracellular signaling pathways, especially cancerogenic processes, such as proliferation, metastasis, invasion, and immune regulation of cancer cells. Besides, cancer-derived exosomes are also involved in tumor diagnosis and therapy as biomarkers and nanotransport devices. This article reviews the latest research progress on the biological regulation and disease diagnosis of exosomes in tumors, with the aim of providing new ideas for the clinical treatment of cancers.
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Affiliation(s)
- Tong Wu
- Department
of Oncology, First Affiliated Hospital of
Dalian Medical University, Dalian 116011, P.R. China
| | - Ying Liu
- Department
of Oncology, First Affiliated Hospital of
Dalian Medical University, Dalian 116011, P.R. China
- Department
of Oncology, Affiliated Zhongshan Hospital
of Dalian University, Dalian 116011, P.R. China
| | - Nasra Mohamoud Ali
- Department
of Oncology, First Affiliated Hospital of
Dalian Medical University, Dalian 116011, P.R. China
| | - Bin Zhang
- Department
of Oncology, First Affiliated Hospital of
Dalian Medical University, Dalian 116011, P.R. China
| | - Xiaonan Cui
- Department
of Oncology, First Affiliated Hospital of
Dalian Medical University, Dalian 116011, P.R. China
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20
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Zhou Z, Guo S, Lai S, Wang T, Du Y, Deng J, Zhang S, Gao G, Zhang J. Integrated single-cell and bulk RNA sequencing analysis identifies a cancer-associated fibroblast-related gene signature for predicting survival and therapy in gastric cancer. BMC Cancer 2023; 23:108. [PMID: 36717783 PMCID: PMC9887891 DOI: 10.1186/s12885-022-10332-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 11/18/2022] [Indexed: 02/01/2023] Open
Abstract
As the dominant component of the tumor microenvironment, cancer-associated fibroblasts (CAFs), play a vital role in tumor progression. An increasing number of studies have confirmed that CAFs are involved in almost every aspect of tumors including tumorigenesis, metabolism, invasion, metastasis and drug resistance, and CAFs provide an attractive therapeutic target. This study aimed to explore the feature genes of CAFs for potential therapeutic targets and reliable prediction of prognosis in patients with gastric cancer (GC). Bioinformatic analysis was utilized to identify the feature genes of CAFs in GC by performing an integrated analysis of single-cell and transcriptome RNA sequencing using R software. Based on these feature genes, a CAF-related gene signature was constructed for prognostic prediction by LASSO. Simultaneously, survival analysis and nomogram were performed to validate the prognostic predictive value of this gene signature, and qRT-PCR and immunohistochemical staining verified the expression of the feature genes of CAFs. In addition, small molecular drugs for gene therapy of CAF-related gene signatures in GC patients were identified using the connectivity map (CMAP) database. A combination of nine CAF-related genes was constructed to characterize the prognosis of GC, and the prognostic potential and differential expression of the gene signature were initially validated. Additionally, three small molecular drugs were deduced to have anticancer properties on GC progression. By integrating single-cell and bulk RNA sequencing analyses, a novel gene signature of CAFs was constructed. The results provide a positive impact on future research and clinical studies involving CAFs for GC.
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Affiliation(s)
- Zhiyang Zhou
- grid.412604.50000 0004 1758 4073Department of General Surgery, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province China
| | - Sixuan Guo
- grid.260463.50000 0001 2182 8825Nanchang University, Nanchang, Jiangxi Province China
| | - Shuhui Lai
- grid.260463.50000 0001 2182 8825Nanchang University, Nanchang, Jiangxi Province China
| | - Tao Wang
- grid.412604.50000 0004 1758 4073Department of Day Ward, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province China
| | - Yao Du
- grid.412604.50000 0004 1758 4073Department of General Surgery, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province China
| | - Junping Deng
- grid.412604.50000 0004 1758 4073Department of General Surgery, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province China
| | - Shun Zhang
- grid.412604.50000 0004 1758 4073Department of General Surgery, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province China
| | - Ge Gao
- grid.412604.50000 0004 1758 4073Department of General Surgery, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province China
| | - Jiangnan Zhang
- grid.412604.50000 0004 1758 4073Department of General Surgery, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province China
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21
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Siqueira IR, Batabyal RA, Freishtat R, Cechinel LR. Potential involvement of circulating extracellular vesicles and particles on exercise effects in malignancies. Front Endocrinol (Lausanne) 2023; 14:1121390. [PMID: 36936170 PMCID: PMC10020195 DOI: 10.3389/fendo.2023.1121390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 02/07/2023] [Indexed: 03/06/2023] Open
Abstract
Physical activity and exercise have been widely related to prevention, treatment, and control for several non-communicable diseases. In this context, there are innumerous pre-clinical and clinical evidence indicating the potential role of exercise, beyond cancer prevention and survival, improved quality of life, including on psychological components, bone health and cachexia, from cancer survivors is described as well. This mini-review raises the potential role of circulating extracellular and particles vesicles (EVPs) cargo, as exerkines, conducting several positive effects on adjacent and/or distant tissues such as tumor, immune, bone and muscle cells. We highlighted new perspectives about microRNAs into EVPs changes induced by exercise and its benefits on malignancies, since microRNAs can be implicated with intricated physiopathological processes. Potential microRNAs into EVPs were pointed out here as players spreading beneficial effects of exercise, such as miR-150-5p, miR-124, miR-486, and miRNA-320a, which have previous findings on involvement with clinical outcomes and as well as tumor microenvironment, regulating intercellular communication and tumor growth. For example, high-intensity interval aerobic exercise program seems to increase miR-150 contents in circulating EVPs obtained from women with normal weight or overweight. In accordance circulating EVPs miR-150-5p content is correlated with prognosis colorectal cancer, and ectopic expression of miR-150 may reduce cell proliferation, invasion and metastasis. Beyond the involvement of bioactive miRNAs into circulating EVPs and their pathways related to clinical and preclinical findings, this mini review intends to support further studies on EVPs cargo and exercise effects in oncology.
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Affiliation(s)
- Ionara Rodrigues Siqueira
- Graduate Program in Biological Sciences: Pharmacology and Therapeutics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
- Graduate Program in Biological Sciences: Physiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
- *Correspondence: Ionara Rodrigues Siqueira,
| | - Rachael A. Batabyal
- Center for Genetic Medicine Research, Children’s National Research Institute, Washington, DC, United States
- Division of Emergency Medicine, Children’s National Hospital, Washington, DC, United States
- Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
| | - Robert Freishtat
- Center for Genetic Medicine Research, Children’s National Research Institute, Washington, DC, United States
| | - Laura Reck Cechinel
- Center for Genetic Medicine Research, Children’s National Research Institute, Washington, DC, United States
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22
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Rajabi A, Kayedi M, Rahimi S, Dashti F, Mirazimi SMA, Homayoonfal M, Mahdian SMA, Hamblin MR, Tamtaji OR, Afrasiabi A, Jafari A, Mirzaei H. Non-coding RNAs and glioma: Focus on cancer stem cells. Mol Ther Oncolytics 2022; 27:100-123. [PMID: 36321132 PMCID: PMC9593299 DOI: 10.1016/j.omto.2022.09.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Glioblastoma and gliomas can have a wide range of histopathologic subtypes. These heterogeneous histologic phenotypes originate from tumor cells with the distinct functions of tumorigenesis and self-renewal, called glioma stem cells (GSCs). GSCs are characterized based on multi-layered epigenetic mechanisms, which control the expression of many genes. This epigenetic regulatory mechanism is often based on functional non-coding RNAs (ncRNAs). ncRNAs have become increasingly important in the pathogenesis of human cancer and work as oncogenes or tumor suppressors to regulate carcinogenesis and progression. These RNAs by being involved in chromatin remodeling and modification, transcriptional regulation, and alternative splicing of pre-mRNA, as well as mRNA stability and protein translation, play a key role in tumor development and progression. Numerous studies have been performed to try to understand the dysregulation pattern of these ncRNAs in tumors and cancer stem cells (CSCs), which show robust differentiation and self-regeneration capacity. This review provides recent findings on the role of ncRNAs in glioma development and progression, particularly their effects on CSCs, thus accelerating the clinical implementation of ncRNAs as promising tumor biomarkers and therapeutic targets.
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Affiliation(s)
- Ali Rajabi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mehrdad Kayedi
- Department of Radiology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shiva Rahimi
- School of Medicine,Fasa University of Medical Sciences, Fasa, Iran
| | - Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mina Homayoonfal
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Amin Mahdian
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Omid Reza Tamtaji
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Afrasiabi
- Department of Internal Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ameneh Jafari
- Advanced Therapy Medicinal Product (ATMP) Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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23
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Chen L, Deng J. Role of non-coding RNA in immune microenvironment and anticancer therapy of gastric cancer. J Mol Med (Berl) 2022; 100:1703-1719. [PMID: 36329206 DOI: 10.1007/s00109-022-02264-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022]
Abstract
Gastric cancer remains one of the cancers with the highest mortality in the world; therefore, it is very important to investigate its pathogenesis to improve the prognosis of gastric cancer patients. Recently, noncoding RNAs have become a research hotspot in the field of oncology. These RNA molecules play complex roles in the regulation of tumor cells, immune cells, and the tumor microenvironment. Therefore, studying their ability to regulate the gastric cancer immune microenvironment will provide us with a better perspective to understand their potential role in anticancer therapy. In this review, we discuss the regulatory effects of several common noncoding RNAs on the immune microenvironment of gastric cancer and their prospects in anticancer therapy to provide some novel insight into the identification of valuable diagnostic markers and improving the prognosis of gastric cancer patients.
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Affiliation(s)
- Liqiao Chen
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Jingyu Deng
- Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China.
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24
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Naito Y, Yoshioka Y, Ochiya T. Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via extracellular vesicles. Cancer Cell Int 2022; 22:367. [PMID: 36424598 PMCID: PMC9686122 DOI: 10.1186/s12935-022-02784-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 10/20/2022] [Indexed: 11/25/2022] Open
Abstract
Intercellular communication plays an important role in cancer initiation and progression through direct contact and indirect interactions, such as via secretory molecules. Cancer-associated fibroblasts (CAFs) are one of the principal components of such communication with cancer cells, modulating cancer metastasis and tumour mechanics and influencing angiogenesis, the immune system, and therapeutic resistance. Over the past few years, there has been a significant increase in research on extracellular vesicles (EVs) as regulatory agents in intercellular communication. EVs enable the transfer of functional molecules, including proteins, mRNAs and microRNAs (miRNAs), to recipient cells. Cancer cells utilize EVs to dictate the specific characteristics of CAFs within the tumour microenvironment, thereby promoting cancer progression. In response to such "education" by cancer cells, CAFs contribute to cancer progression via EVs. In this review, we summarize experimental data indicating the pivotal roles of EVs in intercellular communication between cancer cells and CAFs.
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Affiliation(s)
- Yutaka Naito
- grid.410821.e0000 0001 2173 8328Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-Ku, Tokyo, 113-8602 Japan
| | - Yusuke Yoshioka
- grid.410793.80000 0001 0663 3325Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjuku, Shinjuku-Ku, Tokyo, 160-0023 Japan
| | - Takahiro Ochiya
- grid.410793.80000 0001 0663 3325Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjuku, Shinjuku-Ku, Tokyo, 160-0023 Japan
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25
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Wang Y, Liang H, Zheng J. Exosomal microRNAs mediating crosstalk between cancer cells and cancer-associated fibroblasts in the tumor microenvironment. Pathol Res Pract 2022; 239:154159. [DOI: 10.1016/j.prp.2022.154159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 08/17/2022] [Accepted: 10/05/2022] [Indexed: 11/26/2022]
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26
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Ebrahimi N, Faghihkhorasani F, Fakhr SS, Moghaddam PR, Yazdani E, Kheradmand Z, Rezaei-Tazangi F, Adelian S, Mobarak H, Hamblin MR, Aref AR. Tumor-derived exosomal non-coding RNAs as diagnostic biomarkers in cancer. Cell Mol Life Sci 2022; 79:572. [PMID: 36308630 PMCID: PMC11802992 DOI: 10.1007/s00018-022-04552-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 09/02/2022] [Accepted: 09/04/2022] [Indexed: 12/24/2022]
Abstract
Almost all clinical oncologists agree that the discovery of reliable, accessible, and non-invasive biomarkers is necessary to decrease cancer mortality. It is possible to employ reliable biomarkers to diagnose cancer in the early stages, predict the patient prognosis, follow up the response to treatment, and estimate the risk of disease recurrence with high sensitivity and specificity. Extracellular vesicles (EVs), especially exosomes, have been the focus of translational research to develop such biomarkers over the past decade. The abundance and distribution of exosomes in bodily fluids, including serum, saliva, and urine, as well as their ability to transport various biomolecules (nucleic acids, proteins, and lipids) derived from their parent cells, make exosomes reliable, accessible, and potent biomarkers for diagnosis and follow-up of solid and hematopoietic tumors. In addition, exosomes play a vital role in various cellular processes, including tumor progression, by participating in intercellular communication. Although these advantages underline the high potential of tumor-derived exosomes as diagnostic biomarkers, the lack of standardized effective methods for their isolation, identification, and precise characterization makes their application challenging in clinical settings. We discuss the importance of non-coding RNAs (ncRNAs) in cellular processes, and the role of tumor-derived exosomes containing ncRNAs as potential biomarkers in several types of cancer. In addition, the advantages and challenges of these studies for translation into clinical applications are covered.
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Affiliation(s)
- Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
| | | | - Siavash Seifollahy Fakhr
- Division of Biotechnology, Faculty of Applied Ecology, Agricultural Sciences and Biotechnology, Campus, Hamar, Norway
| | - Parichehr Roozbahani Moghaddam
- Department of Molecular Genetics, Faculty of Science, Tonekabon Branch, Islamic Azad University, Tehran, Mazandaran, Iran
| | - Elnaz Yazdani
- Department of Biology, Faculty of Science, University of Isfahan, Isfahan, Iran
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Zahra Kheradmand
- Department of Agriculture, Islamic Azad University Maragheh Branch, Maragheh, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Samaneh Adelian
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Halimeh Mobarak
- Clinical Pathologist, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa.
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
- Translational Medicine Group, Xsphera Biosciences, 6 Tide Street, Boston, MA, 02210, USA.
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27
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Wang D, Zhang W, Zhang C, Wang L, Chen H, Xu J. Exosomal non-coding RNAs have a significant effect on tumor metastasis. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 29:16-35. [PMID: 35784014 PMCID: PMC9207556 DOI: 10.1016/j.omtn.2022.05.034] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/10/2023]
Abstract
Exosomes are produced by the majority of eukaryotic cells and are capable of transporting a variety of substances, including non-coding RNAs, between cells. Metastasis is a significant cause of death from cancer. Numerous studies have established an important role for exosomal non-coding RNAs in tumor metastasis. Exosomal non-coding RNAs from a variety of cells have been shown to affect tumor metastasis via several mechanisms. Exosomes transmit non-coding RNAs between tumor cells, fibroblasts, endothelial cells, and immune cells within the tumor microenvironment. Exosomal non-coding RNAs also have an effect on epithelial-mesenchymal transition, angiogenesis, and lymphangiogenesis. Exosomes derived from tumor cells have the ability to transport non-coding RNAs to distant organs, thereby facilitating the formation of the metastatic niche. Due to their role in tumor metastasis, exosomal non-coding RNAs have the potential to serve as diagnostic or prognostic markers as well as therapeutic targets for tumors. The purpose of this paper is to review and discuss the mechanisms of exosomal non-coding RNAs, their role in tumor metastasis, and their clinical utility, aiming to establish new directions for tumor metastasis, diagnosis, and treatment research.
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Affiliation(s)
- Di Wang
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
| | - Wei Zhang
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
| | - Chunxi Zhang
- Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Liwei Wang
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
| | - Heng Chen
- Shenzhen Key Laboratory of Special Functional Materials, College of Materials Science and Engineering, Shenzhen University, Nanshan District, Shenzhen 518060, P.R. China
| | - Jianbin Xu
- Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
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28
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Zhao M, Zhuang A, Fang Y. Cancer-Associated Fibroblast-Derived Exosomal miRNA-320a Promotes Macrophage M2 Polarization In Vitro by Regulating PTEN/PI3K γ Signaling in Pancreatic Cancer. JOURNAL OF ONCOLOGY 2022; 2022:9514697. [PMID: 35813857 PMCID: PMC9270150 DOI: 10.1155/2022/9514697] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 12/20/2021] [Accepted: 06/03/2022] [Indexed: 12/21/2022]
Abstract
Our previous study has indicated that cancer-associated fibroblasts (CAFs) play a crucial role in regulating gemcitabine resistance through transferring exosomal miRNA-106b to cancer cells. Tumor-associated macrophages (TAMs) are recently verified to facilitate gemcitabine resistance. However, the effect of CAFs in regulating TAMs function in pancreatic cancer (PCa) remains unclear. Here, primary CAFs were extracted from tumor tissues of PCa patients, and CAFs-derived exosomes (CAFs-Exo) were acquired and authenticated by transmission electron microscopy, qNano, and western blot analysis. The role of exosomal miRNA-320a in facilitating macrophage M2 polarization was investigated in vitro. We found that CAFs-derived conditioned medium (CM) possessed a higher potential to promote macrophage M2 polarization compared with normal fibroblasts (NFs) or PCa cell-derived CM. Furthermore, CAFs-Exo treatment polarized macrophage to M2 phenotype. miRNA-320a levels were remarkably increased in CAFs-Exo versus NFs-Exo. More important, miRNA-320a could be transferred from CAFs to macrophages through exosomes, and miRNA-320a overexpression in macrophages facilitated its M2 polarization. Functionally, miRNA-320a-overexpressed macrophages facilitated PCa cell proliferation and invasion. CAFs pretreated with miRNA-320a inhibitor reduced miRNA-320a expression in CAFs-Exo and led to decreased M2 macrophage polarization. Finally, we verified that miRNA-320a polarized macrophage to M2 phenotype by regulating PTEN/PI3Kγ signaling. Taken together, the current data demonstrated that CAFs-derived exosomal miRNA-320a facilitated macrophage M2 polarization to accelerate malignant behavior of PCa cells.
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Affiliation(s)
- Mingkun Zhao
- Department of General Surgery, Shanghai Public Health Clinical Center, Zhongshan Hospital (South), Fudan University, Shanghai 200032, China
| | - Aobo Zhuang
- Department of General Surgery, Shanghai Public Health Clinical Center, Zhongshan Hospital (South), Fudan University, Shanghai 200032, China
| | - Yuan Fang
- Department of General Surgery, Shanghai Public Health Clinical Center, Zhongshan Hospital (South), Fudan University, Shanghai 200032, China
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29
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Zhang Y, Liu Q, Zhang X, Huang H, Tang S, Chai Y, Xu Z, Li M, Chen X, Liu J, Yang C. Recent advances in exosome-mediated nucleic acid delivery for cancer therapy. J Nanobiotechnology 2022; 20:279. [PMID: 35701788 PMCID: PMC9194774 DOI: 10.1186/s12951-022-01472-z] [Citation(s) in RCA: 153] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 05/19/2022] [Indexed: 02/07/2023] Open
Abstract
Cancer is a leading public health problem worldwide. Its treatment remains a daunting challenge, although significant progress has been made in existing treatments in recent years. A large concern is the poor therapeutic effect due to lack of specificity and low bioavailability. Gene therapy has recently emerged as a powerful tool for cancer therapy. However, delivery methods limit its therapeutic effects. Exosomes, a subset of extracellular vesicles secreted by most cells, have the characteristics of good biocompatibility, low toxicity and immunogenicity, and great designability. In the past decades, as therapeutic carriers and diagnostic markers, they have caught extensive attention. This review introduced the characteristics of exosomes, and focused on their applications as delivery carriers in DNA, messenger RNA (mRNA), microRNA (miRNA), small interfering RNA (siRNA), circular RNA (circRNA) and other nucleic acids. Meanwhile, their application in cancer therapy and exosome-based clinical trials were presented and discussed. Through systematic summarization and analysis, the recent advances and current challenges of exosome-mediated nucleic acid delivery for cancer therapy are introduced, which will provide a theoretical basis for the development of nucleic acid drugs.
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Affiliation(s)
- Ying Zhang
- Central Laboratory of Longgang District People's Hospital of Shenzhen & The Second Affiliated Hospital, The Chinese University of Hong Kong, Shenzhen, 518172, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Qiqi Liu
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Xinmeng Zhang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Haoqiang Huang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Shiqi Tang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Yujuan Chai
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Zhourui Xu
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Meirong Li
- Central Laboratory of Longgang District People's Hospital of Shenzhen & The Second Affiliated Hospital, The Chinese University of Hong Kong, Shenzhen, 518172, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Xin Chen
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Jia Liu
- Central Laboratory of Longgang District People's Hospital of Shenzhen & The Second Affiliated Hospital, The Chinese University of Hong Kong, Shenzhen, 518172, China.
| | - Chengbin Yang
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China.
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30
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Peng L, Wang D, Han Y, Huang T, He X, Wang J, Ou C. Emerging Role of Cancer-Associated Fibroblasts-Derived Exosomes in Tumorigenesis. Front Immunol 2022; 12:795372. [PMID: 35058933 PMCID: PMC8764452 DOI: 10.3389/fimmu.2021.795372] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/13/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) are the most important component of the stromal cell population in the tumor microenvironment and play an irreplaceable role in oncogenesis and cancer progression. Exosomes, a class of small extracellular vesicles, can transfer biological information (e.g., proteins, nucleic acids, and metabolites as messengers) from secreting cells to target recipient cells, thereby affecting the progression of human diseases, including cancers. Recent studies revealed that CAF-derived exosomes play a crucial part in tumorigenesis, tumor cell proliferation, metastasis, drug resistance, and the immune response. Moreover, aberrant expression of CAF-derived exosomal noncoding RNAs and proteins strongly correlates with clinical pathological characterizations of cancer patients. Gaining deeper insight into the participation of CAF-derived exosomes in tumorigenesis may lead to novel diagnostic biomarkers and therapeutic targets in human cancers.
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Affiliation(s)
- Lushan Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Dan Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Yingying Han
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Tao Huang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyun He
- Department of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha, China
| | - Junpu Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.,Department of Pathology, School of Basic Medicine, Central South University, Changsha, China.,Key Laboratory of Hunan Province in Neurodegenerative Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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31
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Li Q, Wang D, Ding D, Feng Y, Hou R, Liu D, Lin C, Gao Y. The Role and Application of Exosomes in Gastric and Colorectal Cancer. Front Pharmacol 2022; 12:825475. [PMID: 35111071 PMCID: PMC8801572 DOI: 10.3389/fphar.2021.825475] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 12/27/2021] [Indexed: 12/29/2022] Open
Abstract
Gastric cancer and colorectal cancer are malignant tumors found in the human gastrointestinal tract. Bidirectional communication between tumor cells and their microenvironment can be realized through the transmission of exosomes—small, cell-derived vesicles containing complex RNA and proteins. Exosomes play an important role in the proliferation, metastasis, immune response, and drug resistance of cancer cells. In this review, we focus on the role and application of exosomes in gastric and colorectal cancer. We also summarize the role of exosomes secreted by different types of cells in tumor development and as drug carriers in cancer treatment.
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Affiliation(s)
- Qirong Li
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.,Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Dayong Ding
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Ye Feng
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Ruizhi Hou
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Dianfeng Liu
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Chao Lin
- School of Grain Science and Technology, Jilin Business and Technology College, Changchun, China
| | - Yongjian Gao
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
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32
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Roles and mechanisms of exosomal non-coding RNAs in human health and diseases. Signal Transduct Target Ther 2021; 6:383. [PMID: 34753929 PMCID: PMC8578673 DOI: 10.1038/s41392-021-00779-x] [Citation(s) in RCA: 209] [Impact Index Per Article: 52.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 09/23/2021] [Accepted: 09/26/2021] [Indexed: 02/07/2023] Open
Abstract
Exosomes play a role as mediators of cell-to-cell communication, thus exhibiting pleiotropic activities to homeostasis regulation. Exosomal non-coding RNAs (ncRNAs), mainly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are closely related to a variety of biological and functional aspects of human health. When the exosomal ncRNAs undergo tissue-specific changes due to diverse internal or external disorders, they can cause tissue dysfunction, aging, and diseases. In this review, we comprehensively discuss the underlying regulatory mechanisms of exosomes in human diseases. In addition, we explore the current knowledge on the roles of exosomal miRNAs, lncRNAs, and circRNAs in human health and diseases, including cancers, metabolic diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and infectious diseases, to determine their potential implication in biomarker identification and therapeutic exploration.
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33
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Tang XH, Guo T, Gao XY, Wu XL, Xing XF, Ji JF, Li ZY. Exosome-derived noncoding RNAs in gastric cancer: functions and clinical applications. Mol Cancer 2021; 20:99. [PMID: 34330299 PMCID: PMC8323226 DOI: 10.1186/s12943-021-01396-6] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/20/2021] [Indexed: 02/07/2023] Open
Abstract
Exosomes are a subpopulation of the tumour microenvironment (TME) that transmit various biological molecules to promote intercellular communication. Exosomes are derived from nearly all types of cells and exist in all body fluids. Noncoding RNAs (ncRNAs) are among the most abundant contents in exosomes, and some ncRNAs with biological functions are specifically packaged into exosomes. Recent studies have revealed that exosome-derived ncRNAs play crucial roles in the tumorigenesis, progression and drug resistance of gastric cancer (GC). In addition, regulating the expression levels of exosomal ncRNAs can promote or suppress GC progression. Moreover, the membrane structures of exosomes protect ncRNAs from degradation by enzymes and other chemical substances, significantly increasing the stability of exosomal ncRNAs. Specific hallmarks within exosomes that can be used for exosome identification, and specific contents can be used to determine their origin. Therefore, exosomal ncRNAs are suitable for use as diagnostic and prognostic biomarkers or therapeutic targets. Regulating the biogenesis of exosomes and the expression levels of exosomal ncRNAs may represent a new way to block or eradicate GC. In this review, we summarized the origins and characteristics of exosomes and analysed the association between exosomal ncRNAs and GC development.
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Affiliation(s)
- Xiao-Huan Tang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China.,Department of Gastrointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China
| | - Ting Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China
| | - Xiang-Yu Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China.,Department of Gastrointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China
| | - Xiao-Long Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China.,Department of Gastrointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China
| | - Xiao-Fang Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China.
| | - Jia-Fu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China. .,Department of Gastrointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China.
| | - Zi-Yu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China. .,Department of Gastrointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, P.R. China.
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Zhang H, Yang M, Wu X, Li Q, Li X, Zhao Y, Du F, Chen Y, Wu Z, Xiao Z, Shen J, Wen Q, Hu W, Cho CH, Chen M, Zhou Y, Li M. The distinct roles of exosomes in tumor-stroma crosstalk within gastric tumor microenvironment. Pharmacol Res 2021; 171:105785. [PMID: 34311072 DOI: 10.1016/j.phrs.2021.105785] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/19/2021] [Accepted: 07/22/2021] [Indexed: 02/07/2023]
Abstract
Gastric cancer (GC) development is a complex process displaying polytropic cell and molecular landscape within gastric tumor microenvironment (TME). Stromal cells in TME, including fibroblasts, endothelial cells, mesenchymal stem cells, and various immune cells, support tumor growth, metastasis, and recurrence, functioning as the soil for gastric tumorigenesis. Importantly, exosomes secreted by either stromal cells or tumor cells during tumor-stroma crosstalk perform as crucial transporter of agents including RNAs and proteins for cell-cell communication in GC pathogenesis. Therefore, given the distinct roles of exosomes secreted by various cell types in GC TME, increasing evidence has indicated that exosomes present as new biomarkers for GC diagnosis and prognosis and shed light on novel approaches for GC treatment.
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Affiliation(s)
- Hanyu Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; Nanchong Key Laboratory of Individualized Drug Therapy, Department of Pharmacy, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong 637000, Sichuan, China
| | - Min Yang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Qianxiu Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Xin Li
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Zhigui Wu
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Wei Hu
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen 518000, Guangzhou, China
| | - Chi Hin Cho
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China
| | - Meijuan Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.
| | - Yejiang Zhou
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China; South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China.
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Wang X, Wang X, Xu M, Sheng W. Effects of CAF-Derived MicroRNA on Tumor Biology and Clinical Applications. Cancers (Basel) 2021; 13:cancers13133160. [PMID: 34202583 PMCID: PMC8268754 DOI: 10.3390/cancers13133160] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/21/2021] [Accepted: 06/21/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs), prominent cell components of the tumor microenvironment (TME) in most types of solid tumor, play an essential role in tumor cell growth, proliferation, invasion, migration, and chemoresistance. MicroRNAs (miRNAs) are small, non-coding, single-strand RNAs that negatively regulate gene expression by post-transcription modification. Increasing evidence has suggested the dysregulation of miRNAs in CAFs, which facilitates the conversion of normal fibroblasts (NFs) into CAFs, then enhances the tumor-promoting capacity of CAFs. To understand the process of tumor progression, as well as the development of chemoresistance, it is important to explore the regulatory function of CAF-derived miRNAs and the associated molecular mechanisms, which may become potential diagnostic and prognostic biomarkers and targets of anti-tumor therapeutics. In this review, we describe miRNAs that are differentially expressed by NFs and CAFs, summarize the modulating role of CAF-derived miRNAs in fibroblast activation and tumor advance, and eventually identify a potential clinical application for CAF-derived miRNAs as diagnostic/prognostic biomarkers and therapeutic targets in several tumors.
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Affiliation(s)
- Xu Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, China; (X.W.); (X.W.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Institute of Pathology, Fudan University, Shanghai 200032, China
| | - Xin Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, China; (X.W.); (X.W.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Institute of Pathology, Fudan University, Shanghai 200032, China
| | - Midie Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, China; (X.W.); (X.W.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Correspondence: (M.X.); (W.S.); Tel.: +86-21-64175590 (M.X. & W.S.); Fax: +86-21-64174774 (M.X. & W.S.)
| | - Weiqi Sheng
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, China; (X.W.); (X.W.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Correspondence: (M.X.); (W.S.); Tel.: +86-21-64175590 (M.X. & W.S.); Fax: +86-21-64174774 (M.X. & W.S.)
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Hu F, Liu J, Liu H, Li F, Wan M, Zhang M, Jiang Y, Rao M. Role of Exosomal Non-coding RNAs in Gastric Cancer: Biological Functions and Potential Clinical Applications. Front Oncol 2021; 11:700168. [PMID: 34195097 PMCID: PMC8238120 DOI: 10.3389/fonc.2021.700168] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 05/25/2021] [Indexed: 12/19/2022] Open
Abstract
Gastric cancer (GC) is one of the most common fatal cancers worldwide. The communication between GC and other cells in the GC microenvironment directly affects GC progression. Recently, exosomes have been revealed as new players in intercellular communication. They play an important role in human health and diseases, including cancer, owing to their ability to carry various bioactive molecules, including non-coding RNAs (ncRNAs). NcRNAs, including micro RNAs, long non-coding RNAs, and circular RNAs, play a significant role in various pathophysiological processes, especially cancer. Increasing evidence has shown that exosomal ncRNAs are involved in the regulation of tumor proliferation, invasion, metastasis, angiogenesis, immune regulation, and treatment resistance in GC. In addition, exosomal ncRNAs have promising potential as diagnostic and prognostic markers for GC. Considering the biocompatibility of exosomes, they can also be used as biological carriers for targeted therapy. This review summarizes the current research progress on exosomal ncRNAs in gastric cancer, focusing on their biological role in GC and their potential as new biomarkers for GC and therapeutics. Our review provides insight into the mechanisms involved in GC progression, which may provide a new point cut for the discovery of new diagnostic markers and therapeutic strategies.
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Affiliation(s)
- Feng Hu
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Jixuan Liu
- Department of Pathology, The First Hospital of Jilin University, Changchun, China
| | - Huibo Liu
- Department of Dermatology, The First Hospital of Jilin University, Changchun, China
| | - Fan Li
- Department of Anesthesia, The First Hospital of Jilin University, Changchun, China
| | - Minjie Wan
- Department of Central Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Manli Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Yanfang Jiang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, China
| | - Min Rao
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
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Wu F, Yang J, Liu J, Wang Y, Mu J, Zeng Q, Deng S, Zhou H. Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer. Signal Transduct Target Ther 2021; 6:218. [PMID: 34108441 PMCID: PMC8190181 DOI: 10.1038/s41392-021-00641-0] [Citation(s) in RCA: 348] [Impact Index Per Article: 87.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/20/2021] [Accepted: 05/06/2021] [Indexed: 02/05/2023] Open
Abstract
To flourish, cancers greatly depend on their surrounding tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in TME are critical for cancer occurrence and progression because of their versatile roles in extracellular matrix remodeling, maintenance of stemness, blood vessel formation, modulation of tumor metabolism, immune response, and promotion of cancer cell proliferation, migration, invasion, and therapeutic resistance. CAFs are highly heterogeneous stromal cells and their crosstalk with cancer cells is mediated by a complex and intricate signaling network consisting of transforming growth factor-beta, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase, Wnt, Janus kinase/signal transducers and activators of transcription, epidermal growth factor receptor, Hippo, and nuclear factor kappa-light-chain-enhancer of activated B cells, etc., signaling pathways. These signals in CAFs exhibit their own special characteristics during the cancer progression and have the potential to be targeted for anticancer therapy. Therefore, a comprehensive understanding of these signaling cascades in interactions between cancer cells and CAFs is necessary to fully realize the pivotal roles of CAFs in cancers. Herein, in this review, we will summarize the enormous amounts of findings on the signals mediating crosstalk of CAFs with cancer cells and its related targets or trials. Further, we hypothesize three potential targeting strategies, including, namely, epithelial-mesenchymal common targets, sequential target perturbation, and crosstalk-directed signaling targets, paving the way for CAF-directed or host cell-directed antitumor therapy.
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Affiliation(s)
- Fanglong Wu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Jin Yang
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Junjiang Liu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Ye Wang
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Jingtian Mu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Qingxiang Zeng
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Shuzhi Deng
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Hongmei Zhou
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People's Republic of China.
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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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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: 68] [Impact Index Per Article: 17.0] [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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Joshi RS, Kanugula SS, Sudhir S, Pereira MP, Jain S, Aghi MK. The Role of Cancer-Associated Fibroblasts in Tumor Progression. Cancers (Basel) 2021; 13:cancers13061399. [PMID: 33808627 PMCID: PMC8003545 DOI: 10.3390/cancers13061399] [Citation(s) in RCA: 121] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/10/2021] [Accepted: 03/14/2021] [Indexed: 12/15/2022] Open
Abstract
In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, which may help advance the cancer treatment paradigm to determine the next generation of cancer therapy. The aim of this review is to provide a detailed overview of the key roles that CAFs play in the scope of systemic disease, the mechanisms by which they enhance protumoral effects, and the primary CAF-related markers that may offer potential targets for novel therapeutics.
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Affiliation(s)
- Rushikesh S. Joshi
- School of Medicine, University of California, San Diego, La Jolla, CA 92092, USA;
| | | | - Sweta Sudhir
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Matheus P. Pereira
- School of Medicine, University of California, San Francisco, CA 94143, USA;
| | - Saket Jain
- Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA;
| | - Manish K. Aghi
- Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA;
- Correspondence: ; Tel.: +1-415-514-9820
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Wang H, Li H, Jiang Q, Dong X, Li S, Cheng S, Shi J, Liu L, Qian Z, Dong J. HOTAIRM1 Promotes Malignant Progression of Transformed Fibroblasts in Glioma Stem-Like Cells Remodeled Microenvironment via Regulating miR-133b-3p/TGFβ Axis. Front Oncol 2021; 11:603128. [PMID: 33816233 PMCID: PMC8017308 DOI: 10.3389/fonc.2021.603128] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 02/24/2021] [Indexed: 12/11/2022] Open
Abstract
Recent studies have reported that cancer associated fibroblasts (CAFs) and glioma stem-like cells (GSCs) played active roles in glioma progression in tumor microenvironment (TME). Long non-coding RNAs (lncRNAs) have been found to be closely associated with glioma development in recent years, however, their molecular regulatory mechanisms on CAFs in GSCs remodeled TME kept largely unelucidated. Our study found that GSCs could induce malignant transformation of fibroblasts (t-FBs) based on dual-color fluorescence tracing orthotopic model. Associated with poor prognosis, Lnc HOXA transcript antisense RNA, myeloid-specific 1 (HOTAIRM1) was highly expressed in high-grade gliomas and t-FBs. Depleting HOTAIRM1 inhibited the proliferation, invasion, migration, and even tumorigenicity of t-FB. Conversely, overexpression of HOTAIRM1 promoted malignancy phenotype of t-FB. Mechanistically, HOTAIRM1 directly bound with miR-133b-3p, and negatively regulated the latter. MiR-133b-3p partly decreased the promotion effect of HOTAIRM1 on t-FBs. Furthermore, transforming growth factor-β (TGFβ) was verified to be a direct target of miR-133b-3p. HOTAIRM1 can modulate TGFβ via competing with miR-133b-3p. Collectively, HOTAIRM1/miR-133b-3p/TGFβ axis was involved in modulating t-FBs malignancy in TME remodeled by GSCs, which had the potential to serve as a target against gliomas.
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Affiliation(s)
- Haiyang Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Haoran Li
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Qianqian Jiang
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xuchen Dong
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Suwen Li
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Shan Cheng
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jia Shi
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Liang Liu
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhiyuan Qian
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jun Dong
- Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Wen T, Wang H, Li Y, Lin Y, Zhao S, Liu J, Chen B. Bone mesenchymal stem cell-derived extracellular vesicles promote the repair of intervertebral disc degeneration by transferring microRNA-199a. Cell Cycle 2021; 20:256-270. [PMID: 33499725 DOI: 10.1080/15384101.2020.1863682] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Extracellular vesicles (EVs) secreted by bone marrow mesenchymal stem cells (BMSCs) protect intervertebral disc degeneration (IDD) by regulating nucleus pulposus cell (NPC) apoptosis. But the mechanism of BMSCs-EVs-microRNA (miR)-199a in IDD remains unclear. In this study, after the acquisition and identification of BMSCs and BMSCs-EVs, IDD mouse model was established and treated with BMSCs-EVs. The pathological changes of NPCs, positive expression of MMP-2, MMP-6 and TIMP1, and the senescence and apoptosis of NPCs were evaluated. Microarray analysis was employed to analyze the differentially expressed miRs and genes after EV treatment. NPCs were treated with EVs/miR-199a/TGF-β agonist SRI-011381. The positive expression of col II and Aggrecan was assessed. The target gene and downstream pathway of miR-199a were analyzed. In vivo experiment, after BMSCs-EV treatment, MMP-2, MMP-6, TIMP1 and TUNEL-positive cells in IDD mice were decreased, and miR-199a was increased. In vitro experiments, the expression of col Ⅱ and Aggrecan, SA-β gal positive cells and apoptosis rate of NPCs were decreased after EV intervention. The protective effect of BMSCs-EVs on NPCs was impaired by reducing miR-199a carried by EVs. miR-199a could target GREM1 to inactivate the TGF-β pathway. miR-199a carried by BMSCs-EVs promotes IDD repair by targeting GREM1 and downregulating the TGF-β pathway. Our work confers a promising therapeutic strategy for IDD.
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Affiliation(s)
- Tao Wen
- Department of Spine Center, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine , Guangzhou, Guangdong, China
| | - Hongshen Wang
- Department of Spine Center, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine , Guangzhou, Guangdong, China
| | - Yongjin Li
- Department of Spine Center, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine , Guangzhou, Guangdong, China
| | - Yongpeng Lin
- Department of Spine Center, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine , Guangzhou, Guangdong, China
| | - Shuai Zhao
- Department of Spine Center, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine , Guangzhou, Guangdong, China
| | - Jinggong Liu
- Department of Spine Center, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine , Guangzhou, Guangdong, China
| | - Bolai Chen
- Department of Spine Center, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine , Guangzhou, Guangdong, China
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Wang M, Zhao Y, Yu ZY, Zhang RD, Li SA, Zhang P, Shan TK, Liu XY, Wang ZM, Zhao PC, Sun HW. Glioma exosomal microRNA-148a-3p promotes tumor angiogenesis through activating the EGFR/MAPK signaling pathway via inhibiting ERRFI1. Cancer Cell Int 2020; 20:518. [PMID: 33117083 PMCID: PMC7590612 DOI: 10.1186/s12935-020-01566-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 09/23/2020] [Indexed: 12/12/2022] Open
Abstract
Background Glioma is the most frequent and lethal primary brain malignancy. Amounting evidence has highlighted the importance of exosomal microRNAs (miRNAs or miRs) in this malignancy. This study aimed to investigate the regulatory role of exosomal miR-148a-3p in glioma. Methods Bioinformatics analysis was firstly used to predict the target genes of miR-148a-3p. Exosomes were then extracted from normal human astrocytes and glioma cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was applied to determine the expression patterns of miR-148a-3p and ERBB receptor feedback inhibitor 1 (ERRFI1). Dual-luciferase reporter gene assay was applied to verify the direct binding between miR-148a-3p and ERRFI1. Cell counting kit-8 and tube formation assays were further conducted to assess the proliferation and angiogenic properties of human umbilical vein endothelial cells (HUVECs) in the co-culture system with exosomes. Lastly, glioma tumor models were established in BALB/c nude mice to study the role of exosomal miR-148a-3p in vivo. Results miR-148a-3p was highly expressed, while ERRFI1 was poorly expressed in glioma. miR-148a-3p was found to be enriched in glioma cells-derived exosomes and could be transferred to HUVECs via exosomes to promote their proliferation and angiogenesis. ERRFI1 was identified as a target gene of miR-148a-3p. In addition, miR-148a-3p activated the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signaling pathway by inhibiting ERRFI1. In the co-culture system, our data demonstrated that glioma cells-derived exosomal miR-148a-3p down-regulated ERRFI1 and activated the EGFR/MAPK signaling pathway, so as to promote cell proliferation and angiogenesis. In vivo experimentation further demonstrated that this mechanism was responsible for the promotive role of exosomal miR-148a-3p in tumorigenesis and angiogenesis. Conclusion Taken together, glioma-derived exosomal miR-148a-3p promoted tumor angiogenesis through activation of the EGFR/MAPK signaling pathway by ERRFI1 inhibition.
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Affiliation(s)
- Meng Wang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East RoadHenan Province, Zhengzhou, 450052 Henan Province People's Republic of China
| | - Yi Zhao
- Department of Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000 People's Republic of China
| | - Zhi-Yun Yu
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East RoadHenan Province, Zhengzhou, 450052 Henan Province People's Republic of China
| | - Ren-De Zhang
- Department of Medical, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Shu-Ang Li
- Clinical Systems Biology Laboratories, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000 People's Republic of China
| | - Peng Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East RoadHenan Province, Zhengzhou, 450052 Henan Province People's Republic of China
| | - Ti-Kun Shan
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East RoadHenan Province, Zhengzhou, 450052 Henan Province People's Republic of China
| | - Xue-You Liu
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East RoadHenan Province, Zhengzhou, 450052 Henan Province People's Republic of China
| | - Ze-Ming Wang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East RoadHenan Province, Zhengzhou, 450052 Henan Province People's Republic of China
| | - Pei-Chao Zhao
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East RoadHenan Province, Zhengzhou, 450052 Henan Province People's Republic of China
| | - Hong-Wei Sun
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East RoadHenan Province, Zhengzhou, 450052 Henan Province People's Republic of China
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