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Safaei M, Rajabi SS, Tirgar M, Namdar N, Dalfardi M, Mohammadifar F, Goodarzi A, Farmani AR, Ramezani V, Abpeikar Z. Exosome-based approaches in cancer along with unlocking new insights into regeneration of cancer-prone tissues. Regen Ther 2025; 29:202-216. [DOI: https:/doi.org/10.1016/j.reth.2025.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2025] Open
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Safaei M, Rajabi SS, Tirgar M, Namdar N, Dalfardi M, Mohammadifar F, Goodarzi A, Farmani AR, Ramezani V, Abpeikar Z. Exosome-based approaches in cancer along with unlocking new insights into regeneration of cancer-prone tissues. Regen Ther 2025; 29:202-216. [PMID: 40225049 PMCID: PMC11992408 DOI: 10.1016/j.reth.2025.03.005] [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: 02/09/2025] [Revised: 03/01/2025] [Accepted: 03/18/2025] [Indexed: 04/15/2025] Open
Abstract
Most eukaryotic cells secrete extracellular vesicles called exosomes, which are involved in intercellular communication. Exosomes play a role in tumor development and metastasis by transporting bioactive chemicals from cancerous cells to other cells in local and distant microenvironments. However, the potential of exosomes can be used by engineering them and considering different therapeutic approaches to overcome tumors. Exosomes are a promising drug delivery approach that can help decrease side effects from traditional treatments like radiation and chemotherapy by acting as targeted agents at the tumor site. The present review provides an overview of exosomes and various aspects of the role of exosomes in cancer development, which include these items: exosomes in cancer diagnosis, exosomes and drug delivery, exosomes and drug resistance, exosomal microRNAs and exosomes in tumor microenvironment, etc. Cancer stem cells release exosomes that nurture tumors, promoting unwanted growth and regeneration, and these types of exosomes should be inhibited. Ironically, exosomes from other cells, such as hepatocytes or mesenchymal stem cells (MSCs), are vital for healing organs like the liver and repairing gastric ulcers. Without proper treatment, this healing process can backfire, potentially leading to disease progression or even cancer. What can be found from various studies about the role of exosomes in the field of cancer is that exosomes act like a double-edged sword; on the other hand, natural exosomes in the body may play an important role in the process and progression of cancer, but by engineering exosomes, they can be directed towards target therapy and targeted delivery of drugs to tumor cells. By examining the role and application of exosomes in various mechanisms of cancer, it is possible to help treat this disease more efficiently and quickly in preclinical and clinical research.
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Affiliation(s)
- Mohsen Safaei
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Seyedeh Somayeh Rajabi
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Mahtab Tirgar
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Najmeh Namdar
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Mahsa Dalfardi
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Farnia Mohammadifar
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Arash Goodarzi
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Ahmad Reza Farmani
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Vahid Ramezani
- Department of Pharmaceutics, School of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Zahra Abpeikar
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
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Jin Z, Zhang C, Shen L, Cao Y. Harnessing Exosomes: From Tumor Immune Escape to Therapeutic Innovation in Gastric Cancer Immunotherapy. Cancer Lett 2025:217792. [PMID: 40409451 DOI: 10.1016/j.canlet.2025.217792] [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: 02/23/2025] [Revised: 04/21/2025] [Accepted: 05/11/2025] [Indexed: 05/25/2025]
Abstract
Gastric cancer ranks fifth among the most prevalent cancers globally, with a dismal prognosis. In recent years, immunotherapy, particularly immune checkpoint inhibitors, has emerged as a glimmer of hope for advanced gastric cancer patients. However, not all patients can benefit from this treatment modality, as the tumor microenvironment significantly influences treatment efficacy. Exosomes, pivotal mediators of intercellular communication, exert intricate and diverse effects in shaping and regulating the tumor microenvironment. This review provides a comprehensive overview of the functional mechanisms of exosomes within the gastric cancer tumor microenvironment. It delves into their biogenesis, functions, and impact on innate and adaptive immune cells (such as dendritic cells, myeloid-derived suppressor cells, and T cells) and cancer-associated fibroblasts. Additionally, the potential applications of exosomes in gastric cancer immunotherapy are explored, including their use as biomarkers to predict responses to immune checkpoint inhibitors, and drug delivery vectors, and in the development of exosome-based vaccines and gene therapy. Notably, this review emphasizes the dual nature of exosomes: they can facilitate tumor immune escape, yet they also serve as promising targets for innovative therapeutic strategies. It also compares potential exosome-based strategies with existing immunotherapies like ICIs and emerging CAR-T cell therapies. Finally, insights into the future of exosomes in precision immunotherapy for gastric cancer are offered, presenting a forward-looking perspective on this emerging field.
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Affiliation(s)
- Zhao Jin
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Cell & Gene Therapy for Solid Tumor, Department of GI Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
| | - Cheng Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Cell & Gene Therapy for Solid Tumor, Department of GI Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
| | - Lin Shen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Cell & Gene Therapy for Solid Tumor, Department of GI Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
| | - Yanshuo Cao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Cell & Gene Therapy for Solid Tumor, Department of GI Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
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Chen D, Huang J, Yang A, Xiong Z. Prognostic and immunological implications of protein kinases in gastric cancer: a focus on hub gene ABL2 and its impact on the polarization of M2 macrophages. Biol Direct 2025; 20:35. [PMID: 40128818 PMCID: PMC11934801 DOI: 10.1186/s13062-025-00636-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 03/16/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Protein kinases are essential cellular signal modulators involved in tumorigenesis, metastasis, immune response, and drug resistance. However, the comprehensive features and clinical significance of protein kinases in gastric cancer (GC) remain inconclusive. METHODS We analyzed the transcriptional profiles of protein kinases in GC patients from the GEO and TCGA databases. Based on differentially expressed kinase genes (DE-KGs), a novel cluster was identified to assess its association with patient survival and the tumor microenvironment (TME) in GC. Subsequently, an optimal DE-KGs-based model (DE-KGsM) was determined using 101 machine-learning algorithm combinations. This model was evaluated using multi-omics data to investigate its associations with patient prognosis, clinical features, tumor microenvironment, tumor-infiltrating immune cells (TIICs), and immunotherapy response. Furthermore, scRNA-seq analysis and TIMER algorithm were applied to determine the correlation between the hub gene (ABL2) in the DE-KGsM and Macrophages. Finally, in vitro experiments were performed to explore the immune-related mechanisms of ABL2 in GC. RESULTS We identified two molecular subtypes of GC patients based on 64 DE-KGs expression. Significant differences were observed in overall survival and TIIC characteristics between Cluster 1 and Cluster 2. Among these 64 DE-KGs, we identified an optimal DE-KGsM that could be a prognostic indicator in GC. TIICs and TIDE analyses exhibited that GC patients in the high-DE-KGsM score group had a higher proportion of M2 macrophages and lower response rates to ICI treatment. scRNA-seq analysis indicated that ABL2 might play an indispensable role in tumor immunity. Furthermore, in vitro experiments demonstrated that ABL2 accelerated the proliferation, migration, and invasion of GC cells, as well as the polarization of M2 macrophages. CONCLUSIONS The DE-KGsM could be a powerful predictor of GC patients' survival and might facilitate the development of personalized therapy. Furthermore, as a hub gene in the DE-KGsM, ABL2 could be an immunological biomarker that modulates the polarization of M2 macrophages, thereby promoting GC progression. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Di Chen
- Department of Gastroenterology, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Ju Huang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
| | - Aiming Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China.
| | - Zhifan Xiong
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China.
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Han Y, Gong WS, Xing XS, Zhou H, Wang XL, Xu Y, Zhou XL, Xue WL. miR-183-5p-enriched extracellular vesicles promote the crosstalk between hepatocellular carcinoma cell and endothelial cell via SIK1/PI3K/AKT and CCL20/CCR6 signaling pathways. Front Oncol 2025; 15:1532239. [PMID: 40115013 PMCID: PMC11922695 DOI: 10.3389/fonc.2025.1532239] [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: 11/21/2024] [Accepted: 02/13/2025] [Indexed: 03/22/2025] Open
Abstract
Background The cancer-related mortality of primary liver cancer ranks third globally, and hepatocellular carcinoma (HCC) is predominant, posing a serious threat to patients' health. Understanding HCC's pathogenesis and target molecules is crucial for early diagnosis and prognosis. Extracellular vesicles (EVs) and their carried miRNAs impact tumor progression. This study aims to investigate miR-183-5p in HCC cell-derived EVs on angiogenesis, progression, and metastasis, and provide diagnostic and therapeutic evidence. Methods qRT-PCR was used to evaluate the expression of miR-183-5p in HCC tissue and plasma EV samples. Contrast-enhanced ultrasound and The Cancer Genome Atlas evaluated its correlation with angiogenesis and prognosis. In vitro, cell counting kit-8 (CCK-8), colony formation, transwell, tube formation, and permeability assays examined the effect of HCC cell-derived EVs on human umbilical vein endothelial cells (HUVECs). Subcutaneous tumor and lung metastasis models in nude mice verified it in vivo effects. RNA sequencing and databases predicted downstream genes and pathways, and dual luciferase and western blotting assays verified binding and activation. Conditioned medium from treated HUVECs was used on HCC cells, and chemokine levels measured. The CCL20/CCR6 axis effect was studied in vitro and in vivo by knocking down CCR6. Results This study revealed the abnormal upregulation of miR-183-5p in both tissues and plasma EVs from patients with HCC, and its association with unfavorable prognosis. In vivo experiments, the promoting effects of miR-183-5p in HCC cell-derived EVs on the progression, metastasis and angiogenesis were verified by employing subcutaneous tumor formation models and lung metastasis models in nude mice. We demonstrated that miR-183-5p in HCC cell-derived EVs induced HUVECs proliferation, migration, angiogenesis and permeability by downregulating SIK1 expression and activating the PI3K/AKT signaling pathway in vitro. Moreover, stimulated HUVECs could secrete the chemokine CCL20 and induce HCC progression and metastasis through the CCL20/CCR6 signal pathway in vitro and in vivo. Conclusion The findings indicated that miR-183-5p delivered by EVs from HCC cells is crucial in mediating the communication between HUVECs and HCC cells by modulating the SIK1/PI3K/AKT and CCL20/CCR6 signaling pathways, and EVs-miR-183-5p might be a potential therapeutic target for HCC patients.
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Affiliation(s)
- Ye Han
- In-Patient Ultrasound Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wu-Shuang Gong
- In-Patient Ultrasound Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xue-Sha Xing
- In-Patient Ultrasound Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hang Zhou
- In-Patient Ultrasound Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiao-Lei Wang
- In-Patient Ultrasound Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Xian-Li Zhou
- In-Patient Ultrasound Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wei-Li Xue
- In-Patient Ultrasound Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Zhang Y, Wang B, Chen J, Li T. Role of exosomal miRNAs and macrophage polarization in gastric cancer: A novel therapeutic strategy. Eur J Pharmacol 2025; 990:177268. [PMID: 39805486 DOI: 10.1016/j.ejphar.2025.177268] [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: 10/04/2024] [Revised: 01/09/2025] [Accepted: 01/09/2025] [Indexed: 01/16/2025]
Abstract
Gastric cancer (GC) is one of the most common gastrointestinal cancers worldwide, with consistently high morbidity and mortality rates and poor prognosis. Most patients are diagnosed at an advanced stage due to the lack of specific presentation in the early stages. Exosomes are a class of extracellular vesicles (EVs) widely found in body fluids and can release genetic material or multiple proteins to facilitate intercellular communication. In recent years, exosomal miRNAs have gained attention for their role in various cancers. These exosomal miRNAs can impact GC development and progression by targeting specific genes or influencing signaling pathways and cytokines involved in Angiogenesis, epithelial-mesenchymal transition (EMT), drug resistance, and immune regulation. They show great potential in terms of diagnosis, prognosis, and treatment of GC. Notably, the gastrointestinal tract has the largest number of macrophages, which play a significant role in GC progression. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and can influence macrophage programming through various mediators, including macrophage polarization. Macrophage polarization is involved in inflammatory responses and significantly impacts the GC process.
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Affiliation(s)
- Yun Zhang
- School of Clinical Medicine, Ningxia Medical University, Ningxia, China; General Hospital of Ningxia Medical University, Ningxia, China
| | - Baozhen Wang
- School of Clinical Medicine, Ningxia Medical University, Ningxia, China; General Hospital of Ningxia Medical University, Ningxia, China
| | - Jing Chen
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
| | - Tao Li
- Department of Surgical Oncology, Tumor Hospital, The General Hospital of Ningxia Medical University, Ningxia, China.
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Liu X, To KK, Zeng Q, Fu L. Effect of Extracellular Vesicles Derived From Tumor Cells on Immune Evasion. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2417357. [PMID: 39899680 PMCID: PMC11948033 DOI: 10.1002/advs.202417357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Indexed: 02/05/2025]
Abstract
The crosstalk between immunity and cancer in the regulation of tumor growth is considered a hallmark of cancer. Antitumor immunity refers to the innate and adaptive immune responses that regulate cancer development and proliferation. Tumor immune evasion represents a major hindrance to effective anticancer treatment. Extracellular vesicles (EVs) are nano-sized and lipid-bilayer-enclosed particles that are secreted to the extracellular space by all cell types. They are critically involved in numerous biological functions including intercellular communication. Tumor-derived extracellular vesicles (TEVs) can transport a variety of cargo to modulate immune cells in the tumor microenvironment (TME). This review provides the latest update about how tumor cells evade immune surveillance by exploiting TEVs. First, the biogenesis of EVs and the cargo-sorting machinery are discussed. Second, how tumor cells modulate immune cell differentiation, activation, and function via TEVs to evade immune surveillance is illustrated. Last but not least, the novel antitumor strategies that can reverse immune escape are summarized.
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Affiliation(s)
- Xuanfan Liu
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhou510080P. R. China
| | - Kenneth K.W. To
- School of PharmacyThe Chinese University of Hong KongHong Kong999077P. R. China
| | - Qinsong Zeng
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhou510080P. R. China
- Guangxi Hospital Division of The First Affiliated HospitalSun Yat‐sen UniversityNanning530025P. R. China
| | - Liwu Fu
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
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Chen X, Yuan Y, Zhou F, Li L, Pu J, Jiang X. m6A RNA methylation: a pivotal regulator of tumor immunity and a promising target for cancer immunotherapy. J Transl Med 2025; 23:245. [PMID: 40022120 PMCID: PMC11871626 DOI: 10.1186/s12967-025-06221-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 02/11/2025] [Indexed: 03/03/2025] Open
Abstract
M6A modification is one of the most common regulatory mechanisms of gene expression in eukaryotic cells, influencing processes such as RNA splicing, degradation, stability, and protein translation. Studies have shown that m6A methylation is closely associated with tumorigenesis and progression, and it plays a key regulatory role in tumor immune responses. m6A modification participates in regulating the differentiation and maturation of immune cells, as well as related anti-tumor immune responses. In the tumor microenvironment, m6A modification can also affect immune cell recruitment, activation, and polarization, thereby promoting or inhibiting tumor cell proliferation and metastasis, and reshaping the tumor immune microenvironment. In recent years, immunotherapies for tumors, such as immune checkpoint inhibitors and adoptive cell immunotherapy, have been increasingly applied in clinical settings, achieving favorable outcomes. Targeting m6A modifications to modulate the immune system, such as using small-molecule inhibitors to target dysregulated m6A regulatory factors or inducing immune cell reprogramming, can enhance anti-tumor immune responses and strengthen immune cell recognition and cytotoxicity against tumor cells. m6A modification represents a new direction in tumor immunotherapy with promising clinical potential. This review discusses the regulatory role of m6A methylation on immune cells and tumor immune responses and explores new strategies for immunotherapy.
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Affiliation(s)
- Xi Chen
- Key Laboratory of Neurological and Psychiatric Disease Research of Yunnan Province, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650223, China
- NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, Yunnan, 650500, China
| | - Yixiao Yuan
- Department of Medicine, UF Health Cancer Center, University of Florida, Gainesville, FL, 32610, USA
| | - Fan Zhou
- Key Laboratory of Neurological and Psychiatric Disease Research of Yunnan Province, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650223, China
- NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, Yunnan, 650500, China
| | - Lihua Li
- NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, Yunnan, 650500, China
| | - Jun Pu
- Key Laboratory of Neurological and Psychiatric Disease Research of Yunnan Province, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650223, China.
- NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, Kunming, Yunnan, 650500, China.
| | - Xiulin Jiang
- Department of Medicine, UF Health Cancer Center, University of Florida, Gainesville, FL, 32610, USA.
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Zheng Z, Zhai Y, Yan X, Wang Z, Zhang H, Xu R, Liu X, Cai J, Zhang Z, Shang Y, Zhang J, Yin J. Functions and Clinical Applications of Exosomes in Gastric Cancer. Int J Biol Sci 2025; 21:2330-2345. [PMID: 40083701 PMCID: PMC11900809 DOI: 10.7150/ijbs.98087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 02/04/2025] [Indexed: 03/16/2025] Open
Abstract
Gastric cancer is a common and highly invasive type of malignant tumor, the pathogenesis of which remains unclarified. However, exosomes are now known to play important roles in gastric cancer development and treatment. Cells use exosomes for the packaging and transportation of a variety of bioactive molecules, such as proteins, double-stranded DNA, and micro-ribonucleic acids, to other sites. Exosome-specific membrane structures and exosomal contents are widely involved in processes that facilitate material exchange and intercellular communication between gastric cancer cells. They help in forming a pre-metastatic microenvironment, promoting the proliferation and apoptosis of gastric cancer cells, and driving invasion, metastasis, and resistance to anti-tumor drugs. In this review, we aimed to summarize the findings of research articles indexed in the PubMed, Web of Science, and Embase databases and published up to May 31, 2024, on the role of exosomes in the pathogenesis of gastric cancer and their potential clinical applications in its treatment. Thus, research on exosomes may lead to breakthroughs in the early diagnosis of gastric cancer and identification of novel treatments.
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Affiliation(s)
- Zhi Zheng
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Yuhao Zhai
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Xiaosheng Yan
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Zimeng Wang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Haiqiao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Rui Xu
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaoye Liu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Jun Cai
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Yuxi Shang
- Department of Hematology, Fuxing Hospital, Eighth Clinical Medical College, Capital Medical University, Beijing, China
| | - Jun Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Jie Yin
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
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Tang L, Zhang W, Qi T, Jiang Z, Tang D. Exosomes play a crucial role in remodeling the tumor microenvironment and in the treatment of gastric cancer. Cell Commun Signal 2025; 23:82. [PMID: 39948541 PMCID: PMC11827163 DOI: 10.1186/s12964-024-02009-7] [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: 09/03/2024] [Accepted: 12/21/2024] [Indexed: 02/16/2025] Open
Abstract
Gastric cancer (GC) is a common and frequent malignant cancer of the digestive system with a poor prognosis. In addition to common therapies such as surgical resection and chemotherapy, novel biological interventions are quite valuable for research. Exosomes are extracellular vesicles (EVs) that originate from various cell types and contain proteins, RNA, DNA, and other components that transmit biological signals and mediate intercellular communication. Numerous studies have shown that exosomes shape the tumor microenvironment (TME) by affecting hypoxia, inflammation, immunity, metabolism, and interstitial changes in the tumor, playing a crucial role in the development and metastasis of GC. This article reviews the important role of exosomes in the TME of GC and explores their potential clinical applications in GC treatment.
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Affiliation(s)
- Lingyun Tang
- Clinical Medical College, Yangzhou University, Yangzhou, 225000, China
| | - Wenjie Zhang
- School of Medicine, Chongqing University, Chongqing, 400030, China
| | - Teng Qi
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, 225000, China
| | - Zhengting Jiang
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, 225000, China.
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Northern Jiangsu People's Hospital; The Yangzhou Clinical Medical College of Xuzhou Medical University; The Yangzhou School of Clinical Medicine of Dalian Medical University; The Yangzhou School of Clinical Medicine of Nanjing Medical University; Northern Jiangsu People's Hospital, Clinical Teaching Hospital of Medical School, Nanjing University, Yangzhou, 225000, China.
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Hsu CY, Ahmed AT, Bansal P, Hjazi A, Al-Hetty HRAK, Qasim MT, Sapaev I, Deorari M, Mustafa YF, Elawady A. MicroRNA-enriched exosome as dazzling dancer between cancer and immune cells. J Physiol Biochem 2024; 80:811-829. [PMID: 39316240 DOI: 10.1007/s13105-024-01050-x] [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: 04/19/2024] [Accepted: 09/11/2024] [Indexed: 09/25/2024]
Abstract
Exosomes are widely recognized for their roles in numerous biological processes and as intercellular communication mediators. Human cancerous and normal cells can both produce massive amounts of exosomes. They are extensively dispersed in tumor-modeling animals' pleural effusions, ascites, and plasma from people with cancer. Tumor cells interact with host cells by releasing exosomes, which allow them to interchange various biological components. Tumor growth, invasion, metastasis, and even tumorigenesis can all be facilitated by this delicate and complex system by modifying the nearby and remote surroundings. Due to the existence of significant levels of biomolecules like microRNA, exosomes can modulate the immune system's stimulation or repression, which in turn controls tumor growth. However, the role of microRNA in exosome-mediated communication between immunological and cancer cells is still poorly understood. This study aims to get the most recent information on the "yin and yang" of exosomal microRNA in the regulation of tumor immunity and immunotherapy, which will aid current cancer treatment and diagnostic techniques.
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Affiliation(s)
- Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, Arizona 85004, USA
| | - Abdulrahman T Ahmed
- Department of Nursing, Al-Maarif University College, Ramadi, AL-Anbar Governorate, Iraq
| | - Pooja Bansal
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, 560069, Karnataka, India
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | | | - Maytham T Qasim
- College of Health and Medical Technology, Al-Ayen University, Thi-Qar, 64001, Iraq
| | - Ibrokhim Sapaev
- Tashkent Institute of Irrigation and Agricultural Mechanization Engineers" National Research University, Tashkent, Uzbekistan
- School of Engineering, Central Asian University, Tashkent, 111221, Uzbekistan
- Western Caspian University, Scientific researcher, Baku, Azerbaijan
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Ahmed Elawady
- College of Technical Engineering, the Islamic University, Najaf, Iraq
- College of Technical Engineering, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, the Islamic University of Babylon, Babylon, Iraq
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12
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Yu X, Zhang Y, Luo F, Zhou Q, Zhu L. The role of microRNAs in the gastric cancer tumor microenvironment. Mol Cancer 2024; 23:170. [PMID: 39164671 PMCID: PMC11334576 DOI: 10.1186/s12943-024-02084-x] [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: 06/25/2024] [Accepted: 08/13/2024] [Indexed: 08/22/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the deadliest malignant tumors with unknown pathogenesis. Due to its treatment resistance, high recurrence rate, and lack of reliable early detection techniques, a majority of patients have a poor prognosis. Therefore, identifying new tumor biomarkers and therapeutic targets is essential. This review aims to provide fresh insights into enhancing the prognosis of patients with GC by summarizing the processes through which microRNAs (miRNAs) regulate the tumor microenvironment (TME) and highlighting their critical role in the TME. MAIN TEXT A comprehensive literature review was conducted by focusing on the interactions among tumor cells, extracellular matrix, blood vessels, cancer-associated fibroblasts, and immune cells within the GC TME. The role of noncoding RNAs, known as miRNAs, in modulating the TME through various signaling pathways, cytokines, growth factors, and exosomes was specifically examined. Tumor formation, metastasis, and therapy in GC are significantly influenced by interactions within the TME. miRNAs regulate tumor progression by modulating these interactions through multiple signaling pathways, cytokines, growth factors, and exosomes. Dysregulation of miRNAs affects critical cellular processes such as cell proliferation, differentiation, angiogenesis, metastasis, and treatment resistance, contributing to the pathogenesis of GC. CONCLUSIONS miRNAs play a crucial role in the regulation of the GC TME, influencing tumor progression and patient prognosis. By understanding the mechanisms through which miRNAs control the TME, potential biomarkers and therapeutic targets can be identified to improve the prognosis of patients with GC.
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Affiliation(s)
- Xianzhe Yu
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China
- Department of Gastrointestinal Surgery, Chengdu Second People's Hospital, Sichuan Province, No. 10 Qinyun Nan Street, Chengdu, 610041, People's Republic of China
| | - Yin Zhang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fengming Luo
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Qinghua Zhou
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China.
| | - Lingling Zhu
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China.
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13
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Skryabin GO, Beliaeva AA, Enikeev AD, Tchevkina EM. Extracellular Vesicle miRNAs in Diagnostics of Gastric Cancer. BIOCHEMISTRY. BIOKHIMIIA 2024; 89:1211-1238. [PMID: 39218020 DOI: 10.1134/s0006297924070058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 05/24/2024] [Accepted: 05/30/2024] [Indexed: 09/04/2024]
Abstract
Gastric cancer (GC) poses a significant global health challenge because of its high mortality rate attributed to the late-stage diagnosis and lack of early symptoms. Early cancer diagnostics is crucial for improving the survival rates in GC patients, which emphasizes the importance of identifying GC markers for liquid biopsy. The review discusses a potential use of extracellular vesicle microRNAs (EV miRNAs) as biomarkers for the diagnostics and prognostics of GC. Methods. Original articles on the identification of EV miRNA as GC markers published in the Web of Science and Scopus indexed issues were selected from the PubMed and Google Scholar databases. We focused on the methodological aspects of EV analysis, including the choice of body fluid, methods for EV isolation and validation, and approaches for EV miRNA analysis. Conclusions. Out of 33 found articles, the majority of authors investigated blood-derived extracellular vesicles (EVs); only a few utilized EVs from other body fluids, including tissue-specific local biofluids (washing the tumor growth areas), which may be a promising source of EVs in the context of cancer diagnostics. GC-associated miRNAs identified in different studies using different methods of EV isolation and analysis varied considerably. However, three miRNAs (miR-10b, miR-21, and miR-92a) have been found in several independent studies and shown to be associated with GC in experimental models. Further studies are needed to determine the optimal miRNA marker panel. Another essential step necessary to improve the reliability and reproducibility of EV-based diagnostics is standardization of methodologies for EV handling and analysis of EV miRNA.
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Affiliation(s)
- Gleb O Skryabin
- Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, 115522, Russia.
| | - Anastasiya A Beliaeva
- Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, 115522, Russia
| | - Adel D Enikeev
- Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, 115522, Russia
| | - Elena M Tchevkina
- Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, 115522, Russia
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14
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Yang S, Wei S, Wei F. Extracellular vesicles mediated gastric cancer immune response: tumor cell death or immune escape? Cell Death Dis 2024; 15:377. [PMID: 38816455 PMCID: PMC11139918 DOI: 10.1038/s41419-024-06758-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 05/16/2024] [Accepted: 05/16/2024] [Indexed: 06/01/2024]
Abstract
Gastric cancer (GC) is a major global health issue, being the fifth most prevalent cancer and the third highest contributor to cancer-related deaths. Although treatment strategies for GC have diversified, the prognosis for advanced GC remains poor. Hence, there is a critical need to explore new directions for GC treatment to enhance diagnosis, treatment, and patient prognosis. Extracellular vesicles (EVs) have emerged as key players in tumor development and progression. Different sources of EVs carry different molecules, resulting in distinct biological functions. For instance, tumor-derived EVs can promote tumor cell proliferation, alter the tumor microenvironment and immune response, while EVs derived from immune cells carry molecules that regulate immune function and possess tumor-killing capabilities. Numerous studies have demonstrated the crucial role of EVs in the development, immune escape, and immune microenvironment remodeling in GC. In this review, we discuss the role of GC-derived EVs in immune microenvironment remodeling and EVs derived from immune cells in GC development. Furthermore, we provide an overview of the potential uses of EVs in immunotherapy for GC.
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Affiliation(s)
- Shuo Yang
- Department of the Seventh General surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110000̥, Liaoning Province, PR China
| | - Shibo Wei
- Department of the Seventh General surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110000̥, Liaoning Province, PR China.
| | - Fang Wei
- Department of the Seventh General surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110000̥, Liaoning Province, PR China.
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15
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Afra F, Eftekhar SP, Farid AS, Ala M. Non-coding RNAs in cancer immunotherapy: A solution to overcome immune resistance? PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 209:215-240. [PMID: 39461753 DOI: 10.1016/bs.pmbts.2024.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
With the rapid advancement in immunotherapy, cancer immune resistance has become more evident, which demands new treatment approaches to achieve greater efficacy. Non-coding RNAs (ncRNAs) are a heterogeneous group of RNAs that are not translated to proteins but instead regulate different stages of gene expression. Recent studies have increasingly supported the critical role of ncRNAs in immune cell-cancer cell cross-talk, and numerous ncRNAs have been implicated in the immune evasion of cancer cells. Cancer cells take advantage of ncRNAs to modulate several signaling pathways and upregulate the expression of immune checkpoints and anti-inflammatory mediators, thereby dampening the anti-tumor response of M1 macrophages, dendritic cells, cytotoxic T cells, and natural killer cells or potentiating the immunosuppressive properties of M2 macrophages, regulatory T cells, and myeloid-derived suppressive cells. Upregulation of immunosuppressive ncRNAs or downregulation of immunogenic ncNRAs is a major driver of resistance to immune checkpoint inhibitors, cancer vaccines, and other means of cancer immunotherapy, making ncRNAs ideal targets for treatment. In addition, ncRNAs released by cancer cells have been demonstrated to possess prognostic values for patients who undergo cancer immunotherapy. Future clinical trials are urged to consider the potential of ncRNAs in cancer immunotherapy.
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Affiliation(s)
- Fatemeh Afra
- Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Parsa Eftekhar
- Student Research Committee, Health Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Amir Salehi Farid
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Ala
- Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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16
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Jou E, Chaudhury N, Nasim F. Novel therapeutic strategies targeting myeloid-derived suppressor cell immunosuppressive mechanisms for cancer treatment. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:187-207. [PMID: 38464388 PMCID: PMC10918238 DOI: 10.37349/etat.2024.00212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 12/10/2023] [Indexed: 03/12/2024] Open
Abstract
Cancer is the leading cause of death globally superseded only by cardiovascular diseases, and novel strategies to overcome therapeutic resistance against existing cancer treatments are urgently required. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with potent immunosuppressive capacity against well-established anti-tumour effectors such as natural killer cells (NK cells) and T cells thereby promoting cancer initiation and progression. Critically, MDSCs are readily identified in almost all tumour types and human cancer patients, and numerous studies in the past decade have recognised their role in contributing to therapeutic resistance against all four pillars of modern cancer treatment, namely surgery, chemotherapy, radiotherapy and immunotherapy. MDSCs suppress anti-tumour immunity through a plethora of mechanisms including the well-characterised arginase 1 (Arg1), inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS)-mediated pathways, along with several other more recently discovered. MDSCs are largely absent in healthy homeostatic states and predominantly exist in pathological conditions, making them attractive therapeutic targets. However, the lack of specific markers identified for MDSCs to date greatly hindered therapeutic development, and currently there are no clinically approved drugs that specifically target MDSCs. Methods to deplete MDSCs clinically and inhibit their immunosuppressive function will be crucial in advancing cancer treatment and to overcome treatment resistance. This review provides a detailed overview of the current understandings behind the mechanisms of MDSC-mediated suppression of anti-tumour immunity, and discusses potential strategies to target MDSC immunosuppressive mechanisms to overcome therapeutic resistance.
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Affiliation(s)
- Eric Jou
- Medical Sciences Division, Oxford University Hospitals, University of Oxford, OX3 9DU Oxford, UK
- Kellogg College, University of Oxford, OX2 6PN Oxford, UK
- Wexham Park Hospital, Frimley Health NHS Foundation Trust, SL2 4HL Slough, UK
| | - Natasha Chaudhury
- Wexham Park Hospital, Frimley Health NHS Foundation Trust, SL2 4HL Slough, UK
| | - Fizza Nasim
- Wexham Park Hospital, Frimley Health NHS Foundation Trust, SL2 4HL Slough, UK
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17
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Qiu Y, Lu G, Li N, Hu Y, Tan H, Jiang C. Exosome-mediated communication between gastric cancer cells and macrophages: implications for tumor microenvironment. Front Immunol 2024; 15:1327281. [PMID: 38455041 PMCID: PMC10917936 DOI: 10.3389/fimmu.2024.1327281] [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: 10/24/2023] [Accepted: 01/25/2024] [Indexed: 03/09/2024] Open
Abstract
Gastric cancer (GC) is a malignant neoplasm originating from the epithelial cells of the gastric mucosa. The pathogenesis of GC is intricately linked to the tumor microenvironment within which the cancer cells reside. Tumor-associated macrophages (TAMs) primarily differentiate from peripheral blood monocytes and can be broadly categorized into M1 and M2 subtypes. M2-type TAMs have been shown to promote tumor growth, tissue remodeling, and angiogenesis. Furthermore, they can actively suppress acquired immunity, leading to a poorer prognosis and reduced tolerance to chemotherapy. Exosomes, which contain a myriad of biologically active molecules including lipids, proteins, mRNA, and noncoding RNAs, have emerged as key mediators of communication between tumor cells and TAMs. The exchange of these molecules via exosomes can markedly influence the tumor microenvironment and consequently impact tumor progression. Recent studies have elucidated a correlation between TAMs and various clinicopathological parameters of GC, such as tumor size, differentiation, infiltration depth, lymph node metastasis, and TNM staging, highlighting the pivotal role of TAMs in GC development and metastasis. In this review, we aim to comprehensively examine the bidirectional communication between GC cells and TAMs, the implications of alterations in the tumor microenvironment on immune escape, invasion, and metastasis in GC, targeted therapeutic approaches for GC, and the efficacy of potential GC drug resistance strategies.
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Affiliation(s)
- Yue Qiu
- Medical Oncology Department of Gastrointestinal Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Guimei Lu
- Department of Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Na Li
- Medical Oncology Department of Gastrointestinal Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Yanyan Hu
- Medical Oncology Department of Gastrointestinal Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Hao Tan
- Thoracic Esophageal Radiotherapy Department, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Chengyao Jiang
- Department of Gastric Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China
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18
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Jari M, Abdoli S, Bazi Z, Shamsabadi FT, Roshanmehr F, Shahbazi M. Enhancing protein production and growth in chinese hamster ovary cells through miR-107 overexpression. AMB Express 2024; 14:16. [PMID: 38302631 PMCID: PMC10834913 DOI: 10.1186/s13568-024-01670-y] [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: 10/12/2023] [Accepted: 01/16/2024] [Indexed: 02/03/2024] Open
Abstract
Chinese Hamster Ovary (CHO) cells are widely employed as host cells for biopharmaceutical production. The manufacturing of biopharmaceuticals poses several challenges, including restricted growth potential and inadequate productivity of the host cells. MicroRNAs play a crucial role in regulating gene expression and are considered highly promising tools for cell engineering to enhance protein production. Our study aimed to evaluate the effects of miR-107, which is recognized as an onco-miR, on erythropoietin-producing CHO cells (CHO-hEPO). To assess the impact of miR-107 on CHO cells, a DNA plasmid containing miR-107 was introduced to CHO-hEPO cells through transfection. Cell proliferation and viability were assessed using the trypan blue dye exclusion method. Cell cycle analysis was conducted by utilizing propidium iodide (PI) staining. The quantification of EPO was determined using an immunoassay test. Moreover, the impact of miR-107 on the expression of downstream target genes was evaluated using qRT-PCR. Our findings highlight and underscore the substantial impact of transient miR-107 overexpression, which led to a remarkable 2.7-fold increase in EPO titers and a significant 1.6-fold increase in the specific productivity of CHO cells (p < 0.01). Furthermore, this intervention resulted in significant enhancements in cell viability and growth rate (p < 0.05). Intriguingly, the overexpression of miR‑107 was linked to the downregulation of LATS2, PTEN, and TSC1 genes while concurrently driving upregulation in transcript levels of MYC, YAP, mTOR, and S6K genes within transgenic CHO cells. In conclusion, this study collectively underscores the feasibility of utilizing cancer-associated miRNAs as a powerful tool for CHO cell engineering. However, more in-depth exploration is warranted to unravel the precise molecular intricacies of miR-107's effects in the context of CHO cells.
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Affiliation(s)
- Maryam Jari
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Shastkola Road, Falsafi Complex, Gorgan, Zip code: 4934174611, Iran
- Department of Medical Biotechnology School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Shahriyar Abdoli
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Shastkola Road, Falsafi Complex, Gorgan, Zip code: 4934174611, Iran
- Department of Medical Biotechnology School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Zahra Bazi
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Shastkola Road, Falsafi Complex, Gorgan, Zip code: 4934174611, Iran
- Department of Medical Biotechnology School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Fatemeh Tash Shamsabadi
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Shastkola Road, Falsafi Complex, Gorgan, Zip code: 4934174611, Iran
- Department of Medical Biotechnology School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Farnaz Roshanmehr
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Shastkola Road, Falsafi Complex, Gorgan, Zip code: 4934174611, Iran
- Department of Medical Biotechnology School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Majid Shahbazi
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Shastkola Road, Falsafi Complex, Gorgan, Zip code: 4934174611, Iran.
- AryaTina Gene (ATG) Biopharmaceutical Company Gorgan, Gorgan, Iran.
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Jia X, Xi J, Tian B, Zhang Y, Wang Z, Wang F, Li Z, Long J, Wang J, Fan GH, Li Q. The Tautomerase Activity of Tumor Exosomal MIF Promotes Pancreatic Cancer Progression by Modulating MDSC Differentiation. Cancer Immunol Res 2024; 12:72-90. [PMID: 37956411 DOI: 10.1158/2326-6066.cir-23-0205] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 07/28/2023] [Accepted: 11/09/2023] [Indexed: 11/15/2023]
Abstract
Pancreatic cancer is a deadly disease that is largely resistant to immunotherapy, in part because of the accumulation of immunosuppressive cells in the tumor microenvironment (TME). Much evidence suggests that tumor-derived exosomes (TDE) contribute to the immunosuppressive activity mediated by myeloid-derived suppressor cells (MDSC) within the pancreatic cancer TME. However, the underlying mechanisms remain elusive. Herein, we report that macrophage migration inhibitory factor (MIF) in TDEs has a key role in inducing MDSC formation in pancreatic cancer. We identified MIF in both human and murine pancreatic cancer-derived exosomes. Upon specific shRNA-mediated knockdown of MIF, the ability of pancreatic cancer-derived exosomes to promote MDSC differentiation was abrogated. This phenotype was rescued by reexpression of the wild-type form of MIF rather than a tautomerase-null mutant or a thiol-protein oxidoreductase-null mutant, indicating that both MIF enzyme activity sites play a role in exosome-induced MDSC formation in pancreatic cancer. RNA sequencing data indicated that MIF tautomerase regulated the expression of genes required for MDSC differentiation, recruitment, and activation. We therefore developed a MIF tautomerase inhibitor, IPG1576. The inhibitor effectively inhibited exosome-induced MDSC differentiation in vitro and reduced tumor growth in an orthotopic pancreatic cancer model, which was associated with decreased numbers of MDSCs and increased infiltration of CD8+ T cells in the TME. Collectively, our findings highlight a pivotal role for MIF in exosome-induced MDSC differentiation in pancreatic cancer and underscore the potential of MIF tautomerase inhibitors to reverse the immunosuppressive pancreatic cancer microenvironment, thereby augmenting anticancer immune responses.
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Affiliation(s)
- Xuebing Jia
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianbei Xi
- Department of Medicinal Chemistry, Immunophage Biotech Co., Ltd., Shanghai, China
| | - Binle Tian
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuanyuan Zhang
- Department of Oncology, Immunophage Biotech Co., Ltd., Shanghai, China
| | - Zhilong Wang
- Department of Oncology, Immunophage Biotech Co., Ltd., Shanghai, China
| | - Fan Wang
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zheng Li
- Department of Autoimmune Disease, Immunophage Biotech Co., Ltd., Shanghai, China
| | - Jiang Long
- Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - JianFei Wang
- Excecutive Office, Immunophage Biotech Co., Ltd., Shanghai, China
- Shanghai Laboratory Animal Research Center, Shanghai, China
| | - Guo-Huang Fan
- Excecutive Office, Immunophage Biotech Co., Ltd., Shanghai, China
| | - Qi Li
- Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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20
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Ahmadi M, Abbasi R, Rezaie J. Tumor immune escape: extracellular vesicles roles and therapeutics application. Cell Commun Signal 2024; 22:9. [PMID: 38167133 PMCID: PMC10763406 DOI: 10.1186/s12964-023-01370-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 10/28/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Immune escape, a process by which tumor cells evade immune surveillance, remains a challenge for cancer therapy. Tumor cells produce extracellular vesicles (EVs) that participate in immune escape by transferring bioactive molecules between cells. EVs refer to heterogeneous vesicles that participate in intercellular communication. EVs from tumor cells usually carry tumor antigens and have been considered a source of tumor antigens to induce anti-tumor immunity. However, evidence also suggests that these EVs can accelerate immune escape by carrying heat shock proteins (HSPs), programmed death-ligand 1 (PD-L1), etc. to immune cells, suppressing function and exhausting the immune cells pool. EVs are progressively being evaluated for therapeutic implementation in cancer therapies. EVs-based immunotherapies involve inhibiting EVs generation, using natural EVs, and harnessing engineering EVs. All approaches are associated with advantages and disadvantages. The EVs heterogeneity and diverse physicochemical properties are the main challenges to their clinical applications. SHORT CONCLUSION Although EVs are criminal; they can be useful for overcoming immune escape. This review discusses the latest knowledge on EVs population and sheds light on the function of tumor-derived EVs in immune escape. It also describes EVs-based immunotherapies with a focus on engineered EVs, followed by challenges that hinder the clinical translation of EVs that are essential to be addressed in future investigations. Video Abstract.
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Affiliation(s)
- Mahdi Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Abbasi
- Department of Biology, Urmia University, Urmia, Iran
| | - Jafar Rezaie
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran.
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21
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Gu X, Wei F, Tong J, Liu Y, Chen S, Zheng L, Xing Y. MiR-9 promotes G-MDSC recruitment and tumor proliferation by targeting SOCS3 in breast cancer. FASEB J 2024; 38:e23388. [PMID: 38145323 DOI: 10.1096/fj.202301764rr] [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: 08/30/2023] [Revised: 11/17/2023] [Accepted: 12/11/2023] [Indexed: 12/26/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of cells that differentiate from myeloid cells, proliferate in cancer and inflammatory reactions, and mainly exert immunosuppressive functions. Nonetheless, the precise mechanisms that dictate both the accumulation and function of MDSCs remain only partially elucidated. In the course of our investigation, we observed a positive correlation between the content of MDSCs especially G-MDSCs and miR-9 level in the tumor tissues derived from miR-9 knockout MMTV-PyMT mice and 4T1 tumor-bearing mice with miR-9 overexpression. Combined with RNA-seq analysis, we identified SOCS2 and SOCS3 as direct targets of miR-9. Additionally, our research unveiled the pivotal role of the CCL5/CCR5 axis in orchestrating the chemotactic recruitment of G-MDSCs within the tumor microenvironment, a process that is enhanced by miR-9. These findings provide fresh insights into the molecular mechanisms governing the accumulation of MDSCs within the framework of breast cancer development.
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Affiliation(s)
- Xinyue Gu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Fang Wei
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Jinzhe Tong
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Yichen Liu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Simiao Chen
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Lufeng Zheng
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Yingying Xing
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
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22
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Keyvani V, Ghale-Noie ZN, Mollazadeh S, Mahmoudian RA, Ghorbani E, Naderi H, Khazaei M, Hassanian SM, Ferns GA, Avan A, Anvari K. Recent Progress in the Application of Exosome Analysis in Ovarian Cancer Management. Curr Cancer Drug Targets 2024; 24:920-929. [PMID: 38284712 DOI: 10.2174/0115680096281906231213055422] [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: 09/12/2023] [Revised: 10/22/2023] [Accepted: 10/25/2023] [Indexed: 01/30/2024]
Abstract
Exosomes are very small (nano-sized) vesicles participating in tumor development by involvement in intercellular communication mediated by transferring biocomponents. Exosomes appear to play vital roles in various cancer development, such as ovarian cancer, a common malignancy in women. Several hallmarks of ovarian cancer are reported to be affected by the exosomemediated cellular cross-talk, including modulating peritoneal dissemination and chemoresistance. Since the expression of some biomolecules, such as miRNAs and mRNA, is changed in ovarian cancer, these exo-biomolecules can be applied as prognostic, diagnostic, and therapeutic biomarkers. Also, the selective loading of specific chemotherapeutic agents into exosomes highlights these biocarries as potential delivery devices. Exosomes could be artificially provided and engineered to better target the site of interest in ovarian cancer. In the present review, we summarize the notable achievement of exosome application in ovarian cancer management to gain applicable transitional insight against this cancer.
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Affiliation(s)
- Vahideh Keyvani
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zari Naderi Ghale-Noie
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samaneh Mollazadeh
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Reihaneh Alsadat Mahmoudian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elnaz Ghorbani
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- College of Medicine, University of Warith Al-Anbiyaa, Karbala, Iraq
| | - Hamid Naderi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex, BN1 9PH, UK
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, 4059, Australia
- College of Medicine and Health Sciences, National University of Science and Technology, Sultanate of Oman
| | - Kazem Anvari
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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23
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Mizuhara K, Shimura Y, Tsukamoto T, Kanai A, Kuwahara-Ota S, Yamaguchi J, Muramatsu A, Okamoto H, Taminishi-Katsuragawa Y, Kawaji-Kanayama Y, Isa R, Mizutani S, Inaba T, Kuroda J. Tumour-derived exosomes promote the induction of monocytic myeloid-derived suppressor cells from peripheral blood mononuclear cells by delivering miR-106a-5p and miR-146a-5p in multiple myeloma. Br J Haematol 2023; 203:426-438. [PMID: 37584109 DOI: 10.1111/bjh.19049] [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: 03/21/2023] [Revised: 07/17/2023] [Accepted: 08/07/2023] [Indexed: 08/17/2023]
Abstract
The shift of the tumour immune microenvironment to a suppressive state promotes not only the development and progression of the disease in multiple myeloma (MM) but also the development of resistance to immunotherapy. We previously demonstrated that myeloma cells can induce monocytic myeloid-derived suppressor cells (M-MDSCs) from healthy peripheral blood mononuclear cells (PBMCs) via the concomitant secretion of CC motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF), but an unknown mediator also promotes M-MDSC induction. This study demonstrates that miR-106a-5p and miR-146a-5p delivered by tumour-derived exosomes (TEXs) from myeloma cells play essential roles in M-MDSC induction in MM. MiR-106a-5p and miR-146a-5p upregulate various immunosuppressive/inflammatory molecules in PBMCs, such as IDO1, CD38, programmed death-ligand 1, CCL5 or MYD88, which are involved in interferon (IFN)-α response, IFN-γ response, inflammatory response, tumour necrosis factor-α signalling and Interleukin-6-JAK-STAT3 signalling. These molecular features mirror the increases in myeloid cellular compartments of PBMCs when co-cultured with myeloma cells. MiR-106a-5p and miR-146a-5p have a compensatory relationship, and these two miRNAs collaborate with CCL5 and MIF to promote M-MDSC induction. Collectively, novel therapeutic candidates may be involved in TEX-mediated sequential cellular and molecular events underlying M-MDSC induction, potentially improving the efficacy of immunotherapy.
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Affiliation(s)
- Kentaro Mizuhara
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuji Shimura
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Taku Tsukamoto
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Akinori Kanai
- Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
- Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | - Saeko Kuwahara-Ota
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Department of Hematology, Japan Community Health Care Organization, Kyoto Kuramaguchi Medical Center, Kyoto, Japan
| | - Junko Yamaguchi
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Department of Hematology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan
| | - Ayako Muramatsu
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Haruya Okamoto
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoko Taminishi-Katsuragawa
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuka Kawaji-Kanayama
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Reiko Isa
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shinsuke Mizutani
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshiya Inaba
- Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Junya Kuroda
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
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24
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Wang M, Yu F, Li P. Noncoding RNAs as an emerging resistance mechanism to immunotherapies in cancer: basic evidence and therapeutic implications. Front Immunol 2023; 14:1268745. [PMID: 37767098 PMCID: PMC10520974 DOI: 10.3389/fimmu.2023.1268745] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
The increasing knowledge in the field of oncoimmunology has led to extensive research into tumor immune landscape and a plethora of clinical immunotherapy trials in cancer patients. Immunotherapy has become a clinically beneficial alternative to traditional treatments by enhancing the power of the host immune system against cancer. However, it only works for a minority of cancers. Drug resistance continues to be a major obstacle to the success of immunotherapy in cancer. A fundamental understanding of the detailed mechanisms underlying immunotherapy resistance in cancer patients will provide new potential directions for further investigations of cancer treatment. Noncoding RNAs (ncRNAs) are tightly linked with cancer initiation and development due to their critical roles in gene expression and epigenetic modulation. The clear appreciation of the role of ncRNAs in tumor immunity has opened new frontiers in cancer research and therapy. Furthermore, ncRNAs are increasingly acknowledged as a key factor influencing immunotherapeutic treatment outcomes. Here, we review the available evidence on the roles of ncRNAs in immunotherapy resistance, with an emphasis on the associated mechanisms behind ncRNA-mediated immune resistance. The clinical implications of immune-related ncRNAs are also discussed, shedding light on the potential ncRNA-based therapies to overcome the resistance to immunotherapy.
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Affiliation(s)
- Man Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | | | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
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25
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Xia B, Liu Y, Wang J, Lu Q, Lv X, Deng K, Yang J. Emerging role of exosome-shuttled noncoding RNAs in gastrointestinal cancers: From intercellular crosstalk to clinical utility. Pharmacol Res 2023; 195:106880. [PMID: 37543095 DOI: 10.1016/j.phrs.2023.106880] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 07/27/2023] [Accepted: 08/01/2023] [Indexed: 08/07/2023]
Abstract
Gastrointestinal cancer remains a significant global health burden. The pursuit of advancing the comprehension of tumorigenesis, along with the identification of reliable biomarkers and the development of precise therapeutic strategies, represents imperative objectives in this field. Exosomes, small membranous vesicles released by most cells, commonly carry functional biomolecules, including noncoding RNAs (ncRNAs), which are specifically sorted and encapsulated by exosomes. Exosome-mediated communication involves the release of exosomes from tumor or stromal cells and the uptake by nearby or remote recipient cells. The bioactive cargoes contained within these exosomes exert profound effects on the recipient cells, resulting in significant modifications in the tumor microenvironment (TME) and distinct alterations in gastrointestinal tumor behaviors. Due to the feasibility of isolating exosomes from various bodily fluids, exosomal ncRNAs have shown great potential as liquid biopsy-based indicators for different gastrointestinal cancers, using blood, ascites, saliva, or bile samples. Moreover, exosomes are increasingly recognized as natural delivery vehicles for ncRNA-based therapeutic interventions. In this review, we elucidate the processes of ncRNA-enriched exosome biogenesis and uptake, examine the regulatory and functional roles of exosomal ncRNA-mediated intercellular crosstalk in gastrointestinal TME and tumor behaviors, and explore their potential clinical utility in diagnostics, prognostics, and therapeutics.
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Affiliation(s)
- Bihan Xia
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Yuzhi Liu
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Jin Wang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Qing Lu
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Xiuhe Lv
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Kai Deng
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China.
| | - Jinlin Yang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China.
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26
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Koni M, Lopatina T, Grange C, Sarcinella A, Cedrino M, Bruno S, Buffolo F, Femminò S, Camussi G, Brizzi MF. Circulating extracellular vesicles derived from tumor endothelial cells hijack the local and systemic anti-tumor immune response: Role of mTOR/G-CSF pathway. Pharmacol Res 2023; 195:106871. [PMID: 37506784 DOI: 10.1016/j.phrs.2023.106871] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/12/2023] [Accepted: 07/25/2023] [Indexed: 07/30/2023]
Abstract
Circulating tumour-derived extracellular vesicles are supposed to contribute to the spreading of distant metastasis. In this study, we investigated the impact of circulating extracellular vesicles derived from tumour-endothelial cells (TEVs) in the expansion of the metastatic bulk. We focus on the role of immune cells in controlling this process using the 4T1 triple negative breast cancer (TNBC) syngeneic model. 4T1 cells were intravenously injected and exposed to circulating TEVs from day 7. The lung, spleen, and bone marrow (BM) were recovered and analysed. We demonstrated that circulating TEVs boost lung metastasis and angiogenesis. FACS and immunohistochemically analyses revealed a significant enrichment of Ly6G+/F4/80+/CD11b+ cells and Ly6G+/F4/80-/CD11b+ in the lung and in the spleen, while Ly6G+/F4/80-/CD11b+ in the BM, indicating the occurrence of a systemic and local immune suppression. TEV immune suppressive properties were further supported by the increased expression of PD-L1, PD-1, and iNOS in the tumour mass. In addition, in vitro experiments demonstrated an increase of CD11+ cells, PD-L1+ myeloid and cancer cells, upregulation of LAG3, CTLA4 and PD-1 in T-cells, release of ROS and NOS, and impaired T-cell-mediated cytotoxic effect in co-culture of TEVs-preconditioned PBMCs and cancer cells. Granulocyte-colony stimulating factor (G-CSF) level was increased in vivo, and was involved in reshaping the immune response. Mechanistically, we also found that mTOR enriched TEVs support G-CSF release and trigger the phosphorylation of the S6 (Ser235/236) mTOR downstream target. Overall, we provided evidence that circulating TEVs enriched in mTOR supported G-CSF release thereby granting tumour immune suppression and metastasis outgrowth.
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Affiliation(s)
- Malvina Koni
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Tatiana Lopatina
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Cristina Grange
- Department of Medical Sciences, University of Turin, Turin, Italy
| | | | | | - Stefania Bruno
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Fabrizio Buffolo
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Saveria Femminò
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, Turin, Italy
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27
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Wu Y, Zhang X, Liu C, Li Z, Wen Y, Zheng R, Xu C, Tian J, Wei L, Wang J, Yan Q, Zheng X, Ma J. Epstein-Barr virus microRNA miR-BART2-5p accelerates nasopharyngeal carcinoma metastasis by suppressing RNase Ⅲ endonuclease DICER1. J Biol Chem 2023; 299:105082. [PMID: 37495108 PMCID: PMC10470218 DOI: 10.1016/j.jbc.2023.105082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 07/08/2023] [Accepted: 07/11/2023] [Indexed: 07/28/2023] Open
Abstract
The development and progression of nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. NPC is usually asymptomatic until it spreads to other sites, and more than 70% of cases are classified as locally advanced disease at diagnosis. EBV-positive nasopharyngeal cancer tissues express only limited viral latent proteins, but express high levels of the EBV-encoded BamHI-A rightward transcript (BART) miRNA molecules. Here, we report that EBV-miRNA-BART2-5p (BART2-5p) promotes NPC cell invasion and metastasis in vivo and in vitro but has no effect on NPC cell proliferation and apoptosis. In addition, BART2-5p altered the mRNA and miRNA expression profiles of NPC cells. The development of human tumors has been reported to be associated with altered miRNAs expression, and overall miRNAs expression is reduced in many types of tumors. We found that BART2-5p downregulated the expression of several miRNAs that could exert oncogenic functions. Mechanistically, BART2-5p directly targets the RNase III endonuclease DICER1, inhibiting its function of cleaving double-stranded stem-loop RNA into short double-stranded RNA, which in turn causes altered expression of a series of key epithelial-mesenchymal transition molecules, and reverting DICER1 expression can rescue this phenotype. Furthermore, analysis from clinical samples showed a negative correlation between BART2-5p and DICER1 expression. According to our study, high expression of BART2-5p in tissues and plasma of patients with NPC is associated with poor prognosis. Our results suggest that, BART2-5p can accelerate NPC metastasis through modulating miRNA profiles which are mediated by DICER1, implying a novel role of EBV miRNAs in the pathogenesis of NPC.
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Affiliation(s)
- Yangge Wu
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Xiaoyue Zhang
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Can Liu
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Zhengshuo Li
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Yuqing Wen
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Run Zheng
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Chenxiao Xu
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Junrui Tian
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China
| | - Lingyu Wei
- Department of Pathology and Immunology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Jia Wang
- Department of Pathology and Immunology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Qun Yan
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, China.
| | - Xiang Zheng
- Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China.
| | - Jian Ma
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, China; Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China.
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28
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Tang JY, Chuang YT, Shiau JP, Yen CY, Chang FR, Tsai YH, Farooqi AA, Chang HW. Connection between Radiation-Regulating Functions of Natural Products and miRNAs Targeting Radiomodulation and Exosome Biogenesis. Int J Mol Sci 2023; 24:12449. [PMID: 37569824 PMCID: PMC10419287 DOI: 10.3390/ijms241512449] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 07/29/2023] [Accepted: 08/02/2023] [Indexed: 08/13/2023] Open
Abstract
Exosomes are cell-derived membranous structures primarily involved in the delivery of the payload to the recipient cells, and they play central roles in carcinogenesis and metastasis. Radiotherapy is a common cancer treatment that occasionally generates exosomal miRNA-associated modulation to regulate the therapeutic anticancer function and side effects. Combining radiotherapy and natural products may modulate the radioprotective and radiosensitizing responses of non-cancer and cancer cells, but there is a knowledge gap regarding the connection of this combined treatment with exosomal miRNAs and their downstream targets for radiation and exosome biogenesis. This review focuses on radioprotective natural products in terms of their impacts on exosomal miRNAs to target radiation-modulating and exosome biogenesis (secretion and assembly) genes. Several natural products have individually demonstrated radioprotective and miRNA-modulating effects. However, the impact of natural-product-modulated miRNAs on radiation response and exosome biogenesis remains unclear. In this review, by searching through PubMed/Google Scholar, available reports on potential functions that show radioprotection for non-cancer tissues and radiosensitization for cancer among these natural-product-modulated miRNAs were assessed. Next, by accessing the miRNA database (miRDB), the predicted targets of the radiation- and exosome biogenesis-modulating genes from the Gene Ontology database (MGI) were retrieved bioinformatically based on these miRNAs. Moreover, the target-centric analysis showed that several natural products share the same miRNAs and targets to regulate radiation response and exosome biogenesis. As a result, the miRNA-radiomodulation (radioprotection and radiosensitization)-exosome biogenesis axis in regard to natural-product-mediated radiotherapeutic effects is well organized. This review focuses on natural products and their regulating effects on miRNAs to assess the potential impacts of radiomodulation and exosome biogenesis for both the radiosensitization of cancer cells and the radioprotection of non-cancer cells.
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Affiliation(s)
- Jen-Yang Tang
- School of Post-Baccalaureate Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ya-Ting Chuang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jun-Ping Shiau
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Ching-Yu Yen
- School of Dentistry, Taipei Medical University, Taipei 11031, Taiwan;
- Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Tainan 71004, Taiwan
| | - Fang-Rong Chang
- Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (F.-R.C.); (Y.-H.T.)
| | - Yi-Hong Tsai
- Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (F.-R.C.); (Y.-H.T.)
| | - Ammad Ahmad Farooqi
- Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 54000, Pakistan
| | - Hsueh-Wei Chang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
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29
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Hu M, Kenific CM, Boudreau N, Lyden D. Tumor-derived nanoseeds condition the soil for metastatic organotropism. Semin Cancer Biol 2023; 93:70-82. [PMID: 37178822 PMCID: PMC10362948 DOI: 10.1016/j.semcancer.2023.05.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/07/2023] [Accepted: 05/08/2023] [Indexed: 05/15/2023]
Abstract
Primary tumors secrete a variety of factors to turn distant microenvironments into favorable and fertile 'soil' for subsequent metastases. Among these 'seeding' factors that initiate pre-metastatic niche (PMN) formation, tumor-derived extracellular vesicles (EVs) are of particular interest as tumor EVs can direct organotropism depending on their surface integrin profiles. In addition, EVs also contain versatile, bioactive cargo, which include proteins, metabolites, lipids, RNA, and DNA fragments. The cargo incorporated into EVs is collectively shed from cancer cells and cancer-associated stromal cells. Increased understanding of how tumor EVs promote PMN establishment and detection of EVs in bodily fluids highlight how tumor EVs could serve as potential diagnostic and prognostic biomarkers, as well as provide a therapeutic target for metastasis prevention. This review focuses on tumor-derived EVs and how they direct organotropism and subsequently modulate stromal and immune microenvironments at distal sites to facilitate PMN formation. We also outline the progress made thus far towards clinical applications of tumor EVs.
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Affiliation(s)
- Mengying Hu
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Candia M Kenific
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Nancy Boudreau
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
| | - David Lyden
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
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30
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Shokati E, Safari E. The immunomodulatory role of exosomal microRNA networks in the crosstalk between tumor-associated myeloid-derived suppressor cells and tumor cells. Int Immunopharmacol 2023; 120:110267. [PMID: 37276829 DOI: 10.1016/j.intimp.2023.110267] [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: 11/22/2022] [Revised: 04/26/2023] [Accepted: 04/28/2023] [Indexed: 06/07/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are considered a heterogeneous group of immature myeloid cells engaging in aggressive tumor progression and metastasis in the tumor microenvironment (TME) of patients diagnosed with cancer, through downregulation of anti-tumor immune responses. Exosomes are small vesicles carrying specific cargos, including proteins, lipids, and MicroRNA (miRNAs). Such exosomal miRNAs delivered by MDSCs and tumor cells are short noncoding RNAs mediating some of the immunosuppressive characteristics of MDSCs in the TME. However, when it comes to cancer diseases, how these miRNAs interact with MDSCs and encourage MDSCs differentiation and function need further investigations. In this review, we discuss MDSC-derived exosomal miRNAs and those derived from tumor cells (TDE) could modulate anti-tumor immunity and regulate the interaction between tumor cells and MDSCs in the TME. Afterward, we focus on dividing miRNAs, as an important substance interacting with MDSCs and tumor cells in the TME, into those have an immunosuppressive or stimulating effect not only on MDSCs expansion, differentiation, and suppressive function but also on tumor evasion.
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Affiliation(s)
- Elham Shokati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Elahe Safari
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran
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31
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J Saadh M, Abedi Kiasari B, Shahrtash SA, Arias-Gonzáles JL, Chaitanya M, Cotrina-Aliaga JC, Kadham MJ, Sârbu I, Akhavan-Sigari R. Exosomal non-coding RNAs' role in immune regulation and potential therapeutic applications. Pathol Res Pract 2023; 247:154522. [PMID: 37201467 DOI: 10.1016/j.prp.2023.154522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 05/07/2023] [Accepted: 05/08/2023] [Indexed: 05/20/2023]
Abstract
Exosomes are now significant players in both healthy and unhealthy cell-to-cell communication. Exosomes can mediate immune activation or immunosuppression, which can influence the growth of tumors. Exosomes affect the immune responses to malignancies in various ways by interacting with tumor cells and the environment around them. Exosomes made by immune cells can control the growth, metastasis, and even chemosensitivity of tumor cells. In contrast, exosomes produced by cancer cells can encourage immune responses that support the tumor. Exosomes carry circular RNAs, long non-coding RNAs, and microRNAs (miRNAs), all involved in cell-to-cell communication. In this review, we focus on the most recent findings concerning the role of exosomal miRNAs, lncRNAs, and circRNAs in immune modulation and the potential therapeutic implications of these discoveries.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan; Applied Science Research Center. Applied Science Private University, Amman, Jordan
| | - Bahman Abedi Kiasari
- Virology Department, Faculty of Veterinary Medicine, The University of Tehran, Tehran, Iran
| | - Seyed Abbas Shahrtash
- Department of Pharmaceutical Engineering, Alborz Campus, University of Tehran, Tehran, Iran
| | | | - Mvnl Chaitanya
- Department of Pharmacognosy, School of Pharmacy, Lovely professional university Phagwara, Punjab 144001, India
| | | | | | - Ioan Sârbu
- 2nd Department of Surgery - Pediatric Surgery and Orthopedics, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iași, Romania.
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Germany; Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University Warsaw, Poland
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32
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Samarpita S, Li X. Leveraging Exosomes as the Next-Generation Bio-Shuttles: The Next Biggest Approach against Th17 Cell Catastrophe. Int J Mol Sci 2023; 24:ijms24087647. [PMID: 37108809 PMCID: PMC10142210 DOI: 10.3390/ijms24087647] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/12/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
In recent years, the launch of clinical-grade exosomes is rising expeditiously, as they represent a new powerful approach for the delivery of advanced therapies and for diagnostic purposes for various diseases. Exosomes are membrane-bound extracellular vesicles that can act as biological messengers between cells, in the context of health and disease. In comparison to several lab-based drug carriers, exosome exhibits high stability, accommodates diverse cargo loads, elicits low immunogenicity and toxicity, and therefore manifests tremendous perspectives in the development of therapeutics. The efforts made to spur exosomes in drugging the untreatable targets are encouraging. Currently, T helper (Th) 17 cells are considered the most prominent factor in the establishment of autoimmunity and several genetic disorders. Current reports have indicated the importance of targeting the development of Th17 cells and the secretion of its paracrine molecule, interleukin (IL)-17. However, the present-day targeted approaches exhibit drawbacks, such as high cost of production, rapid transformation, poor bioavailability, and importantly, causing opportunistic infections that ultimately hamper their clinical applications. To overcome this hurdle, the potential use of exosomes as vectors seem to be a promising approach for Th17 cell-targeted therapies. With this standpoint, this review discusses this new concept by providing a snapshot of exosome biogenesis, summarizes the current clinical trials of exosomes in several diseases, analyzes the prospect of exosomes as an established drug carrier and delineates the present challenges, with an emphasis on their practical applications in targeting Th17 cells in diseases. We further decode the possible future scope of exosome bioengineering for targeted drug delivery against Th17 cells and its catastrophe.
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Affiliation(s)
- Snigdha Samarpita
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Xiaogang Li
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
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33
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Bhardwaj V, Ansell SM. Modulation of T-cell function by myeloid-derived suppressor cells in hematological malignancies. Front Cell Dev Biol 2023; 11:1129343. [PMID: 37091970 PMCID: PMC10113446 DOI: 10.3389/fcell.2023.1129343] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 03/15/2023] [Indexed: 04/08/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes that negatively regulate the immune response to cancer and chronic infections. Abnormal myelopoiesis and pathological activation of myeloid cells generate this heterogeneous population of myeloid-derived suppressor cells. They are characterized by their distinct transcription, phenotypic, biochemical, and functional features. In the tumor microenvironment (TME), myeloid-derived suppressor cells represent an important class of immunosuppressive cells that correlate with tumor burden, stage, and a poor prognosis. Myeloid-derived suppressor cells exert a strong immunosuppressive effect on T-cells (and a broad range of other immune cells), by blocking lymphocyte homing, increasing production of reactive oxygen and nitrogen species, promoting secretion of various cytokines, chemokines, and immune regulatory molecules, stimulation of other immunosuppressive cells, depletion of various metabolites, and upregulation of immune checkpoint molecules. Additionally, the heterogeneity of myeloid-derived suppressor cells in cancer makes their identification challenging. Overall, they serve as a major obstacle for many cancer immunotherapies and targeting them could be a favorable strategy to improve the effectiveness of immunotherapeutic interventions. However, in hematological malignancies, particularly B-cell malignancies, the clinical outcomes of targeting these myeloid-derived suppressor cells is a field that is still to be explored. This review summarizes the complex biology of myeloid-derived suppressor cells with an emphasis on the immunosuppressive pathways used by myeloid-derived suppressor cells to modulate T-cell function in hematological malignancies. In addition, we describe the challenges, therapeutic strategies, and clinical relevance of targeting myeloid-derived suppressor cells in these diseases.
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Liu CG, Chen J, Goh RMWJ, Liu YX, Wang L, Ma Z. The role of tumor-derived extracellular vesicles containing noncoding RNAs in mediating immune cell function and its implications from bench to bedside. Pharmacol Res 2023; 191:106756. [PMID: 37019192 DOI: 10.1016/j.phrs.2023.106756] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 03/16/2023] [Accepted: 04/02/2023] [Indexed: 04/05/2023]
Abstract
Extracellular vesicles (EVs) are membrane-encapsulated vesicles released by almost all cell types, which participate in intercellular communication by delivering different types of molecular cargoes, such as non-coding RNAs (ncRNAs). Accumulating evidence suggests that tumor-derived EVs act as a bridge for intercellular crosstalk between tumor cells and surrounding cells, including immune cells. Tumor-derived EVs containing ncRNAs (TEV-ncRNAs) mediate intercellular crosstalk to manipulate immune responses and affect the malignant phenotypes of cancer cells. In this review, we summarize the double-edged roles and the underlying mechanisms of TEV-ncRNAs in regulating innate and adaptive immune cells. We also highlight the advantages of using TEV-ncRNAs in liquid biopsies for cancer diagnosis and prognosis. Moreover, we outline the use of engineered EVs to deliver ncRNAs and other therapeutic agents for cancer therapy.
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35
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Zhang H, Wang S, Sun M, Cui Y, Xing J, Teng L, Xi Z, Yang Z. Exosomes as smart drug delivery vehicles for cancer immunotherapy. Front Immunol 2023; 13:1093607. [PMID: 36733388 PMCID: PMC9888251 DOI: 10.3389/fimmu.2022.1093607] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 12/23/2022] [Indexed: 01/19/2023] Open
Abstract
Exosomes (Exos) as drug delivery vehicles have been widely used for cancer immunotherapy owing to their good biocompatibility, low toxicity, and low immunogenicity. Some Exos-based cancer immunotherapy strategies such as tuning of immunosuppressive tumor microenvironment, immune checkpoint blockades, and cancer vaccines have also been investigated in recent years, which all showed excellent therapeutic effects for malignant tumor. Furthermore, some Exos-based drug delivery systems (DDSs) for cancer immunotherapy have also undergone clinic trails, indicating that Exos are a promising drug delivery carrier. In this review, in order to promote the development of Exos-based DDSs in cancer immunotherapy, the biogenesis and composition of Exos, and Exos as drug delivery vehicles for cancer immunotherapy are summarized. Meanwhile, their clinical translation and challenges are also discussed. We hope this review will provide a good guidance for Exos as drug delivery vehicles for cancer immunotherapy.
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Affiliation(s)
- Huan Zhang
- School of Life Sciences, Jilin University, Changchun, China
| | - Simiao Wang
- School of Life Sciences, Jilin University, Changchun, China
| | - Man Sun
- School of Life Sciences, Jilin University, Changchun, China
| | - Yaxin Cui
- School of Life Sciences, Jilin University, Changchun, China
| | - Jianming Xing
- School of Life Sciences, Jilin University, Changchun, China
| | - Lesheng Teng
- School of Life Sciences, Jilin University, Changchun, China
| | - Zhifang Xi
- School of Horticulture and Food, Guangdong Eco-Engineering Polytechnic, Guangzhou, China,*Correspondence: Zhifang Xi, ; Zhaogang Yang,
| | - Zhaogang Yang
- School of Life Sciences, Jilin University, Changchun, China,*Correspondence: Zhifang Xi, ; Zhaogang Yang,
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36
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Cao Y, Xu P, Shen Y, Wu W, Chen M, Wang F, Zhu Y, Yan F, Gu W, Lin Y. Exosomes and cancer immunotherapy: A review of recent cancer research. Front Oncol 2023; 12:1118101. [PMID: 36727049 PMCID: PMC9885269 DOI: 10.3389/fonc.2022.1118101] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 12/29/2022] [Indexed: 01/18/2023] Open
Abstract
As phospholipid extracellular vesicles (EVs) secreted by various cells, exosomes contain non-coding RNA (ncRNA), mRNA, DNA fragments, lipids, and proteins, which are essential for intercellular communication. Several types of cells can secrete exosomes that contribute to cancer initiation and progression. Cancer cells and the immune microenvironment interact and restrict each other. Tumor-derived exosomes (TDEs) have become essential players in this balance because they carry information from the original cancer cells and express complexes of MHC class I/II epitopes and costimulatory molecules. In the present study, we aimed to identify potential targets for exosome therapy by examining the specific expression and mechanism of exosomes derived from cancer cells. We introduced TDEs and explored their role in different tumor immune microenvironment (TIME), with a particular emphasis on gastrointestinal cancers, before briefly describing the therapeutic strategies of exosomes in cancer immune-related therapy.
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Affiliation(s)
- Yue Cao
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Peng Xu
- Department of Hematology, Soochow Hopes Hematology Hospital, Suzhou, Jiangsu, China
| | - Yangling Shen
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Wei Wu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Min Chen
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Fei Wang
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Yuandong Zhu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Feng Yan
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Weiying Gu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China,*Correspondence: Yan Lin, ; Weiying Gu,
| | - Yan Lin
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China,*Correspondence: Yan Lin, ; Weiying Gu,
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Ng WL, Ansell SM, Mondello P. Insights into the tumor microenvironment of B cell lymphoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:362. [PMID: 36578079 PMCID: PMC9798587 DOI: 10.1186/s13046-022-02579-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 12/20/2022] [Indexed: 12/30/2022]
Abstract
The standard therapies in lymphoma have predominantly focused on targeting tumor cells with less of a focus on the tumor microenvironment (TME), which plays a critical role in favoring tumor growth and survival. Such an approach may result in increasingly refractory disease with progressively reduced responses to subsequent treatments. To overcome this hurdle, targeting the TME has emerged as a new therapeutic strategy. The TME consists of T and B lymphocytes, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and other components. Understanding the TME can lead to a comprehensive approach to managing lymphoma, resulting in therapeutic strategies that target not only cancer cells, but also the supportive environment and thereby ultimately improve survival of lymphoma patients. Here, we review the normal function of different components of the TME, the impact of their aberrant behavior in B cell lymphoma and the current TME-direct therapeutic avenues.
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Affiliation(s)
- Wern Lynn Ng
- grid.66875.3a0000 0004 0459 167XDivision of Hematology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905 USA
| | - Stephen M. Ansell
- grid.66875.3a0000 0004 0459 167XDivision of Hematology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905 USA
| | - Patrizia Mondello
- grid.66875.3a0000 0004 0459 167XDivision of Hematology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905 USA
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38
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DSCR9/miR-21-5p axis inhibits pancreatic cancer proliferation and resistance to gemcitabine via BTG2 signaling. Acta Biochim Biophys Sin (Shanghai) 2022; 54:1775-1788. [PMID: 36789695 PMCID: PMC10157615 DOI: 10.3724/abbs.2022194] [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] [Indexed: 12/15/2022] Open
Abstract
The outcome of pancreatic adenocarcinoma (PAAD) patients is poor, given resistance to gemcitabine. Long noncoding RNA (lncRNA) has been implicated in the carcinogenesis of pancreatic cancer; however, its function and mechanism in PAAD resistance to gemcitabine (GEM) are yet unknown. Herein, we demonstrate that lncRNA DSCR9 is significantly reduced in PAAD in vitro and in vivo. CCK-8, BrdU and flow cytometry assays show that overexpression of DSCR9 markedly suppresses pancreatic cancer cell proliferation and invasion, and promotes apoptosis under gemcitabine treatment. BTG2 acts as a tumor suppressor by reducing the proliferation and invasion of pancreatic cancer cells and increasing gemcitabine-induced apoptosis. Immunofluorescence (IF) staining combined with fluorescence in situ hybridization (FISH) of pancreatic cancer tissues shows that DSCR9 and BTG2 are both increased in pancreatic cancer tissues. Luciferase assay shows that miR-21-5p simultaneously binds to DSCR9 and 3'UTR of BTG2; DSCR9 relieves miR-21-5p-induced inhibition of BTG2 by competing with BTG2 for miR-21-5p binding. Overexpression of miR-21-5p enhances the invasiveness of pancreatic cancer cells by promoting cancer cell proliferation and invasion and attenuating gemcitabine-induced apoptosis. Overexpression of miR-21-5p attenuates the effect of DSCR9 overexpression on BTG2 expression and invasiveness of pancreatic cancer cells. Finally, miR-21-5p expression is increased, while BTG2 expression is decreased in pancreatic cancer tissues. miR-21-5p is negatively correlated with DSCR9 and BTG2. In conclusion, the DSCR9/miR-21-5p/BTG2 axis modulates pancreatic cancer proliferation, invasion, and gemcitabine resistance.
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39
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Contributions and therapeutic potential of tumor-derived microRNAs containing exosomes to cancer progression. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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40
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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: 23] [Impact Index Per Article: 7.7] [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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Exosomes carrying immune checkpoints, a promising therapeutic approach in cancer treatment. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:183. [PMID: 36071295 DOI: 10.1007/s12032-022-01781-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 06/20/2022] [Indexed: 10/14/2022]
Abstract
Exosomes are a subgroup of extracellular vesicles generated by distinct cells. Tumor-derived extracellular vesicles convey immunological checkpoint molecules. TEXs as critical mediators in tumor development, metastasis, and immune escape have recently become the focus of scientific research. Exosomes are involved in the regulation of the immune system. Exosomes interact with target cells in the tumor microenvironment, changing their function based on the cargo they contain. Exosomal immune checkpoints might be exploited to track tumor immune evasion, treatment response, and patient prognosis while enhancing tumor cell proliferation and spread. This review focuses on tumor-derived exosomes, their immunosuppressive effects in mice models, and their role in cancer immunotherapy. Exosomes are being studied as possible cancer vaccines, with numerous uses in tumor immunotherapy. Exosomes can carry chemotherapeutics, siRNA, and monoclonal antibodies. Exosomes produced by macrophages might be used to treat cancer. These and other clinical consequences provide new doors for cancer treatment.
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42
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Siemińska I, Baran J. Myeloid-Derived Suppressor Cells as Key Players and Promising Therapy Targets in Prostate Cancer. Front Oncol 2022; 12:862416. [PMID: 35860573 PMCID: PMC9289201 DOI: 10.3389/fonc.2022.862416] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 06/06/2022] [Indexed: 12/27/2022] Open
Abstract
Prostate cancer (PC) is the second most often diagnosed malignancy in men and one of the major causes of cancer death worldwide. Despite genetic predispositions, environmental factors, including a high-fat diet, obesity, a sedentary lifestyle, infections of the prostate, and exposure to chemicals or ionizing radiation, play a crucial role in PC development. Moreover, due to a lack of, or insufficient T-cell infiltration and its immunosuppressive microenvironment, PC is frequently classified as a “cold” tumor. This is related to the absence of tumor-associated antigens, the lack of T-cell activation and their homing into the tumor bed, and the presence of immunological cells with regulatory functions, including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Treg), and tumor-associated macrophages (TAMs). All of them, by a variety of means, hamper anti-tumor immune response in the tumor microenvironment (TME), stimulating tumor growth and the formation of metastases. Therefore, they emerge as potential anti-cancer therapy targets. This article is focused on the function and role of MDSCs in the initiation and progression of PC. Clinical trials directly targeting this cell population or affecting its biological functions, thus limiting its pro-tumorigenic activity, are also presented.
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Affiliation(s)
- Izabela Siemińska
- Department of Clinical Immunology, Jagiellonian University Medical College, Cracow, Poland
- University Centre of Veterinary Medicine, Jagiellonian University - University of Agriculture, Cracow, Poland
| | - Jarek Baran
- Department of Clinical Immunology, Jagiellonian University Medical College, Cracow, Poland
- *Correspondence: Jarek Baran,
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43
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Liang L, Xu X, Li J, Yang C. Interaction Between microRNAs and Myeloid-Derived Suppressor Cells in Tumor Microenvironment. Front Immunol 2022; 13:883683. [PMID: 35634311 PMCID: PMC9130582 DOI: 10.3389/fimmu.2022.883683] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 03/29/2022] [Indexed: 01/08/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells generated during a series of pathologic conditions including cancer. MicroRNA (miRNA) has been considered as a regulator in different tumor microenvironments. Recent studies have begun to unravel the crosstalk between miRNAs and MDSCs. The knowledge of the effect of both miRNAs and MDSCs in tumor may improve our understanding of the tumor immune escape and metastasis. The miRNAs target cellular signal pathways to promote or inhibit the function of MDSCs. On the other hand, MDSCs transfer bioinformation through exosomes containing miRNAs. In this review, we summarized and discussed the bidirectional regulation between miRNAs and MDSCs in the tumor microenvironment.
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Affiliation(s)
- Lifei Liang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Xiaoqing Xu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jiawei Li
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Cheng Yang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.,Fudan Zhangjiang Institute of Fudan University, Shanghai, China
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Hatmal MM, Al-Hatamleh MAI, Olaimat AN, Alshaer W, Hasan H, Albakri KA, Alkhafaji E, Issa NN, Al-Holy MA, Abderrahman SM, Abdallah AM, Mohamud R. Immunomodulatory Properties of Human Breast Milk: MicroRNA Contents and Potential Epigenetic Effects. Biomedicines 2022; 10:1219. [PMID: 35740242 PMCID: PMC9219990 DOI: 10.3390/biomedicines10061219] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 05/15/2022] [Accepted: 05/17/2022] [Indexed: 02/07/2023] Open
Abstract
Infants who are exclusively breastfed in the first six months of age receive adequate nutrients, achieving optimal immune protection and growth. In addition to the known nutritional components of human breast milk (HBM), i.e., water, carbohydrates, fats and proteins, it is also a rich source of microRNAs, which impact epigenetic mechanisms. This comprehensive work presents an up-to-date overview of the immunomodulatory constituents of HBM, highlighting its content of circulating microRNAs. The epigenetic effects of HBM are discussed, especially those regulated by miRNAs. HBM contains more than 1400 microRNAs. The majority of these microRNAs originate from the lactating gland and are based on the remodeling of cells in the gland during breastfeeding. These miRNAs can affect epigenetic patterns by several mechanisms, including DNA methylation, histone modifications and RNA regulation, which could ultimately result in alterations in gene expressions. Therefore, the unique microRNA profile of HBM, including exosomal microRNAs, is implicated in the regulation of the genes responsible for a variety of immunological and physiological functions, such as FTO, INS, IGF1, NRF2, GLUT1 and FOXP3 genes. Hence, studying the HBM miRNA composition is important for improving the nutritional approaches for pregnancy and infant's early life and preventing diseases that could occur in the future. Interestingly, the composition of miRNAs in HBM is affected by multiple factors, including diet, environmental and genetic factors.
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Affiliation(s)
- Ma’mon M. Hatmal
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan;
| | - Mohammad A. I. Al-Hatamleh
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu 16150, Malaysia;
| | - Amin N. Olaimat
- Department of Clinical Nutrition and Dietetics, Faculty of Applied Medical Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan; (A.N.O.); (M.A.A.-H.)
| | - Walhan Alshaer
- Cell Therapy Center (CTC), The University of Jordan, Amman 11942, Jordan;
| | - Hanan Hasan
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan;
| | - Khaled A. Albakri
- Faculty of Medicine, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan;
| | - Enas Alkhafaji
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan;
| | - Nada N. Issa
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan;
| | - Murad A. Al-Holy
- Department of Clinical Nutrition and Dietetics, Faculty of Applied Medical Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan; (A.N.O.); (M.A.A.-H.)
| | - Salim M. Abderrahman
- Department of Biology and Biotechnology, Faculty of Sciences, The Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan;
| | - Atiyeh M. Abdallah
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha 2713, Qatar;
| | - Rohimah Mohamud
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu 16150, Malaysia;
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45
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Exosomes for Regulation of Immune Responses and Immunotherapy. JOURNAL OF NANOTHERANOSTICS 2022. [DOI: 10.3390/jnt3010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Exosomes are membrane-enveloped nanosized (30–150 nm) extracellular vesicles of endosomal origin produced by almost all cell types and encompass a multitude of functioning biomolecules. Exosomes have been considered crucial players of cell-to-cell communication in physiological and pathological conditions. Accumulating evidence suggests that exosomes can modulate the immune system by delivering a plethora of signals that can either stimulate or suppress immune responses, which have potential applications as immunotherapies for cancer and autoimmune diseases. Here, we discuss the current knowledge about the active biomolecular components of exosomes that contribute to exosomal function in modulating different immune cells and also how these immune cell-derived exosomes play critical roles in immune responses. We further discuss the translational potential of engineered exosomes as immunotherapeutic agents with their advantages over conventional nanocarriers for drug delivery and ongoing clinical trials.
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Liu X, Zhao S, Sui H, Liu H, Yao M, Su Y, Qu P. MicroRNAs/LncRNAs Modulate MDSCs in Tumor Microenvironment. Front Oncol 2022; 12:772351. [PMID: 35359390 PMCID: PMC8963964 DOI: 10.3389/fonc.2022.772351] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 02/14/2022] [Indexed: 12/31/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature cells derived from bone marrow that play critical immunosuppressive functions in the tumor microenvironment (TME), promoting cancer progression. According to base length, Non-coding RNAs (ncRNAs) are mainly divided into: microRNAs (miRNAs), lncRNAs, snRNAs and CircRNAs. Both miRNA and lncRNA are transcribed by RNA polymerase II, and they play an important role in gene expression under both physiological and pathological conditions. The increasing data have shown that MiRNAs/LncRNAs regulate MDSCs within TME, becoming one of potential breakthrough points at the investigation and treatment of cancer. Therefore, we summarize how miRNAs/lncRNAs mediate the differentiation, expansion and immunosuppressive function of tumor MDSCs in TME. We will then focus on the regulatory mechanisms of exosomal MicroRNAs/LncRNAs on tumor MDSCs. Finally, we will discuss how the interaction of miRNAs/lncRNAs modulates tumor MDSCs.
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Affiliation(s)
- Xiaocui Liu
- Department of Histology and Embryology, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong, China
| | - Shang Zhao
- Department of Pathophysiology, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong, China
| | - Hongshu Sui
- Department of Histology and Embryology, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong, China
| | - Hui Liu
- Department of Histology and Embryology, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong, China
| | - Minhua Yao
- Department of Histology and Embryology, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong, China
| | - Yanping Su
- Department of Histology and Embryology, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong, China
- *Correspondence: Yanping Su, ; Peng Qu,
| | - Peng Qu
- Department of Histology and Embryology, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong, China
- National Institutes of Health (NIH), Bethesda, MD, United States
- *Correspondence: Yanping Su, ; Peng Qu,
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47
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Arora S, Khan S, Zaki A, Tabassum G, Mohsin M, Bhutto HN, Ahmad T, Fatma T, Syed MA. Integration of chemokine signaling with non-coding RNAs in tumor microenvironment and heterogeneity in different cancers. Semin Cancer Biol 2022; 86:720-736. [DOI: 10.1016/j.semcancer.2022.03.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/15/2022] [Accepted: 03/02/2022] [Indexed: 02/07/2023]
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Li J, Sun L, Chen Y, Zhu J, Shen J, Wang J, Gu Y, Zhang G, Wang M, Shi T, Chen W. Gastric cancer-derived exosomal miR-135b-5p impairs the function of Vγ9Vδ2 T cells by targeting specificity protein 1. Cancer Immunol Immunother 2022; 71:311-325. [PMID: 34159436 DOI: 10.1007/s00262-021-02991-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 06/16/2021] [Indexed: 12/24/2022]
Abstract
Recent studies have shown that tumor-derived exosomes participate in the communication between tumor cells and their microenvironment and mediate malignant biological behaviors including immune escape. In this study, we found that gastric cancer (GC) cell-derived exosomes could be effectively uptaken by Vγ9Vδ2 T cells, decrease the cell viability of Vγ9Vδ2 T cells, induce apoptosis, and reduce the production of cytotoxic cytokines IFN-γ and TNF-α. Furthermore, we demonstrated that exosomal miR-135b-5p was delivered into Vγ9Vδ2 T cells. Exosomal miR-135b-5p impaired the function of Vγ9Vδ2 T cells by targeting specificity protein 1 (SP1). More importantly, blocking the SP1 function by Plicamycin, an SP1 inhibitor, abolished the effect of stable miR-135b-5p knockdown GC cell-derived exosomes on Vγ9Vδ2 T cell function. Collectively, our results suggest that GC cell-derived exosomes impair the function of Vγ9Vδ2 T cells via miR-135b-5p/SP1 pathway, and targeting exosomal miR-135b-5p/SP1 axis may improve the efficiency of GC immunotherapy based on Vγ9Vδ2 T cells.
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Affiliation(s)
- Juntao Li
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, China
| | - Linqing Sun
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, China
| | - Yanjun Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, China
| | - Jinghan Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, China
| | - Jin Shen
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
| | - Jiayu Wang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 708 Renmin Road, Suzhou, China
| | - Yanzheng Gu
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 708 Renmin Road, Suzhou, China
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
| | - Guangbo Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 708 Renmin Road, Suzhou, China
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China
| | - Mingyuan Wang
- Suzhou Red Cross Blood Center, 355 Shizi Road, Suzhou, China
| | - Tongguo Shi
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China.
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 708 Renmin Road, Suzhou, China.
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China.
- Jiangsu Province, 708 Renmin Road, Suzhou, 215100, China.
| | - Weichang Chen
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Renmin Road, Suzhou, China.
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, China.
- Jiangsu Province, 50 Donghuan Road, Suzhou, 215100, China.
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49
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Hao Q, Wu Y, Wu Y, Wang P, Vadgama JV. Tumor-Derived Exosomes in Tumor-Induced Immune Suppression. Int J Mol Sci 2022; 23:1461. [PMID: 35163380 PMCID: PMC8836190 DOI: 10.3390/ijms23031461] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/19/2022] [Accepted: 01/25/2022] [Indexed: 02/07/2023] Open
Abstract
Exosomes are a class of small membrane-bound extracellular vesicles released by almost all cell types and present in all body fluids. Based on the studies of exosome content and their interactions with recipient cells, exosomes are now thought to mediate "targeted" information transfer. Tumor-derived exosomes (TEX) carry a cargo of molecules different from that of normal cell-derived exosomes. TEX functions to mediate distinct biological effects such as receptor discharge and intercellular cross-talk. The immune system defenses, which may initially restrict tumor progression, are progressively blunted by the broad array of TEX molecules that activate suppressive pathways in different immune cells. Herein, we provide a review of the latest research progress on TEX in the context of tumor-mediated immune suppression and discuss the potential as well as challenges of TEX as a target of immunotherapy.
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Affiliation(s)
- Qiongyu Hao
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
| | - Yong Wu
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Yanyuan Wu
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
| | - Piwen Wang
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
| | - Jaydutt V. Vadgama
- Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA; (Y.W.); (Y.W.)
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
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50
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Ma ES, Wang ZX, Zhu MQ, Zhao J. Immune evasion mechanisms and therapeutic strategies in gastric cancer. World J Gastrointest Oncol 2022; 14:216-229. [PMID: 35116112 PMCID: PMC8790417 DOI: 10.4251/wjgo.v14.i1.216] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/22/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a malignancy with a high incidence and mortality. The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression. Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion. In this review, we systematically summarize the intricate crosstalk between GC cells and immune cells, including tumor-associated macrophages, neutrophils, myeloid-derived suppressor cells, natural killer cells, effector T cells, regulatory T cells, and B cells. We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack. We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies, both alone and in combination with conventional therapies. Anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment. However, the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients. This review provides a comprehensive understanding of the immune evasion mechanisms of GC, and highlights promising immunotherapeutic strategies.
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Affiliation(s)
- En-Si Ma
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Organ Transplantation, Fudan University, Shanghai 200040, China
| | - Zheng-Xin Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Organ Transplantation, Fudan University, Shanghai 200040, China
| | - Meng-Qi Zhu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Jing Zhao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
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