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Ahmadizad Firouzjaei A, Aghaee-Bakhtiari SH. Integrating cuproptosis and immunosenescence: A novel therapeutic strategy in cancer treatment. Biochem Biophys Rep 2025; 42:101983. [PMID: 40224540 PMCID: PMC11986980 DOI: 10.1016/j.bbrep.2025.101983] [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: 01/18/2025] [Revised: 03/01/2025] [Accepted: 03/17/2025] [Indexed: 04/15/2025] Open
Abstract
Recent advancements in our understanding of cell death mechanisms have progressed beyond traditional apoptosis to encompass various forms of regulated cell death, notably cuproptosis. This copper-dependent cell death occurs when copper interacts with lipoylated enzymes in the tricarboxylic acid cycle, leading to protein aggregation and subsequent cell death. Alongside this, immunosenescence the gradual decline in immune function due to aging has emerged as a significant factor in cancer progression and response to treatment. Innovative strategies that integrate cuproptosis and immunosenescence are showing considerable promise in cancer therapy. By leveraging the altered copper metabolism in cancer cells, cuproptosis can selectively induce cell death, effectively targeting and eliminating tumors. Simultaneously, addressing immunosenescence can rejuvenate the aging immune system, enhancing its capacity to identify and destroy cancer cells. This dual approach creates a synergistic effect, optimizing therapeutic efficacy by directly attacking tumor cells while revitalizing the immune response. Such integration bolsters the defense against cancer progression and recurrence and holds great potential for advancing cancer treatment modalities and improving patient outcomes. This paper delves into the interactions between cuproptosis and immunosenescence, emphasizing their implications for developing innovative cancer therapies.
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Affiliation(s)
- Ali Ahmadizad Firouzjaei
- Bioinformatics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Hamid Aghaee-Bakhtiari
- Bioinformatics Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biotechnology and Nanotechnology, Mashhad University of Medical Sciences, Mashhad, Iran
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Guo Z, Chen D, Yao L, Sun Y, Li D, Le J, Dian Y, Zeng F, Chen X, Deng G. The molecular mechanism and therapeutic landscape of copper and cuproptosis in cancer. Signal Transduct Target Ther 2025; 10:149. [PMID: 40341098 PMCID: PMC12062509 DOI: 10.1038/s41392-025-02192-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 12/13/2024] [Accepted: 02/17/2025] [Indexed: 05/10/2025] Open
Abstract
Copper, an essential micronutrient, plays significant roles in numerous biological functions. Recent studies have identified imbalances in copper homeostasis across various cancers, along with the emergence of cuproptosis, a novel copper-dependent form of cell death that is crucial for tumor suppression and therapeutic resistance. As a result, manipulating copper levels has garnered increasing interest as an innovative approach to cancer therapy. In this review, we first delineate copper homeostasis at both cellular and systemic levels, clarifying copper's protumorigenic and antitumorigenic functions in cancer. We then outline the key milestones and molecular mechanisms of cuproptosis, including both mitochondria-dependent and independent pathways. Next, we explore the roles of cuproptosis in cancer biology, as well as the interactions mediated by cuproptosis between cancer cells and the immune system. We also summarize emerging therapeutic opportunities targeting copper and discuss the clinical associations of cuproptosis-related genes. Finally, we examine potential biomarkers for cuproptosis and put forward the existing challenges and future prospects for leveraging cuproptosis in cancer therapy. Overall, this review enhances our understanding of the molecular mechanisms and therapeutic landscape of copper and cuproptosis in cancer, highlighting the potential of copper- or cuproptosis-based therapies for cancer treatment.
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Affiliation(s)
- Ziyu Guo
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China
- Furong Laboratory, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Danyao Chen
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lei Yao
- Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuming Sun
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Daishi Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China
- Furong Laboratory, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Jiayuan Le
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China
- Furong Laboratory, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Yating Dian
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China
- Furong Laboratory, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Furong Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China.
- Furong Laboratory, Changsha, Hunan, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China.
| | - Guangtong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China.
- Furong Laboratory, Changsha, Hunan, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China.
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Wang H, Wang T, Yan S, Tang J, Zhang Y, Wang L, Xu H, Tu C. Crosstalk of pyroptosis and cytokine in the tumor microenvironment: from mechanisms to clinical implication. Mol Cancer 2024; 23:268. [PMID: 39614288 PMCID: PMC11607834 DOI: 10.1186/s12943-024-02183-9] [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: 07/13/2024] [Accepted: 11/22/2024] [Indexed: 12/01/2024] Open
Abstract
In the realm of cancer research, the tumor microenvironment (TME) plays a crucial role in tumor initiation and progression, shaped by complex interactions between cancer cells and surrounding non-cancerous cells. Cytokines, as essential immunomodulatory agents, are secreted by various cellular constituents within the TME, including immune cells, cancer-associated fibroblasts, and cancer cells themselves. These cytokines facilitate intricate communication networks that significantly influence tumor initiation, progression, metastasis, and immune suppression. Pyroptosis contributes to TME remodeling by promoting the release of pro-inflammatory cytokines and sustaining chronic inflammation, impacting processes such as immune escape and angiogenesis. However, challenges remain due to the complex interplay among cytokines, pyroptosis, and the TME, along with the dual effects of pyroptosis on cancer progression and therapy-related complications like cytokine release syndrome. Unraveling these complexities could facilitate strategies that balance inflammatory responses while minimizing tissue damage during therapy. This review delves into the complex crosstalk between cytokines, pyroptosis, and the TME, elucidating their contribution to tumor progression and metastasis. By synthesizing emerging therapeutic targets and innovative technologies concerning TME, this review aims to provide novel insights that could enhance treatment outcomes for cancer patients.
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Affiliation(s)
- Hua Wang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Tao Wang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Shuxiang Yan
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Jinxin Tang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Yibo Zhang
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Liming Wang
- School of Biomedical Sciences, Hunan University, Changsha, Hunan, 410011, China.
| | - Haodong Xu
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
| | - Chao Tu
- Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Shenzhen Research Institute of Central South University, Guangdong, 518063, China.
- Hunan Engineering Research Center of AI Medical Equipment, The Second Xiangya Hospital of Central, South University, Changsha, Hunan, 410011, China.
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Wang Y, Chen Y, Zhang J, Yang Y, Fleishman JS, Wang Y, Wang J, Chen J, Li Y, Wang H. Cuproptosis: A novel therapeutic target for overcoming cancer drug resistance. Drug Resist Updat 2024; 72:101018. [PMID: 37979442 DOI: 10.1016/j.drup.2023.101018] [Citation(s) in RCA: 84] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/06/2023] [Accepted: 11/08/2023] [Indexed: 11/20/2023]
Abstract
Cuproptosis is a newly identified form of cell death driven by copper. Recently, the role of copper and copper triggered cell death in the pathogenesis of cancers have attracted attentions. Cuproptosis has garnered enormous interest in cancer research communities because of its great potential for cancer therapy. Copper-based treatment exerts an inhibiting role in tumor growth and may open the door for the treatment of chemotherapy-insensitive tumors. In this review, we provide a critical analysis on copper homeostasis and the role of copper dysregulation in the development and progression of cancers. Then the core molecular mechanisms of cuproptosis and its role in cancer is discussed, followed by summarizing the current understanding of copper-based agents (copper chelators, copper ionophores, and copper complexes-based dynamic therapy) for cancer treatment. Additionally, we summarize the emerging data on copper complexes-based agents and copper ionophores to subdue tumor chemotherapy resistance in different types of cancers. We also review the small-molecule compounds and nanoparticles (NPs) that may kill cancer cells by inducing cuproptosis, which will shed new light on the development of anticancer drugs through inducing cuproptosis in the future. Finally, the important concepts and pressing questions of cuproptosis in future research that should be focused on were discussed. This review article suggests that targeting cuproptosis could be a novel antitumor therapy and treatment strategy to overcome cancer drug resistance.
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Affiliation(s)
- Yumin Wang
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing 100049, PR China.
| | - Yongming Chen
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, PR China
| | - Junjing Zhang
- Department of Hepato-Biliary Surgery, Department of Surgery, Huhhot First Hospital, Huhhot 010030, PR China
| | - Yihui Yang
- Beijing Key Laboratory of Drug Target and Screening Research, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China
| | - Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Yan Wang
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research & Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital of Central South University, Changsha 410011, PR China
| | - Jinhua Wang
- Beijing Key Laboratory of Drug Target and Screening Research, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China
| | - Jichao Chen
- Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing 100049, PR China
| | - Yuanfang Li
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, PR China.
| | - Hongquan Wang
- Department of Neurology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China.
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Chen SC, Fan KC, Yen IW, Yang CY, Lin CH, Hsu CY, Lyu YP, Juan HC, Lin HH, Lin MS, Shih SR, Li HY, Kuo CH. Serum vascular adhesion protein-1 is associated with twelve-year risk of incident cancer, cancer mortality, and all-cause mortality: a community-based cohort study. Front Oncol 2023; 13:1308353. [PMID: 38162479 PMCID: PMC10754676 DOI: 10.3389/fonc.2023.1308353] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 11/28/2023] [Indexed: 01/03/2024] Open
Abstract
Background Vascular adhesion protein-1 (VAP-1), a dual-function glycoprotein, has been reported to play a crucial role in inflammation and tumor progression. We conducted a community-based cohort study to investigate whether serum VAP-1 could be a potential biomarker for predicting incident cancers and mortality. Method From 2006 to 2018, we enrolled 889 cancer-free subjects at baseline. Serum VAP-1 levels were measured using a time-resolved immunofluorometric assay. Cancer and vital status of the participants were obtained by linking records with the computerized cancer registry and death certificates in Taiwan. Results During a median follow-up of 11.94 years, 69 subjects developed incident cancers and 66 subjects died, including 29 subjects who died from malignancy. Subjects in the highest tertile of serum VAP-1 had a significantly higher risk of cancer incidence (p=0.0006), cancer mortality (p=0.0001), and all-cause mortality (p=0.0002) than subjects in the other tertiles. The adjusted hazard ratios per one standard deviation increase in serum VAP-1 concentrations were 1.28 for cancer incidence (95% CI=1.01-1.62), 1.60 for cancer mortality (95% CI=1.14-2.23), and 1.38 for all-cause mortality (95% CI=1.09-1.75). The predictive performance of serum VAP-1 was better than that of gender, smoking, body mass index, hypertension, diabetes, and estimated glomerular filtration rate but lower than that of age for cancer incidence, cancer mortality, and all-cause mortality, as evidenced by higher increments in concordance statistics and area under the receiver operating characteristic curve. Conclusion Serum VAP-1 levels are associated with a 12-year risk of incident cancer, cancer mortality, and all-cause mortality in a general population.
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Affiliation(s)
- Szu-Chi Chen
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei City Hospital, Taipei, Taiwan
| | - Kang-Chih Fan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - I-Weng Yen
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu, Taiwan
| | - Chung-Yi Yang
- Department of Medical Imaging, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Chia-Hung Lin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu, Taiwan
| | - Chih-Yao Hsu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei City Hospital, Taipei, Taiwan
| | - Ya-Pin Lyu
- Department of Obstetrics & Gynecology, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsien-Chia Juan
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Heng-Huei Lin
- Department of Obstetrics & Gynecology, National Taiwan University Hospital, Taipei, Taiwan
| | - Mao-Shin Lin
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Shyang-Rong Shih
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Center of Anti-Aging and Health Consultation, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Yuan Li
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Heng Kuo
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
- Department of Internal Medicine, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City, Taiwan
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Bai Y, Jiao X, Hu J, Xue W, Zhou Z, Wang W. WTAP promotes macrophage recruitment and increases VEGF secretion via N6-methyladenosine modification in corneal neovascularization. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166708. [PMID: 37019244 DOI: 10.1016/j.bbadis.2023.166708] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 03/03/2023] [Accepted: 03/28/2023] [Indexed: 04/05/2023]
Abstract
BACKGROUND Corneal neovascularization (CNV) can be caused by chemical burns. Macrophages are involved in angiogenesis and lymphangiogenesis during CNV. The aim of this study was to investigate whether Wilms' tumor 1-associated protein (WTAP) is involved in macrophage recruitment and VEGF secretion via N6-methyladenosine (m6A) modification. METHODS A CNV mouse model was established by corneal alkali burn. Tumor necrosis factor alpha (TNF-α) was used to stimulate vascular endothelial cells. m6A immunoprecipitation qPCR was used to determine the enrichment of m6A levels in mRNAs. The H3K9me3 enrichment in the promoter region of CC motif chemokine ligand 2 (CCL2) was detected by chromatin immunoprecipitation assay. The WTAP inhibition in vivo was performed using the adeno-associated virus. RESULTS In the alkali burn corneal tissues, angiogenesis and lymphangiogenesis were promoted as CD31 and LYVE-1 expressions were elevated, and the number of macrophages as well as WTAP expression were increased. Under the TNF-α stimulation, WTAP promoted the recruitment of endothelial cells to macrophages by promoting CCL2 secretion. Mechanistically, WTAP affected the enrichment of H3K9me3 at the CCL2 promoter by regulating the m6A level of SUV39H1 mRNA. The in vivo experiment showed that VEGFA/C/D secretion of macrophages was reduced after WTAP interference. Mechanistically, WTAP regulated the translational efficiency of HIF-1α via m6A modification. CONCLUSION WTAP affected macrophage recruitment to endothelial cells via regulation of H3K9me3-mediated CCL2 transcription. WTAP also affected macrophage secretion of VEGFA/C/D via m6A-mediated translation regulation of HIF-1α. Both pathways were involved in the WTAP regulation of angiogenesis and lymphangiogenesis during CNV.
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Wang X, Zhou M, Liu Y, Si Z. Cope with copper: From copper linked mechanisms to copper-based clinical cancer therapies. Cancer Lett 2023; 561:216157. [PMID: 37011869 DOI: 10.1016/j.canlet.2023.216157] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/04/2023]
Abstract
Recent studies have established a strong link between copper and cancer biology, as copper is necessary for cancer growth and metastasis. Beyond the conventional concept of copper serving as a catalytic cofactor of metalloenzymes, emerging evidence demonstrates copper as a regulator for signaling transduction and gene expression, which are vital for tumorigenesis and cancer progression. Interestingly, strong redox-active properties make copper both beneficial and detrimental to cancer cells. Cuproplasia is copper-dependent cell growth and proliferation, whereas cuproptosis is copper-dependent cell death. Both mechanisms act in cancer cells, suggesting that copper depletion and copper supplementation may be viable approaches for developing novel anticancer therapies. In this review, we summarized the current understanding of copper's biological role and related molecular mechanisms in cancer proliferation, angiogenesis, metastasis, autophagy, immunosuppressive microenvironment development, and copper-mediated cancer cell death. We also highlighted copper-based strategies for cancer treatment. The current challenges of copper in cancer biology and therapy and their potential solutions were also discussed. Further investigation in this field will yield a more comprehensive molecular explanation for the causal relationship between copper and cancers. It will reveal a series of key regulators governing copper-dependent signaling pathways, thereby providing potential targets for developing copper-related anticancer drugs.
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Affiliation(s)
- Xidi Wang
- Medical Research Center, The First Affiliated Hospital of Ningbo University, Ningbo, PR China; Department of Pathology, Health Science Center, Ningbo University, Ningbo, Ningbo, PR China.
| | - Miao Zhou
- Medical Research Center, The First Affiliated Hospital of Ningbo University, Ningbo, PR China
| | - Yu Liu
- Department of Physiology and Pharmacology, Health Science Center, Ningbo University, Ningbo, PR China
| | - Zizhen Si
- Department of Physiology and Pharmacology, Health Science Center, Ningbo University, Ningbo, PR China.
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Tan Z, Xue H, Sun Y, Zhang C, Song Y, Qi Y. The Role of Tumor Inflammatory Microenvironment in Lung Cancer. Front Pharmacol 2021; 12:688625. [PMID: 34079469 PMCID: PMC8166205 DOI: 10.3389/fphar.2021.688625] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 04/29/2021] [Indexed: 12/12/2022] Open
Abstract
Lung cancer is the most common and fatal malignant tumor in the world. The tumor microenvironment (TME) is closely related to the occurrence and development of lung cancer, in which the inflammatory microenvironment plays an important role. Inflammatory cells and inflammatory factors in the tumor inflammatory microenvironment promote the activation of the NF-κB and STAT3 inflammatory pathways and the occurrence, development, and metastasis of lung cancer by promoting immune escape, tumor angiogenesis, epithelial-mesenchymal transition, apoptosis, and other mechanisms. Clinical and epidemiological studies have also shown a strong relationship among chronic infection, inflammation, inflammatory microenvironment, and lung cancer. The relationship between inflammation and lung cancer can be better understood through the gradual understanding of the tumor inflammatory microenvironment, which is advantageous to find more therapeutic targets for lung cancer.
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Affiliation(s)
- Zhaofeng Tan
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
- Departments of Oncology Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Haibin Xue
- Eighth Medical Center of the General Hospital of the Chinese People’s Liberation Army, Beijing, China
| | - Yuli Sun
- Departments of Oncology Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chuanlong Zhang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yonglei Song
- Departments of Oncology Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yuanfu Qi
- Departments of Oncology Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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Unzeta M, Hernàndez-Guillamon M, Sun P, Solé M. SSAO/VAP-1 in Cerebrovascular Disorders: A Potential Therapeutic Target for Stroke and Alzheimer's Disease. Int J Mol Sci 2021; 22:ijms22073365. [PMID: 33805974 PMCID: PMC8036996 DOI: 10.3390/ijms22073365] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/22/2021] [Accepted: 03/23/2021] [Indexed: 12/24/2022] Open
Abstract
The semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1) or primary amine oxidase (PrAO), is a deaminating enzyme highly expressed in vessels that generates harmful products as a result of its enzymatic activity. As a multifunctional enzyme, it is also involved in inflammation through its ability to bind and promote the transmigration of circulating leukocytes into inflamed tissues. Inflammation is present in different systemic and cerebral diseases, including stroke and Alzheimer’s disease (AD). These pathologies show important affectations on cerebral vessels, together with increased SSAO levels. This review summarizes the main roles of SSAO/VAP-1 in human physiology and pathophysiology and discusses the mechanisms by which it can affect the onset and progression of both stroke and AD. As there is an evident interrelationship between stroke and AD, basically through the vascular system dysfunction, the possibility that SSAO/VAP-1 could be involved in the transition between these two pathologies is suggested. Hence, its inhibition is proposed to be an interesting therapeutical approach to the brain damage induced in these both cerebral pathologies.
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Affiliation(s)
- Mercedes Unzeta
- Department of Biochemistry and Molecular Biology, Institute of Neurosciences, Universitat Auònoma de Barcelona, 08193 Barcelona, Spain;
| | - Mar Hernàndez-Guillamon
- Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain;
- Correspondence: ; Tel.: +34-934-896-766
| | - Ping Sun
- Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA;
| | - Montse Solé
- Neurovascular Research Laboratory, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain;
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Kinoshita T, Sayem MA, Yaguchi T, Kharma B, Morii K, Kato D, Ohta S, Mashima Y, Asamura H, Kawakami Y. Inhibition of vascular adhesion protein-1 enhances the anti-tumor effects of immune checkpoint inhibitors. Cancer Sci 2021; 112:1390-1401. [PMID: 33453147 PMCID: PMC8019209 DOI: 10.1111/cas.14812] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 01/10/2021] [Accepted: 01/12/2021] [Indexed: 02/07/2023] Open
Abstract
Modulation of the immunosuppressive tumor microenvironment (TME) is essential for enhancing the anti‐tumor effects of immune checkpoint inhibitors (ICIs). Adhesion molecules and enzymes such as vascular adhesion protein‐1 (VAP‐1), which are expressed in some cancers and tumor vascular endothelial cells, may be involved in the generation of an immunosuppressive TME. In this study, the role of VAP‐1 in TME was investigated in 2 murine colon cancer models and human cancer cells. Intraperitoneal administration of the VAP‐1‐specific inhibitor U‐V296 inhibited murine tumor growth by enhancing IFN‐γ‐producing tumor antigen‐specific CD8+ T cells. U‐V296 exhibited significant synergistic anti‐tumor effects with ICIs. In the TME of mice treated with U‐V296, the expression of genes associated with M2‐like macrophages, Th2 cells (Il4, Retnla, and Irf4), angiogenesis (Pecam1), and fibrosis (Acta2, Loxl2) were significantly decreased, and the Th1/Th2 balance was increased. H2O2, an enzymatic product of VAP‐1, which promoted the production of IL‐4 by mouse Th2 and inhibited IFN‐γ by mouse Th1 and human tumor‐infiltrating lymphocytes, was decreased in tumors and CD31+ tumor vascular endothelial cells in the TMEs of mice treated with VAP‐1 inhibitor. TCGA database analysis showed that VAP‐1 expression was a negative prognostic factor in human cancers, exhibiting a significant positive correlation with IL‐4, IL4R, and IL‐13 expression and a negative correlation with IFN‐γ expression. These results indicated that VAP‐1 is involved in the immunosuppressive TMEs through H2O2‐associated Th2/M2 conditions and may be an attractive target for the development of combination cancer immunotherapy with ICIs.
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Affiliation(s)
- Tomonari Kinoshita
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.,Division of General Thoracic Surgery, Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Mohammad Abu Sayem
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.,Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Tangail, Bangladesh
| | - Tomonori Yaguchi
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Budiman Kharma
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Kenji Morii
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Daiki Kato
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.,Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Shigeki Ohta
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Yukihiko Mashima
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Hisao Asamura
- Division of General Thoracic Surgery, Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yutaka Kawakami
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.,Department of Immunology, School of Medicine, International University of Health and Welfare, Chiba, Japan
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11
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Gharanei S, Fishwick K, Peter Durairaj R, Jin T, Siamantouras E, Liu KK, Straube A, Lucas ES, Weston CJ, Rantakari P, Salmi M, Jalkanen S, Brosens JJ, Tan BK. Vascular Adhesion Protein-1 Determines the Cellular Properties of Endometrial Pericytes. Front Cell Dev Biol 2021; 8:621016. [PMID: 33537312 PMCID: PMC7848099 DOI: 10.3389/fcell.2020.621016] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 12/16/2020] [Indexed: 12/12/2022] Open
Abstract
Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible adhesion molecule and a primary amine oxidase involved in immune cell trafficking. Leukocyte extravasation into tissues is mediated by adhesion molecules expressed on endothelial cells and pericytes. Pericytes play a major role in the angiogenesis and vascularization of cycling endometrium. However, the functional properties of pericytes in the human endometrium are not known. Here we show that pericytes surrounding the spiral arterioles in midluteal human endometrium constitutively express VAP-1. We first characterize these pericytes and demonstrate that knockdown of VAP-1 perturbed their biophysical properties and compromised their contractile, migratory, adhesive and clonogenic capacities. Furthermore, we show that loss of VAP-1 disrupts pericyte-uterine natural killer cell interactions in vitro. Taken together, the data not only reveal that endometrial pericytes represent a cell population with distinct biophysical and functional properties but also suggest a pivotal role for VAP-1 in regulating the recruitment of innate immune cells in human endometrium. We posit that VAP-1 could serve as a potential biomarker for pregnancy pathologies caused by a compromised perivascular environment prior to conception.
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Affiliation(s)
- Seley Gharanei
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire National Health Service Trust, Coventry, United Kingdom
| | | | | | - Tianrong Jin
- School of Engineering, University of Warwick, Coventry, United Kingdom
| | | | - Kuo-Kang Liu
- School of Engineering, University of Warwick, Coventry, United Kingdom
| | - Anne Straube
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Centre for Mechanochemical Cell Biology, University of Warwick, Coventry, United Kingdom
| | - Emma S. Lucas
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Tommy's National Centre for Miscarriage Research, Coventry, United Kingdom
| | - Christopher J. Weston
- Centre for Liver Research & National Institute for Health Research Birmingham Biomedical Research Unit, Level 5 Institute for Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - Pia Rantakari
- Medicity Research Laboratory and Institute of Biomedicine, University of Turku, Turku, Finland
| | - Marko Salmi
- Medicity Research Laboratory and Institute of Biomedicine, University of Turku, Turku, Finland
| | - Sirpa Jalkanen
- Medicity Research Laboratory and Institute of Biomedicine, University of Turku, Turku, Finland
| | - Jan J. Brosens
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Tommy's National Centre for Miscarriage Research, Coventry, United Kingdom
| | - Bee Kang Tan
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Department of Cardiovascular Sciences and Diabetes Research Centre, University of Leicester, Leicester, United Kingdom
- Department of Obstetrics and Gynaecology, University Hospitals of Leicester National Health Service Trust, Leicester, United Kingdom
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12
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Shepherd EL, Karim S, Newsome PN, Lalor PF. Inhibition of vascular adhesion protein-1 modifies hepatic steatosis in vitro and in vivo. World J Hepatol 2020; 12:931-948. [PMID: 33312420 PMCID: PMC7701969 DOI: 10.4254/wjh.v12.i11.931] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/23/2020] [Accepted: 09/15/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance and dyslipidaemia and currently is estimated to affect up to a third of all individuals in developed countries. Current standard of care for patients varies according to disease stage, but includes lifestyle interventions common insulin sensitizers, antioxidants and lipid modifiers. However, to date specific therapies have shown little histological or fibrosis stage improvement in large clinical trials, and there is still no licensed therapy for NAFLD. Given the high prevalence, limited treatment options and significant screening costs for the general population, new treatments are urgently required.
AIM To assess the potential for inhibition of the amine oxidase enzyme vascular adhesion protein-1 (VAP-1) to modify hepatic lipid accumulation in NAFLD.
METHODS We have used immunochemical and qPCR analysis to document expression of VAP-1 and key functional proteins and transporters across the NAFLD spectrum. We then utilised hepatocytes in culture and human precision cut liver slices in concert with selective enzyme activity inhibitors to test the effects of activating the semicarbazide-sensitive amine oxidase activity of VAP-1 on hepatic lipid uptake and triglyceride export. A murine model of NAFLD was also used to determine the consequences of VAP-1 knockout and gene expression arrays were used to quantify the effects of VAP-1 activity on key lipid modifying and proinflammatory gene expression.
RESULTS We confirmed that increasing severity of NAFLD and progression to cirrhosis was associated with a significant increase in hepatocellular VAP-1 expression. Hepatocytes in vitro exposed to recombinant VAP-1 and its substrate methylamine showed increased lipid accumulation as determined by quantification of Oil Red O uptake. This was recapitulated using hydrogen peroxide, and lipid accumulation was accompanied by changes in expression of the lipid transporter molecules FABP3, FATP6, insulin receptor subunits and PPARα. Human liver tissue exposed to recombinant VAP-1 or substrates for endo/exogenous VAP-1 produced less triglyceride than untreated tissue and demonstrated an increase in steatosis. This response could be inhibited by using bromoethylamine to inhibit the SSAO activity of VAP-1, and mice deficient in VAP-1/AOC3 also demonstrated reduced steatosis on high fat diet. Exposure of human liver tissue to methylamine to activate VAP-1 resulted in increased expression of FABP2 and 4, FATP3-5, caveolin-1, VLDLR, PPARGC1 and genes associated with the inflammatory response.
CONCLUSION Our data confirm that the elevations in hepatic VAP-1 expression reported in nonalcoholic steatohepatitis can contribute to steatosis, metabolic disturbance and inflammation. This suggests that targeting the semicarbazide sensitive amine oxidase capacity of VAP-1 may represent a useful adjunct to other therapeutic strategies in NAFLD.
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Affiliation(s)
- Emma L Shepherd
- Centre for Liver and Gastroenterology Research, Birmingham National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, West Midlands, United Kingdom
| | - Sumera Karim
- Centre for Liver and Gastroenterology Research, Birmingham National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, West Midlands, United Kingdom
| | - Philip N Newsome
- Centre for Liver and Gastroenterology Research, Birmingham National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, West Midlands, United Kingdom
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2TT, West Midlands, United Kingdom
| | - Patricia F Lalor
- Centre for Liver and Gastroenterology Research, Birmingham National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, West Midlands, United Kingdom
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13
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Chang SJ, Tu HP, Lai YCC, Luo CW, Nejo T, Tanaka S, Chai CY, Kwan AL. Increased Vascular Adhesion Protein 1 (VAP-1) Levels are Associated with Alternative M2 Macrophage Activation and Poor Prognosis for Human Gliomas. Diagnostics (Basel) 2020; 10:diagnostics10050256. [PMID: 32349342 PMCID: PMC7278017 DOI: 10.3390/diagnostics10050256] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 04/23/2020] [Accepted: 04/26/2020] [Indexed: 12/19/2022] Open
Abstract
Glioma is characterized by a high heterogeneity in the brain tumor. Abundant tumor-associated macrophages (TAMs) exist as neoplastic tissues, implicating tumor plasticity and thus leading to therapeutic challenges. Vascular adhesion protein (VAP-1) potentially serves as a mediator for TAM immunity in tumor milieu. We previously demonstrated that VAP-1 could contribute to tumor malignancy, but its characteristics in TAM immunity of glioma progression are still unclear. This study explored the association of VAP-1 expression with TAM distribution as well as the resulting clinical significance and prognostic value in human gliomas. An in-depth analysis of AOC3 (VAP-1) gene expression was performed using 695 glioma samples derived from the cancer genome atlas (TCGA)-lower grade glioma and glioblastoma (GBMLGG) cohort. Bioinformatic analysis confirmed that VAP-1 expression is associated with poor prognosis of glioma patients (p = 0.0283). VAP-1 and TAM biomarkers (CD68, iNOS, and CD163) were evaluated by immunohistochemistry in 108 gliomas from Kaohsiung Medical University Hospital. VAP-1+ was expressed in 56 (51.85%) cases and this phenotype revealed a significant association with overall survival in Kaplan–Meier analysis (p < 0.0001). Immunohistochemical double staining showed that VAP-1 immunoreactivity was present around CD163+ M2 infiltration location, including aggressive lesions and neighboring neovasculature. We demonstrated that high VAP-1 expression levels positively correlated with CD163+ M2 activation and coexpression of these two proteins was associated with worse survival in gliomas (p < 0.0001). Multivariate analysis indicated that VAP-1 alone and co-expressed with CD163 were the significantly independent indicators (both p < 0.0001). Furthermore, VAP-1/CD163 coexpression exhibited excellent diagnostic accuracy in gliomas (AUC = 0.8008). In conclusion, VAP-1 and TAM CD163 M2 coexpression was found in glioma tissues belonging to a highly malignant subgroup that was associated with poor prognosis. These results implied VAP-1 abundance is closely linked to alternative M2 activation during glioma progression. From the aforementioned data, a reasonable inference is that VAP-1 combined with targeting M2 immunity might be an effective therapeutic target for human gliomas.
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Affiliation(s)
- Shu-Jyuan Chang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Hung-Pin Tu
- Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Yen-Chang Clark Lai
- Department of Pathology, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 80756, Taiwan;
| | - Chi-Wen Luo
- Division of Breast Surgery, Department of Surgery, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 80756, Taiwan;
- Department of Surgery, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 80756, Taiwan
| | - Takahide Nejo
- Department of Neurosurgery, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; (T.N.); (S.T.)
| | - Shota Tanaka
- Department of Neurosurgery, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; (T.N.); (S.T.)
| | - Chee-Yin Chai
- Department of Pathology, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 80756, Taiwan;
- Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
- Correspondence: (C.-Y.C.); (A.-L.K.); Tel.: +88-6-7312-1101 (ext. 7081) (C.-Y.C.); +88-6-7312-1101 (ext. 5880) (A.-L.K.); Fax: +88-6-7313-6681 (C.-Y.C.); +88-6-7321-5039 (A.-L.K.)
| | - Aij-Lie Kwan
- Department of Neurosurgery, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 80756, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Correspondence: (C.-Y.C.); (A.-L.K.); Tel.: +88-6-7312-1101 (ext. 7081) (C.-Y.C.); +88-6-7312-1101 (ext. 5880) (A.-L.K.); Fax: +88-6-7313-6681 (C.-Y.C.); +88-6-7321-5039 (A.-L.K.)
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14
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Sasaki F, Yokomizo T. The leukotriene receptors as therapeutic targets of inflammatory diseases. Int Immunol 2020; 31:607-615. [PMID: 31135881 DOI: 10.1093/intimm/dxz044] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 05/27/2019] [Indexed: 12/11/2022] Open
Abstract
Leukotrienes (LTs) are inflammatory mediators derived from arachidonic acid. LTs include the di-hydroxy acid LT (LTB4) and the cysteinyl LTs (CysLTs; LTC4, LTD4 and LTE4), all of which are involved in both acute and chronic inflammation. We and other groups identified a high-affinity LTB4 receptor, BLT1; the LTC4 and LTD4 receptors, CysLT1 and CysLT2; and the LTE4 receptor, GPR99. Pharmacological studies have shown that BLT1 signaling stimulates degranulation, chemotaxis and phagocytosis of neutrophils, whereas CysLT1 and CysLT2 signaling induces airway inflammation by increasing vascular permeability and the contraction of bronchial smooth muscle. Recently, we and other groups suggested that the LTB4-BLT1 axis and the cysteinyl LTs-CysLT1/2 axis are involved in chronic inflammatory diseases including asthma, atopic dermatitis, psoriasis, atherosclerosis, arthritis, obesity, cancer and age-related macular degeneration using animal models for disease and gene knockout mice. This review describes the classical and novel functions of LTs and their receptors in several inflammatory diseases and discusses the potential clinical applications of antagonists for LT receptors and inhibitors of LT biosynthesis.
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Affiliation(s)
- Fumiyuki Sasaki
- Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan
| | - Takehiko Yokomizo
- Department of Biochemistry, Juntendo University Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan
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15
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Involvement of lncRNAs and Macrophages: Potential Regulatory Link to Angiogenesis. J Immunol Res 2020; 2020:1704631. [PMID: 32190702 PMCID: PMC7066414 DOI: 10.1155/2020/1704631] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 01/29/2020] [Accepted: 02/04/2020] [Indexed: 12/12/2022] Open
Abstract
Macrophages are involved in angiogenesis, an essential process for organ growth and tissue repair, and could contribute to the pathogenesis of angiogenesis-related diseases such as malignant tumors and diabetic retinopathy. Recently, long noncoding RNAs (lncRNAs) have been proved to be important in cell differentiation, organismal development, and various diseases of pathological angiogenesis. Moreover, it has been indicated that numerous lncRNAs exhibit different functions in macrophage infiltration and polarization and regulate the secretion of inflammatory cytokines released by macrophages. Therefore, the focus of macrophage-related lncRNAs could be considered to be a potential method in therapeutic targeting angiogenesis-related diseases. This review mainly summarizes the roles played by lncRNAs which associated with macrophages in angiogenesis. The possible mechanisms of the regulatory link between lncRNAs and macrophages in various angiogenesis-related diseases were also discussed.
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16
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Brezovakova V, Jadhav S. Identification of Lyve-1 positive macrophages as resident cells in meninges of rats. J Comp Neurol 2020; 528:2021-2032. [PMID: 32003471 DOI: 10.1002/cne.24870] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/22/2020] [Accepted: 01/24/2020] [Indexed: 01/13/2023]
Abstract
Meningeal immunity along with its associated lymphatic vasculatures is widely discussed recently. Lymphatic vessels in meninges drain interstitial fluid into the deep-cervical lymph nodes. The vessels are composed of cells that express the cardinal marker for lymphatic endothelium-the lymphatic vessel hyaluronan receptor-1 (Lyve-1). However, studies also show the presence of nonendothelial Lyve-1 expressing cells in certain tissues. Therefore, we were curious if nonendothelial Lyve-1+ cells are also present in dura mater of meninges. We show that Lyve-1+ endothelial cells are distributed adjacent to the blood vessels in the brain dura mater of rats. We did not observe any lymphatic vessels in spinal dura mater. Interestingly, we also observed isolated population of nonlymphatic Lyve-1+ cells in both brain and spinal dura mater. Morphologically, the Lyve-1+ cells were extensively pleomorphic, sometimes elongated or round. Surprisingly, the thoracolumbal meningeal Lyve-1+ cells were predominantly round in morphology. Using endothelial specific marker VEGFR3 and macrophage markers CD68 and CD169, we observed that the isolated Lyve-1+ cells lacked endothelial cell signature, but were either CD68+ or CD169+ macrophages. Moreover, we observed that the Lyve-1+ cells colocalized with collagen fibers in the meninges, and some of Lyve-1+ cells had intracellular collagen. The study for the first time demonstrates the presence of Lyve-1 positive macrophages in the lymphatic and nonlymphatic regions in the meninges of rats.
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Affiliation(s)
- Veronika Brezovakova
- Slovak Academy of Sciences, Centre of Excellence for Alzheimer's Disease and Related Disorders, Institute of Neuroimmunology, Bratislava, Slovakia
| | - Santosh Jadhav
- Slovak Academy of Sciences, Centre of Excellence for Alzheimer's Disease and Related Disorders, Institute of Neuroimmunology, Bratislava, Slovakia
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17
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Abstract
Significance: Vascular adhesion protein-1 (VAP-1) is an ectoenzyme that oxidates primary amines in a reaction producing also hydrogen peroxide. VAP-1 on the blood vessel endothelium regulates leukocyte extravasation from the blood into tissues under physiological and pathological conditions. Recent Advances: Inhibition of VAP-1 by neutralizing antibodies and by several novel small-molecule enzyme inhibitors interferes with leukocyte trafficking and alleviates inflammation in many experimental models. Targeting of VAP-1 also shows beneficial effects in several other diseases, such as ischemia/reperfusion, fibrosis, and cancer. Moreover, soluble VAP-1 levels may serve as a new prognostic biomarker in selected diseases. Critical Issues: Understanding the contribution of the enzyme activity-independent and enzyme activity-dependent functions, which often appear to be mediated by the hydrogen peroxide production, in the VAP-1 biology will be crucial. Similarly, there is a pressing need to understand which of the VAP-1 functions are regulated through the modulation of leukocyte trafficking, and what is the role of VAP-1 synthesized in adipose and smooth muscle cells. Future Directions: The specificity and selectivity of new VAP-1 inhibitors, and their value in animal models under therapeutic settings need to be addressed. Results from several programs studying the therapeutic potential of VAP-1 inhibition, which now are in clinical trials, will reveal the relevance of this amine oxidase in humans.
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Affiliation(s)
- Marko Salmi
- 1 MediCity , Turku, Finland .,2 Institute of Biomedicine, University of Turku, Turku, Finland
| | - Sirpa Jalkanen
- 1 MediCity , Turku, Finland .,2 Institute of Biomedicine, University of Turku, Turku, Finland
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18
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Sasaki F, Koga T, Ohba M, Saeki K, Okuno T, Ishikawa K, Nakama T, Nakao S, Yoshida S, Ishibashi T, Ahmadieh H, Kanavi MR, Hafezi-Moghadam A, Penninger JM, Sonoda KH, Yokomizo T. Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models. JCI Insight 2018; 3:96902. [PMID: 30232269 DOI: 10.1172/jci.insight.96902] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 08/07/2018] [Indexed: 12/18/2022] Open
Abstract
Age-related macular degeneration (AMD), a progressive chronic disease of the central retina, is associated with aging and is a leading cause of blindness worldwide. Here, we demonstrate that leukotriene B4 (LTB4) receptor 1 (BLT1) promotes laser-induced choroidal neovascularization (CNV) in a mouse model for wet-type AMD. CNV was significantly less in BLT1-deficient (BLT1-KO) mice compared with BLT1-WT controls. Expression of several proangiogenic and profibrotic factors was lower in BLT1-KO eyes than in BLT1-WT eyes. LTB4 production in the eyes was substantially increased in the early phase after laser injury. BLT1 was highly expressed in M2 macrophages in vitro and in vivo, and ocular BLT1+ M2 macrophages were increased in the aged eyes after laser injury. Furthermore, M2 macrophages were rapidly attracted by LTB4 and subsequently produced VEGF-A- through BLT1-mediated signaling. Consequently, intravitreal injection of M2 macrophages augmented CNV formation, which was attenuated by BLT1 deficiency. Thus, laser-induced injury to the retina triggered LTB4 production and attracted M2 macrophages via BLT1, leading to development of CNV. A selective BLT1 antagonist (CP105696) and 3 LTB4 inhibitors (zileuton, MK-886, and bestatin) reduced CNV in a dose-dependent manner. CP105696 also inhibited the accumulation of BLT1+ M2 macrophages in the laser-injured eyes of aged mice. Together, these results indicate that the LTB4-BLT1 axis is a potentially novel therapeutic target for CNV of wet-type AMD.
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Affiliation(s)
- Fumiyuki Sasaki
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan
| | - Tomoaki Koga
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan
| | - Mai Ohba
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan
| | - Kazuko Saeki
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan
| | - Toshiaki Okuno
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan
| | - Keijiro Ishikawa
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takahito Nakama
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shintaro Nakao
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shigeo Yoshida
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tatsuro Ishibashi
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hamid Ahmadieh
- Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mozhgan Rezaei Kanavi
- Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Hafezi-Moghadam
- Molecular Biomarkers Nano-Imaging Laboratory, Brigham & Women's Hospital, and Department of Radiology, Harvard Medical School, Boston, Massachusetts, USA
| | - Josef M Penninger
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria
| | - Koh-Hei Sonoda
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takehiko Yokomizo
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan
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19
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Mukai S, Ogawa Y, Kawakami Y, Mashima Y, Tsubota K. Inhibition of Vascular Adhesion Protein‐1 for Treatment of Graft‐Versus‐Host Disease in Mice. FASEB J 2018; 32:4085-4095. [DOI: 10.1096/fj.201700176r] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Shin Mukai
- Department of OphthalmologyKeio University School of MedicineTokyoJapan
- Division of Cellular SignalingInstitute for Advanced Medical ResearchKeio University School of MedicineTokyoJapan
| | - Yoko Ogawa
- Department of OphthalmologyKeio University School of MedicineTokyoJapan
| | - Yutaka Kawakami
- Division of Cellular SignalingInstitute for Advanced Medical ResearchKeio University School of MedicineTokyoJapan
| | - Yukihiko Mashima
- Department of OphthalmologyKeio University School of MedicineTokyoJapan
- Sucampo Pharmaceuticals, IncorporatedTokyoJapan
| | - Kazuo Tsubota
- Department of OphthalmologyKeio University School of MedicineTokyoJapan
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20
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Zhou YD, Yoshida S, Peng YQ, Kobayashi Y, Zhang LS, Tang LS. Diverse roles of macrophages in intraocular neovascular diseases: a review. Int J Ophthalmol 2017; 10:1902-1908. [PMID: 29259911 PMCID: PMC5733520 DOI: 10.18240/ijo.2017.12.18] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Accepted: 11/06/2017] [Indexed: 12/21/2022] Open
Abstract
Macrophages are involved in angiogenesis, and might also contribute to the pathogenesis of intraocular neovascular diseases. Recent studies indicated that macrophages exert different functions in the process of intraocular neovascularization, and the polarization of M1 and M2 phenotypes plays extremely essential roles in the diverse functions of macrophages. Moreover, a large number of cytokines released by macrophages not only participate in macrophage polarization, but also associate with retinal and choroidal neovascular diseases. Therefore, macrophage might be considered as a novel therapeutic target to the treatment of pathological neovascularization in the eye. This review mainly summarizes diverse roles of macrophages and discusses the possible mechanisms in retinal and choroidal neovascularization.
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Affiliation(s)
- Ye-Di Zhou
- Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha 410011, Hunan Province, China
| | - Shigeo Yoshida
- Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan
| | - Ying-Qian Peng
- Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha 410011, Hunan Province, China
| | - Yoshiyuki Kobayashi
- Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan
| | - Lu-Si Zhang
- Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha 410011, Hunan Province, China
| | - Luo-Sheng Tang
- Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
- Hunan Clinical Research Center of Ophthalmic Disease, Changsha 410011, Hunan Province, China
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Nakao S, Zandi S, Sun D, Hafezi-Moghadam A. Cathepsin B-mediated CD18 shedding regulates leukocyte recruitment from angiogenic vessels. FASEB J 2017; 32:143-154. [PMID: 28904019 DOI: 10.1096/fj.201601229r] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 08/21/2017] [Indexed: 01/19/2023]
Abstract
Cathepsin B (CtsB) contributes to atherosclerosis and cancer progression by processing the extracellular matrix and promoting angiogenesis. Although CtsB was reported to promote and reduce angiogenesis, there is no mechanistic explanation that reconciles this apparent discrepancy. CtsB cleaves CD18 from the surface of immune cells, but its contribution to angiogenesis has not been studied. We developed an in vivo technique for visualization of immune cell transmigration from corneal vessels toward implanted cytokines. Wild-type (WT) leukocytes extravasated from limbal vessels, angiogenic stalks, and growing tip vessels and migrated toward the cytokines, indicating immune competence of angiogenic vessels. Compared to WT leukocytes, CtsB-/- leukocytes accumulated in a higher number in angiogenic vessels, but extravasated less toward the implanted cytokine. The accumulated CtsB-/- leukocytes in angiogenic vessels expressed more CD18. CD18-/- leukocytes extravasated later than WT leukocytes. However, once extravasated, CD18-/- leukocytes transmigrated more rapidly than their WT counterparts. These results suggest that, although CD18 facilitates efficient extravasation, outside of the vessel CD18 interaction with the extracellular matrix, it reduced transmigration velocity. Our results reveal an unexpected role for CtsB in leukocyte extravasation and transmigration, which advances our understanding of the complex contribution of CtsB to angiogenesis.-Nakao, S., Zandi, S., Sun, D., Hafezi-Moghadam, A. Cathepsin B-mediated CD18 shedding regulates leukocyte recruitment from angiogenic vessels.
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Affiliation(s)
- Shintaro Nakao
- Molecular Biomarkers Nano-Imaging Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and.,Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Souska Zandi
- Molecular Biomarkers Nano-Imaging Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and
| | - Dawei Sun
- Molecular Biomarkers Nano-Imaging Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and
| | - Ali Hafezi-Moghadam
- Molecular Biomarkers Nano-Imaging Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and
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Weichand B, Popp R, Dziumbla S, Mora J, Strack E, Elwakeel E, Frank AC, Scholich K, Pierre S, Syed SN, Olesch C, Ringleb J, Ören B, Döring C, Savai R, Jung M, von Knethen A, Levkau B, Fleming I, Weigert A, Brüne B. S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β. J Exp Med 2017; 214:2695-2713. [PMID: 28739604 PMCID: PMC5584110 DOI: 10.1084/jem.20160392] [Citation(s) in RCA: 214] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 06/12/2017] [Accepted: 07/05/2017] [Indexed: 12/21/2022] Open
Abstract
Metastasis is the primary cause of cancer death. Weichand et al. describe a new mechanism explaining how tumor-associated macrophages contribute to metastatic spread, which involves promoting tumor lymphangiogenesis via S1P receptor 1 and the NLRP3 inflammasome. Metastasis is the primary cause of cancer death. The inflammatory tumor microenvironment contributes to metastasis, for instance, by recruiting blood and lymph vessels. Among tumor-infiltrating immune cells, tumor-associated macrophages (TAMs) take a center stage in promoting both tumor angiogenesis and metastatic spread. We found that genetic deletion of the S1P receptor 1 (S1pr1) alone in CD11bhi CD206+ TAMs infiltrating mouse breast tumors prevents pulmonary metastasis and tumor lymphangiogenesis. Reduced lymphangiogenesis was also observed in the nonrelated methylcholanthrene-induced fibrosarcoma model. Transcriptome analysis of isolated TAMs from both entities revealed reduced expression of the inflammasome component Nlrp3 in S1PR1-deficient TAMs. Macrophage-dependent lymphangiogenesis in vitro was triggered upon inflammasome activation and required both S1PR1 signaling and IL-1β production. Finally, NLRP3 expression in tumor-infiltrating macrophages correlated with survival, lymph node invasion, and metastasis of mammary carcinoma patients. Conceptually, our study indicates an unappreciated role of the NLRP3 inflammasome in promoting metastasis via the lymphatics downstream of S1PR1 signaling in macrophages.
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Affiliation(s)
- Benjamin Weichand
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Rüdiger Popp
- Institute of Vascular Signaling, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Sarah Dziumbla
- Institute of Vascular Signaling, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Javier Mora
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Elisabeth Strack
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Eiman Elwakeel
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Ann-Christin Frank
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Klaus Scholich
- Institute of Clinical Pharmacology/Center for Drug Research, Development and Safety (ZAFES), Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Sandra Pierre
- Institute of Clinical Pharmacology/Center for Drug Research, Development and Safety (ZAFES), Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Shahzad N Syed
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Catherine Olesch
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Julia Ringleb
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Bilge Ören
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Claudia Döring
- Dr. Senckenberg Institute for Pathology, Goethe-University Frankfurt, Frankfurt, Germany
| | - Rajkumar Savai
- Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodeling, German Center for Lung Research (DZL), Bad Nauheim, Germany
| | - Michaela Jung
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Andreas von Knethen
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Bodo Levkau
- Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ingrid Fleming
- Institute of Vascular Signaling, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Andreas Weigert
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Bernhard Brüne
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
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23
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Taher M, Nakao S, Zandi S, Melhorn MI, Hayes KC, Hafezi-Moghadam A. Phenotypic transformation of intimal and adventitial lymphatics in atherosclerosis: a regulatory role for soluble VEGF receptor 2. FASEB J 2016; 30:2490-9. [PMID: 27006449 DOI: 10.1096/fj.201500112] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 03/03/2016] [Indexed: 01/23/2023]
Abstract
The role of lymphatics in atherosclerosis is not yet understood. Here, we investigate lymphatic growth dynamics and marker expression in atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. The prolymphangiogenic growth factor, VEGF-C, was elevated in atherosclerotic aortic walls. Despite increased VEGF-C, we found that adventitial lymphatics regress during the course of formation of atherosclerosis (P < 0.01). Similar to lymphatic regression, the number of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1(+)) macrophages decreased in the aortic adventitia of apoE(-/-) mice with atherosclerosis (P < 0.01). Intimal lymphatics in the atherosclerotic lesions exhibited an atypical phenotype, with the expression of podoplanin and VEGF receptor 3 (VEGFR-3) but not of LYVE-1 and prospero homeobox protein 1. In the aortas of atherosclerotic animals, we found markedly increased soluble VEGFR-2. We hypothesized that the elevated soluble VEGFR-2 that was found in the aortas of apoE(-/-) mice with atherosclerosis binds to and diminishes the activity of VEGF-C. This trapping mechanism explains, despite increased VEGF-C in the atherosclerotic aortas, how adventitial lymphatics regress. Lymphatic regression impedes the drainage of lipids, growth factors, inflammatory cytokines, and immune cells. Insufficient lymphatic drainage could thus exacerbate atherosclerosis formation. Our study contributes new insights to previously unknown dynamic changes of adventitial lymphatics. Targeting soluble VEGFR-2 in atherosclerosis may provide a new strategy for the liberation of endogenous VEGF-C and the prevention of lymphatic regression.-Taher, M., Nakao, S., Zandi, S., Melhorn, M. I., Hayes, K. C., Hafezi-Moghadam, A. Phenotypic transformation of intimal and adventitial lymphatics in atherosclerosis: a regulatory role for soluble VEGF receptor 2.
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Affiliation(s)
- Mahdi Taher
- Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Radiology and Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA; Institute of Biochemistry, Charité University Medical Center, Berlin, Germany; and
| | - Shintaro Nakao
- Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Radiology and Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Souska Zandi
- Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Radiology and Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Mark I Melhorn
- Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Radiology and Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - K C Hayes
- Department of Biology, Brandeis University, Waltham, Massachusetts, USA
| | - Ali Hafezi-Moghadam
- Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Radiology and Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA;
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Nakao S, Hafezi-Moghadam A. The Corneal Micropocket Assay: A Model of Angiogenesis and Lymphangiogenesis. Methods Mol Biol 2016; 1430:311-316. [PMID: 27172963 DOI: 10.1007/978-1-4939-3628-1_21] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
The cornea is a transparent tissue that lacks blood and lymphatic vessels. In addition, the cornea is readily accessible, which makes it convenient for direct visualization of angiogenesis and lymphangiogenesis. The corneal micropocket assay is a commonly used quantitative technique, in which a growth factor containing pellet is micro-surgically implanted into the cornea of a rodent. Subsequently, the growth of the preexisting limbal vessels toward the growth factor is visualized by live microscopy or immunohistochemistry. Recently, there has been significant interest in the process of lymphangiogenesis and the factors that regulate it. To facilitate these studies, we introduce a novel technique for visualization of the immune response during growth factor induced angiogenesis and lymphangiogenesis in the cornea.
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Affiliation(s)
- Shintaro Nakao
- Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA
- Department of Radiology, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Ali Hafezi-Moghadam
- Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.
- Department of Radiology, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
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25
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Pannecoeck R, Serruys D, Benmeridja L, Delanghe JR, van Geel N, Speeckaert R, Speeckaert MM. Vascular adhesion protein-1: Role in human pathology and application as a biomarker. Crit Rev Clin Lab Sci 2015; 52:284-300. [PMID: 26287391 DOI: 10.3109/10408363.2015.1050714] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Vascular adhesion protein-1 (VAP-1) is a member of the copper-containing amine oxidase/semicarbazide-sensitive amine oxidase (AOC/SSAO) enzyme family. SSAO enzymes catalyze oxidative deamination of primary amines, which results in the production of the corresponding aldehyde, hydrogen peroxide and ammonium. VAP-1 is continuously expressed as a transmembrane glycoprotein in the vascular wall during development and facilitates the accumulation of inflammatory cells into the inflamed environment in concert with other leukocyte adhesion molecules. The soluble form of VAP-1 is released into the circulation mainly from vascular endothelial cells. Over- and under-expression of sVAP-1 result in alterations of the reported reaction product levels, which are involved in the pathogenesis of multiple human diseases. The combination of enzymatic and adhesion capacities as well as its strong association with inflammatory pathologies makes VAP-1 an interesting therapeutic target for drug discovery. In this article, we will review the general characteristics and biological functions of VAP-1, focusing on its important role as a prognostic biomarker in human pathologies. In addition, the potential therapeutic application of VAP-1 inhibitors will be discussed.
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Affiliation(s)
| | | | | | | | - Nanja van Geel
- c Department of Dermatology , Ghent University Hospital , Gent , Belgium
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26
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Park PJ, Chang M, Garg N, Zhu J, Chang JH, Shukla D. Corneal lymphangiogenesis in herpetic stromal keratitis. Surv Ophthalmol 2014; 60:60-71. [PMID: 25444520 DOI: 10.1016/j.survophthal.2014.06.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 05/23/2014] [Accepted: 06/04/2014] [Indexed: 12/26/2022]
Abstract
Corneal lymphangiogenesis is the extension of lymphatic vessels into the normally alymphatic cornea, a process that compromises the cornea's immune-privileged state and facilitates herpetic stromal keratitis (HSK). HSK results most commonly from infection by herpes simplex virus-1 (HSV-1) and is characterized by immune- and inflammation-mediated damage to the deep layers of the cornea. Current research demonstrates the potential of anti-lymphangiogenic therapy to decrease and prevent herpes-induced lymphangiogenesis.
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Affiliation(s)
- Paul J Park
- Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Michael Chang
- Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Nitin Garg
- Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Jimmy Zhu
- Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA; Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Jin-Hong Chang
- Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA; Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Deepak Shukla
- Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA; Department Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
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27
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Bu P, Vin AP, Sethupathi P, Ambrecht LA, Zhai Y, Nikolic N, Qiao L, Bouchard CS. Effects of activated omental cells on rat limbal corneal alkali injury. Exp Eye Res 2014; 121:143-6. [PMID: 24582890 DOI: 10.1016/j.exer.2014.02.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 01/27/2014] [Accepted: 02/15/2014] [Indexed: 11/28/2022]
Abstract
Omental cells (OCs) are shown to help wound healing. The purpose of this study is to investigate if OCs improve cornea repair after alkali injury by subconjunctival injection of activated OCs in rats. Forty eight hours after limbal corneal alkali injury, fresh isolated OCs were injected subconjunctivally into the recipient rat's eye. Prior to the injury and at 0, 4 and 8 days after injury, the eyes were examined using slit lamp biomicroscopy. Corneal opacification and corneal neovascularization were graded in a masked fashion. The inflammatory response to the injury was evaluated by counting neutrophil cell numbers in the cornea under microscope. There was no significant difference in corneal opacification between the control and OCs treatment groups; however, the corneal neovascularization was significantly less in the eyes treated with OCs as compared to the controls. Also OCs treatment markedly decreased neutrophil infiltration after corneal-limbal alkali injury. Our results suggest that OCs may have a beneficial role in corneal healing after limbal corneal alkali injury by suppressing inflammatory cell infiltrates and corneal neovascularization.
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Affiliation(s)
- Ping Bu
- Department of Ophthalmology, Loyola University Chicago, Maywood, IL, USA.
| | - Anita P Vin
- Department of Ophthalmology, Loyola University Chicago, Maywood, IL, USA
| | - Periannan Sethupathi
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL, USA
| | - Lindsay A Ambrecht
- Department of Ophthalmology, Loyola University Chicago, Maywood, IL, USA
| | - Yougang Zhai
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL, USA
| | - Nicole Nikolic
- Department of Ophthalmology, Loyola University Chicago, Maywood, IL, USA
| | - Liang Qiao
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL, USA
| | - Charles S Bouchard
- Department of Ophthalmology, Loyola University Chicago, Maywood, IL, USA
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28
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Ji RC. Hypoxia and lymphangiogenesis in tumor microenvironment and metastasis. Cancer Lett 2013; 346:6-16. [PMID: 24333723 DOI: 10.1016/j.canlet.2013.12.001] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 11/28/2013] [Accepted: 12/04/2013] [Indexed: 12/29/2022]
Abstract
Hypoxia and lymphangiogenesis are closely related processes that play a pivotal role in tumor invasion and metastasis. Intratumoral hypoxia is exacerbated as a result of oxygen consumption by rapidly proliferating tumor cells, insufficient blood supply and poor lymph drainage. Hypoxia induces functional responses in lymphatic endothelial cells (LECs), including cell proliferation and migration. Multiple factors (e.g., ET-1, AP-1, C/EBP-δ, EGR-1, NF-κB, and MIF) are involved in the events of hypoxia-induced lymphangiogenesis. Among them, HIF-1α is known to be the master regulator of cellular oxygen homeostasis, mediating transcriptional activation of lymphangiogenesis via regulation of signaling cascades like VEGF-A/-C/-D, TGF-β and Prox-1 in experimental and human tumors. Although the underlying molecular mechanisms remain incompletely elucidated, the investigation of lymphangiogenesis in hypoxic conditions may provide insight into potential therapeutic targets for lymphatic metastasis.
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Affiliation(s)
- Rui-Cheng Ji
- Department of Human Anatomy, Oita University Faculty of Medicine, Oita, Japan.
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29
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Yoshikawa N, Noda K, Ozawa Y, Mashima Y, Ishida S. Blockade for vascular adhesion protein-1 suppresses pathological neovascularization in oxygen-induced retinopathy. Acta Ophthalmol 2013; 91:e409-10. [PMID: 23844859 DOI: 10.1111/aos.12128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Vascular adhesion protein 1 in the eye. J Ophthalmol 2013; 2013:925267. [PMID: 23840939 PMCID: PMC3687510 DOI: 10.1155/2013/925267] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Revised: 04/17/2013] [Accepted: 05/14/2013] [Indexed: 11/29/2022] Open
Abstract
Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1), a dual-function molecule with adhesive and enzymatic properties, is expressed on the surface of vascular endothelial cells of mammals. It also exists as a soluble form (sVAP-1), which is implicated in oxidative stress via its enzymatic activity and can be a prognostic biomarker. Recent evidence suggests that VAP-1 is an important therapeutic target for several inflammation-related ocular diseases, such as uveitis, age-related macular degeneration (AMD), and diabetic retinopathy (DR), by involving in the recruitment of leukocytes at sites of inflammation. Furthermore, VAP-1 plays an important role in the pathogenesis of conjunctival inflammatory diseases such as pyogenic granulomas and the progression of conjunctival lymphoma. VAP-1 may be an alternative therapeutic target in ocular diseases. The in vivo imaging of inflammation using VAP-1 as a target molecule is a novel approach with a potential for early detection and characterization of inflammatory diseases. This paper reviews the critical roles of VAP-1 in ophthalmological diseases which may provide a novel research direction or a potent therapeutic strategy.
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31
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Nakao S, Zandi S, Kohno RI, Sun D, Nakama T, Ishikawa K, Yoshida S, Enaida H, Ishibashi T, Hafezi-Moghadam A. Lack of lymphatics and lymph node-mediated immunity in choroidal neovascularization. Invest Ophthalmol Vis Sci 2013; 54:3830-6. [PMID: 23580489 DOI: 10.1167/iovs.12-10341] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Inflammation and immune cells regulate choroidal neovascularization (CNV) and could become therapeutic targets in age-related macular degeneration (AMD). Lymphangiogenesis is a key component of various inflammatory diseases. Whether lymphangiogenesis and lymph node-mediated immunity are involved in the pathogenesis of AMD is not understood. METHODS To investigate lymphangiogenesis in CNV, we generated CNV in animals by laser and studied surgically removed CNV membranes from uveitis and AMD patients. Immunohistochemistry was performed with lymphatic vessel endothelial hyaluronate receptor 1 (LYVE-1) and podoplanin antibodies. VEGF-C and VEGFR-3 expressions were examined with immunohistochemistry and Western blotting. To examine the role of lymph node in CNV, we lasered lymphotoxin alpha-deficient mice (LTα-/-) and measured the CNV volume. RESULTS Immunohistochemistry showed that LYVE-1(+) macrophages infiltrated in acutely induced CNV, although lymphatic tubes did not form. CNV membranes from patients did not show LYVE-1(+)podoplanin(+) vessels, suggesting the lack of lymphangiogenesis in AMD and uveitis. Western blots and immunostaining revealed VEGF-C and VEGFR-3 expression in CNV lesions, mainly in macrophages and angiogenic endothelial cells. Using fluorescent microsphere tracers, we show a path for cellular migration from the eye to the cervical lymph nodes (LNs) during CNV. However, CNV injury did not cause LN swelling. CNV volume did not differ between wild-type and LN-deficient mice, suggesting that LN is not a key component of early CNV formation. CONCLUSIONS Laser-induced CNV is not primarily dependent on acquired immunity, nor does the fundus injury affect peripheral LNs. Our results reveal a previously unknown cellular connection between the ocular fundus and the cervical LNs. This connection that in function resembles lymphatics is actively utilized in CNV.
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Affiliation(s)
- Shintaro Nakao
- Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, Boston, MA 02115, USA
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Li R, Li H, Luo HJ, Lin ZX, Jiang ZW, Luo WH. SSAO inhibitors suppress hepatocellular tumor growth in mice. Cell Immunol 2013; 283:61-9. [PMID: 23850964 DOI: 10.1016/j.cellimm.2013.06.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Revised: 05/16/2013] [Accepted: 06/13/2013] [Indexed: 02/05/2023]
Abstract
Vascular adhesion protein-1 (VAP-1) is both an endothelial adhesion molecule involved in leukocytes emigration, and an oxidase belonging to the family of semicarbazide-sensitive amine oxidases (SSAOs). The enzyme activity of VAP-1 plays an important role in the migration of myeloid-derived suppressor cells (MDSCs) into tumor site, and SSAO inhibitors can block the function of VAP-1. The effects of SSAO inhibitors on leukocyte infiltration and tumor progression were evaluated in H22 hepatocellular carcinoma-bearing C57BL/6 mice. Tumor weight and volume were measured after SSAO inhibitor treatment. Then, MDSCs recruitment and neo-angiogenesis were determined using immunostaining. SSAO inhibitors significantly blocked the catalytic activity of VAP-1 in tumor, attenuated tumor progression, and reduced neo-angiogenesis. CD11b(+) and Gr-1(+) MDSCs, which normally infiltrate into tumors, were significantly diminished in tumor-bearing mice treated with SSAO inhibitors. The present study demonstrated that SSAO inhibitors might have an anti-tumor effect on hepatocellular carcinoma by inhibiting recruitment of CD11b(+) and Gr-1(+) cells and hindering angiogenesis, which could be attributed to impairing the catalytic activity of VAP-1.
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Affiliation(s)
- Rui Li
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China
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Ferjančič Š, Gil-Bernabé AM, Hill SA, Allen PD, Richardson P, Sparey T, Savory E, McGuffog J, Muschel RJ. VCAM-1 and VAP-1 recruit myeloid cells that promote pulmonary metastasis in mice. Blood 2013; 121:3289-97. [PMID: 23407548 DOI: 10.1182/blood-2012-08-449819] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Pulmonary metastasis is a frequent cause of poor outcome in cancer patients. The formation of pulmonary metastasis is greatly facilitated by recruitment of myeloid cells, which are crucial for tumor cell survival and extravasation. During inflammation, homing of myeloid cells is mediated by endothelial activation, raising the question of a potential role for endothelial activation in myeloid cell recruitment during pulmonary metastasis. Here, we show that metastatic tumor cell attachment causes the induction of the endothelial activation markers vascular cell adhesion molecule-1 (VCAM-1) and vascular adhesion protein-1 (VAP-1). Induction of VCAM-1 is dependent on tumor cell-clot formation, decreasing upon induction of tissue factor pathway inhibitor or treatment with hirudin. Furthermore, inhibition of endothelial activation with a VCAM-1 blocking antibody or a VAP-1 small molecule inhibitor leads to reduced myeloid cell recruitment and diminished tumor cell survival and metastasis without affecting tumor cell adhesion. Simultaneous inhibition of VCAM-1 and VAP-1 does not result in further reduction in myeloid cell recruitment and tumor cell survival, suggesting that both act through closely related mechanisms. These results establish VCAM-1 and VAP-1 as mediators of myeloid cell recruitment in metastasis and identify VAP-1 as a potential target for therapeutic intervention to combat early metastasis.
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Affiliation(s)
- Špela Ferjančič
- Department of Oncology, Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford OX3 7DQ, United Kingdom
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Baluk P, Hogmalm A, Bry M, Alitalo K, Bry K, McDonald DM. Transgenic overexpression of interleukin-1β induces persistent lymphangiogenesis but not angiogenesis in mouse airways. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 182:1434-47. [PMID: 23391392 DOI: 10.1016/j.ajpath.2012.12.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Revised: 12/21/2012] [Accepted: 12/31/2012] [Indexed: 01/03/2023]
Abstract
These studies used bi-transgenic Clara cell secretory protein (CCSP)/IL-1β mice that conditionally overexpress IL-1β in Clara cells to determine whether IL-1β can promote angiogenesis and lymphangiogenesis in airways. Doxycycline treatment induced rapid, abundant, and reversible IL-1β production, influx of neutrophils and macrophages, and conspicuous and persistent lymphangiogenesis, but surprisingly no angiogenesis. Gene profiling showed many up-regulated genes, including chemokines (Cxcl1, Ccl7), cytokines (tumor necrosis factor α, IL-1β, and lymphotoxin-β), and leukocyte genes (S100A9, Aif1/Iba1). Newly formed lymphatics persisted after IL-1β overexpression was stopped. Further studies examined how IL1R1 receptor activation by IL-1β induced lymphangiogenesis. Inactivation of vascular endothelial growth factor (VEGF)-C and VEGF-D by adeno-associated viral vector-mediated soluble VEGFR-3 (VEGF-C/D Trap) completely blocked lymphangiogenesis, showing its dependence on VEGFR-3 ligands. Consistent with this mechanism, VEGF-C immunoreactivity was present in some Aif1/Iba1-immunoreactive macrophages. Because neutrophils contribute to IL-1β-induced lung remodeling in newborn mice, we examined their potential role in lymphangiogenesis. Triple-transgenic CCSP/IL-1β/CXCR2(-/-) mice had the usual IL-1β-mediated lymphangiogenesis but no neutrophil recruitment, suggesting that neutrophils are not essential. IL1R1 immunoreactivity was found on some epithelial basal cells and neuroendocrine cells, suggesting that these cells are targets of IL-1β, but was not detected on lymphatics, blood vessels, or leukocytes. We conclude that lymphangiogenesis triggered by IL-1β overexpression in mouse airways is driven by VEGF-C/D from macrophages, but not neutrophils, recruited by chemokines from epithelial cells that express IL1R1.
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Affiliation(s)
- Peter Baluk
- Cardiovascular Research Institute, University of California, San Francisco, California 94143-0130, USA.
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Abstract
PURPOSE OF REVIEW The purpose of the present review is to describe new antilymphangiogenic treatment strategies and recent findings on strain-dependency of corneal lymphangiogenesis and the interdependency between blood and lymphatic vessel growth. RECENT FINDINGS Studies on mice have revealed that apart from haemangiogenesis, lymphangiogenesis can also differ markedly between several mouse strains under normal and inflammatory conditions. Although haemangiogenesis and lymphangiogenesis are closely interconnected in their spatial-temporal patterning, recent data suggest that they can also occur independently. SUMMARY Understanding the coordinated regulation of blood and lymphatic vessel growth and genetic factors determining lymphangiogenesis in more detail could improve the development of specifically targeted antihaemangiogenic or antilymphangiogenic strategies.
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Nakao S, Zandi S, Lara-Castillo N, Taher M, Ishibashi T, Hafezi-Moghadam A. Larger therapeutic window for steroid versus VEGF-A inhibitor in inflammatory angiogenesis: surprisingly similar impact on leukocyte infiltration. Invest Ophthalmol Vis Sci 2012; 53:3296-302. [PMID: 22427602 DOI: 10.1167/iovs.11-8114] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
PURPOSE The current treatments against inflammatory angiogenesis are steroids and anti-VEGF-A, such as dexamethasone and bevacizumab, respectively. However, the therapeutic windows for dexamethasone and bevacizumab against inflammatory angiogenesis are unknown. METHODS To investigate the therapeutic windows for dexamethasone and bevacizumab, we used the corneal pocket assay. IL-1β pellets were implanted in corneas of BALB/c mice that were then treated with dexamethasone or bevacizumab at different time points. Angiogenesis (area, number of vessels, and sprouting) was quantitated at various time points after implantation. Nuclear Factor-κB (NF-κB) signaling and leukocyte accumulation in inflammatory angiogenesis were examined by Western blotting, by immunohistochemistry, and in the authors' novel leukocyte transmigration assay. RESULTS Dexamethasone inhibited IL-1β-induced angiogenesis when treatment started 4 days after IL-1β implantation, while bevacizumab only inhibited angiogenesis by day 2 after implantation. Both bevacizumab and dexamethasone inhibited angiogenic sprouting. Interestingly, bevacizumab did not affect NF-κB activation, which is one of the main signaling targets for steroid action. The authors' new imaging approach revealed that bevacizumab and steroid treatment blocked leukocyte infiltration into implanted corneas. CONCLUSIONS VEGF-A inhibition affected angiogenic sprouting, while it was not effective against matured vessels. Both dexamethasone and bevacizumab inhibited leukocyte transmigration from angiogenic vessels; however, dexamethasone had a larger therapeutic window. These insights improve the treatment strategy in angiogenic disorders.
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Affiliation(s)
- Shintaro Nakao
- Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02115, USA
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Lymphatics and lymphangiogenesis in the eye. J Ophthalmol 2012; 2012:783163. [PMID: 22523652 PMCID: PMC3317234 DOI: 10.1155/2012/783163] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2011] [Revised: 11/20/2011] [Accepted: 11/21/2011] [Indexed: 12/22/2022] Open
Abstract
Lymphatic is a prerequisite for the maintenance of tissue fluid balance and immunity in the body. A body of evidence also shows that lymphangiogenesis plays important roles in the pathogenesis of diseases such as tumor metastasis and inflammation. The eye was thought to lack lymphatic vessels except for the conjunctiva; however, advances in the field, including the identification of lymphatic endothelial markers (e.g., LYVE-1 or podoplanin) and lymphangiogenic factors (e.g., VEGF-C), have revealed the exsitence and possible roles of lymphatics and lymphangiogenesis in the eye. Recent studies have shown that corneal limbus, ciliary body, lacrimal gland, orbital meninges, and extraocular muscles contain lymphatic vessels and that the choroid might have a lymphatic-like system. There is no known lymphatic outflow from the eye. However, several lymphatic channels including uveolymphatic pathway might serve the ocular fluid homeostasis. Furthermore, lymphangiogenesis plays important roles in pathological conditions in the eye including corneal transplant rejection and ocular tumor progression. Yet, the role of lymphangiogenesis in most eye diseases, especially inflammatory disease or edema, remains unknown. A better understanding of lymphatic and lymphangiogenesis in the eye will open new therapeutic opportunities to prevent vision loss in ocular diseases.
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Kuo PL, Huang MS, Cheng DE, Hung JY, Yang CJ, Chou SH. Lung cancer-derived galectin-1 enhances tumorigenic potentiation of tumor-associated dendritic cells by expressing heparin-binding EGF-like growth factor. J Biol Chem 2012; 287:9753-9764. [PMID: 22291012 DOI: 10.1074/jbc.m111.321190] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The interaction between cancer cells and their microenvironment is a vicious cycle that enhances the survival and progression of cancer, resulting in metastasis. This study is the first to indicate that lung cancer-derived galectin-1 secretion is responsible for stimulating tumor-associated dendritic cells (TADCs) production of mature heparin-binding EGF-like growth factor (HB-EGF), which, in turn, increases cancer progression. Treatment of galectin-1, present in large amounts in lung cancer conditioned medium and lung cancer patient sera, mimicked the inductive effect of lung cancer conditioned medium on the expression and ectodomain shedding of HB-EGF by TNFα-converting enzyme/a disintegrin and metalloproteinase 9 (ADAM9) and ADAM17. Significant up-regulation of HB-EGF has been seen in tumor-infiltrating CD11c(+) dendritic cells in human lung cancer samples. Active cleavage of HB-EGF in TADCs by ADAM9 and ADAM17 is associated with increased protein kinase C δ and Lyn signaling. Enhancement of HB-EGF production in TADCs increased the proliferation, migration, and epithelial-to-mesenchymal transition abilities of lung cancer. In contrast, inhibiting HB-EGF by siRNA suppressed TADC-mediated cancer progression. Moreover, mice injected with galectin-1 knockdown Lewis lung carcinoma showed decreased expression and ectodomain shedding of HB-EGF and reduced incidence of cancer development, resulting in increased survival rates. We demonstrate here for the first time that human and mouse DCs are a source of HB-EGF, an EGFR ligand with tumorigenic properties. Antagonists of the effect of lung cancer-derived galectin-1 on DCs and anti-HB-EGF blocking antibodies could, therefore, have therapeutic potential as antitumor agents.
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Affiliation(s)
- Po-Lin Kuo
- Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan,; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
| | - Ming-Shyan Huang
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Da-En Cheng
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, and
| | - Jen-Yu Hung
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan,; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, and
| | - Chih-Jen Yang
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan,; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, and
| | - Shah-Hwa Chou
- Department of Chest Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
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