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Capik O, Karatas OF. Pathways and outputs orchestrated in tumor microenvironment cells by hypoxia-induced tumor-derived exosomes in pan-cancer. Cell Oncol (Dordr) 2025; 48:539-557. [PMID: 39928285 PMCID: PMC12119682 DOI: 10.1007/s13402-025-01042-z] [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] [Accepted: 01/30/2025] [Indexed: 02/11/2025] Open
Abstract
Hypoxia is a critical microenvironmental condition that plays a major role in driving tumorigenesis and cancer progression. Increasing evidence has revealed novel functions of hypoxia in intercellular communication. The hypoxia induced tumor derived exosomes (hiTDExs) released in high quantities by tumor cells under hypoxia are packed with unique cargoes that are essential for cancer cells' interactions within their microenvironment. These hiTDExs facilitate not only immune evasion but also promote cancer cell growth, survival, angiogenesis, EMT, resistance to therapy, and the metastatic spread of the disease. Nevertheless, direct interventions targeting hypoxia signaling in cancer therapy face challenges related to tumor progression and resistance, limiting their clinical effectiveness. Therefore, deepening our understanding of the molecular processes through which hiTDExs remodels tumors and their microenvironment, as well as how tumor cells adjust to hypoxic conditions, remains essential. This knowledge will pave the way for novel approaches in treating hypoxic tumors. In this review, we discuss recent work revealing the hiTDExs mediated interactions between tumor and its microenvironment. We have described key hiTDExs cargos (lncRNA, circRNAs, cytokines, etc.) and their targets in the receipt cells, responsible for various biological effects. Moreover, we emphasized the importance of hiTDExs as versatile elements of cell communication in the tumor microenvironment. Finally, we highlighted the effects of hiTDExs on the molecular changes in target cells by executing molecular cargo transfer between cells and altering signaling pathways. Currently, hiTDExs show promise in the treatment of diseases. Understanding the molecular processes through which hiTDExs influence tumor behavior and their microenvironment, along with how tumor cells adapt to and survive in low-oxygen conditions, remains a central focus in cancer research, paving the way for innovative strategies in treating hypoxic tumors and enhancing immunotherapy.
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Affiliation(s)
- Ozel Capik
- Department of Molecular Biology and Genetics, Erzurum Technical University, Omer Nasuhi Bilmen Mah. Havaalani Yolu Cad. No: 53 Yakutiye, Erzurum, Turkey.
- Cancer Therapeutics Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey.
| | - Omer Faruk Karatas
- Department of Molecular Biology and Genetics, Erzurum Technical University, Omer Nasuhi Bilmen Mah. Havaalani Yolu Cad. No: 53 Yakutiye, Erzurum, Turkey
- Cancer Therapeutics Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
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Niazi V, Ghafouri-Fard S. Effect of hypoxia on extracellular vesicles in malignant and non-malignant conditions. Cancer Treat Res Commun 2025; 43:100924. [PMID: 40209539 DOI: 10.1016/j.ctarc.2025.100924] [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: 02/22/2025] [Revised: 03/21/2025] [Accepted: 04/04/2025] [Indexed: 04/12/2025]
Abstract
Extracellular vesicles (EVs) are produced by virtually all types of cells and can be detected in nearly all extracellular places. These particles mediate intercellular communication and transfer their cargo to the recipient cells, inducing a variety of processes in these cells through transmission of several biomolecules such as miRNAs, lncRNAs, other transcripts and a variety of proteins. It has been documented that size, quantity, and expression of biomolecules in the EVs are influenced by the level of oxygen. In fact, hypoxia can affect several cellular processes through modulation of the cargo of these vesicles. Hypoxic exosomes derived from tumor cells have several protumoral effects on the recipient cells, including enhancement of proliferation, migration, and invasion in other tumoral cells, induction of metastasis in distant organs, stimulation of angiogenesis in the endothelial cells, and modulation of macrophage polarization. Hypoxic EVs also contribute to several non-malignant diseases. This review summarizes the effect of hypoxia on EVs cargo in malignant and nonmalignant diseases of different organs.
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Affiliation(s)
- Vahid Niazi
- Stem Cell Research Center, Golestan University of Medical Science, Gorgan, Iran; School of Advanced Technologies in Medicine, Golestan University of Medical Science, Gorgan, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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3
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Branco H, Xavier CPR, Riganti C, Vasconcelos MH. Hypoxia as a critical player in extracellular vesicles-mediated intercellular communication between tumor cells and their surrounding microenvironment. Biochim Biophys Acta Rev Cancer 2025; 1880:189244. [PMID: 39672279 DOI: 10.1016/j.bbcan.2024.189244] [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: 06/18/2024] [Revised: 12/06/2024] [Accepted: 12/09/2024] [Indexed: 12/15/2024]
Abstract
In the past years, increasing attention has been paid to the role of extracellular vesicles (EVs) as mediators of intercellular communication in cancer. These small size particles mediate the intercellular transfer of important bioactive molecules involved in malignant initiation and progression. Hypoxia, or low partial pressure of oxygen, is recognized as a remarkable feature of solid tumors and has been demonstrated to exert a profound impact on tumor prognosis and therapeutic efficacy. Indeed, the high-pitched growth rate and chaotic neovascular architecture that embodies solid tumors results in a profound reduction in oxygen pressure within the tumor microenvironment (TME). In response to oxygen-deprived conditions, tumor cells and their surrounding milieu develop homeostatic adaptation mechanisms that contribute to the establishment of a pro-tumoral phenotype. Latest evidence suggests that the hypoxic microenvironment that surrounds the tumor bulk may be a clincher for the observed elevated levels of circulating EVs in cancer patients. Thus, it is proposed that EVs may play a role in mediating intercellular communication in response to hypoxic conditions. This review focuses on the EVs-mediated crosstalk that is established between tumor cells and their surrounding immune, endothelial, and stromal cell populations, within the hypoxic TME.
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Affiliation(s)
- Helena Branco
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal; Department of Biological Sciences, FFUP - Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - Cristina P R Xavier
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, Toxicologic Pathology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), 4585-116 Gandra, Portugal; Associate Laboratory i4HB - Institute for Health and Bioeconomy, University Institute of Health Sciences - CESPU, 4585-116 Gandra, Portugal.
| | - Chiara Riganti
- Department of Oncology, University of Torino, 10126 Torino, Italy; Interdepartmental Research Center for Molecular Biotechnology "G. Tarone", University of Torino, 10126 Torino, Italy
| | - M Helena Vasconcelos
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal; Department of Biological Sciences, FFUP - Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
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4
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Tripathi S, Sharma Y, Kumar D. Biological Cargo: Exosomes and their Role in Cancer Progression and Metastasis. Curr Top Med Chem 2025; 25:263-285. [PMID: 38984577 DOI: 10.2174/0115680266304636240626055711] [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: 01/16/2024] [Revised: 05/23/2024] [Accepted: 05/23/2024] [Indexed: 07/11/2024]
Abstract
Cancer cells are among the many types of cells that release exosomes, which are nanovesicles. Because of their many potential applications, exosomes have recently garnered much attention from cancer researchers. The bioactive substances that exosomes release as cargo have been the subject of several investigations. The substances in question may operate as biomarkers for diagnosis or affect apoptosis, the immune system, the development and spread of cancer, and other processes. Others have begun to look at exosomes in experimental therapeutic trials because they believe they may be useful in the treatment of cancer. This review started with a short description of exosome biogenesis and key features. Next, the potential of tumor-derived exosomes and oncosomes to influence the immune system throughout the development of cancer, as well as alter tumor microenvironments (TMEs) and pre-metastatic niche creation, was investigated. Finally, there was talk of exosomes' possible use in cancer treatment. Furthermore, there is emerging consensus about the potential application of exosomes to be biological reprogrammers of cancer cells, either as carriers of naturally occurring chemicals, including anticancer medications, or as carriers of anticancer vaccines for immunotherapy as well as boron neutron capture therapy (BNCT). We briefly review the key ideas and logic behind this intriguing therapy recommendation.
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Affiliation(s)
- Siddhant Tripathi
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
| | - Yashika Sharma
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
| | - Dileep Kumar
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
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5
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Sekar S, Srikanth S, Mukherjee AG, Gopalakrishnan AV, Wanjari UR, Vellingiri B, Renu K, Madhyastha H. Biogenesis and functional implications of extracellular vesicles in cancer metastasis. Clin Transl Oncol 2024:10.1007/s12094-024-03815-8. [PMID: 39704958 DOI: 10.1007/s12094-024-03815-8] [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: 06/21/2024] [Accepted: 11/23/2024] [Indexed: 12/21/2024]
Abstract
Extracellular vesicles (EVs) play a crucial role in the complex process of cancer metastasis by facilitating cellular communication and influencing the microenvironment to promote the spread and establishment of cancer cells in distant locations. This paper explores the process of EV biogenesis, explaining their various sources that range from endosomal compartments to plasma membrane shedding. It also discusses the complex mechanisms that control the sorting of cargo within EVs, determining their chemical makeup. We investigate the several functions of EVs in promoting the spread of cancer to other parts of the body. These functions include influencing the immune system, creating environments that support the formation of metastases before they occur, and aiding in the transformation of cells from an epithelial to a mesenchymal state. Moreover, we explore the practical consequences of EV cargo, such as nucleic acids, proteins, and lipids, in influencing the spread of cancer cells, from the beginning of invasion to the creation of secondary tumor sites. Examining recent progress in the field of EV-based diagnostics and treatments, we explore the potential of EVs as highly promising biomarkers for predicting the course of cancer and as targets for therapeutic intervention. This review aims to provide a complete understanding of the biology of EVs in the context of cancer metastasis. By unravelling the nuances of EV biology, it seeks to pave the way for new tactics in cancer detection, treatment, and management.
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Affiliation(s)
- Sneha Sekar
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Sandhya Srikanth
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India.
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Balachandar Vellingiri
- Stem Cell and Regenerative Medicine/Translational Research, Department of Zoology, School of Basic Sciences, Central University of Punjab (CUPB), Bathinda, Punjab, 151401, India
| | - Kaviyarasi Renu
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, 600077, India
| | - Harishkumar Madhyastha
- Department of Cardiovascular Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan
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6
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Sengupta R, Topiwala IS, Shakthi A M, Dhar R, Devi A. Immune Cell-Derived Exosomes: A Cell-Free Cutting-Edge Tumor Immunotherapy. ACS APPLIED BIO MATERIALS 2024; 7:7076-7087. [PMID: 39495624 DOI: 10.1021/acsabm.4c00660] [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] [Indexed: 11/06/2024]
Abstract
Extracellular vesicles (EVs) are cellular communication molecules and are classified into three major subpopulations, such as microvesicles, apoptotic bodies, and exosomes. Among these, exosomes-based cancer research is a cutting-edge investigation approach to cancer understanding. During cancer progression , tumor-derived exosomes can reprogram the cellular system and promote cancer. Circulating exosomes in the body fluids such as blood, plasma, serum, saliva, CSF, sweat, and tears play a key role in identifying diagnostic and prognostic cancer biomarkers. Diverse therapeutic sources of exosomes including stem cells, plants, and immune cells, etc. exhibit significant cancer-healing properties. Although cancer-targeting immunotherapy is an effective strategy, it has limitations such as toxicity, and high costs. In comparison, immune cell-derived exosomes-based immunotherapy is a cell-free approach for cancer treatment and has advantages like less toxicity, biocompatibility, reduced immunogenicity, and efficient, target-specific cancer therapeutic development. This review highlights the therapeutic signature of immune cell-derived exosomes for cancer treatment.
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Affiliation(s)
- Ranjini Sengupta
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, TamilNadu 603203, India
| | - Ibrahim S Topiwala
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, TamilNadu 603203, India
| | - Meghana Shakthi A
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, TamilNadu 603203, India
| | - Rajib Dhar
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, TamilNadu 603203, India
| | - Arikketh Devi
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu District, TamilNadu 603203, India
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Yuan L, Ji H, Cao Y, Yi H, Leng Q, Zhou J, Mei X. Exosomes in esophageal cancer: Promising nanocarriers in cancer progression, diagnosis, prognosis, and therapy. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2024; 16:e1989. [PMID: 39217461 DOI: 10.1002/wnan.1989] [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: 03/03/2023] [Revised: 06/26/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024]
Abstract
Esophageal cancer (EC) is one of the most fatal cancers all over the world. Sensitive detection modalities for early-stage EC and efficient treatment methods are urgently needed for the improvement of the prognosis of EC. Exosomes are small vesicles for intercellular communication, mediating many biological responses including cancer progression, which are not only promising biomarkers for diagnosis and prognosis but also therapeutic tools for EC. This review provides an overview of the relationships between exosomes and EC progression, as well as the application of exosomes in the diagnosis, prognosis, and treatment of EC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
- Ligong Yuan
- Department of Thoracic Surgery, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Haoran Ji
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yang Cao
- Peking University Health Science Center, Peking University, Beijing, China
| | - Hang Yi
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qihao Leng
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Jie Zhou
- Department of Chemistry and Biochemistry, University of California San Diego, San Diego, California, USA
| | - Xinyu Mei
- Department of Thoracic Surgery, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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8
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Wang C, Xu S, Yang X. Hypoxia-Driven Changes in Tumor Microenvironment: Insights into Exosome-Mediated Cell Interactions. Int J Nanomedicine 2024; 19:8211-8236. [PMID: 39157736 PMCID: PMC11328847 DOI: 10.2147/ijn.s479533] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 08/06/2024] [Indexed: 08/20/2024] Open
Abstract
Hypoxia, as a prominent feature of the tumor microenvironment, has a profound impact on the multicomponent changes within this environment. Under hypoxic conditions, the malignant phenotype of tumor cells, the variety of cell types within the tumor microenvironment, as well as intercellular communication and material exchange, undergo complex alterations. These changes provide significant prospects for exploring the mechanisms of tumor development under different microenvironmental conditions and for devising therapeutic strategies. Exosomes secreted by tumor cells and stromal cells are integral components of the tumor microenvironment, serving as crucial mediators of intercellular communication and material exchange, and have consequently garnered increasing attention from researchers. This review focuses on the mechanisms by which hypoxic conditions promote the release of exosomes by tumor cells and alter their encapsulated contents. It also examines the effects of exosomes derived from tumor cells, immune cells, and other cell types under hypoxic conditions on the tumor microenvironment. Additionally, we summarize current research progress on the potential clinical applications of exosomes under hypoxic conditions and propose future research directions in this field.
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Affiliation(s)
- Churan Wang
- Dalian Medical University, Dalian, 116000, People’s Republic of China
| | - Shun Xu
- Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang, 110002, People’s Republic of China
| | - Xiao Yang
- Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang, 110002, People’s Republic of China
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Miao H, Gao W, Zhong L, Li H, Chen D, Xu C, Wen Z, Chen Y. VBP1 promotes tumor proliferation as a part of the hypoxia-related signature in esophageal squamous cell carcinoma. Hum Cell 2024; 37:1141-1155. [PMID: 38700744 PMCID: PMC11194215 DOI: 10.1007/s13577-024-01068-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 04/22/2024] [Indexed: 06/24/2024]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor in East Asia. Hypoxia, a hallmark of solid tumors, significantly alters redox homeostasis inside tumor microenvironment. This alteration drives tumor proliferation, invasion, and metastasis, leading to poor prognostic outcomes. However, the role of hypoxia-related genes in ESCC remains poorly understood. We employed RNA sequencing to identify differentially expressed genes in ESCC. Clinical data, transcriptome profiles, and a hypoxia-related gene set were extracted from open-source databases. A prognostic model was constructed using least absolute shrinkage and selection operator (LASSO) regression, which was then validated through Cox regression analysis. Within this prognostic model, we pinpointed and investigated a key hypoxia-related gene affecting prognosis. The gene's expression was validated using real-time PCR and immunohistochemistry in both esophageal carcinoma and normal tissues. Tumor proliferation was examined through in vitro and in vivo assays, including the Cell Counting Kit-8, EdU, colony formation, and subcutaneous tumor models. A robust four-gene prognostic model (VBP1, BGN, CDKN1A, and PPFIA1) was successfully constructed and validated. Among these, VBP1 emerged as a key gene, exhibiting high expression levels that correlated with poor prognosis in ESCC. Functional experiments confirmed that VBP1 significantly accelerated tumor proliferation both in vitro and in vivo. VBP1 is identified as a pivotal gene within the hypoxia-related prognostic signature, and it significantly promotes tumor proliferation in ESCC.
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Affiliation(s)
- Huikai Miao
- Department of Thoracic Surgery, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Department of Thoracic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China
| | - Wuyou Gao
- Department of Thoracic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China
| | - Leqi Zhong
- Department of Thoracic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China
| | - Hongmu Li
- Department of Thoracic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China
| | - Dongni Chen
- Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chunmei Xu
- Department of Endocrinology, Shandong Provincial Hospital affiliated to, Shandong First Medical University, Jinan, China
| | - Zhesheng Wen
- Department of Thoracic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China.
| | - Youfang Chen
- Department of Thoracic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China.
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Hao MJ, Cheng ZY, Gao Y, Xin L, Yu CT, Wang TL, Li ZS, Wang LW. Liquid biopsy of oesophageal squamous cell carcinoma: implications in diagnosis, prognosis, and treatment monitoring. Scand J Gastroenterol 2024; 59:698-709. [PMID: 38466190 DOI: 10.1080/00365521.2024.2310167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/18/2024] [Accepted: 01/20/2024] [Indexed: 03/12/2024]
Abstract
Oesophageal squamous cell carcinoma (ESCC) is a common malignant tumour of the gastrointestinal tract. Early detection and access to appropriate treatment are crucial for the long-term survival of patients. However, limited diagnostic and monitoring methods are available for identifying early stage ESCC. Endoscopic screening and surgical resection are commonly used to diagnose and treat early ESCC. However, these methods have disadvantages, such as high recurrence, lethality, and mortality rates. Therefore, methods to improve early diagnosis of ESCC and reduce its mortality rate are urgently required. In 1961, Gary et al. proposed a novel liquid biopsy approach for clinical diagnosis. This involved examining exosomes, circulating tumour cells, circulating free DNA, and circulating free RNA in body fluids. The ability of liquid biopsy to obtain samples repeatedly, wide detection range, and fast detection speed make it a feasible option for non-invasive tumour detection. In clinical practice, liquid biopsy technology has gained popularity for early screening, diagnosis, treatment efficacy monitoring, and prognosis assessment. Thus, this is a highly promising examination method. However, there have been no comprehensive reviews on the four factors of liquid biopsy in the context of ESCC. This review aimed to analyse the progress of liquid biopsy research for ESCC, including its classification, components, and potential future applications.
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Affiliation(s)
- Mei-Juan Hao
- University of Shanghai for Science and Technology, Shanghai, China
- Department of Gastroenterology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
- Department of Anaesthesia and Surgery, Guiyang Fourth People's Hospital, Guiyang, China
| | - Zhi-Yuan Cheng
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ye Gao
- Department of Gastroenterology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Lei Xin
- Department of Gastroenterology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Chu-Ting Yu
- Department of Gastroenterology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Ting-Lu Wang
- Department of Gastroenterology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Zhao-Shen Li
- Department of Gastroenterology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Luo-Wei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
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11
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Hu Y, Yu C, Cheng L, Zhong C, An J, Zou M, Liu B, Gao X. Flavokawain C inhibits glucose metabolism and tumor angiogenesis in nasopharyngeal carcinoma by targeting the HSP90B1/STAT3/HK2 signaling axis. Cancer Cell Int 2024; 24:158. [PMID: 38711062 DOI: 10.1186/s12935-024-03314-4] [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: 12/19/2023] [Accepted: 03/26/2024] [Indexed: 05/08/2024] Open
Abstract
OBJECTIVE Over the past decade, heat shock protein 90 (HSP90) inhibitors have emerged as promising anticancer drugs in solid and hematological malignancies. Flavokawain C (FKC) is a naturally occurring chalcone that has been found to exert considerable anti-tumor efficacy by targeting multiple molecular pathways. However, the efficacy of FKC has not been studied in nasopharyngeal carcinoma (NPC). Metabolic abnormalities and uncontrolled angiogenesis are two important features of malignant tumors, and the occurrence of these two events may involve the regulation of HSP90B1. Therefore, this study aimed to explore the effects of FKC on NPC proliferation, glycolysis, and angiogenesis by regulating HSP90B1 and the underlying molecular regulatory mechanisms. METHODS HSP90B1 expression was analyzed in NPC tissues and its relationship with patient's prognosis was further identified. Afterward, the effects of HSP90B1 on proliferation, apoptosis, glycolysis, and angiogenesis in NPC were studied by loss-of-function assays. Next, the interaction of FKC, HSP90B1, and epidermal growth factor receptor (EGFR) was evaluated. Then, in vitro experiments were designed to analyze the effect of FKC treatment on NPC cells. Finally, in vivo experiments were allowed to investigate whether FKC treatment regulates proliferation, glycolysis, and angiogenesis of NPC cells by HSP90B1/EGFR pathway. RESULTS HSP90B1 was highly expressed in NPC tissues and was identified as a poor prognostic factor in NPC. At the same time, knockdown of HSP90B1 can inhibit the proliferation of NPC cells, trigger apoptosis, and reduce glycolysis and angiogenesis. Mechanistically, FKC affects downstream EGFR phosphorylation by regulating HSP90B1, thereby regulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. FKC treatment inhibited the proliferation, glycolysis, and angiogenesis of NPC cells, which was reversed by introducing overexpression of HSP90B1. In addition, FKC can affect NPC tumor growth and metastasis in vivo by regulating the HSP90B1/EGFR pathway. CONCLUSION Collectively, FKC inhibits glucose metabolism and tumor angiogenesis in NPC by targeting the HSP90B1/EGFR/PI3K/Akt/mTOR signaling axis.
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Affiliation(s)
- YuQiang Hu
- Department of Otolaryngology Head and Neck Surgery, Drum Tower Clinical Medical College, Nanjing Medical University, No.321, Zhongshan Road, Nanjing, 210008, Jiangsu, China
- Department of Otolaryngology Head and Neck Surgery, XuZhou Central Hospital, (Xuzhou Clinical School of Nanjing Medical University), No.199, Jiefang South Roa, Xuzhou, 221009, Jiangsu, China
- Department of Otolaryngology Head and Neck Surgery, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - ChenJie Yu
- Department of Otolaryngology Head and Neck Surgery, Drum Tower Clinical Medical College, Nanjing Medical University, No.321, Zhongshan Road, Nanjing, 210008, Jiangsu, China
| | - LiangJun Cheng
- Department of Otolaryngology Head and Neck Surgery, XuZhou Central Hospital, (Xuzhou Clinical School of Nanjing Medical University), No.199, Jiefang South Roa, Xuzhou, 221009, Jiangsu, China
- Department of Otolaryngology Head and Neck Surgery, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Chang Zhong
- Department of Otolaryngology Head and Neck Surgery, XuZhou Central Hospital, (Xuzhou Clinical School of Nanjing Medical University), No.199, Jiefang South Roa, Xuzhou, 221009, Jiangsu, China
- Department of Otolaryngology Head and Neck Surgery, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Jun An
- Department of Otolaryngology Head and Neck Surgery, XuZhou Central Hospital, (Xuzhou Clinical School of Nanjing Medical University), No.199, Jiefang South Roa, Xuzhou, 221009, Jiangsu, China
- Department of Otolaryngology Head and Neck Surgery, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - MingZhen Zou
- Department of Otolaryngology Head and Neck Surgery, XuZhou Central Hospital, (Xuzhou Clinical School of Nanjing Medical University), No.199, Jiefang South Roa, Xuzhou, 221009, Jiangsu, China
- Department of Otolaryngology Head and Neck Surgery, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Bing Liu
- Department of Otolaryngology Head and Neck Surgery, XuZhou Central Hospital, (Xuzhou Clinical School of Nanjing Medical University), No.199, Jiefang South Roa, Xuzhou, 221009, Jiangsu, China.
- Department of Otolaryngology Head and Neck Surgery, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
| | - Xia Gao
- Department of Otolaryngology Head and Neck Surgery, Drum Tower Clinical Medical College, Nanjing Medical University, No.321, Zhongshan Road, Nanjing, 210008, Jiangsu, China.
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Tian Z, Zhu L, Xie Y, Hu H, Ren Q, Liu J, Wang Q. The mechanism of high mobility group box-1 protein and its bidirectional regulation in tumors. BIOMOLECULES & BIOMEDICINE 2024; 24:477-485. [PMID: 37897664 PMCID: PMC11088895 DOI: 10.17305/bb.2023.9760] [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: 09/03/2023] [Revised: 10/01/2023] [Accepted: 10/26/2023] [Indexed: 10/30/2023]
Abstract
High-mobility group box-1 protein (HMGB1) is a nonhistone chromatin-related protein widely found in eukaryotic cells. It is involved in the transcription, replication, and repair of DNA to maintain nuclear homeostasis. It participates in cell growth, differentiation, and signal transduction. Recent studies showed that HMGB1 has a bidirectional regulatory effect on tumors by regulating TLR4/MYD88/NF-κB and RAGE/AMPK/mTOR signaling pathways. On the one hand, it is highly expressed in a variety of tumors, promoting tumor proliferation and invasion, while on the other hand, it induces autophagy and apoptosis of tumor cells and stimulates tumor-infiltrating lymphocytes to produce an anti-tumor immune response. At present, HMGB1 could be used as a target to regulate the drug resistance and prognostication in cancer. Clinical applications of HMGB1 in cancer need further in-depth studies.
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Affiliation(s)
- Zhongjia Tian
- The Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
| | - Lin Zhu
- The Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
| | - Yutong Xie
- The Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
| | - Huan Hu
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Qunli Ren
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Jianguo Liu
- The Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
| | - Qian Wang
- The Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
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13
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Nakamura ET, Park A, Pereira MA, Kikawa D, Tustumi F. Prognosis value of heat-shock proteins in esophageal and esophagogastric cancer: A systematic review and meta-analysis. World J Gastrointest Oncol 2024; 16:1578-1595. [PMID: 38660660 PMCID: PMC11037039 DOI: 10.4251/wjgo.v16.i4.1578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 12/24/2023] [Accepted: 01/23/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Heat shock proteins (HSPs) are molecular chaperones that play an important role in cellular protection against stress events and have been reported to be overexpressed in many cancers. The prognostic significance of HSPs and their regulatory factors, such as heat shock factor 1 (HSF1) and CHIP, are poorly understood. AIM To investigate the relationship between HSP expression and prognosis in esophageal and esophagogastric cancer. METHODS A systematic review was conducted in accordance with PRISMA recommendations (PROSPERO: CRD42022370653), on Embase, PubMed, Cochrane, and LILACS. Cohort, case-control, and cross-sectional studies of patients with esophagus or esophagogastric cancer were included. HSP-positive patients were compared with HSP-negative, and the endpoints analyzed were lymph node metastasis, tumor depth, distant metastasis, and overall survival (OS). HSPs were stratified according to the HSP family, and the summary risk difference (RD) was calculated using a random-effect model. RESULTS The final selection comprised 27 studies, including esophageal squamous cell carcinoma (21), esophagogastric adenocarcinoma (5), and mixed neoplasms (1). The pooled sample size was 3465 patients. HSP40 and 60 were associated with a higher 3-year OS [HSP40: RD = 0.22; 95% confidence interval (CI): 0.09-0.35; HSP60: RD = 0.33; 95%CI: 0.17-0.50], while HSF1 was associated with a poor 3-year OS (RD = -0.22; 95%CI: -0.32 to -0.12). The other HSP families were not associated with long-term survival. HSF1 was associated with a higher probability of lymph node metastasis (RD = -0.16; 95%CI: -0.29 to -0.04). HSP40 was associated with a lower probability of lymph node dissemination (RD = 0.18; 95%CI: 0.03-0.33). The expression of other HSP families was not significantly related to tumor depth and lymph node or distant metastasis. CONCLUSION The expression levels of certain families of HSP, such as HSP40 and 60 and HSF1, are associated with long-term survival and lymph node dissemination in patients with esophageal and esophagogastric cancer.
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Affiliation(s)
- Eric Toshiyuki Nakamura
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
- Department of Scientific Initiation, Universidade Mogi das Cruzes, São Paulo 08780911, Brazil
| | - Amanda Park
- Department of Evidence-Based Medicine, Centro Universitário Lusíada, Centre for Evidence-Based Medicine, Centro Universitário Lusíada (UNILUS), Santos, Brazil
| | - Marina Alessandra Pereira
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
| | - Daniel Kikawa
- Department of Scientific Initiation, Universidade Mogi das Cruzes, São Paulo 08780911, Brazil
| | - Francisco Tustumi
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
- Department of Surgery, Hospital Israelita Albert Einstein, São Paulo 05652900, Brazil
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Mao Y, Wang J, Wang Y, Fu Z, Dong L, Liu J. Hypoxia induced exosomal Circ-ZNF609 promotes pre-metastatic niche formation and cancer progression via miR-150-5p/VEGFA and HuR/ZO-1 axes in esophageal squamous cell carcinoma. Cell Death Discov 2024; 10:133. [PMID: 38472174 DOI: 10.1038/s41420-024-01905-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 02/28/2024] [Accepted: 03/04/2024] [Indexed: 03/14/2024] Open
Abstract
Exosomes derived from cancer are regarded as significant mediators of cancer-host crosstalk. Hypoxia, on the other hand, is one of the essential characteristics of solid tumors. This research set out to discover how circulating exosomes from hypoxic esophageal squamous cell carcinoma (ESCC) contribute to the formation of metastatic niches and distant metastasis. First, we noticed that human umbilical vein endothelial cells (HUVECs) had their tight connections disrupted and the expression of proteins involved in angiogenesis boosted by ESCC hypoxic exosomes. Hypoxia significantly induced Circ-ZNF609 expression in exosomes from ESCC, which was then internalized by HUVECs, as determined by circular RNA screening. High Circ-ZNF609 expression in HUVECs facilitated angiogenesis and vascular permeability, thereby promoting pre-metastatic niche formation, and enhancing distant metastasis in vitro and in vivo. Exosomal Circ-ZNF609 activated vascular endothelial growth factor A (VEGFA) mechanistically by sponging miR-150-5p. Exosomal Circ-ZNF609 also interacted with HuR and inhibited HuR binding to ZO-1, Claudin-1, and Occludin mRNAs, thereby reducing their translation. Collectively, our findings identified an essential function for exosomal Circ-ZNF609 from ESCC cells, suggesting the potential therapeutic value of exosomes for ESCC patients.
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Affiliation(s)
- Yu Mao
- Department of Oncology, First Hospital of Qinhuangdao, Qinhuangdao, Hebei, China.
- Key Laboratory of Research on Molecular Mechanism of Gastrointestinal Tumors in Qinhuangdao, Qinhuangdao, Hebei, China.
| | - Jiahao Wang
- Department of Oncology, First Hospital of Qinhuangdao, Qinhuangdao, Hebei, China
| | - Yimin Wang
- Key Laboratory of Research on Molecular Mechanism of Gastrointestinal Tumors in Qinhuangdao, Qinhuangdao, Hebei, China
- Department of General Surgery, First Hospital of Qinhuangdao, Hebei Medical University, Qinhuangdao, China
| | - Zhanzhao Fu
- Department of Oncology, First Hospital of Qinhuangdao, Qinhuangdao, Hebei, China
| | - Lixin Dong
- Department of Oncology, First Hospital of Qinhuangdao, Qinhuangdao, Hebei, China
| | - Jia Liu
- Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Boston, MA, USA
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Liu Y, Wu H, Sang Y, Chong W, Shang L, Li L. Research progress of exosomes in the angiogenesis of digestive system tumour. Discov Oncol 2024; 15:33. [PMID: 38341827 PMCID: PMC10859358 DOI: 10.1007/s12672-024-00879-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 01/30/2024] [Indexed: 02/13/2024] Open
Abstract
Malignant tumours of the digestive system cover a wide range of diseases that affect the health of people to a large extent. Angiogenesis is indispensable in the development, and metastasis of tumours, mainly in two ways: occupation or formation. Vessels can provide nutrients, oxygen, and growth factors for tumours to encourage growth and metastasis, so cancer progression depends on simultaneous angiogenesis. Recently, exosomes have been proven to participate in the angiogenesis of tumours. They influence angiogenesis by binding to tyrosine kinase receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 with different affinities, regulating Yap-VEGF pathway, Akt pathway or other signaling pathway. Additionally, exosomes are potential therapeutic vectors that can deliver many types of cargoes to different cells. In this review, we summarize the roles of exosomes in the angiogenesis of digestive system tumours and highlight the clinical application prospects, directly used as targers or delivery vehicles, in antiangiogenic therapy.
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Affiliation(s)
- Yuan Liu
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
- Department of Gastrointestinal Surgery, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital, Jinan, 250021, China
- Department of Gastrointestinal Surgery, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - Hao Wu
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yaodong Sang
- Department of Gastrointestinal Surgery, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital, Jinan, 250021, China
- Department of Gastrointestinal Surgery, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - Wei Chong
- Department of Gastrointestinal Surgery, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital, Jinan, 250021, China.
- Department of Gastrointestinal Surgery, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China.
| | - Liang Shang
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
- Department of Gastrointestinal Surgery, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital, Jinan, 250021, China.
- Department of Gastrointestinal Surgery, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China.
| | - Leping Li
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
- Department of Gastrointestinal Surgery, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital, Jinan, 250021, China.
- Department of Gastrointestinal Surgery, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China.
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Ning XY, Ma JH, He W, Ma JT. Role of exosomes in metastasis and therapeutic resistance in esophageal cancer. World J Gastroenterol 2023; 29:5699-5715. [PMID: 38075847 PMCID: PMC10701334 DOI: 10.3748/wjg.v29.i42.5699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 09/13/2023] [Accepted: 11/08/2023] [Indexed: 11/13/2023] Open
Abstract
Esophageal cancer (EC) has a high incidence and mortality rate and is emerging as one of the most common health problems globally. Owing to the lack of sensitive detection methods, uncontrollable rapid metastasis, and pervasive treatment resistance, EC is often diagnosed in advanced stages and is susceptible to local recurrence. Exosomes are important components of intercellular communication and the exosome-mediated crosstalk between the cancer and surrounding cells within the tumor microenvironment plays a crucial role in the metastasis, progression, and therapeutic resistance of EC. Considering the critical role of exosomes in tumor pathogenesis, this review focused on elucidating the impact of exosomes on EC metastasis and therapeutic resistance. Here, we summarized the relevant signaling pathways involved in these processes. In addition, we discussed the potential clinical applications of exosomes for the early diagnosis, prognosis, and treatment of EC.
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Affiliation(s)
- Xing-Yu Ning
- The Second School of Clinical Medicine, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Jin-Hu Ma
- The Second School of Clinical Medicine, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Wei He
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
| | - Jun-Ting Ma
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
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Ju T, Dong J, Wang B, Qu K, Cheng C, He X, Tian Y, Crabbe MJC, Wang Z, Chen Y. Cancer Development in Hepatocytes by Long-Term Induction of Hypoxic Hepatocellular Carcinoma Cell (HCC)-Derived Exosomes In Vivo and In Vitro. Mol Pharm 2023; 20:5579-5592. [PMID: 37844208 DOI: 10.1021/acs.molpharmaceut.3c00488] [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] [Indexed: 10/18/2023]
Abstract
Hypoxic tumor cell-derived exosomes play a key role in the occurrence, development, and metastasis of tumors. However, the mechanism of hypoxia-mediated metastasis remains unclear. In this study, hypoxic hepatocellular carcinoma cell (HCC-LM3)-derived exosomes (H-LM3-exos) were used to induce hepatocytes (HL-7702) over a long term (40 passages in 120 days). A nude mouse experiment further verified the effect of H-LM3-exos on tumor growth and metastasis. The process of cancer development in hepatocytes induced by H-LM3-exos was analyzed using both biological and physical techniques, and the results showed that the proliferation and soft agar growth abilities of the transformed cells were enhanced. The concentration of tumor markers secreted by transformed cells was increased, the cytoskeleton was disordered, and the migration ability was enhanced and was accompanied by epithelial-mesenchymal transition (EMT). Transcriptome results showed that differentially expressed genes between transformed cells and hepatocytes were enriched in cancer-related signaling pathways. The degree of cancer development in transformed cells was enhanced by an increase in H-LM3-exos-induced passages. Nude mice treated with different concentrations of H-LM3-exos showed different degrees of tumor growth and liver lesions. The physical properties of the cells were characterized by atomic force microscopy. Compared with the hepatocytes, the height and roughness of the transformed cells were increased, while the adhesion and elastic modulus were decreased. The changes in physical properties of primary tumor cells and hepatocytes in nude mice were consistent with this trend. Our study linking omics with the physical properties of cells provides a new direction for studying the mechanisms of cancer development and metastasis.
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Affiliation(s)
- Tuoyu Ju
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Jianjun Dong
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Bowei Wang
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Kaige Qu
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Can Cheng
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Xiuxia He
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Yanling Tian
- School of Engineering, University of Warwick, Coventry CF4 7AL, U.K
| | - M James C Crabbe
- Wolfson College, University of Oxford, Oxford OX2 6UD, U.K
- Institute of Biomedical and Environmental Science & Technology, and Institute for Research in Applicable Computing, University of Bedfordshire, Luton LU1 3JU, U.K
| | - Zuobin Wang
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
- Institute of Biomedical and Environmental Science & Technology, and Institute for Research in Applicable Computing, University of Bedfordshire, Luton LU1 3JU, U.K
| | - Yujuan Chen
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China
- Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China
- Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
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Yoo S, Choi S, Kim I, Kim IS. Hypoxic regulation of extracellular vesicles: Implications for cancer therapy. J Control Release 2023; 363:201-220. [PMID: 37739015 DOI: 10.1016/j.jconrel.2023.09.034] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 08/18/2023] [Accepted: 09/18/2023] [Indexed: 09/24/2023]
Abstract
Extracellular vesicles (EVs) play a pivotal role in intercellular communication and have been implicated in cancer progression. Hypoxia, a pervasive hallmark of cancer, is known to regulate EV biogenesis and function. Hypoxic EVs contain a specific set of proteins, nucleic acids, lipids, and metabolites, capable of reprogramming the biology and fate of recipient cells. Enhancing the intrinsic therapeutic efficacy of EVs can be achieved by strategically modifying their structure and contents. Moreover, the use of EVs as drug delivery vehicles holds great promise for cancer treatment. However, various hurdles must be overcome to enable their clinical application as cancer therapeutics. In this review, we aim to discuss the current knowledge on the hypoxic regulation of EVs. Additionally, we will describe the underlying mechanisms by which EVs contribute to cancer progression in hypoxia and outline the progress and limitations of hypoxia-related EV therapeutics for cancer.
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Affiliation(s)
- Seongkyeong Yoo
- Department of Pharmacology and Program in Biomedical Science and Engineering, Inha University College of Medicine, Incheon 22212, South Korea; Research Center for Controlling Intercellular Communication, Inha University College of Medicine, Incheon 22212, South Korea
| | - Sanga Choi
- Department of Pharmacology and Program in Biomedical Science and Engineering, Inha University College of Medicine, Incheon 22212, South Korea; Research Center for Controlling Intercellular Communication, Inha University College of Medicine, Incheon 22212, South Korea
| | - Iljin Kim
- Department of Pharmacology and Program in Biomedical Science and Engineering, Inha University College of Medicine, Incheon 22212, South Korea; Research Center for Controlling Intercellular Communication, Inha University College of Medicine, Incheon 22212, South Korea.
| | - In-San Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, South Korea; Chemical and Biological Integrative Research Center, Biomedical Research Institute, Korea Institute Science and Technology, Seoul 02792, South Korea.
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Xi Y, Shen Y, Chen L, Tan L, Shen W, Niu X. Exosome-mediated metabolic reprogramming: Implications in esophageal carcinoma progression and tumor microenvironment remodeling. Cytokine Growth Factor Rev 2023; 73:78-92. [PMID: 37696716 DOI: 10.1016/j.cytogfr.2023.08.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 08/28/2023] [Indexed: 09/13/2023]
Abstract
Esophageal carcinoma is among the most fatal malignancies with increasing incidence globally. Tumor onset and progression can be driven by metabolic reprogramming, especially during esophageal carcinoma development. Exosomes, a subset of extracellular vesicles, display an average size of ∼100 nanometers, containing multifarious components (nucleic acids, proteins, lipids, etc.). An increasing number of studies have shown that exosomes are capable of transferring molecules with biological functions into recipient cells, which play crucial roles in esophageal carcinoma progression and tumor microenvironment that is a highly heterogeneous ecosystem through rewriting the metabolic processes in tumor cells and environmental stromal cells. The review introduces the reprogramming of glucose, lipid, amino acid, mitochondrial metabolism in esophageal carcinoma, and summarize current pharmaceutical agents targeting such aberrant metabolism rewiring. We also comprehensively overview the biogenesis and release of exosomes, and recent advances of exosomal cargoes and functions in esophageal carcinoma and their promising clinical application. Moreover, we discuss how exosomes trigger tumor growth, metastasis, drug resistance, and immunosuppression as well as tumor microenvironment remodeling through focusing on their capacity to transfer materials between cells or between cells and tissues and modulate metabolic reprogramming, thus providing a theoretical reference for the design potential pharmaceutical agents targeting these mechanisms. Altogether, our review attempts to fully understand the significance of exosome-based metabolic rewriting in esophageal carcinoma progression and remodeling of the tumor microenvironment, bringing novel insights into the prevention and treatment of esophageal carcinoma in the future.
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Affiliation(s)
- Yong Xi
- Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo 315040, Zhejiang, China; Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Yaxing Shen
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Lijie Chen
- School of Medicine, Xiamen University, Xiamen 361102, Fujian, China; China Medical University, Shenyang 110122, Liaoning, China
| | - Lijie Tan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Weiyu Shen
- Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo 315040, Zhejiang, China.
| | - Xing Niu
- China Medical University, Shenyang 110122, Liaoning, China.
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Yuan H, Zhao Z, Xu J, Zhang R, Ma L, Han J, Zhao W, Guo M, Song Y. Hypoxia-induced TMTC3 expression in esophageal squamous cell carcinoma potentiates tumor angiogenesis through Rho GTPase/STAT3/VEGFA pathway. J Exp Clin Cancer Res 2023; 42:249. [PMID: 37752569 PMCID: PMC10521530 DOI: 10.1186/s13046-023-02821-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 09/02/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND Hypoxia is one of most typical features in the tumor microenvironment of solid tumor and an inducer of endoplasmic reticulum (ER) stress, and HIF-1α functions as a key transcription factor regulator to promote tumor angiogenesis in the adaptive response to hypoxia. Increasing evidence has suggested that hypoxia plays an important regulatory role of ER homeostasis. We previously identified TMTC3 as an ER stress mediator under nutrient-deficiency condition in esophageal squamous cell carcinoma (ESCC), but the molecular mechanism in hypoxia is still unclear. METHODS RNA sequencing data of TMTC3 knockdown cells and TCGA database were analyzed to determine the association of TMTC3 and hypoxia. Moreover, ChIP assay and dual-luciferase reporter assay were performed to detect the interaction of HIF-1α and TMTC3 promoter. In vitro and in vivo assays were used to investigate the function of TMTC3 in tumor angiogenesis. The molecular mechanism was determined using co-immunoprecipitation assays, immunofluorescence assays and western blot. The TMTC3 inhibitor was identified by high-throughput screening of FDA-approved drugs. The combination of TMTC3 inhibitor and cisplatin was conducted to confirm the efficiency in vitro and in vivo. RESULTS The expression of TMTC3 was remarkably increased under hypoxia and regulated by HIF-1α. Knockdown of TMTC3 inhibited the capability of tumor angiogenesis and ROS production in ESCC. Mechanistically, TMTC3 promoted the production of GTP through interacting with IMPDH2 Bateman domain. The activity of Rho GTPase/STAT3, regulated by cellular GTP levels, decreased in TMTC3 knockdown cells, whereas reversed by IMPDH2 overexpression. Additionally, TMTC3 regulated the expression of VEGFA through Rho GTPase/STAT3 pathway. Allopurinol inhibited the expression of TMTC3 and further reduced the phosphorylation and activation of STAT3 signaling pathway in a dose-dependent manner in ESCC. Additionally, the combination of allopurinol and cisplatin significantly inhibited the cell viability in vitro and tumor growth in vivo, comparing with single drug treatment, respectively. CONCLUSIONS Collectively, our study clarified the molecular mechanism of TMTC3 in regulating tumor angiogenesis and highlighted the potential therapeutic combination of TMTC3 inhibitor and cisplatin, which proposed a promising strategy for the treatment of ESCC.
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Affiliation(s)
- Hongyu Yuan
- Department of Gastroenterology & Hepatology, The First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Zitong Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jing Xu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Ruiping Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Liying Ma
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jing Han
- Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, 050000, Hebei, China
| | - Weihong Zhao
- Medical Department, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China
| | - Mingzhou Guo
- Department of Gastroenterology & Hepatology, The First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
| | - Yongmei Song
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Mitchell MI, Loudig O. Communicator Extraordinaire: Extracellular Vesicles in the Tumor Microenvironment Are Essential Local and Long-Distance Mediators of Cancer Metastasis. Biomedicines 2023; 11:2534. [PMID: 37760975 PMCID: PMC10526527 DOI: 10.3390/biomedicines11092534] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/30/2023] [Accepted: 09/03/2023] [Indexed: 09/29/2023] Open
Abstract
Human tumors are increasingly being described as a complex "ecosystem", that includes many different cell types, secreted growth factors, extracellular matrix (ECM) components, and microvessels, that altogether create the tumor microenvironment (TME). Within the TME, epithelial cancer cells control the function of surrounding stromal cells and the non-cellular ECM components in an intricate orchestra of signaling networks specifically designed for cancer cells to exploit surrounding cells for their own benefit. Tumor-derived extracellular vesicles (EVs) released into the tumor microenvironment are essential mediators in the reprogramming of surrounding stromal cells, which include cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), and tumor endothelial cells (TECs), which are responsible for the promotion of neo-angiogenesis, immune cell evasion, and invasion which are essential for cancer progression. Perhaps most importantly, tumor-derived EVs play critical roles in the metastatic dissemination of tumor cells through their two-fold role in initiating cancer cell invasion and the establishment of the pre-metastatic niche, both of which are vital for tumor cell migration, homing, and colonization at secondary tumor sites. This review discusses extracellular vesicle trafficking within the tumor microenvironment and pre-metastatic niche formation, focusing on the complex role that EVs play in orchestrating cancer-to-stromal cell communication in order to promote the metastatic dissemination of cancer cells.
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Affiliation(s)
| | - Olivier Loudig
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA;
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22
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Georgieva I, Tchekalarova J, Iliev D, Tzoneva R. Endothelial Senescence and Its Impact on Angiogenesis in Alzheimer's Disease. Int J Mol Sci 2023; 24:11344. [PMID: 37511104 PMCID: PMC10379128 DOI: 10.3390/ijms241411344] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/07/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Endothelial cells are constantly exposed to environmental stress factors that, above a certain threshold, trigger cellular senescence and apoptosis. The altered vascular function affects new vessel formation and endothelial fitness, contributing to the progression of age-related diseases. This narrative review highlights the complex interplay between senescence, oxidative stress, extracellular vesicles, and the extracellular matrix and emphasizes the crucial role of angiogenesis in aging and Alzheimer's disease. The interaction between the vascular and nervous systems is essential for the development of a healthy brain, especially since neurons are exceptionally dependent on nutrients carried by the blood. Therefore, anomalies in the delicate balance between pro- and antiangiogenic factors and the consequences of disrupted angiogenesis, such as misalignment, vascular leakage and disturbed blood flow, are responsible for neurodegeneration. The implications of altered non-productive angiogenesis in Alzheimer's disease due to dysregulated Delta-Notch and VEGF signaling are further explored. Additionally, potential therapeutic strategies such as exercise and caloric restriction to modulate angiogenesis and vascular aging and to mitigate the associated debilitating symptoms are discussed. Moreover, both the roles of extracellular vesicles in stress-induced senescence and as an early detection marker for Alzheimer's disease are considered. The intricate relationship between endothelial senescence and angiogenesis provides valuable insights into the mechanisms underlying angiogenesis-related disorders and opens avenues for future research and therapeutic interventions.
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Affiliation(s)
- Irina Georgieva
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. George Bonchev, Str. Bl. 21, 1113 Sofia, Bulgaria
| | - Jana Tchekalarova
- Institute of Neurobiology, Bulgarian Academy of Sciences, Acad. George Bonchev, Str. Bl. 23, 1113 Sofia, Bulgaria
| | - Dimitar Iliev
- Institute of Molecular Biology, Bulgarian Academy of Sciences, Acad. George Bonchev, Str. Bl. 21, 1113 Sofia, Bulgaria
| | - Rumiana Tzoneva
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. George Bonchev, Str. Bl. 21, 1113 Sofia, Bulgaria
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23
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Miao Y, Wang X, Lai Y, Huang Y, Yin H, Meng X, Liu H, Hou R, Lin W, Zhang X, Zhang X, Chai BC, Zhang F, Guo L, Yang S. Targeting the mitochondrial calcium uniporter inhibits cancer progression and alleviates cisplatin resistance in esophageal squamous cell carcinoma. Int J Oncol 2023; 63:82. [PMID: 37264968 PMCID: PMC10552700 DOI: 10.3892/ijo.2023.5530] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 05/05/2023] [Indexed: 06/03/2023] Open
Abstract
Cisplatin is the standard chemotherapeutic drug used for the treatment of esophageal squamous cell carcinoma (ESCC). Acquired cisplatin resistance is the primary obstacle to prolonging patient survival time. Here, the therapeutic effects of mitochondrial calcium uniporter (MCU) inhibition on tumor growth and cisplatin resistance in ESCC were assessed. MCU was stably overexpressed or knocked down in three ESCC cell lines and three cisplatin‑resistant ESCC cell lines. Then, proliferation, migration, and mitochondrial membrane potential (MMP) were measured by colony formation, wound healing, Transwell, and JC‑1 staining assays. MCU, MICU2, MICU1, and PD‑L1 levels were detected through western blotting and immunofluorescence. ESCC and cisplatin‑resistant ESCC xenograft mouse models were established. After MCU knockdown, tumor volume was measured. The expression levels of proliferation markers (CyclinD1 and Ki‑67), MICU1/2, PD‑L1, epithelial-mesenchymal transition (EMT) markers (vimentin, β‑catenin, and E‑cadherin), and the angiogenesis marker CD34 were detected through western blotting, immunohistochemistry, or immunofluorescence. The results showed that MCU overexpression significantly promoted proliferation, migration, and MMP in ESCC cells and cisplatin‑resistant ESCC cells. However, proliferation, migration, and MMP were suppressed following MCU knockdown. In ESCC cells, MCU overexpression markedly increased MICU2, MICU1, and PD‑L1 levels, and the opposite results were observed when MCU was stably knocked down. Similarly, MCU inhibition decreased MICU2, MICU1, and PD‑L1 expression in cisplatin‑resistant ESCC cells. Moreover, MCU knockdown substantially decreased tumor growth, EMT, and angiogenesis in ESCC and cisplatin‑resistant ESCC xenograft mice. Collectively, targeting MCU may inhibit cancer progression and alleviate cisplatin resistance in ESCC.
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Affiliation(s)
- Yu Miao
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004
| | - Xiaofei Wang
- Pathology Department, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebie 063000
| | - Yafang Lai
- Department of Gastroenterology, Ordos Central Hospital, Ordos, Inner Mongolia Autonomous Region 017000
| | - Ying Huang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004
| | - Hua Yin
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004
| | - Xiangkun Meng
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004
| | - Hao Liu
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004
| | - Ruirui Hou
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004
| | - Wan Lin
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004
| | - Xiaoxu Zhang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004
| | - Xu Zhang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004
| | - Bei Cho Chai
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004
| | - Feixiong Zhang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004
| | - Le Guo
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
| | - Shaoqi Yang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004
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24
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Cao W, Yang J, Zhu C, Zeng Z, Yang C, Chen T, Zhu J. Carbonic Anhydrase IX Targeting Mn(II)-Based Magnetic Resonance Molecular Imaging Probe for Hypoxia Tumors. Bioconjug Chem 2023; 34:1166-1175. [PMID: 37285478 DOI: 10.1021/acs.bioconjchem.3c00232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Physiological hypoxic conditions in the tumor microenvironment and consequential overexpression of carbonic anhydrase IX (CA IX) are two characteristics shared by numerous types of solid malignant tumors. Early detection with hypoxia assessment is crucial to improve the prognosis and therapy outcomes of hypoxia tumors. Herein, using acetazolamide (AZA) as a CA IX-targeting moiety, we design and synthesize an Mn(II)-based MR imaging probe (named AZA-TA-Mn) incorporating AZA and two Mn(II) chelates of Mn-TyEDTA on a rigid triazine (TA) scaffold. The per Mn relaxivity of AZA-TA-Mn is 2-fold higher than its monomeric Mn-TyEDTA, which allows it for low-dose imaging of hypoxic tumors. In a xenograft mice model of esophageal squamous cell carcinoma (ESCC), a low dosage of AZA-TA-Mn (0.05 mmol/kg) can selectively produce prolonged and stronger contrast enhancement in the tumor compared to the non-specific Gd-DTPA (0.1 mmol/kg). A competition study of co-injection of free AZA and Mn(II) probes confirms the in vivo tumor selectivity of AZA-TA-Mn, resulting in a more than 2.5-fold decreased tumor-to-muscle contrast-to-noise ratio (ΔCNR) at 60 min post-injection. MR imaging results were further supported by the quantitative analysis of Mn tissue levels, as the co-injection of free AZA resulted in significantly reduced Mn accumulation in tumor tissues. Finally, immunofluorescence staining of tissue sections confirms the positive correlation between the tumor accumulation of AZA-TA-Mn and CA IX overexpression. Hence, using CA IX as the hypoxia biomarker, our results illustrate a practical strategy for the development of novel imaging probes for hypoxic tumors.
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Affiliation(s)
- Weidong Cao
- Medical Imaging Key Laboratory of Sichuan Province, Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Maoyuan Road 1, Nanchong City, Sichuan 637000, China
- School of Pharmacy, North Sichuan Medical College, Fujiang Road 234, Nanchong City, Sichuan 637000, China
| | - Jianqiong Yang
- Medical Imaging Key Laboratory of Sichuan Province, Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Maoyuan Road 1, Nanchong City, Sichuan 637000, China
- Department of Radiology, The Second Clinical Medical School of North Sichuan Medical College, Nanchong Central Hospital, Nanchong City, Sichuan 637000, China
| | - Chunrong Zhu
- Medical Imaging Key Laboratory of Sichuan Province, Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Maoyuan Road 1, Nanchong City, Sichuan 637000, China
| | - Zuhua Zeng
- Medical Imaging Key Laboratory of Sichuan Province, Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Maoyuan Road 1, Nanchong City, Sichuan 637000, China
- School of Pharmacy, North Sichuan Medical College, Fujiang Road 234, Nanchong City, Sichuan 637000, China
| | - Chenwu Yang
- Medical Imaging Key Laboratory of Sichuan Province, Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Maoyuan Road 1, Nanchong City, Sichuan 637000, China
| | - Tianwu Chen
- Medical Imaging Key Laboratory of Sichuan Province, Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Maoyuan Road 1, Nanchong City, Sichuan 637000, China
| | - Jiang Zhu
- Medical Imaging Key Laboratory of Sichuan Province, Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Maoyuan Road 1, Nanchong City, Sichuan 637000, China
- School of Pharmacy, North Sichuan Medical College, Fujiang Road 234, Nanchong City, Sichuan 637000, China
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25
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Garima, Sharma D, Kumar A, Mostafavi E. Extracellular vesicle-based biovectors in chronic wound healing: Biogenesis and delivery approaches. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 32:822-840. [PMID: 37273778 PMCID: PMC10238601 DOI: 10.1016/j.omtn.2023.05.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/29/2023]
Abstract
Chronic wounds remain an unresolved medical issue because of major social and therapeutic repercussions that require extensive focus. Recent related theragnostic focuses only on wound management and is not effectively promoting chronic wound healing. The rising number of patients with either under-healing or over-healing wounds highlights the ineffectiveness of current wound-healing treatments, and thus, there is an unmet need to focus on alternative treatments. To cover this gap, extracellular vesicles (EVs), for targeted delivery of therapeutics, are emerging as a potential therapy to treat both acute and persistent wounds. To address these issues, we explore the core biology of EVs, associated pharmacology, comprehension of immunogenic outcomes, and potential for long-term wound treatment with improved effectiveness and their nonacceptable side effects. Additionally, the therapeutic role of EVs in severe wound infections through biogenetic moderation, in combination with biomaterials (functional in nature), as well as drug carriers that can offer opportunities for the development of new treatments for this long-term condition, are also carefully elaborated, with an emphasis on biomaterial-based drug delivery systems. It is observed that exploring difficulties and potential outcomes of clinical translation of EV-based therapeutics for wound management has the potential to be adopted as a future therapy.
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Affiliation(s)
- Garima
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
- M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to Be University), Mullana-Ambala, Haryana 133207, India
| | - Deepika Sharma
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, UPES, Dehradun, India
| | - Arun Kumar
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya 824209, India
| | - Ebrahim Mostafavi
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
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26
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Salimi L, Seyedaghamiri F, Karimipour M, Mobarak H, Mardi N, Taghavi M, Rahbarghazi R. Physiological and pathological consequences of exosomes at the blood-brain-barrier interface. Cell Commun Signal 2023; 21:118. [PMID: 37208741 DOI: 10.1186/s12964-023-01142-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/22/2023] [Indexed: 05/21/2023] Open
Abstract
Blood-brain barrier (BBB) interface with multicellular structure controls strictly the entry of varied circulating macromolecules from the blood-facing surface into the brain parenchyma. Under several pathological conditions within the central nervous system, the integrity of the BBB interface is disrupted due to the abnormal crosstalk between the cellular constituents and the recruitment of inflammatory cells. Exosomes (Exos) are nano-sized extracellular vesicles with diverse therapeutic outcomes. These particles transfer a plethora of signaling molecules with the potential to modulate target cell behavior in a paracrine manner. Here, in the current review article, the therapeutic properties of Exos and their potential in the alleviation of compromised BBB structure were discussed. Video Abstract.
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Affiliation(s)
- Leila Salimi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemehsadat Seyedaghamiri
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Karimipour
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Halimeh Mobarak
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narges Mardi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Taghavi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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27
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Zhang J, Liu L, Wang Z, Hou M, Dong Z, Yu J, Sun R, Cui G. Ubiquitin-proteasome system-based signature to predict the prognosis and drug sensitivity of hepatocellular carcinoma. Front Pharmacol 2023; 14:1172908. [PMID: 37180696 PMCID: PMC10166894 DOI: 10.3389/fphar.2023.1172908] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 04/17/2023] [Indexed: 05/16/2023] Open
Abstract
Background: Ubiquitin-proteasome system (UPS) is implicated in cancer occurrence and progression. Targeting UPS is emerging as a promising therapeutic target for cancer treatment. Nevertheless, the clinical significance of UPS in hepatocellular carcinoma (HCC) has not been entirely elucidated. Methods: Differentially expressed UPS genes (DEUPS) were screened from LIHC-TCGA datasets. The least absolute shrinkage and selection operator (LASSO) and stepwise multivariate regression analysis were conducted to establish a UPS-based prognostic risk model. The robustness of the risk model was further validated in HCCDB18, GSE14520, and GSE76427 cohorts. Subsequently, immune features, clinicopathologic characteristics, enrichment pathways, and anti-tumor drug sensitivity of the model were further evaluated. Moreover, a nomogram was established to improve the predictive ability of the risk model. Results: Seven UPS-based signatures (ATG10, FBXL7, IPP, MEX3A, SOCS2, TRIM54, and PSMD9) were developed for the prognostic risk model. Individuals with HCC with high-risk scores presented a more dismal prognosis than those with low-risk scores. Moreover, larger tumor size, advanced TNM stage, and tumor grade were observed in the high-risk group. Additionally, cell cycle, ubiquitin-mediated proteolysis, and DNA repair pathways were intimately linked to the risk score. In addition, obvious immune cell infiltration and sensitive drug response were identified in low-risk patients. Furthermore, both nomogram and risk score showed a significant prognosis-predictive ability. Conclusion: Overall, we established a novel UPS-based prognostic risk model in HCC. Our results will facilitate a deep understanding of the functional role of UPS-based signature in HCC and provide a reliable prediction of clinical outcomes and anti-tumor drug responses for patients with HCC.
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Affiliation(s)
- Jianxiang Zhang
- Department of General Surgery Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Liwen Liu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zenghan Wang
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mingyang Hou
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zihui Dong
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jia Yu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ranran Sun
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangying Cui
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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28
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Arifianto MR, Meizikri R, Haq IBI, Susilo RI, Wahyuhadi J, Hermanto Y, Faried A. Emerging hallmark of gliomas microenvironment in evading immunity: a basic concept. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2023. [DOI: 10.1186/s41983-023-00635-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2023] Open
Abstract
Abstract
Background
Over the last decade, since clinical trials examining targeted therapeutics for gliomas have failed to demonstrate a meaningful increase in survival, the emphasis has recently been switched toward innovative techniques for modulating the immune response against tumors and their microenvironments (TME). Cancerous cells have eleven hallmarks which make it distinct from normal ones, among which is immune evasion. Immune evasion in glioblastoma helps it evade various treatment modalities.
Summary
Glioblastoma’s TME is composed of various array of cellular actors, ranging from peripherally derived immune cells to a variety of organ-resident specialized cell types. For example, the blood–brain barrier (BBB) serves as a selective barrier between the systemic circulation and the brain, which effectively separates it from other tissues. It is capable of blocking around 98% of molecules that transport different medications to the target tumor.
Objectives
The purpose of this paper is to offer a concise overview of fundamental immunology and how ‘clever’ gliomas avoid the immune system despite the discovery of immunotherapy for glioma.
Conclusions
Herein, we highlight the complex interplay of the tumor, the TME, and the nearby normal structures makes it difficult to grasp how to approach the tumor itself. Numerous researchers have found that the brain TME is a critical regulator of glioma growth and treatment efficacy.
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Yuan F, Yin XY, Huang Y, Cai XW, Jin L, Dai GC, Zang YC, Sun Y, Liu XL, Xue BX. Exosomal miR-93-5p as an important driver of bladder cancer progression. Transl Androl Urol 2023; 12:286-299. [PMID: 36915886 PMCID: PMC10006004 DOI: 10.21037/tau-22-872] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 02/06/2023] [Indexed: 03/16/2023] Open
Abstract
Background Tumor-derived exosomes are involved in the process of tumor metastasis and angiogenesis. MicroRNAs (miRNAs) are the most widely investigated factors in exosomes. Therefore, we hope to find a new therapeutic target in bladder cancer (BLCA), which has high incidence rate and mortality. Methods Exosomal microRNA(miR)-93-5p expression level, downstream target molecules, and biological functions were examined with bioinformatics technology. Exosomes were extracted by sequential differential centrifugation and verified by transmission electron microscopy. The exosomal miR-93-5p on cell proliferation, invasion, and angiogenesis abilities in 5637 and T24 cells was determined by Cell Counting Kit 8 (CCK-8), colony-forming assay, Transwell assay, and vascular ring formation assay. A mouse xenograft model with intratumor injection was adopted to evaluate the correlation between BLCA-derived exosomes and tumor growth in vivo. Results The results revealed that exosomes play an important role in the biological progression of BLCA, with miR-93-5p being a particularly important molecule. Compared to normal cells, more malignant cells release more exosomal miR-93-5p, and tumor-derived exosomal miR-93-5p could significantly promote cell proliferation, invasion, and angiogenesis in vitro and in vivo. We identified phosphatase and tensin homolog (PTEN) as the most significant target of miR-93-5p in BLCA and human umbilical vein endothelial cells. Conclusions Our study successfully revealed the biological role and mechanism of BLCA-derived exosomes in tumor progression. Target at tumor exosomes and exosomal miR-93-5p may be an effective treatment in BLCA.
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Affiliation(s)
- Feng Yuan
- Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiao-Yu Yin
- School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China
| | - Yu Huang
- School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China
| | - Xiao-Wei Cai
- Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Lu Jin
- Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Guang-Cheng Dai
- Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Ya-Cheng Zang
- Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yi Sun
- School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China
| | - Xiao-Long Liu
- Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Bo-Xin Xue
- Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Formation of pre-metastatic niches induced by tumor extracellular vesicles in lung metastasis. Pharmacol Res 2023; 188:106669. [PMID: 36681367 DOI: 10.1016/j.phrs.2023.106669] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/17/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023]
Abstract
There are a number of malignant tumors that metastasize into the lung as one of their most common sites of dissemination. The successful infiltration of tumor cells into distant organs is the result of the cooperation between tumor cells and distant host cells. When tumor cells have not yet reached distant organs, in situ tumor cells secrete extracellular vesicles (EVs) carrying important biological information. In recent years, scholars have found that tumor cells-derived EVs act as the bridge between orthotopic tumors and secondary metastases by promoting the formation of a pre-metastatic niche (PMN), which plays a key role in awakening dormant circulating tumor cells and promoting tumor cell colonization. This review provides an overview of multiple routes and mechanisms underlying PMN formation induced by EVs and summaries study findings that underline a potential role of EVs in the intervention of lung PMN, both as a target or a carrier for drug design. In this review, the underlying mechanisms of EVs in lung PMN formation are highlighted as well as potential applications to lung metastasis diagnosis and treatment.
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31
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Shahverdi M, Darvish M. Exosomal microRNAs: A Diagnostic and Therapeutic Small Bio-molecule in Esophageal Cancer. Curr Mol Med 2023; 23:312-323. [PMID: 35319366 DOI: 10.2174/1566524022666220321125134] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 12/07/2021] [Accepted: 12/20/2021] [Indexed: 02/08/2023]
Abstract
Esophageal cancer (EC) is one of the major causes of cancer-related death worldwide. EC is usually diagnosed at a late stage, and despite aggressive therapy, the five-year survival rate of patients remains poor. Exosomes play important roles in cancer biology. Indeed, exosomes are implicated in tumor proliferation, angiogenesis, and invasion. They contain bioactive molecules such as lipids, proteins, and non-coding RNAs. Exosome research has recently concentrated on microRNAs, which are tiny noncoding endogenous RNAs that can alter gene expression and are linked to nearly all physiological and pathological processes, including cancer. It is suggested that deregulation of miRNAs results in cancer progression and directly induces tumor initiation. In esophageal cancer, miRNA dysregulation plays an important role in cancer prognosis and patients' responsiveness to therapy, indicating that miRNAs are important in tumorigenesis. In this review, we summarize the impact of exosomal miRNAs on esophageal cancer pathogenesis and their potential applications for EC diagnosis and therapy.
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Affiliation(s)
- Mahshid Shahverdi
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Maryam Darvish
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
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32
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Wang Y, Zhang Y, Li Y, Kou X, Xue Z. Mechanisms of Biochanin A Alleviating PM2.5 Organic Extracts-Induced EMT of A549 Cells through the PI3K/Akt Pathway. JOURNAL OF NATURAL PRODUCTS 2022; 85:2290-2301. [PMID: 36181478 DOI: 10.1021/acs.jnatprod.2c00457] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Epithelial-mesenchymal transition (EMT) is an important step in tumor progression, which enables tumor cells to acquire migration and invasion characteristics. The aim of this study was to investigate the mechanism of biological biochanin A (BCA) in ameliorating fine particulate matter (PM2.5) lung injury. The results showed that PM2.5 could induce spindle-like changes in cell morphology, causing the ability of migration and invasion. However, they were significantly inhibited by BCA treatment (10/20/30 μm). After BCA treatment, the release and transcription of chemokine CXCL12 and its receptor gene CXCR4 were inhibited, and the release of growth inducer TGF-β1 was significantly reduced. In addition, BCA promoted the transcription of E-cadherin and β-catenin, inhibiting the expression of N-cadherin, vimentin, and fibronectin, and down-regulated the expression of MMP-2/9. We found that BCA effectively interfered with the PI3K/Akt signaling pathway activated by PM2.5. In conclusion, PM2.5 can induce EMT in lung cancer cells, and BCA may reverse this process by activating the PI3K/Akt signaling pathway.
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Affiliation(s)
- Yumeng Wang
- Department of Food Science, School of Chemical Engineering and Technology, Tianjin University, 300350, Tianjin, China
| | - Yixia Zhang
- Department of Food Science, School of Chemical Engineering and Technology, Tianjin University, 300350, Tianjin, China
| | - Yonghui Li
- Cardiovascular Department, Tianjin Fourth Center Hospital, 300140, Tianjin, China
| | - Xiaohong Kou
- Department of Food Science, School of Chemical Engineering and Technology, Tianjin University, 300350, Tianjin, China
| | - Zhaohui Xue
- Department of Food Science, School of Chemical Engineering and Technology, Tianjin University, 300350, Tianjin, China
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33
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Shao X, Hua S, Feng T, Ocansey DKW, Yin L. Hypoxia-Regulated Tumor-Derived Exosomes and Tumor Progression: A Focus on Immune Evasion. Int J Mol Sci 2022; 23:ijms231911789. [PMID: 36233088 PMCID: PMC9570495 DOI: 10.3390/ijms231911789] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/24/2022] [Accepted: 09/29/2022] [Indexed: 11/16/2022] Open
Abstract
Tumor cells express a high quantity of exosomes packaged with unique cargos under hypoxia, an important characteristic feature in solid tumors. These hypoxic tumor-derived exosomes are, crucially, involved in the interaction of cancer cells with their microenvironment, facilitating not only immune evasion, but increased cell growth and survival, enhanced angiogenesis, epithelial–mesenchymal transition (EMT), therapeutic resistance, autophagy, pre-metastasis, and metastasis. This paper explores the tumor microenvironment (TME) remodeling effects of hypoxic tumor-derived exosome towards facilitating the tumor progression process, particularly, the modulatory role of these factors on tumor cell immune evasion through suppression of immune cells, expression of surface recognition molecules, and secretion of antitumor soluble factor. Tumor-expressed exosomes educate immune effector cells, including macrophages, monocytes, T cells, natural killer (NK) cells, dendritic cells (DCs), γδ T lymphocytes, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), mast cells, and B cells, within the hypoxic TME through the release of factors that regulate their recruitment, phenotype, and function. Thus, both hypoxia and tumor-derived exosomes modulate immune cells, growth factors, cytokines, receptor molecules, and other soluble factors, which, together, collaborate to form the immune-suppressive milieu of the tumor environment. Exploring the contribution of exosomal cargos, such as RNAs and proteins, as indispensable players in the cross-talk within the hypoxic tumor microenvironmental provides a potential target for antitumor immunity or subverting immune evasion and enhancing tumor therapies.
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Zhang G, Li M, Zhou D, Yang X, Zhang W, Gao R. Loss of endothelial EMCN drives tumor lung metastasis through the premetastatic niche. J Transl Med 2022; 20:446. [PMID: 36184589 PMCID: PMC9528146 DOI: 10.1186/s12967-022-03649-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 09/18/2022] [Indexed: 11/24/2022] Open
Abstract
Background Metastasis is the primary cause of cancer-related mortality. Metastasis involves a complex multistep process during which individual tumor cells spread primarily through destruction of the endothelial barrier, entering the circulatory system to colonize distant organs. However, the role of the endothelial barrier as the rate-limiting process in tumor metastasis and how these processes affect the regulation of the host microenvironment at the molecular level are poorly understood. Methods Here, we analyzed differentially expressed genes in breast cancer and lung adenocarcinoma, including metastatic and recurrent specimens, using TCGA dataset. The effects of EMCN on endothelial cells in vitro and in vivo were analyzed by assessing angiogenesis and vascular permeability, respectively. We established a syngeneic mouse model of endothelial cell-specific knockout of EMCN (EMCNecko) to study the role of EMCN in tumor growth and metastasis. Transcriptome sequencing, Western blotting, qPCR and immunofluorescence confirmed important factors in the premetastatic niche. A mouse model of allograft tumor resection with lung metastasis was established to confirm the therapeutic effect of a notch inhibitor combined with an anti-TGF-β antibody. Results We found a strong correlation of EMCN deficiency with tumor recurrence and metastasis. Comparative experiments in WT and EMCNecko mice revealed that endothelial EMCN deficiency did not affect primary tumor growth significantly but strongly promoted spontaneous metastasis. EMCN deficiency was associated with gene profiles that regulate cell junctions in vitro and enhance vascular permeability in vivo. Mechanistically, EMCN deficiency mainly affected the host microenvironment and led to the formation of a lung premetastatic niche by recruiting Ly6G+ neutrophils and upregulating MMP9, S100A8/A9 and TGF-β expression. Anti-TGF-β antibody effectively eliminated TGF-β-induced neutrophil polarization, thereby reducing lung metastasis. Notably, the combination of a Notch inhibitor and an anti-TGF-β antibody effectively inhibited tumor growth and lung metastasis and prolonged the survival time of mice. Conclusions We present a new translational strategy of EMCN as a new key player in tumor lung metastasis by affecting the host microenvironment. These findings could provide a sound theoretical basis for clinical treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03649-4.
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Affiliation(s)
- Guoxin Zhang
- National Human Diseases Animal Model Resource Center, The Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China.,NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Beijing, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Beijing, China
| | - Mengyuan Li
- National Human Diseases Animal Model Resource Center, The Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China.,NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Beijing, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Beijing, China
| | - Dandan Zhou
- National Human Diseases Animal Model Resource Center, The Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China.,NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Beijing, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Beijing, China
| | - Xingjiu Yang
- National Human Diseases Animal Model Resource Center, The Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China.,NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Beijing, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Beijing, China
| | - Wenlong Zhang
- National Human Diseases Animal Model Resource Center, The Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China.,NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Beijing, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Beijing, China
| | - Ran Gao
- National Human Diseases Animal Model Resource Center, The Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China. .,NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Beijing, China. .,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Beijing, China.
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35
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Extracellular vesicles secreted by human uterine stromal cells regulate decidualization, angiogenesis, and trophoblast differentiation. Proc Natl Acad Sci U S A 2022; 119:e2200252119. [PMID: 36095212 PMCID: PMC9499590 DOI: 10.1073/pnas.2200252119] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
In humans, the uterus undergoes a dramatic transformation to form an endometrial stroma-derived secretory tissue, termed decidua, during early pregnancy. The decidua secretes various factors that act in an autocrine/paracrine manner to promote stromal differentiation, facilitate maternal angiogenesis, and influence trophoblast differentiation and development, which are critical for the formation of a functional placenta. Here, we investigated the mechanisms by which decidual cells communicate with each other and with other cell types within the uterine milieu. We discovered that primary human endometrial stromal cells (HESCs) secrete extracellular vesicles (EVs) during decidualization and that this process is controlled by a conserved HIF2α-RAB27B pathway. Mass spectrometry revealed that the decidual EVs harbor a variety of protein cargo, including cell signaling molecules, growth modulators, metabolic regulators, and factors controlling endothelial cell expansion and remodeling. We tested the hypothesis that EVs secreted by the decidual cells mediate functional communications between various cell types within the uterus. We demonstrated that the internalization of EVs, specifically those carrying the glucose transporter 1 (GLUT1), promotes glucose uptake in recipient HESCs, supporting and advancing the decidualization program. Additionally, delivery of HESC-derived EVs into human endothelial cells stimulated their proliferation and led to enhanced vascular network formation. Strikingly, stromal EVs also promoted the differentiation of trophoblast stem cells into the extravillous trophoblast lineage. Collectively, these findings provide a deeper understanding of the pleiotropic roles played by EVs secreted by the decidual cells to ensure coordination of endometrial differentiation and angiogenesis with trophoblast function during the progressive phases of decidualization and placentation.
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36
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Lucotti S, Kenific CM, Zhang H, Lyden D. Extracellular vesicles and particles impact the systemic landscape of cancer. EMBO J 2022; 41:e109288. [PMID: 36052513 PMCID: PMC9475536 DOI: 10.15252/embj.2021109288] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 02/16/2022] [Accepted: 03/23/2022] [Indexed: 11/09/2022] Open
Abstract
Intercellular cross talk between cancer cells and stromal and immune cells is essential for tumor progression and metastasis. Extracellular vesicles and particles (EVPs) are a heterogeneous class of secreted messengers that carry bioactive molecules and that have been shown to be crucial for this cell-cell communication. Here, we highlight the multifaceted roles of EVPs in cancer. Functionally, transfer of EVP cargo between cells influences tumor cell growth and invasion, alters immune cell composition and function, and contributes to stromal cell activation. These EVP-mediated changes impact local tumor progression, foster cultivation of pre-metastatic niches at distant organ-specific sites, and mediate systemic effects of cancer. Furthermore, we discuss how exploiting the highly selective enrichment of molecules within EVPs has profound implications for advancing diagnostic and prognostic biomarker development and for improving therapy delivery in cancer patients. Altogether, these investigations into the role of EVPs in cancer have led to discoveries that hold great promise for improving cancer patient care and outcome.
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Affiliation(s)
- Serena Lucotti
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Candia M Kenific
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - Haiying Zhang
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
| | - David Lyden
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer CenterWeill Cornell MedicineNew YorkNYUSA
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Ye H, Hu X, Wen Y, Tu C, Hornicek F, Duan Z, Min L. Exosomes in the tumor microenvironment of sarcoma: from biological functions to clinical applications. J Nanobiotechnology 2022; 20:403. [PMID: 36064358 PMCID: PMC9446729 DOI: 10.1186/s12951-022-01609-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 08/23/2022] [Indexed: 11/10/2022] Open
Abstract
The current diagnosis and treatment of sarcoma continue to show limited timeliness and efficacy. In order to enable the early detection and management of sarcoma, increasing attentions have been given to the tumor microenvironment (TME). TME is a dynamic network composed of multiple cells, extracellular matrix, vasculature, and exosomes. Exosomes are nano-sized extracellular vesicles derived from various cells in the TME. The major function of exosomes is to promote cancer progress and metastasis through mediating bidirectional cellular communications between sarcoma cells and TME cells. Due to the content specificity, cell tropism, and bioavailability, exosomes have been regarded as promising diagnostic and prognostic biomarkers, and therapeutic vehicles for sarcoma. This review summarizes recent studies on the roles of exosomes in TME of sarcoma, and explores the emerging clinical applications.
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Affiliation(s)
- Huali Ye
- West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Xin Hu
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Wen
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Chongqi Tu
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Francis Hornicek
- Sarcoma Biology Laboratory, Department of Orthopaedics, Sylvester Comprehensive Cancer Center, and the University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Zhenfeng Duan
- Sarcoma Biology Laboratory, Department of Orthopaedics, Sylvester Comprehensive Cancer Center, and the University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
| | - Li Min
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China.
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38
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Wang Z, Liang X, Zhang H, Wang Z, Zhang X, Dai Z, Liu Z, Zhang J, Luo P, Li J, Cheng Q. Identification of a Hypoxia-Angiogenesis lncRNA Signature Participating in Immunosuppression in Gastric Cancer. J Immunol Res 2022; 2022:5209607. [PMID: 36052279 PMCID: PMC9427269 DOI: 10.1155/2022/5209607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 06/06/2022] [Indexed: 01/17/2023] Open
Abstract
Hypoxia and angiogenesis are the leading causes of tumor progression, and their strong correlation has been discovered in many cancers. However, their collective function's prognostic and biological roles were not reported in gastric cancer. Hence, we aimed to investigate the effects of hypoxia and angiogenesis on gastric cancer via sequencing data. This study used weighted gene coexpression network analysis and random forest regression to build a hypoxia-angiogenesis-related model (HARM) via the TCGA-STAD lncRNA data. It estimated the HARM's correlation with clinical features and its accuracy for survival prediction. Sequential functional analyses were conducted to investigate its biological role, and we next sought the immune landscape status and immunological function variation by ESTIMATE score calculation and GSVA, respectively. Seven different algorithms were conducted to assess the immunocyte infiltration, and TIDE score and immune checkpoint levels were compared between the high- and low-HARM groups. As a result, we found that HARM predicted patient survival with high accuracy and was correlated with higher stages of gastric cancer. Various cancer-associated pathways and macrophage-related regulations were upregulated in the high-HRAM group. The high-HARM group harbored higher immune levels, and M2 macrophages and cancer-associated fibroblasts were particularly highly unfiltered. Furthermore, globally upregulated immune checkpoints and higher TIDE scores were observed in the high-HARM group. Finally, we filtered eight drugs with lower IC50 in the high-HARM group as potential drugs for the HARM-targeted therapy. We believe this study opens up novel perspectives into the interaction between hypoxia-angiogenesis and immunosuppression and will provide novel insights for gastric cancer immunotherapy.
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Affiliation(s)
- Zicheng Wang
- Hepatobiliary Surgery, Hunan Provincial People's Hospital (The First Affiliate Hospital of Hunan Normal University), Changsha, China
| | - Xisong Liang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Hao Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Zeyu Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xun Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ziyu Dai
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China
| | - Jiarong Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
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Xiao W, Tang P, Sui Z, Han Y, Zhao G, Wu X, Yang Y, Zhu N, Gong L, Yu Z, Zhang H. Establishment of a risk model by integrating hypoxia genes in predicting prognosis of esophageal squamous cell carcinoma. Cancer Med 2022; 12:2117-2133. [PMID: 35789548 PMCID: PMC9883439 DOI: 10.1002/cam4.5002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 06/03/2022] [Accepted: 06/11/2022] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) has a dismal prognosis, and hypoxia plays a key role in metastasis and proliferation of ESCC. Thus, we aimed to develop a hypoxia-based gene signature to assist in the treatment decisions and prognosis. METHODS We performed consensus clustering analysis on samples from GSE53625 dataset from the Gene Expression Omnibus (GEO) database and used weighted gene co-expression network analysis to filter out candidate modules, which were then intersected with differentially expressed genes from clustered subgroups to obtain hypoxia-related genes (HRGs). After that, the aforementioned genes were used to construct risk score models and validated in The Cancer Genome Atlas (TCGA) database and Cox regression analysis were used to construct a nomogram. Immunohistochemical was used to detect protein expression levels of relevant genes. Moreover, the relationship between risk scores and tumor microenvironment was explored. RESULTS A hypoxia risk model containing six genes (PNPLA1, CARD18, IL-18, SLC37A2, ADAMTS18, and FAM83C) was constructed by screening key HRGs. Poorer prognosis in the high-risk group than in the low-risk group. And Cox regression analysis showed that risk score was an independent prognostic factor. The nomogram based on risk scores could well predict 1-, 3-, and 5-year survival. P53, Wnt, and hypoxia signaling pathways may be some regulatory mechanisms of hypoxia associated with the tumor microenvironment. In addition, we confirmed the high expression of BGN and low expression of IL-18 in ESCC tissues. CONCLUSIONS Our study determined the prognostic value of a 6-hypoxia gene signature and a prognostic model, providing potential prognostic predictors and therapeutic targets for ESCC.
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Affiliation(s)
- Wanyi Xiao
- Department of Esophageal CancerTianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for CancerTianjinChina
| | - Peng Tang
- Department of Esophageal CancerTianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for CancerTianjinChina
| | - Zhilin Sui
- Department of Esophageal CancerTianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for CancerTianjinChina,Department of Thoracic SurgeryNational Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and PeKing Union Medical CollegeShenzhenChina
| | - Youming Han
- Department of Respiratory MedicineBinhai Hospital of Tianjin Medical University General HospitalTianjinChina
| | - Gang Zhao
- Department of Gastrointestinal Cancer BiologyTianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for CancerTianjinChina
| | - Xianxian Wu
- Department of Thoracic SurgeryNational Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and PeKing Union Medical CollegeShenzhenChina
| | - Yueyang Yang
- Department of Esophageal CancerTianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for CancerTianjinChina
| | - Ningning Zhu
- Department of Esophageal CancerTianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for CancerTianjinChina
| | - Lei Gong
- Department of Esophageal CancerTianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for CancerTianjinChina
| | - Zhentao Yu
- Department of Thoracic SurgeryNational Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and PeKing Union Medical CollegeShenzhenChina
| | - Hongdian Zhang
- Department of Esophageal CancerTianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for CancerTianjinChina
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40
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Paskeh MDA, Entezari M, Mirzaei S, Zabolian A, Saleki H, Naghdi MJ, Sabet S, Khoshbakht MA, Hashemi M, Hushmandi K, Sethi G, Zarrabi A, Kumar AP, Tan SC, Papadakis M, Alexiou A, Islam MA, Mostafavi E, Ashrafizadeh M. Emerging role of exosomes in cancer progression and tumor microenvironment remodeling. J Hematol Oncol 2022; 15:83. [PMID: 35765040 PMCID: PMC9238168 DOI: 10.1186/s13045-022-01305-4] [Citation(s) in RCA: 317] [Impact Index Per Article: 105.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 06/13/2022] [Indexed: 12/14/2022] Open
Abstract
Cancer is one of the leading causes of death worldwide, and the factors responsible for its progression need to be elucidated. Exosomes are structures with an average size of 100 nm that can transport proteins, lipids, and nucleic acids. This review focuses on the role of exosomes in cancer progression and therapy. We discuss how exosomes are able to modulate components of the tumor microenvironment and influence proliferation and migration rates of cancer cells. We also highlight that, depending on their cargo, exosomes can suppress or promote tumor cell progression and can enhance or reduce cancer cell response to radio- and chemo-therapies. In addition, we describe how exosomes can trigger chronic inflammation and lead to immune evasion and tumor progression by focusing on their ability to transfer non-coding RNAs between cells and modulate other molecular signaling pathways such as PTEN and PI3K/Akt in cancer. Subsequently, we discuss the use of exosomes as carriers of anti-tumor agents and genetic tools to control cancer progression. We then discuss the role of tumor-derived exosomes in carcinogenesis. Finally, we devote a section to the study of exosomes as diagnostic and prognostic tools in clinical courses that is important for the treatment of cancer patients. This review provides a comprehensive understanding of the role of exosomes in cancer therapy, focusing on their therapeutic value in cancer progression and remodeling of the tumor microenvironment.
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Affiliation(s)
- Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hossein Saleki
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohamad Javad Naghdi
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sina Sabet
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Amin Khoshbakht
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Division of Epidemiology, Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, 34396, Istanbul, Turkey
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283, Wuppertal, Germany.
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, Australia
- AFNP Med Austria, Vienna, Austria
| | - Md Asiful Islam
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul, Turkey.
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Huang Y, Kanada M, Ye J, Deng Y, He Q, Lei Z, Chen Y, Li Y, Qin P, Zhang J, Wei J. Exosome-mediated remodeling of the tumor microenvironment: From local to distant intercellular communication. Cancer Lett 2022; 543:215796. [PMID: 35728740 DOI: 10.1016/j.canlet.2022.215796] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/31/2022] [Accepted: 06/15/2022] [Indexed: 11/29/2022]
Abstract
Extracellular vesicles (EVs) are membrane-enveloped nanoscale particles that carry various bioactive signaling molecules secreted by cells. Their biological roles depend on the original cell type from which they are derived and their inclusions. Exosomes, a class of EVs, are released by almost all eukaryotic cell types, including tumor cells. Tumor cell-derived exosomes mediate signal transduction between tumor cells and surrounding non-tumor cells. This intercellular communication actively contributes to the remodeling of the tumor microenvironment (TME) to enable tumor growth, invasion, and metastasis. This review summarizes the latest progress in the exploration of exosome-mediated cell-cell communication implicated in TME remodeling and underlying mechanisms. We focus on the role of cell-cell interactions mediated by tumor cell-derived exosomes in promoting invasion and metastasis, and their potential as a therapeutic intervention target against distant metastasis. We also discuss the clinical translational significance of tumor-derived exosomes for early diagnosis, efficacy and progression evaluations.
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Affiliation(s)
- Yujuan Huang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, China
| | - Masamitsu Kanada
- Department of Pharmacology & Toxicology, Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, East Lansing, MI, 48824, USA
| | - Jiaxiang Ye
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, China
| | - Yayan Deng
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, China
| | - Qian He
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China
| | - Zhengyang Lei
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China
| | - Yong Chen
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, China
| | - Yongqiang Li
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, China
| | - Peiwu Qin
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China
| | - Jinyan Zhang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, China.
| | - Jiazhang Wei
- Department of Otolaryngology & Head and Neck, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 6 Taoyuan Road, Nanning, 530021, China.
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Garcia-Hernandez A, Reyes-Uribe E, Arce-Salinas C, de la Cruz-Lopez KG, Manzo-Merino J, Guzman-Ortiz AL, Quezada H, Cortes-Reynosa P, Breton-Mora F, Elizalde-Acosta I, Thompson-Bonilla R, Salazar EP. Extracellular vesicles from blood of breast cancer women induce angiogenic processes in HUVECs. Tissue Cell 2022; 76:101814. [DOI: 10.1016/j.tice.2022.101814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 12/24/2022]
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Ke S, Fang M, Li R, Wang J, Lu J. Downregulation of long noncoding RNA breast cancer anti-estrogen resistance 4 inhibits cell proliferation, invasion, and migration in esophageal squamous cell carcinoma by regulating the microRNA-181c-5p/LIM and SH3 protein 1 axis. Bioengineered 2022; 13:12998-13010. [PMID: 35611706 PMCID: PMC9275979 DOI: 10.1080/21655979.2022.2060720] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Recently, abnormal expression of long non-coding RNAs (lncRNAs) has been observed in esophageal squamous cell carcinoma (ESCC). In various human cancers, breast cancer anti‑estrogen resistance 4 (BCAR4) was reported to be highly expressed, while the biological roles of BCAR4 in ESCC remain unclear. In ESCC cells and tissues, BCAR4 and microRNA −181c-5p (miR-181c-5p) expression, and phosphorylated signal transducer and activator of transcription (p-STAT3) and COX2 expression were evaluated by real-time reverse transcription PCR (qRT-PCR) and Western blot analysis. Cell function was evaluated by colony formation, CCK-8 assay, transwell and flow cytometer assays. Interactions between BCAR4 and miR-181c-5p, as well as miR-181c-5p and LIM and SH3 protein 1 (LASP1) were evaluated by RIP and luciferase reporter assay. ESCC cell malignancy with inhibition of BCAR4 was confirmed by a tumor xenograft model in vivo. In both ESCC tissues and cell lines, BCAR4 was upregulated. Downregulation of BCAR4 effectively induced cell apoptosis and inhibited invasion and migration in vitro, and reduced tumorigenesis in nude mice. BCAR4 was a sponge of miR-181c-5p to upregulate LASP1. Moreover, knockdown of BCAR4 and overexpression of miR-181c-5p inhibited the activation of the STAT3/COX2 signaling, which was reversed by overexpression of LASP1. In conclusion, BCAR4 promotes ESCC tumorigenesis by targeting the miR-181c-5p/LASP1 axis, which may act as a treatment and diagnosis biomarker for ESCC.
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Affiliation(s)
- Shun Ke
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei Province, China
| | - Minghao Fang
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei Province, China
| | - Ruichao Li
- Department of General Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei Province, China
| | - Jing Wang
- Department of Clinical Oncology, Remin Hospital of Wuhan University, Wuhan City, Hubei Province, China
| | - Jun Lu
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei Province, China
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Zhou S, Sun X, Jin Z, Yang H, Ye W. The role of autophagy in initiation, progression, TME modification, diagnosis, and treatment of esophageal cancers. Crit Rev Oncol Hematol 2022; 175:103702. [PMID: 35577254 DOI: 10.1016/j.critrevonc.2022.103702] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 04/14/2022] [Accepted: 05/02/2022] [Indexed: 10/18/2022] Open
Abstract
Autophagy is a highly conserved metabolic process with a cytoprotective function. Autophagy is involved in cancer, infection, immunity, and inflammation and may be a potential therapeutic target. Increasing evidence has revealed that autophagy has primary implications for esophageal cancer, including its initiation, progression, tumor microenvironment (TME) modification, diagnosis, and treatment. Notably, autophagy displayed excellent application potential in radiotherapy combined with immunotherapy. Radiotherapy combined with immunotherapy is a new potential therapeutic strategy for cancers, including esophageal cancer. Autophagy modulators can work as adjuvant enhancers in radiotherapy or immunotherapy of cancers. This review highlights the most recent data related to the role of autophagy regulation in esophageal cancer.
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Affiliation(s)
- Suna Zhou
- Department of Radiation Oncology, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi 710018, P.R. China; Laboratory of Cellular and Molecular Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, P.R. China; Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou, P.R. China
| | - Xuefeng Sun
- Laboratory of Cellular and Molecular Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, P.R. China; Department of Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou, P.R. China
| | - Zhicheng Jin
- Laboratory of Cellular and Molecular Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, P.R. China; Department of Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou, P.R. China
| | - Haihua Yang
- Laboratory of Cellular and Molecular Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou 317000, Zhejiang, P.R. China; Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou, P.R. China; Department of Radiation Oncology, The Affiliated Taizhou Hospital, Wenzhou Medical University, Taizhou, P.R. China
| | - Wenguang Ye
- Department of Gastroenterology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China.
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Jiang H, Zhao H, Zhang M, He Y, Li X, Xu Y, Liu X. Hypoxia Induced Changes of Exosome Cargo and Subsequent Biological Effects. Front Immunol 2022; 13:824188. [PMID: 35444652 PMCID: PMC9013908 DOI: 10.3389/fimmu.2022.824188] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 02/25/2022] [Indexed: 12/16/2022] Open
Abstract
Exosomes are small extracellular vesicles that are secreted by almost all types of cells and exist in almost all extracellular spaces. As an important mediator of intercellular communication, exosomes encapsulate the miRNA, lncRNA, cirRNA, mRNA, cytokine, enzyme, lipid, and other components from the cytoplasm into its closed single membrane structure and transfer them to recipient units in an autocrine, paracrine, or endocrine manner. Hypoxia is a state of low oxygen tension and is involved in many pathological processes. Hypoxia influences the size, quantity, and expression of exosome cargos. Exosomes derived from hypoxic tumor cells transfer genetics, proteins, and lipids to the recipient units to exert pleiotropic effects. Different donor cells produce different cargo contents, target different recipient units and lead to different biological effects. Hypoxic exosomes derived from tumor cells uptaken by normoxic tumor cells lead to promoted proliferation, migration, and invasion; uptaken by extracellular space or liver lead to promoted metastasis; uptaken by endothelial cells lead to promoted angiogenesis; uptaken by immune cells lead to promoted macrophage polarization and changed tumor immune microenvironment. In addition to various types of tumors, hypoxic exosomes also participate in the development of diseases in the cardiovascular system, neuron system, respiratory system, hematology system, endocrine system, urinary system, reproduction system, and skeletomuscular system. Understanding the special characteristics of hypoxic exosomes provide new insight into elaborating the pathogenesis of hypoxia related disease. This review summarizes hypoxia induced cargo changes and the biological effects of hypoxic exosomes in tumors and non-malignant diseases in different systems.
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Affiliation(s)
- Hongxia Jiang
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Pulmonary Diseases, National Ministry of Health of The People's Republic of China, Wuhan, China
| | - Hanqiu Zhao
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Pulmonary Diseases, National Ministry of Health of The People's Republic of China, Wuhan, China
| | - Mengzhe Zhang
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Pulmonary Diseases, National Ministry of Health of The People's Republic of China, Wuhan, China
| | - Yuanzhou He
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Pulmonary Diseases, National Ministry of Health of The People's Republic of China, Wuhan, China
| | - Xiaochen Li
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Pulmonary Diseases, National Ministry of Health of The People's Republic of China, Wuhan, China
| | - Yongjian Xu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Pulmonary Diseases, National Ministry of Health of The People's Republic of China, Wuhan, China
| | - Xiansheng Liu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Pulmonary Diseases, National Ministry of Health of The People's Republic of China, Wuhan, China
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Message in a Bottle: Endothelial Cell Regulation by Extracellular Vesicles. Cancers (Basel) 2022; 14:cancers14081969. [PMID: 35454874 PMCID: PMC9026533 DOI: 10.3390/cancers14081969] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/06/2022] [Accepted: 04/10/2022] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Elucidating the role of extracellular vesicles (EVs) in the communication mechanisms between cancer and endothelial cells (ECs) within the tumor microenvironment is an exciting challenge. At the same time, due to their ability to convey bioactive molecules, EVs may be potentially relevant from a therapeutic perspective for diverse vascular pathologies. Abstract Intercellular communication is a key biological mechanism that is fundamental to maintain tissue homeostasis. Extracellular vesicles (EVs) have emerged as critical regulators of cell–cell communication in both physiological and pathological conditions, due to their ability to shuttle a variety of cell constituents, such as DNA, RNA, lipids, active metabolites, cytosolic, and cell surface proteins. In particular, endothelial cells (ECs) are prominently regulated by EVs released by neighboring cell types. The discovery that cancer cell-derived EVs can control the functions of ECs has prompted the investigation of their roles in tumor angiogenesis and cancer progression. In particular, here, we discuss evidence that supports the roles of exosomes in EC regulation within the tumor microenvironment and in vascular dysfunction leading to atherosclerosis. Moreover, we survey the molecular mechanisms and exosomal cargoes that have been implicated in explanations of these regulatory effects.
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47
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Lian L, Teng SB, Xia YY, Shen XM, Zheng Y, Han SG, Wang WJ, Xu XF, Zhou C. Development and verification of a hypoxia- and immune-associated prognosis signature for esophageal squamous cell carcinoma. J Gastrointest Oncol 2022; 13:462-477. [PMID: 35557566 PMCID: PMC9086047 DOI: 10.21037/jgo-22-69] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 03/08/2022] [Indexed: 08/21/2023] Open
Abstract
BACKGROUND Esophageal cancer is one of the most common gastrointestinal malignancies worldwide, with high morbidity and mortality in China. The clinical importance of the interaction between hypoxia and immune status in the tumor microenvironment has been established in esophageal squamous cell carcinoma (ESCC). This study aims to develop a new hypoxia- and immune-based gene signature to predict the survival of ESCC patients. METHODS The RNA-sequencing and clinical data of 173 cases of ESCC and 271 normal tissues were obtained from The Cancer Genome Atlas (TCGA) data portal and the Genotype-Tissue Expression (GTEx) database. Hypoxia-related genes (HRGs) and immune-related genes (IRGs) were retrieved from publicly shared data. Differentially expressed gene (DEG) analyses were carried out by the DESeq2 method using the edgeR package in R. Based on the intersection of the DEGs and HRGs/IRGs, differentially expressed HRGs (DEHRGs) and differentially expressed IRGs (DEIRGs) were obtained. DEHRGs and DEIRGs associated with prognosis were evaluated using univariate Cox proportional hazards analysis. A prognostic risk score model was constructed according to the genes acquired through Cox regression. Univariate analysis and Cox proportional hazards analysis were used to determine the independent prognostic factors related to prognosis. A nomogram was developed to predict the 1-, 2-, and 3-year overall survival (OS) probability. RESULTS A total of 73 intersecting genes were obtained as DEHRGs and a total of 548 intersecting genes were obtained as DEIRGs. The risk score was established using 8 genes (FABP7, TLR1, SYTL1, APLN, OSM, EGFR, IL17RD, MYH9) acquired from univariate Cox analysis. Based on this 8-gene-based risk score, a risk prognosis classifier was constructed to classify the samples into high- and low-risk groups according to the median risk score. The nomogram model was constructed to predict the OS of ESCC patients. CONCLUSIONS The hypoxia- and immune-based gene signature might serve as a prognostic classifier for clinical decision-making regarding individualized management, follow-up plans, and treatment strategies for ESCC patients.
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Affiliation(s)
- Lian Lian
- Department of Oncology, Suzhou Xiangcheng People’s Hospital, Suzhou, China
| | - Shi-Bing Teng
- Department of Thoracic Surgery, Suzhou Xiangcheng People’s Hospital, Suzhou, China
| | - You-You Xia
- Department of Radiation Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University (The First People’s Hospital of Lianyungang), Lianyungang, China
| | - Xiao-Ming Shen
- Department of Oncology, Suzhou Xiangcheng People’s Hospital, Suzhou, China
| | - Yan Zheng
- Department of Oncology, Suzhou Xiangcheng People’s Hospital, Suzhou, China
| | - Shu-Guang Han
- Department of General Surgery, Suzhou Xiangcheng People’s Hospital, Suzhou, China
| | - Wen-Jie Wang
- Department of Radio-Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Xue-Fei Xu
- Department of General Surgery, Suzhou Xiangcheng People’s Hospital, Suzhou, China
| | - Chong Zhou
- Department of Radiation Oncology, Xuzhou Central Hospital, Xuzhou, China
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Li F, Niu R, Gao S, Zhao F, Dong Z, Zhang H, Li S. Pro-Angiogenesis Role of LINC00662 From Esophageal Squamous Cell Carcinoma Cells-Derived Extracellular Vehicles. Front Bioeng Biotechnol 2022; 10:772514. [PMID: 35433661 PMCID: PMC9011136 DOI: 10.3389/fbioe.2022.772514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 02/14/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: LINC00662 is oncogenic in some human cancers, but no much was revealed concerning to its specific action in tumor angiogenesis. Given that, our study investigated the role of LINC00662 from esophageal squamous cell carcinoma (ESCC) cells-derived extracellular vehicles (EVs) in angiogenesis through microRNA (miR)-195-5p/vascular endothelial growth factor A (VEGFA) axis.Methods: Clinical tissue samples were collected from patients with ESCC, in which LINC00662, miR-195-5p and VEGFA expression was analyzed. ESCC cells were transfected, from which EVs were isolated. Human umbilical vein endothelial cells (HUVECs) were co-cultured with the pretreated EVs. After that, viability, colony formation ability, invasion, migration and tube formation ability of HUVECs were observed. Tumor xenograft in nude mice was performed to detect the effect of LINC00662, miR-195-5p or EV specific inhibitor GW4869 on tumor development.Results: LINC00662 and VEGFA were upregulated while miR-195-5p was downregulated in the cancer tissue of patients with ESCC. EVs derived from ESCC cells promoted viability, colony formation ability, invasion and tube formation ability of HUVECs. Downregulation of LINC00662 or upregulation of miR-195-5p reversed the promotion of EVs derived from ESCC cells on the viability, colony formation ability, invasion and tube formation ability of HUVECs in vitro and in vivo. VEGFA overexpression reversed EVs carrying restored miR-195-5p induced effects on HUVECs in vitro.Conclusion: In summary, elevated LINC00662 transferred by ESCC cells-derived EVs induces angiogenesis through downregulating miR-195-5p and upregulating VEGFA.
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Affiliation(s)
- Feng Li
- The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ren Niu
- Department of Oncology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - ShaoLin Gao
- Department of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - FangChao Zhao
- Department of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zefang Dong
- Department of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hao Zhang
- Institute of Precision Medicine and Pathology, Jinan University, Guangzhou, China
| | - Shujun Li
- Department of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- *Correspondence: Shujun Li,
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Petroušková P, Hudáková N, Maloveská M, Humeník F, Cizkova D. Non-Exosomal and Exosome-Derived miRNAs as Promising Biomarkers in Canine Mammary Cancer. Life (Basel) 2022; 12:life12040524. [PMID: 35455015 PMCID: PMC9032658 DOI: 10.3390/life12040524] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 02/06/2023] Open
Abstract
Canine mammary cancer (CMC), similar to human breast cancer (HBC) in many aspects, is the most common neoplasm associated with significant mortality in female dogs. Due to the limited therapy options, biomarkers are highly desirable for early clinical diagnosis or cancer progression monitoring. Since the discovery of microRNAs (miRNAs or miRs) as post-transcriptional gene regulators, they have become attractive biomarkers in oncological research. Except for intracellular miRNAs and cell-free miRNAs, exosome-derived miRNAs (exomiRs) have drawn much attention in recent years as biomarkers for cancer detection. Analysis of exosomes represents a non-invasive, pain-free, time- and money-saving alternative to conventional tissue biopsy. The purpose of this review is to provide a summary of miRNAs that come from non-exosomal sources (canine mammary tumor, mammary tumor cell lines or canine blood serum) and from exosomes as promising biomarkers of CMC based on the current literature. As is discussed, some of the miRNAs postulated as diagnostic or prognostic biomarkers in CMC were also altered in HBC (such as miR-21, miR-29b, miR-141, miR-429, miR-200c, miR-497, miR-210, miR-96, miR-18a, miR19b, miR-20b, miR-93, miR-101, miR-105a, miR-130a, miR-200c, miR-340, miR-486), which may be considered as potential disease-specific biomarkers in both CMC and HBC.
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Affiliation(s)
- Patrícia Petroušková
- Centre of Experimental and Clinical Regenerative Medicine, The University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia; (P.P.); (N.H.); (M.M.); (F.H.)
| | - Nikola Hudáková
- Centre of Experimental and Clinical Regenerative Medicine, The University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia; (P.P.); (N.H.); (M.M.); (F.H.)
| | - Marcela Maloveská
- Centre of Experimental and Clinical Regenerative Medicine, The University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia; (P.P.); (N.H.); (M.M.); (F.H.)
| | - Filip Humeník
- Centre of Experimental and Clinical Regenerative Medicine, The University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia; (P.P.); (N.H.); (M.M.); (F.H.)
| | - Dasa Cizkova
- Centre of Experimental and Clinical Regenerative Medicine, The University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia; (P.P.); (N.H.); (M.M.); (F.H.)
- Institute of Neuroimmunology, Slovak Academy of Sciences, Dúbravská Cesta 9, 845 10 Bratislava, Slovakia
- Correspondence: ; Tel.: +421-918-752-157
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50
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Qian W, Li G. Extracellular Vesicles from Esophageal Squamous Cell Carcinoma Promote Angiogenesis and Tumor Growth. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.2896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Angiogenesis is a prerequisite for tumor development and metastasis. Emerging evidence shows that tumor-derived extracellular vesicles (EVs) are an important component of tumor microenvironment, which participate in the communication between normal cells and tumor cells. In this study,
we aimed to investigate the role of EVs derived from esophageal squamous cell carcinoma (ESCC) on tumor angiogenesis. We found that ESCC cell-derived EVs promoted the proliferation, migration, and tubule formation of human umbilical vein endothelial cells in vitro, and enhanced angiogenesis
and tumor growth in vivo. Our results suggest that ESCC cell-derived EVs could promote angio-genesis and tumor growth, which also indicated the application of EVs as a valuable therapeutic strategy of ESCC.
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Affiliation(s)
- Wenxiu Qian
- Department of Pediatrics, Jintan Hospital, Jiangsu University, Jintan, Changzhou, Jiangsu 213200, P. R. China
| | - Guomin Li
- Department of Critical Care Medicine, Jintan Hospital, Jiangsu University, Jintan, Changzhou, Jiangsu 213200, P. R. China
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