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1
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Xu Y, Xu L, Chen Q, Zou C, Huang J, Zhang L. Crosstalk between exosomes and tumor-associated macrophages in hepatocellular carcinoma: implication for cancer progression and therapy. Front Immunol 2025; 16:1512480. [PMID: 40264760 PMCID: PMC12011854 DOI: 10.3389/fimmu.2025.1512480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 02/26/2025] [Indexed: 04/24/2025] Open
Abstract
Hepatocellular carcinoma (HCC), the most prevalent type of primary liver cancer, represents a significant cause of cancer-related mortality. While our understanding of its pathogenesis is comparatively comprehensive, the influence of the tumor microenvironment (TME) on its progression warrants additional investigation. Tumor-associated macrophages (TAMs) have significant impacts on cancer cell proliferation, migration, invasion, and immune response, facilitating a complex interaction within the TME. Exosomes, which measure between 30 and 150 nanometers in size, are categorized into small extracellular vesicles, secreted by a wide range of eukaryotic cells. They can transfer biological molecules including proteins, non-coding RNAs, and lipids, which mediates the intercellular communication within the TME. Emerging evidence has revealed that exosomes regulate macrophage polarization, thus impacting cancer progression and immune responses within the TME of HCC. Moreover, TAM-derived exosomes also play crucial roles in malignant transformation, which hold immense potential for cancer therapy. In this review, we elaborate on the crosstalk between exosomes and TAMs within TME during HCC development. Moreover, we delve into the feasible treatment approaches for exosomes in cancer therapy and emphasize the limitations and challenges for the translation of exosomes derived from TAMs into clinical courses for cancer therapy, which may provide new perspectives on further ameliorations of therapeutic regimes based on exosomes to advance their clinical applications.
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Affiliation(s)
- Ying Xu
- Department of Anesthesiology Operating Room, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Linyue Xu
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China
| | - Qiuyan Chen
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China
| | - Can Zou
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China
| | - Ju Huang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Limei Zhang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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2
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Wei W, Li J, Huang J, Jiang Q, Lin C, Hu R, Wei J, Li Q, Xu G, Chang Z. Exosomal miR‑3681‑3p from M2‑polarized macrophages confers cisplatin resistance to gastric cancer cells by targeting MLH1. Mol Med Rep 2025; 31:94. [PMID: 39981936 PMCID: PMC11851060 DOI: 10.3892/mmr.2025.13459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 01/07/2025] [Indexed: 02/22/2025] Open
Abstract
Cisplatin (DDP) is a key chemotherapeutic agent in the treatment of gastric cancer; however, its efficacy is often limited by chemoresistance, a notable challenge in clinical oncology. The present study aimed to investigate the influence of exosomes derived from M2‑polarized macrophages, which promote this resistance, on the response of gastric cancer cells to DDP, examining both the effects and the underlying mechanisms. M2 macrophages, differentiated from mouse bone marrow cells with interleukin (IL)‑13 and IL‑4, were identified using immunofluorescence staining for CD206 and CD163. Exosomes derived from these macrophages were characterized using transmission electron microscopy and protein markers, including calnexin, tumor susceptibility gene 101 and CD9. The role of exosomal microRNA (miR)‑3681‑3p in DDP resistance was assessed using Cell Counting Kit‑8 and apoptosis assays, while a luciferase reporter assay was used to elucidate the interaction between miR‑3681‑3p and MutL protein homolog 1 (MLH1). Co‑culturing gastric cancer cells with M2 macrophages enhanced DDP resistance, an effect amplified by exosomes from M2 macrophages enriched with miR‑3681‑3p. This microRNA directly targeted and reduced MLH1 protein expression. Overexpression of miR‑3681‑3p through mimic transfection, along with MLH1 silencing by small interfering RNA transfection, significantly increased DDP resistance, as evidenced by elevated IC50 values in AGS cells. By contrast, the overexpression of MLH1 effectively reversed the drug resistance of AGS cells to DDP caused by miR‑3681‑3p mimic transfection, as evidenced by a decrease in the IC50 value. In conclusion, exosomal miR‑3681‑3p from M2 macrophages may have a key role in conferring DDP resistance to gastric cancer by suppressing MLH1, offering a new therapeutic target for overcoming chemoresistance.
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Affiliation(s)
- Wujun Wei
- Center for Clinical Laboratory Diagnosis and Research, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
- Clinic Medicine Research Center of Hepatobiliary Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
- Baise Key Laboratory for Research and Development on Clinical Molecular Diagnosis for High-Incidence Diseases, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Jiaxing Li
- Department of Pharmacy, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Jingjing Huang
- Department of Health Care, Baise Maternity and Child Health Center, Baise, Guangxi 533000, P.R. China
| | - Qi Jiang
- Department of Gastroenterology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Cheng Lin
- Department of Oncology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Rentong Hu
- Center for Clinical Laboratory Diagnosis and Research, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Jiazhu Wei
- Center for Clinical Laboratory Diagnosis and Research, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Qiao Li
- Department of Neurology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Guidan Xu
- Center for Clinical Laboratory Diagnosis and Research, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
| | - Zhengyi Chang
- Center for Clinical Laboratory Diagnosis and Research, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, P.R. China
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3
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Lin F, Luo H, Wang J, Li Q, Zha L. Macrophage-derived extracellular vesicles as new players in chronic non-communicable diseases. Front Immunol 2025; 15:1479330. [PMID: 39896803 PMCID: PMC11782043 DOI: 10.3389/fimmu.2024.1479330] [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: 08/13/2024] [Accepted: 12/23/2024] [Indexed: 02/04/2025] Open
Abstract
Macrophages are innate immune cells present in all tissues and play an important role in almost all aspects of the biology of living organisms. Extracellular vesicles (EVs) are released by cells and transport their contents (micro RNAs, mRNA, proteins, and long noncoding RNAs) to nearby or distant cells for cell-to-cell communication. Numerous studies have shown that macrophage-derived extracellular vesicles (M-EVs) and their contents play an important role in a variety of diseases and show great potential as biomarkers, therapeutics, and drug delivery vehicles for diseases. This article reviews the biological functions and mechanisms of M-EVs and their contents in chronic non-communicable diseases such as cardiovascular diseases, metabolic diseases, cancer, inflammatory diseases and bone-related diseases. In addition, the potential application of M-EVs as drug delivery systems for various diseases have been summarized.
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Affiliation(s)
- Fengjuan Lin
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - Huiyu Luo
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - Jiexian Wang
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - Qing Li
- Department of Clinical Nutrition, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Longying Zha
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration (NMPA) Key Laboratory for Safety Evaluation of Cosmetics, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
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4
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Fang R, Sha C, Xie Q, Yao D, Yao M. Alterations of Krüppel-like Factor Signaling and Potential Targeted Therapy for Hepatocellular Carcinoma. Anticancer Agents Med Chem 2025; 25:75-85. [PMID: 39313900 DOI: 10.2174/0118715206301453240910044913] [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: 04/28/2024] [Revised: 08/08/2024] [Accepted: 08/26/2024] [Indexed: 09/25/2024]
Abstract
Krüppel-like factors (KLFs, total 18 members) from the zinc finger protein (ZFP) super-family have a wide range of biological functions in hepatocellular carcinoma (HCC). This paper reviews the recent some progresses of aberrant KLFs with their potential values for diagnosis, prognosis, and targeted therapy in HCC. The recent advances of oncogenic KLFs in the diagnosis, prognosis, and targeted therapy of HCC were reviewed based on the related literature on PUBMED and clinical investigation. Based on the recent literature, KLFs, according to biological functions in HCC, are divided into 4 subgroups: promoting (KLF5, 7, 8, 13), inhibiting (KLF3, 4, 9~12, 14, 17), dual (KLF2, 6), and unknown functions (KLF1, 15, 16, or 18 ?). HCC-related KLFs regulate downstream gene transcription during hepatocyte malignant transformation, participating in cell proliferation, apoptosis, invasion, and metastasis. Some KLFs have diagnostic or prognostic value, and other KLFs with inhibiting promoting function or over-expressing inhibiting roles might be molecular targets for HCC therapy. These data have suggested that Abnormal expressions of KLFs were associated with HCC progression. Among them, some KLFs have revealed the clinical values of diagnosis or prognosis, and other KLFs with the biological functions of promotion or inhibition might be as effectively molecular targets for HCC therapy.
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Affiliation(s)
- Rongfei Fang
- Research Center of Clinical Medicine, Department of Medical Immunology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Chunxiu Sha
- Research Center of Clinical Medicine, Department of Medical Immunology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Qun Xie
- Department of Infectious Diseases, Nantong Haian People's Hospital, Haian 226600, Jiangsu Province, China
| | - Dengfu Yao
- Research Center of Clinical Medicine, Department of Medical Immunology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Min Yao
- Research Center of Clinical Medicine, Department of Medical Immunology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
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Mahboobnia K, Beveridge DJ, Yeoh GC, Kabir TD, Leedman PJ. MicroRNAs in Hepatocellular Carcinoma Pathogenesis: Insights into Mechanisms and Therapeutic Opportunities. Int J Mol Sci 2024; 25:9393. [PMID: 39273339 PMCID: PMC11395074 DOI: 10.3390/ijms25179393] [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: 07/21/2024] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
Hepatocellular carcinoma (HCC) presents a significant global health burden, with alarming statistics revealing its rising incidence and high mortality rates. Despite advances in medical care, HCC treatment remains challenging due to late-stage diagnosis, limited effective therapeutic options, tumor heterogeneity, and drug resistance. MicroRNAs (miRNAs) have attracted substantial attention as key regulators of HCC pathogenesis. These small non-coding RNA molecules play pivotal roles in modulating gene expression, implicated in various cellular processes relevant to cancer development. Understanding the intricate network of miRNA-mediated molecular pathways in HCC is essential for unraveling the complex mechanisms underlying hepatocarcinogenesis and developing novel therapeutic approaches. This manuscript aims to provide a comprehensive review of recent experimental and clinical discoveries regarding the complex role of miRNAs in influencing the key hallmarks of HCC, as well as their promising clinical utility as potential therapeutic targets.
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Affiliation(s)
- Khadijeh Mahboobnia
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - Dianne J Beveridge
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - George C Yeoh
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
| | - Tasnuva D Kabir
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
| | - Peter J Leedman
- Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, WA 6009, Australia
- Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia
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Yin Y, Feng W, Chen J, Chen X, Wang G, Wang S, Xu X, Nie Y, Fan D, Wu K, Xia L. Immunosuppressive tumor microenvironment in the progression, metastasis, and therapy of hepatocellular carcinoma: from bench to bedside. Exp Hematol Oncol 2024; 13:72. [PMID: 39085965 PMCID: PMC11292955 DOI: 10.1186/s40164-024-00539-x] [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: 02/27/2024] [Accepted: 07/10/2024] [Indexed: 08/02/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with high incidence, recurrence, and metastasis rates. The emergence of immunotherapy has improved the treatment of advanced HCC, but problems such as drug resistance and immune-related adverse events still exist in clinical practice. The immunosuppressive tumor microenvironment (TME) of HCC restricts the efficacy of immunotherapy and is essential for HCC progression and metastasis. Therefore, it is necessary to elucidate the mechanisms behind immunosuppressive TME to develop and apply immunotherapy. This review systematically summarizes the pathogenesis of HCC, the formation of the highly heterogeneous TME, and the mechanisms by which the immunosuppressive TME accelerates HCC progression and metastasis. We also review the status of HCC immunotherapy and further discuss the existing challenges and potential therapeutic strategies targeting immunosuppressive TME. We hope to inspire optimizing and innovating immunotherapeutic strategies by comprehensively understanding the structure and function of immunosuppressive TME in HCC.
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Affiliation(s)
- Yue Yin
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Weibo Feng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Jie Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Xilang Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Guodong Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Shuai Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Xiao Xu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yongzhan Nie
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Daiming Fan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Kaichun Wu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
| | - Limin Xia
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
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7
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Li D, Zhang T, Guo Y, Bi C, Liu M, Wang G. Biological impact and therapeutic implication of tumor-associated macrophages in hepatocellular carcinoma. Cell Death Dis 2024; 15:498. [PMID: 38997297 PMCID: PMC11245522 DOI: 10.1038/s41419-024-06888-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 06/26/2024] [Accepted: 07/02/2024] [Indexed: 07/14/2024]
Abstract
The tumor microenvironment is a complex space comprised of normal, cancer and immune cells. The macrophages are considered as the most abundant immune cells in tumor microenvironment and their function in tumorigenesis is interesting. Macrophages can be present as M1 and M2 polarization that show anti-cancer and oncogenic activities, respectively. Tumor-associated macrophages (TAMs) mainly have M2 polarization and they increase tumorigenesis due to secretion of factors, cytokines and affecting molecular pathways. Hepatocellular carcinoma (HCC) is among predominant tumors of liver that in spite of understanding its pathogenesis, the role of tumor microenvironment in its progression still requires more attention. The presence of TAMs in HCC causes an increase in growth and invasion of HCC cells and one of the reasons is induction of glycolysis that such metabolic reprogramming makes HCC distinct from normal cells and promotes its malignancy. Since M2 polarization of TAMs stimulates tumorigenesis in HCC, molecular networks regulating M2 to M1 conversion have been highlighted and moreover, drugs and compounds with the ability of targeting TAMs and suppressing their M2 phenotypes or at least their tumorigenesis activity have been utilized. TAMs increase aggressive behavior and biological functions of HCC cells that can result in development of therapy resistance. Macrophages can provide cell-cell communication in HCC by secreting exosomes having various types of biomolecules that transfer among cells and change their activity. Finally, non-coding RNA transcripts can mainly affect polarization of TAMs in HCC.
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Affiliation(s)
- Deming Li
- Department of Anesthesiology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China
| | - Ting Zhang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, 110001, PR China
| | - Ye Guo
- Department of Intervention, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China
| | - Cong Bi
- Department of Radiology, The First Hospital of China Medical University, Shenyang, 110001, PR China.
| | - Ming Liu
- Department of Oral Radiology, School of Stomatology, China Medical University, Shenyang, Liaoning, 110002, PR China.
| | - Gang Wang
- Department of Intervention, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, PR China.
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Tian L, Lu J, Ng IOL. Extracellular vesicles and cancer stemness in hepatocellular carcinoma - is there a link? Front Immunol 2024; 15:1368898. [PMID: 38476233 PMCID: PMC10927723 DOI: 10.3389/fimmu.2024.1368898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 02/09/2024] [Indexed: 03/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy, with high recurrence rates and notorious resistance to conventional chemotherapy. Cancer stemness refers to the stem-cell-like phenotype of cancer cells and has been recognized to play important roles in different aspects of hepatocarcinogenesis. Small extracellular vesicles (sEVs) are small membranous particles secreted by cells that can transfer bioactive molecules, such as nucleic acids, proteins, lipids, and metabolites, to neighboring or distant cells. Recent studies have highlighted the role of sEVs in modulating different aspects of the cancer stemness properties of HCC. Furthermore, sEVs derived from diverse cellular sources, such as cancer cells, stromal cells, and immune cells, contribute to the maintenance of the cancer stemness phenotype in HCC. Through cargo transfer, specific signaling pathways are activated within the recipient cells, thus promoting the stemness properties. Additionally, sEVs can govern the secretion of growth factors from non-cancer cells to further maintain their stemness features. Clinically, plasma sEVs may hold promise as potential biomarkers for HCC diagnosis and treatment prediction. Understanding the underlying mechanisms by which sEVs promote cancer stemness in HCC is crucial, as targeting sEV-mediated communication may offer novel strategies in treatment and improve patient outcome.
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Affiliation(s)
- Lu Tian
- Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Department of Pathology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Jingyi Lu
- Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Irene Oi-Lin Ng
- Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Department of Pathology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
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9
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Yuce K, Ozkan AI. The kruppel-like factor (KLF) family, diseases, and physiological events. Gene 2024; 895:148027. [PMID: 38000704 DOI: 10.1016/j.gene.2023.148027] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 11/06/2023] [Accepted: 11/21/2023] [Indexed: 11/26/2023]
Abstract
The Kruppel-Like Factor family of regulatory proteins, which has 18 members, is transcription factors. This family contains zinc finger proteins, regulates the activation and suppression of transcription, and binds to DNA, RNA, and proteins. Klfs related to the immune system are Klf1, Klf2, Klf3, Klf4, Klf6, and Klf14. Klfs related to adipose tissue development and/or glucose metabolism are Klf3, Klf7, Klf9, Klf10, Klf11, Klf14, Klf15, and Klf16. Klfs related to cancer are Klf3, Klf4, Klf5, Klf6, Klf7, Klf8, Klf9, Klf10, Klf11, Klf12, Klf13, Klf14, Klf16, and Klf17. Klfs related to the cardiovascular system are Klf4, Klf5, Klf10, Klf13, Klf14, and Klf15. Klfs related to the nervous system are Klf4, Klf7, Klf8, and Klf9. Klfs are associated with diseases such as carcinogenesis, oxidative stress, diabetes, liver fibrosis, thalassemia, and the metabolic syndrome. The aim of this review is to provide information about the relationship of Klfs with some diseases and physiological events and to guide future studies.
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Affiliation(s)
- Kemal Yuce
- Selcuk University, Medicine Faculty, Department of Basic Medical Sciences, Physiology, Konya, Turkiye.
| | - Ahmet Ismail Ozkan
- Artvin Coruh University, Medicinal-Aromatic Plants Application and Research Center, Artvin, Turkiye.
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10
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Xiang SY, Deng KL, Yang DX, Yang P, Zhou YP. Function of macrophage-derived exosomes in chronic liver disease: From pathogenesis to treatment. World J Hepatol 2023; 15:1196-1209. [DOI: 10.4254/wjh.v15.i11.1196] [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: 09/02/2023] [Revised: 10/09/2023] [Accepted: 10/23/2023] [Indexed: 11/24/2023] Open
Abstract
Chronic liver disease (CLD) imposes a heavy burden on millions of people worldwide. Despite substantial research on the pathogenesis of CLD disorders, no optimal treatment is currently available for some diseases, such as liver cancer. Exosomes, which are extracellular vesicles, are composed of various cellular components. Exosomes have unique functions in maintaining cellular homeostasis and regulating cell communication, which are associated with the occurrence of disease. Furthermore, they have application potential in diagnosis and treatment by carrying diverse curative payloads. Hepatic macrophages, which are key innate immune cells, show extraordinary heterogeneity and polarization. Hence, macrophage-derived exosomes may play a pivotal role in the initiation and progression of various liver diseases. This review focuses on the effects of macrophage-derived exosomes on liver disease etiology and their therapeutic potential, which will provide new insights into alleviating the global pressure of CLD.
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Affiliation(s)
- Shi-Yi Xiang
- Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
| | - Kai-Li Deng
- Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Dong-Xue Yang
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Institute of Digestive Disease of Ningbo University, Ningbo University, Ningbo 315020, Zhejiang Province, China
| | - Ping Yang
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
| | - Yu-Ping Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Institute of Digestive Disease of Ningbo University, Ningbo University, Ningbo 315020, Zhejiang Province, China
- Ningbo Key Laboratory of Translational Medicine Research on Gastroenterology and Hepatology, Ningbo Key Laboratory, Ningbo 315020, Zhejiang Province, China
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11
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Wang HC, Yin WX, Jiang M, Han JY, Kuai XW, Sun R, Sun YF, Ji JL. Function and biomedical implications of exosomal microRNAs delivered by parenchymal and nonparenchymal cells in hepatocellular carcinoma. World J Gastroenterol 2023; 29:5435-5451. [PMID: 37900996 PMCID: PMC10600808 DOI: 10.3748/wjg.v29.i39.5435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/13/2023] [Accepted: 10/16/2023] [Indexed: 10/19/2023] Open
Abstract
Small extracellular vesicles (exosomes) are important components of the tumor microenvironment. They are small membrane-bound vesicles derived from almost all cell types and play an important role in intercellular communication. Exosomes transmit biological molecules obtained from parent cells, such as proteins, lipids, and nucleic acids, and are involved in cancer development. MicroRNAs (miRNAs), the most abundant contents in exosomes, are selectively packaged into exosomes to carry out their biological functions. Recent studies have revealed that exosome-delivered miRNAs play crucial roles in the tumorigenesis, progression, and drug resistance of hepatocellular carcinoma (HCC). In addition, exosomes have great industrial prospects in the diagnosis, treatment, and prognosis of patients with HCC. This review summarized the composition and function of exosomal miRNAs of different cell origins in HCC and highlighted the association between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC. Finally, we described the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC.
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Affiliation(s)
- Hai-Chen Wang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Wen-Xuan Yin
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Meng Jiang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Jia-Yi Han
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Xing-Wang Kuai
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Rui Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Yu-Feng Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Ju-Ling Ji
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
- Department of Pathology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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12
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Agirre-Lizaso A, Huici-Izagirre M, Urretabizkaia-Garmendia J, Rodrigues PM, Banales JM, Perugorria MJ. Targeting the Heterogeneous Tumour-Associated Macrophages in Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:4977. [PMID: 37894344 PMCID: PMC10605535 DOI: 10.3390/cancers15204977] [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: 09/01/2023] [Revised: 09/30/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer that comprises a complex tumour microenvironment (TME). Tumour-associated macrophages (TAMs) are one of the most abundant immune cells present in the TME, and play a key role both in the development and in the progression of HCC. Thus, TAM-based immunotherapy has been presented as a promising strategy to complement the currently available therapies for HCC treatment. Among the novel approaches focusing on TAMs, reprogramming their functional state has emerged as a promising option for targeting TAMs as an immunotherapy in combination with the currently available treatment options. Nevertheless, a further understanding of the immunobiology of TAMs is still required. This review synthesizes current insights into the heterogeneous nature of TAMs in HCC and describes the mechanisms behind their pro-tumoural polarization focusing the attention on their interaction with HCC cells. Furthermore, this review underscores the potential involvement of TAMs' reprogramming in HCC therapy and highlights the urgency of advancing our understanding of these cells within the dynamic landscape of HCC.
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Affiliation(s)
- Aloña Agirre-Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), 20014 Donostia-San Sebastian, Spain; (A.A.-L.); (M.H.-I.); (J.U.-G.); (P.M.R.); (J.M.B.)
| | - Maider Huici-Izagirre
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), 20014 Donostia-San Sebastian, Spain; (A.A.-L.); (M.H.-I.); (J.U.-G.); (P.M.R.); (J.M.B.)
| | - Josu Urretabizkaia-Garmendia
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), 20014 Donostia-San Sebastian, Spain; (A.A.-L.); (M.H.-I.); (J.U.-G.); (P.M.R.); (J.M.B.)
| | - Pedro M. Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), 20014 Donostia-San Sebastian, Spain; (A.A.-L.); (M.H.-I.); (J.U.-G.); (P.M.R.); (J.M.B.)
- Centre for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), 20014 Donostia-San Sebastian, Spain; (A.A.-L.); (M.H.-I.); (J.U.-G.); (P.M.R.); (J.M.B.)
- Centre for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain
| | - Maria J. Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), 20014 Donostia-San Sebastian, Spain; (A.A.-L.); (M.H.-I.); (J.U.-G.); (P.M.R.); (J.M.B.)
- Centre for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 20014 Donostia-San Sebastian, Spain
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13
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Ghionescu AV, Sorop A, Dima SO. The pivotal role of EMT-related noncoding RNAs regulatory axes in hepatocellular carcinoma. Front Pharmacol 2023; 14:1270425. [PMID: 37767397 PMCID: PMC10520284 DOI: 10.3389/fphar.2023.1270425] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a major health problem worldwide, being the leading cause of cancer-related deaths, with limited treatment options, especially in its advanced stages. Tumor resistance is closely associated with the activation of the EMT phenomenon and its reversal, being modulated by different molecules, including noncoding RNAs (ncRNAs). Noncoding RNAs have the potential to function as both tumor suppressors and oncogenic molecules, controlling the malignant potential of HCC cells. Basically, these molecules circulate in the tumor microenvironment, encapsulated in exosomes. Their impact on cell biology is more significant than originally expected, which makes related research rather complex. The temporal and spatial expression patterns, precise roles and mechanisms of specific ncRNAs encapsulated in exosomes remain primarily unknown in different stages of the disease. This review aims to highlight the recent advances in ncRNAs related to EMT and classifies the described mechanism as direct and indirect, for a better summarization. Moreover, we provide an overview of current research on the role of ncRNAs in several drug resistance-related pathways, including the emergence of resistance to sorafenib, doxorubicin, cisplatin and paclitaxel therapy. Nevertheless, we comprehensively discuss the underlying regulatory mechanisms of exosomal ncRNAs in EMT-HCC via intercellular communication pathways.
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Affiliation(s)
| | - Andrei Sorop
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Simona Olimpia Dima
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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14
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Papadakos SP, Machairas N, Stergiou IE, Arvanitakis K, Germanidis G, Frampton AE, Theocharis S. Unveiling the Yin-Yang Balance of M1 and M2 Macrophages in Hepatocellular Carcinoma: Role of Exosomes in Tumor Microenvironment and Immune Modulation. Cells 2023; 12:2036. [PMID: 37626849 PMCID: PMC10453902 DOI: 10.3390/cells12162036] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/03/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate and limited treatment options. Recent research has brought attention to the significant importance of intercellular communication in the progression of HCC, wherein exosomes have been identified as critical agents facilitating cell-to-cell signaling. In this article, we investigate the impact of macrophages as both sources and targets of exosomes in HCC, shedding light on the intricate interplay between exosome-mediated communication and macrophage involvement in HCC pathogenesis. It investigates how exosomes derived from HCC cells and other cell types within the tumor microenvironment (TME) can influence macrophage behavior, polarization, and recruitment. Furthermore, the section explores the reciprocal interactions between macrophage-derived exosomes and HCC cells, stromal cells, and other immune cells, elucidating their role in tumor growth, angiogenesis, metastasis, and immune evasion. The findings presented here contribute to a better understanding of the role of macrophage-derived exosomes in HCC progression and offer new avenues for targeted interventions and improved patient outcomes.
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Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 10679 Athens, Greece;
| | - Nikolaos Machairas
- Second Department of Propaedeutic Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 11527 Athens, Greece;
| | - Ioanna E. Stergiou
- Pathophysiology Department, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Konstantinos Arvanitakis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece; (K.A.); (G.G.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Georgios Germanidis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece; (K.A.); (G.G.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Adam Enver Frampton
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
- Oncology Section, Surrey Cancer Research Institute, Department of Clinical and Experimental Medicine, FHMS, University of Surrey, The Leggett Building, Daphne Jackson Road, Guildford GU2 7WG, UK
- HPB Surgical Unit, Royal Surrey NHS Foundation Trust, Guildford GU2 7XX, UK
| | - Stamatios Theocharis
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 10679 Athens, Greece;
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15
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Zhu J, Teng H, Zhu X, Yuan J, Zhang Q, Zou Y. Pan-cancer analysis of Krüppel-like factor 3 and its carcinogenesis in pancreatic cancer. Front Immunol 2023; 14:1167018. [PMID: 37600783 PMCID: PMC10435259 DOI: 10.3389/fimmu.2023.1167018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 07/10/2023] [Indexed: 08/22/2023] Open
Abstract
Background Krüppel-like factor 3 (KLF3) is a key transcriptional repressor, which is involved in various biological functions such as lipogenesis, erythropoiesis, and B cell development, and has become one of the current research hotspots. However, the role of KLF3 in the pan-cancer and tumor microenvironment remains unclear. Methods TCGA and GTEx databases were used to evaluate the expression difference of KLF3 in pan-cancer and normal tissues. The cBioPortal database and the GSCALite platform analyzed the genetic variation and methylation modification of KLF3. The prognostic role of KLF3 in pan-cancer was identified using Cox regression and Kaplan-Meier analysis. Correlation analysis was used to explore the relationship between KLF3 expression and tumor mutation burden, microsatellite instability, and immune-related genes. The relationship between KLF3 expression and tumor immune microenvironment was calculated by ESTIMATE, EPIC, and MCPCOUNTER algorithms. TISCH and CancerSEA databases analyzed the expression distribution and function of KLF3 in the tumor microenvironment. TIDE, GDSC, and CTRP databases evaluated KLF3-predicted immunotherapy response and sensitivity to small molecule drugs. Finally, we analyzed the role of KLF3 in pancreatic cancer by in vivo and in vitro experiments. Results KLF3 was abnormally expressed in a variety of tumors, which could effectively predict the prognosis of patients, and it was most obvious in pancreatic cancer. Further experiments verified that silencing KLF3 expression inhibited pancreatic cancer progression. Functional analysis and gene set enrichment analysis found that KLF3 was involved in various immune-related pathways and tumor progression-related pathways. In addition, based on single-cell sequencing analysis, it was found that KLF3 was mainly expressed in CD4Tconv, CD8T, monocytes/macrophages, endothelial cells, and malignant cells in most of the tumor microenvironment. Finally, we assessed the value of KLF3 in predicting response to immunotherapy and predicted a series of sensitive drugs targeting KLF3. Conclusion The role of KLF3 in the tumor microenvironment of various types of tumors cannot be underestimated, and it has significant potential as a biomarker for predicting the response to immunotherapy. In particular, it plays an important role in the progression of pancreatic cancer.
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Affiliation(s)
- Jinfeng Zhu
- Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Hong Teng
- Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Department of Medical Genetics, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Xiaojian Zhu
- Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Jingxuan Yuan
- Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Department of Medical Genetics, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Qiong Zhang
- Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Department of Medical Genetics, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Yeqing Zou
- Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Department of Medical Genetics, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- School of Public Health, Nanchang University, Nanchang, Jiangxi, China
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16
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Wang C, Zhang X, Yu J, Bu J, Gu X, Wang Y, Zhu X, Lin J. Spotlights on extracellular vesicles in hepatocellular carcinoma diagnosis and treatment: an update review. Front Bioeng Biotechnol 2023; 11:1215518. [PMID: 37456728 PMCID: PMC10338921 DOI: 10.3389/fbioe.2023.1215518] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 06/22/2023] [Indexed: 07/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC), one of the most prevalent cancers, with a high mortality rate worldwide, seriously impairs patient health. The lack of accurate targets impedes the early screening and diagnosis of HCC and is associated with a poor response to routine therapies. Extracellular vesicles (EVs), comprising exosomes, microvesicles, and apoptotic bodies, are lipid bilayer membrane-derived nanometer-sized vesicles. EVs can be secreted from various cancer cells and release diverse biomolecules, such as DNA, RNA, proteins, metabolites, and lipids, making them a potential source of biomarkers and regulators of the tumor microenvironment. Emerging evidence suggests that EVs are involved in intercellular communication by carrying biological information. These EVs elicit physiological functions and are involved in the oncogenesis of HCC, such as proliferation, invasion, metastasis, and chemoresistance of HCC. EVs have also been considered promising biomarkers and nanotherapeutic targets for HCC. Therefore, this review sheds light on the current understanding of the interactions between EVs and HCC to propose potential biomarkers and nanotherapeutic strategies.
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Affiliation(s)
- Caizheng Wang
- Department of General Surgery, Huangyan Hospital, Wenzhou Medical University, Taizhou, Zhejiang, China
| | - Xiaoying Zhang
- Department of General Surgery, Huangyan Hospital, Wenzhou Medical University, Taizhou, Zhejiang, China
| | - Jiahui Yu
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jiawen Bu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xi Gu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yue Wang
- Department of General Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Xudong Zhu
- Department of General Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Jie Lin
- Department of General Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
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17
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Li T, Jiao J, Ke H, Ouyang W, Wang L, Pan J, Li X. Role of exosomes in the development of the immune microenvironment in hepatocellular carcinoma. Front Immunol 2023; 14:1200201. [PMID: 37457718 PMCID: PMC10339802 DOI: 10.3389/fimmu.2023.1200201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 06/12/2023] [Indexed: 07/18/2023] Open
Abstract
Despite numerous improved treatment methods used in recent years, hepatocellular carcinoma (HCC) is still a disease with a high mortality rate. Many recent studies have shown that immunotherapy has great potential for cancer treatment. Exosomes play a significant role in negatively regulating the immune system in HCC. Understanding how these exosomes play a role in innate and adaptive immunity in HCC can significantly improve the immunotherapeutic effects on HCC. Further, engineered exosomes can deliver different drugs and RNA molecules to regulate the immune microenvironment of HCC by regulating the aforementioned immune pathway, thereby significantly improving the mortality rate of HCC. This study aimed to declare the role of exosomes in the development of the immune microenvironment in HCC and list engineered exosomes that could be used for clinical transformation therapy. These findings might be beneficial for clinical patients.
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Affiliation(s)
- Tanghua Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jiapeng Jiao
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Haoteng Ke
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Wenshan Ouyang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Luobin Wang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jin Pan
- The Department of Electronic Engineering, The Chinese University of Hong Kong, Hongkong, Hongkong SAR, China
| | - Xin Li
- Zhujiang Hospital, Southern Medical University, Guangzhou, China
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18
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Aseervatham J. Dynamic Role of Exosome microRNAs in Cancer Cell Signaling and Their Emerging Role as Noninvasive Biomarkers. BIOLOGY 2023; 12:biology12050710. [PMID: 37237523 DOI: 10.3390/biology12050710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/26/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023]
Abstract
Exosomes are extracellular vesicles that originate from endosomes and are released by all cells irrespective of their origin or type. They play an important role in cell communication and can act in an autocrine, endocrine, or paracrine fashion. They are 40-150 nm in diameter and have a similar composition to the cell of origin. An exosome released by a particular cell is unique since it carries information about the state of the cell in pathological conditions such as cancer. miRNAs carried by cancer-derived exosomes play a multifaceted role by taking part in cell proliferation, invasion, metastasis, epithelial-mesenchymal transition, angiogenesis, apoptosis, and immune evasion. Depending on the type of miRNA that it carries as its cargo, it can render cells chemo- or radiosensitive or resistant and can also act as a tumor suppressor. Since the composition of exosomes is affected by the cellular state, stress, and changes in the environment, they can be used as diagnostic or prognostic biomarkers. Their unique ability to cross biological barriers makes them an excellent choice as vehicles for drug delivery. Because of their easy availability and stability, they can be used to replace cancer biopsies, which are invasive and expensive. Exosomes can also be used to follow the progression of diseases and monitor treatment strategies. A better understanding of the roles and functions of exosomal miRNA can be used to develop noninvasive, innovative, and novel treatments for cancer.
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Affiliation(s)
- Jaya Aseervatham
- Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA
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19
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Ding J, Xu C, Xu M, He XY, Li WN, He F. Emerging role of engineered exosomes in nonalcoholic fatty liver disease. World J Hepatol 2023; 15:386-392. [PMID: 37034232 PMCID: PMC10075012 DOI: 10.4254/wjh.v15.i3.386] [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: 12/26/2022] [Revised: 02/20/2023] [Accepted: 03/15/2023] [Indexed: 04/11/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD comprises a continuum of liver abnormalities from nonalcoholic fatty liver to nonalcoholic steatohepatitis, and can even lead to cirrhosis and liver cancer. However, a well-established treatment for NAFLD has yet to be identified. Exosomes have become an ideal drug delivery tool because of their high transmissibility, low immunogenicity, easy accessibility and targeting. Exosomes with specific modifications, known as engineered exosomes, have the potential to treat a variety of diseases. Here, we review the treatment of NAFLD with engineered exosomes and the potential use of exosomes as biomarkers and therapeutic targets for NAFLD.
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Affiliation(s)
- Jian Ding
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Chen Xu
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Ming Xu
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Xiao-Yue He
- The Affiliated Hospital of Jining Medical University, Jining Medical University, Jining 272067, Shandong Province, China
| | - Wei-Na Li
- School of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
| | - Fei He
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Xi'an 710032, Shaanxi Province, China
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20
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Yao M, Liang S, Cheng B. Role of exosomes in hepatocellular carcinoma and the regulation of traditional Chinese medicine. Front Pharmacol 2023; 14:1110922. [PMID: 36733504 PMCID: PMC9886889 DOI: 10.3389/fphar.2023.1110922] [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: 12/01/2022] [Accepted: 01/03/2023] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) usually occurs on the basis of chronic liver inflammatory diseases and cirrhosis. The liver microenvironment plays a vital role in the tumor initiation and progression. Exosomes, which are nanometer-sized membrane vesicles are secreted by a number of cell types. Exosomes carry multiple proteins, DNAs and various forms of RNA, and are mediators of cell-cell communication and regulate the tumor microenvironment. In the recent decade, many studies have demonstrated that exosomes are involved in the communication between HCC cells and the stromal cells, including endothelial cells, macrophages, hepatic stellate cells and the immune cells, and serve as a regulator in the tumor proliferation and metastasis, immune evasion and immunotherapy. In addition, exosomes can also be used for the diagnosis and treatment HCC. They can potentially serve as specific biomarkers for early diagnosis and drug delivery vehicles of HCC. Chinese herbal medicine, which is widely used in the prevention and treatment of HCC in China, may regulate the release of exosomes and exosomes-mediated intercellular communication. In this review, we summarized the latest progresses on the role of the exosomes in the initiation, progression and treatment of HCC and the potential value of Traditional Chinese medicine in exosomes-mediated biological behaviors of HCC.
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Affiliation(s)
- Man Yao
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (The Second Military Medical University), Shanghai, China
| | - Shufang Liang
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (The Second Military Medical University), Shanghai, China
| | - Binbin Cheng
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (The Second Military Medical University), Shanghai, China,Faculty of Traditional Chinese Medicine, Naval Medical University (The Second Military Medical University), Shanghai, China,*Correspondence: Binbin Cheng,
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21
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Hashemi M, Mirzaei S, Zandieh MA, Rezaei S, Amirabbas Kakavand, Dehghanpour A, Esmaeili N, Ghahremanzade A, Saebfar H, Heidari H, Salimimoghadam S, Taheriazam A, Entezari M, Ahn KS. Long non-coding RNAs (lncRNAs) in hepatocellular carcinoma progression: Biological functions and new therapeutic targets. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 177:207-228. [PMID: 36584761 DOI: 10.1016/j.pbiomolbio.2022.12.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 11/29/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022]
Abstract
Liver is an important organ in body that performs vital functions such as detoxification. Liver is susceptible to development of cancers, and hepatocellular carcinoma (HCC) is among them. 75-85% of liver cancer cases are related to HCC. Therefore, much attention has been directed towards understanding factors mediating HCC progression. LncRNAs are epigenetic factors with more than 200 nucleotides in length located in both nucleus and cytoplasm and they are promising candidates in cancer therapy. Directing studies towards understanding function of lncRNAs in HCC is of importance. LncRNAs regulate cell cycle progression and growth of HCC cells, and they can also induce/inhibit apoptosis in tumor cells. LncRNAs affect invasion and metastasis in HCC mainly by epithelial-mesenchymal transition (EMT) mechanism. Revealing the association between lncRNAs and downstream signaling pathways in HCC is discussed in the current manuscript. Infectious diseases can affect lncRNA expression in mediating HCC development and then, altered expression level of lncRNA is associated with drug resistance and radio-resistance. Biomarker application of lncRNAs and their role in prognosis and diagnosis of HCC are also discussed to pave the way for treatment of HCC patients.
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Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Sahar Rezaei
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Amirabbas Kakavand
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amir Dehghanpour
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Negin Esmaeili
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Azin Ghahremanzade
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hamidreza Saebfar
- European University Association, League of European Research Universities, University of Milan, Italy
| | - Hajar Heidari
- Department of Biomedical Sciences, School of Public Health University at Albany State University of New York, Albany, NY, 12208, USA
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Kwang Seok Ahn
- College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
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22
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Xie D, Qian B, Li X. Nucleic acids and proteins carried by exosomes from various sources: Potential role in liver diseases. Front Physiol 2022; 13:957036. [PMID: 36213232 PMCID: PMC9538374 DOI: 10.3389/fphys.2022.957036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 08/17/2022] [Indexed: 12/24/2022] Open
Abstract
Exosomes are extracellular membrane-encapsulated vesicles that are released into the extracellular space or biological fluids by many cell types through exocytosis. As a newly identified form of intercellular signal communication, exosomes mediate various pathological and physiological processes by exchanging various active substances between cells. The incidence and mortality of liver diseases is increasing worldwide. Therefore, we reviewed recent studies evaluating the role of exosomes from various sources in the diagnosis and treatment of liver diseases.
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Affiliation(s)
- Danna Xie
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Baolin Qian
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xun Li
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
- Department of General Surgery, the First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
- Center for Cancer Prevention and Treatment, School of Medicine, Lanzhou University, Lanzhou, China
- Gansu Provincial Institute of Hepatobiliary and Pancreatic Surgery, Lanzhou, China
- *Correspondence: Xun Li,
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23
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Guan MC, Wang MD, Wang WY, Li C, Yao LQ, Zhu H, Yang T. Exosomes as mediators of tumor immune escape and immunotherapy in hepatocellular carcinoma. LIVER RESEARCH (BEIJING, CHINA) 2022; 6:132-138. [PMID: 39958202 PMCID: PMC11791807 DOI: 10.1016/j.livres.2022.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 07/16/2022] [Accepted: 08/10/2022] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC), a typical inflammatory-related cancer, mainly occurs in patients with chronic liver diseases. Moreover, the liver is an immunologically privileged apparatus with multiple immunosuppressive cell groups. The long process of inflammation-mediated carcinogenesis turns the HCC tumor microenvironment (TME) into one with strong immunosuppression, facilitating the immune escape of HCC cells. Accumulated data have manifested that tumor-associated cell-derived exosomes carry diverse molecular cargoes (e.g., proteins and nucleic acids) for mediating cell-to-cell communication and are implicated in TME remodeling to promote tumor-infiltrating immune cell reprogramming, ultimately creating a tumor-friendly microenvironment. Characterized by several intrinsic attributes, such as good stability (bilayer-like structure) and high biocompatibility (cell secretion), exosomes can be modified or engineered as nanocarriers to deliver tumor-specific antigens or antitumor drugs to targeted cells or organs, thus effectively triggering the HCC cell elimination by the immune system. This review aimed to highlight the pivotal role of exosomes in regulating immune escape mechanisms in HCC and recent advances in exosome-mediated immunotherapy for HCC.
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Affiliation(s)
- Ming-Cheng Guan
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Wan-Yin Wang
- Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Lan-Qing Yao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Hong Zhu
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
- Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, China
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China
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24
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Tian BW, Han CL, Dong ZR, Tan SY, Wang DX, Li T. Role of Exosomes in Immunotherapy of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14164036. [PMID: 36011030 PMCID: PMC9406927 DOI: 10.3390/cancers14164036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/21/2022] [Accepted: 08/18/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma is one of the most lethal malignancies, having a significantly poor prognosis. Immunotherapy, as an emerging tumor treatment option, provides new hope for many cancer patients. However, a large proportion of patients do not benefit from immunotherapy. As a critical cell-to-cell communication mediator in the tumor immune microenvironment, exosomes may play a unique role in hepatocellular carcinoma immune response and thus affect the efficiency of immunotherapy. In this review, we discuss related research on the roles of exosomes in the current immunotherapy resistance mechanism of hepatocellular carcinoma. Furthermore, we also clarify the excellent predictive value of exosomes and the roles they play in improving immunotherapy efficacy for hepatocellular carcinoma patients. We hope that our review can help readers to gain a more comprehensive understanding of exosomes’ roles in hepatocellular carcinoma immunotherapy. Abstract Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, having a significantly poor prognosis and no sufficiently efficient treatments. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has provided new therapeutic approaches for HCC patients. Nevertheless, most patients with HCC do not benefit from immunotherapy. Exosomes are biologically active lipid bilayer nano-sized vesicles ranging in size from 30 to 150 nm and can be secreted by almost any cell. In the HCC tumor microenvironment (TME), numerous cells are involved in tumor progression, and exosomes—derived from tumor cells and immune cells—exhibit unique composition profiles and act as intercellular communicators by transporting various substances. Showing the dual characteristics of tumor promotion and suppression, exosomes exert multiple functions in shaping tumor immune responses in the crosstalk between tumor cells and surrounding immune cells, mediating immunotherapy resistance by affecting the PD-1/PD-L1 axis or the anti-tumor function of immune cells in the TME. Targeting exosomes or the application of exosomes as therapies is involved in many aspects of HCC immunotherapies (e.g., ICIs, tumor vaccines, and adoptive cell therapy) and may substantially enhance their efficacy. In this review, we discuss the impact of exosomes on the HCC TME and comprehensively summarize the role of exosomes in immunotherapy resistance and therapeutic application. We also discuss the potential of exosomes as biomarkers for predicting the efficacy of immunotherapy to help clinicians in identifying HCC patients who are amenable to immunotherapies.
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Affiliation(s)
- Bao-Wen Tian
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250000, China
| | - Cheng-Long Han
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250000, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250000, China
| | - Si-Yu Tan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250000, China
| | - Dong-Xu Wang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250000, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250000, China
- Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan 250000, China
- Correspondence: ; Tel./Fax: +86-531-8216-6651
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25
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Liu J, Xiao P, Jiang W, Wang Y, Huang Y. Diagnostic value of exosomes in patients with liver cancer: a systematic review. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2022; 24:2285-2294. [PMID: 35947296 DOI: 10.1007/s12094-022-02906-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/23/2022] [Indexed: 10/15/2022]
Abstract
BACKGROUND Liver cancer is a disease with high morbidity and mortality. More and more studies have shown that exosomes can be used as biomarkers for the diagnosis of liver cancer, but their diagnostic accuracy is still unclear. Therefore, this meta-analysis summarizes various studies on the diagnostic value of exosomes for liver cancer. METHODS A comprehensive search was carried out based on the set search terms in PubMed, Web of Science and Wiley until April 1, 2022. All statistical analyses were performed by STATA 17 statistical software and Review Manager 5.4. Quality Assessment for Studies of Diagnostic Accuracy 2 tool was applied to evaluate the quality of included articles. Random effects model was used to calculate various diagnostic indicators. RESULTS A total of 47 studies were included in this meta-analysis. The number of participants was 3196. The combined sensitivity, specificity and the area under the curve with 95% confidence intervals (95% CI) were, respectively 0.80 (0.75-0.84), 0.83 (0.79-0.87), 0.89 (0.85-0.91). CONCLUSIONS This meta-analysis shows that exosomes have good diagnostic accuracy for liver cancer and can be used as an effective biomarker for the diagnosis of liver cancer.
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Affiliation(s)
- Jusong Liu
- Department of Transfusion, The Affiliated Hospital of Southwest Medical University, 25 Taiping Road, Luzhou, 646000, Sichuan, People's Republic of China
| | - Pan Xiao
- Department of Transfusion, The Affiliated Hospital of Southwest Medical University, 25 Taiping Road, Luzhou, 646000, Sichuan, People's Republic of China
| | - Wenxue Jiang
- Department of Clinical Medicine, Southwest Medical University, Luzhou, 646000, China
| | - Yuhan Wang
- Department of Transfusion, Yaan People's Hospital, Yaan, 625000, China
| | - Yuanshuai Huang
- Department of Transfusion, The Affiliated Hospital of Southwest Medical University, 25 Taiping Road, Luzhou, 646000, Sichuan, People's Republic of China.
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26
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Ye J, Liu X. Macrophage-Derived Small Extracellular Vesicles in Multiple Diseases: Biogenesis, Function, and Therapeutic Applications. Front Cell Dev Biol 2022; 10:913110. [PMID: 35832790 PMCID: PMC9271994 DOI: 10.3389/fcell.2022.913110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 05/20/2022] [Indexed: 12/24/2022] Open
Abstract
Macrophages (Mφs), as immune cells, play a pivotal role against pathogens and many diseases, such as cancer, inflammation, cardiovascular diseases, orthopedic diseases, and metabolic disorders. In recent years, an increasing number of studies have shown that small extracellular vesicles (sEVs) derived from Mφs (M-sEVs) play important roles in these diseases, suggesting that Mφs carry out their physiological functions through sEVs. This paper reviews the mechanisms underlying M-sEVs production via different forms of polarization and their biological functions in multiple diseases. In addition, the prospects of M-sEVs in disease diagnosis and treatment are described.
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Affiliation(s)
- Jingyao Ye
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xuehong Liu
- The Third School of Clinical Medicine of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Xuehong Liu,
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27
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Zhao XQ, Zhou H. Letter to the editor regarding “miR-660-5p-loaded M2 macrophages-derived exosomes augment hepatocellular carcinoma development through regulating KLF3”. Int Immunopharmacol 2022; 106:108554. [DOI: 10.1016/j.intimp.2022.108554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/16/2022] [Indexed: 11/05/2022]
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