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1
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Deshpande P, Dornbrand-Lo M, Phondge V, Kelly P, Wong AK. Tissue engineering approaches for lymphedema: biomaterial innovations and clinical potential. Front Cell Dev Biol 2025; 13:1537050. [PMID: 40302939 PMCID: PMC12037638 DOI: 10.3389/fcell.2025.1537050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 03/25/2025] [Indexed: 05/02/2025] Open
Abstract
The lymphatic system plays a critical role in maintaining fluid balance and immune regulation. Lymphedema, and other lymphatic disorders, highlight the need for advanced therapeutic approaches, including tissue engineering. This review examines the latest developments in artificial lymphatic tissue engineering, focusing on scaffold materials, lymphangiogenic factors, and regenerative strategies to replicate the intricacy of lymphatic vessels and nodes. We conducted a thorough literature review of current practices and applications in lymphatic tissue engineering. Findings show that biomaterials such as hydrogels, decellularized matrices, and synthetic polymers provide effective scaffolds for lymphatic endothelial cell proliferation and lymphangiogenesis. Advances in growth factor delivery and stem-cell based therapies have further enhanced the viability of engineered lymphatic tissues. Despite promising progress, challenges in achieving functional replication of lymphatic structures and clinical translation of research remain. Ongoing research must address scaffold biocompatibility, optimized growth factor targeting, and scalable production to advance therapeutic options for lymphatic disorders. This review underscores the potential for transformative patient outcomes through innovative bioengineering solutions.
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Affiliation(s)
| | | | | | | | - Alex K. Wong
- Rutgers New Jersey Medical School, Division of Plastic and Reconstructive Surgery, Newark, NJ, United States
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2
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Yao M, Wei J, Chen L, Li C, Jiang GQ. Collagen Hydrogel Loaded With 9-cisRA-Lip Is an Option for Treatment of Secondary Lymphedema after Surgery. Cancer Biother Radiopharm 2025; 40:210-218. [PMID: 39611659 DOI: 10.1089/cbr.2024.0177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2024] Open
Abstract
Background: Secondary upper limb lymphedema commonly occurs after breast cancer surgery, for which treatment is limited. 9-cis-retinoic acid (9-cisRA) has been demonstrated to increase lymphangiogenesis without enhancing tumor metastasis but has disadvantages of poor water solubility, ready decomposition in light, instability to heat, and a short half-life. Methods: Based on this, 9-cisRA-Lip with a particle size of roughly 143 nm and high dispersibility was prepared by thin-film dispersion method and verified by Malvern Laser Particle Size Analyzer and electron microscopy. Results: In vitro, 9-cisRA-Lip demonstrated good biosafety and tumor safety, promoting the proliferation of L929 cells while having no effect on 4T1 and Human Umbilical Vein Endothelial (HUVEC) cells. Compared with 9-cisRA, 9-cisRA-Lip was more effective at stimulating mouse lymphatic endothelial cell (SVEC4-10) migration, proliferation, and tube formation. In vivo, 9-cisRA-Lip-Gel showed good slow release effect. Mice treated with 9-cisRA-Lip-Gel one-time local injection had considerably less tail edema than the control group from day 9 to day 39 postsurgery (p < 0.05). This may be attributed to the greater capacity of 9-cisRA-Lip to enhance the phosphorylation of FGFR3 (Fibroblast Growth Factor Receptor 3) at Tyr 724. Conclusions: 9-cisRA-Lip-Gel presents a potential treatment option for lymphedema following surgery.
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Affiliation(s)
- Min Yao
- General Surgery Department, The Second Affiliated Hospital of Soochow University, Suzhou, China
- Department of Breast Surgery, Huzhou Maternity & Child Health Care Hospital, Huzhou, China
| | - Jinrong Wei
- General Surgery Department, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Lijie Chen
- Department of Breast Surgery, Huzhou Maternity & Child Health Care Hospital, Huzhou, China
| | - Chunyan Li
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine and i-Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, China
| | - Guo-Qin Jiang
- General Surgery Department, The Second Affiliated Hospital of Soochow University, Suzhou, China
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3
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Zhang Z, Zhao R, Wu X, Ma Y, He Y. Research progress on the correlation between corneal neovascularization and lymphangiogenesis (Review). Mol Med Rep 2025; 31:47. [PMID: 39635819 PMCID: PMC11638739 DOI: 10.3892/mmr.2024.13412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 10/23/2024] [Indexed: 12/07/2024] Open
Abstract
The cornea is a clear connective tissue membrane at the front of the outer layer of the eyeball wall. It plays a crucial role in the refractive system of the eyeball, making it essential to maintain its transparency. Neovascularization and lymphangiogenesis in the cornea significantly impact corneal transparency and immune privilege. The growth of corneal neovascularization (CNV) and corneal lymphangiogenesis (CL) vessels is interconnected yet independent. Currently, there is a substantial amount of clinical and experimental research on CNV and CL vessels. However, due to the relatively recent focus on CL vessel research compared with CNV research, most scholars tend to concentrate on CNV, with few articles offering a comprehensive comparison and discussion of the two processes. The present review emphasizes the similarities and differences between CNV and CL and summarizes recent research progress on their correlation in animal models, growth characteristics, cytokine effects and related diseases.
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Affiliation(s)
- Zhaochen Zhang
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Rongxuan Zhao
- Department of Rehabilitation, School of Nursing, Jilin University, Changchun, Jilin 130041, P.R. China
| | - Xuhui Wu
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Yunkun Ma
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Yuxi He
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
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Choi D, Park E, Choi J, Lu R, Yu JS, Kim C, Zhao L, Yu J, Nakashima B, Lee S, Singhal D, Scallan JP, Zhou B, Koh CJ, Lee E, Hong YK. Piezo1 regulates meningeal lymphatic vessel drainage and alleviates excessive CSF accumulation. Nat Neurosci 2024; 27:913-926. [PMID: 38528202 PMCID: PMC11088999 DOI: 10.1038/s41593-024-01604-8] [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: 02/20/2023] [Accepted: 02/15/2024] [Indexed: 03/27/2024]
Abstract
Piezo1 regulates multiple aspects of the vascular system by converting mechanical signals generated by fluid flow into biological processes. Here, we find that Piezo1 is necessary for the proper development and function of meningeal lymphatic vessels and that activating Piezo1 through transgenic overexpression or treatment with the chemical agonist Yoda1 is sufficient to increase cerebrospinal fluid (CSF) outflow by improving lymphatic absorption and transport. The abnormal accumulation of CSF, which often leads to hydrocephalus and ventriculomegaly, currently lacks effective treatments. We discovered that meningeal lymphatics in mouse models of Down syndrome were incompletely developed and abnormally formed. Selective overexpression of Piezo1 in lymphatics or systemic administration of Yoda1 in mice with hydrocephalus or Down syndrome resulted in a notable decrease in pathological CSF accumulation, ventricular enlargement and other associated disease symptoms. Together, our study highlights the importance of Piezo1-mediated lymphatic mechanotransduction in maintaining brain fluid drainage and identifies Piezo1 as a promising therapeutic target for treating excessive CSF accumulation and ventricular enlargement.
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Affiliation(s)
- Dongwon Choi
- Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Eunkyung Park
- Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Joshua Choi
- Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Renhao Lu
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
| | - Jin Suh Yu
- Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Chiyoon Kim
- Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Luping Zhao
- Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - James Yu
- Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Brandon Nakashima
- Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Sunju Lee
- Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Dhruv Singhal
- Division of Plastic and Reconstructive Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Joshua P Scallan
- Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA
| | - Bin Zhou
- New Cornerstone Science Laboratory, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Chester J Koh
- Division of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Esak Lee
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA
| | - Young-Kwon Hong
- Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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Li JJ, Mao JX, Zhong HX, Zhao YY, Teng F, Lu XY, Zhu LY, Gao Y, Fu H, Guo WY. Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma: A comprehensive review. World J Hepatol 2024; 16:537-549. [PMID: 38689749 PMCID: PMC11056903 DOI: 10.4254/wjh.v16.i4.537] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/11/2024] [Accepted: 03/18/2024] [Indexed: 04/24/2024] Open
Abstract
The tumor microenvironment is a complex network of cells, extracellular matrix, and signaling molecules that plays a critical role in tumor progression and metastasis. Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits. However, recent studies have shown that lymphatic endothelial cells (LECs) and blood endothelial cells (BECs) also play multifaceted roles in the tumor microenvironment beyond their structural functions, particularly in hepatocellular carcinoma (HCC). This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC, including their involvement in angiogenesis, immune modulation, lymphangiogenesis, and metastasis. By providing a detailed account of the complex interplay between LECs, BECs, and tumor cells, this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.
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Affiliation(s)
- Jing-Jing Li
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Jia-Xi Mao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Han-Xiang Zhong
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yuan-Yu Zhao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Fei Teng
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Xin-Yi Lu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Li-Ye Zhu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yang Gao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Hong Fu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Wen-Yuan Guo
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
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Mohan G, Khan I, Neumann CR, Jorge MD, Ahmed S, Hulsman L, Sinha M, Gordillo GM, Sen CK, Hassanein AH. Topical tissue nanotransfection of Prox1 is effective in the prophylactic management of lymphedema. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102121. [PMID: 38333673 PMCID: PMC10850858 DOI: 10.1016/j.omtn.2024.102121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/10/2024]
Abstract
Lymphedema is chronic limb swelling resulting from lymphatic dysfunction. There is no cure for the disease. Clinically, a preventive surgical approach called immediate lymphatic reconstruction (ILR) has gained traction. Experimental gene-based therapeutic approaches (e.g., using viral vectors) have had limited translational applicability. Tissue nanotransfection (TNT) technology uses a direct, transcutaneous nonviral vector, gene delivery using a chip with nanochannel poration in response to a rapid (<100 ms) focused electric field. The purpose of this study was to experimentally prevent lymphedema using focal delivery of a specific gene Prox1 (a master regulator of lymphangiogenesis). TNT was applied to the previously optimized lymphedematous mice tail (day 0) directly at the surgical site with genetic cargo loaded into the TNT reservoir: group I (sham) was given pCMV6 (expression vector backbone alone) and group II was treated with pCMV6-Prox1. Group II mice had decreased tail volume (47.8%) compared to sham and greater lymphatic clearance on lymphangiography. Immunohistochemistry showed greater lymphatic vessel density and RNA sequencing exhibited reduced inflammatory markers in group II compared to group I. Prox1 prophylactically delivered using TNT to the surgical site on the day of injury decreased the manifestations of lymphedema in the murine tail model compared to control.
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Affiliation(s)
- Ganesh Mohan
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Imran Khan
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Colby R. Neumann
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Miguel D. Jorge
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Shahnur Ahmed
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Luci Hulsman
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Mithun Sinha
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Gayle M. Gordillo
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
- McGowan Institute for Regenerative Medicine, Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Chandan K. Sen
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
- McGowan Institute for Regenerative Medicine, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Aladdin H. Hassanein
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
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7
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Montenegro-Navarro N, García-Báez C, García-Caballero M. Molecular and metabolic orchestration of the lymphatic vasculature in physiology and pathology. Nat Commun 2023; 14:8389. [PMID: 38104163 PMCID: PMC10725466 DOI: 10.1038/s41467-023-44133-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 11/28/2023] [Indexed: 12/19/2023] Open
Abstract
Lymphangiogenesis refers to the generation of new lymphatic vessels from pre-existing ones. During development and particular adult states, lymphatic endothelial cells (LEC) undergo reprogramming of their transcriptomic and signaling networks to support the high demands imposed by cell proliferation and migration. Although there has been substantial progress in identifying growth factors and signaling pathways controlling lymphangiogenesis in the last decades, insights into the role of metabolism in lymphatic cell functions are just emerging. Despite numerous similarities between the main metabolic pathways existing in LECs, blood ECs (BEC) and other cell types, accumulating evidence has revealed that LECs acquire a unique metabolic signature during lymphangiogenesis, and their metabolic engine is intertwined with molecular regulatory networks, resulting in a tightly regulated and interconnected process. Considering the implication of lymphatic dysfunction in cancer and lymphedema, alongside other pathologies, recent findings hold promising opportunities to develop novel therapeutic approaches. In this review, we provide an overview of the status of knowledge in the molecular and metabolic network regulating the lymphatic vasculature in health and disease.
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Affiliation(s)
- Nieves Montenegro-Navarro
- Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga, Andalucía Tech, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina (IBIMA Plataforma BIONAND), Málaga, Spain
| | - Claudia García-Báez
- Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga, Andalucía Tech, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina (IBIMA Plataforma BIONAND), Málaga, Spain
| | - Melissa García-Caballero
- Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga, Andalucía Tech, Málaga, Spain.
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina (IBIMA Plataforma BIONAND), Málaga, Spain.
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8
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Ji H, Hu C, Yang X, Liu Y, Ji G, Ge S, Wang X, Wang M. Lymph node metastasis in cancer progression: molecular mechanisms, clinical significance and therapeutic interventions. Signal Transduct Target Ther 2023; 8:367. [PMID: 37752146 PMCID: PMC10522642 DOI: 10.1038/s41392-023-01576-4] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 07/04/2023] [Accepted: 07/26/2023] [Indexed: 09/28/2023] Open
Abstract
Lymph nodes (LNs) are important hubs for metastatic cell arrest and growth, immune modulation, and secondary dissemination to distant sites through a series of mechanisms, and it has been proved that lymph node metastasis (LNM) is an essential prognostic indicator in many different types of cancer. Therefore, it is important for oncologists to understand the mechanisms of tumor cells to metastasize to LNs, as well as how LNM affects the prognosis and therapy of patients with cancer in order to provide patients with accurate disease assessment and effective treatment strategies. In recent years, with the updates in both basic and clinical studies on LNM and the application of advanced medical technologies, much progress has been made in the understanding of the mechanisms of LNM and the strategies for diagnosis and treatment of LNM. In this review, current knowledge of the anatomical and physiological characteristics of LNs, as well as the molecular mechanisms of LNM, are described. The clinical significance of LNM in different anatomical sites is summarized, including the roles of LNM playing in staging, prognostic prediction, and treatment selection for patients with various types of cancers. And the novel exploration and academic disputes of strategies for recognition, diagnosis, and therapeutic interventions of metastatic LNs are also discussed.
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Affiliation(s)
- Haoran Ji
- Department of Thoracic Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Chuang Hu
- Department of Thoracic Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Xuhui Yang
- Department of Thoracic Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Yuanhao Liu
- Department of Thoracic Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Guangyu Ji
- Department of Thoracic Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Shengfang Ge
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xiansong Wang
- Department of Thoracic Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
| | - Mingsong Wang
- Department of Thoracic Surgery, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
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Ivanov KI, Samuilova OV, Zamyatnin AA. The emerging roles of long noncoding RNAs in lymphatic vascular development and disease. Cell Mol Life Sci 2023; 80:197. [PMID: 37407839 PMCID: PMC10322780 DOI: 10.1007/s00018-023-04842-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 06/06/2023] [Accepted: 06/19/2023] [Indexed: 07/07/2023]
Abstract
Recent advances in RNA sequencing technologies helped uncover what was once uncharted territory in the human genome-the complex and versatile world of long noncoding RNAs (lncRNAs). Previously thought of as merely transcriptional "noise", lncRNAs have now emerged as essential regulators of gene expression networks controlling development, homeostasis and disease progression. The regulatory functions of lncRNAs are broad and diverse, and the underlying molecular mechanisms are highly variable, acting at the transcriptional, post-transcriptional, translational, and post-translational levels. In recent years, evidence has accumulated to support the important role of lncRNAs in the development and functioning of the lymphatic vasculature and associated pathological processes such as tumor-induced lymphangiogenesis and cancer metastasis. In this review, we summarize the current knowledge on the role of lncRNAs in regulating the key genes and pathways involved in lymphatic vascular development and disease. Furthermore, we discuss the potential of lncRNAs as novel therapeutic targets and outline possible strategies for the development of lncRNA-based therapeutics to treat diseases of the lymphatic system.
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Affiliation(s)
- Konstantin I Ivanov
- Research Center for Translational Medicine, Sirius University of Science and Technology, Sochi, Russian Federation.
- Department of Microbiology, University of Helsinki, Helsinki, Finland.
| | - Olga V Samuilova
- Department of Biochemistry, Sechenov First Moscow State Medical University, Moscow, Russian Federation
- HSE University, Moscow, Russian Federation
| | - Andrey A Zamyatnin
- Research Center for Translational Medicine, Sirius University of Science and Technology, Sochi, Russian Federation
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russian Federation
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russian Federation
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
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10
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Jablon KL, Akerstrom VL, Li M, Braun SE, Norton CE, Castorena-Gonzalez JA. Isolation and short-term culturing of primary lymphatic endothelial cells from collecting lymphatics: A techniques study. Microcirculation 2023; 30:e12778. [PMID: 35879879 PMCID: PMC9873843 DOI: 10.1111/micc.12778] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 07/11/2022] [Accepted: 07/21/2022] [Indexed: 01/27/2023]
Abstract
OBJECTIVE To develop an experimental method for routine isolation and short-term culture of primary lymphatic endothelial cells from specific collecting vessels. METHODS Lymphatic endothelial cell tubes (LECTs) were isolated from micro-dissected collecting vessels. LECTs were allowed to attach and grow for ~3 weeks before being passaged. Non-purified cultures were partially characterized by immunofluorescence and RT-PCR at passages 1-2. RESULTS The method was validated in cultures of primary lymphatic endothelial cells (LECs) from male and female mice. After 1 or 2 passages, >60% of the LECs maintained expression of Prox1. Expression of 22 different genes was assessed using RT-PCR. Prox1, Vegfr3, eNos, Cdh5, Pecam1, Cx43, Cx37, and Cx47, among others, were expressed in these short-term cultured LECs, while Myh11, Cnn1, Desmin, and Cd11b were not detected. Prox1 expression, as determined by western blotting, was similar in cultured LECs from age-matched male and female mice. Confocal imaging of intracellular calcium in cultures of primary LECs from Cdh5-GCaMP8 mice demonstrated that a functional phenotype was maintained, similar to lymphatic endothelial cells in freshly isolated vessels. CONCLUSIONS This method provides an innovative tool for routine isolation and study of primary LECs from specific collecting lymphatic vessels from any mouse, and in fact, from other species.
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Affiliation(s)
- Kelli L. Jablon
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Victoria L. Akerstrom
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Min Li
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, USA
| | - Stephen E. Braun
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA
- Division of Immunology, Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, USA
| | - Charles E. Norton
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, USA
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11
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Patnam M, Dommaraju SR, Masood F, Herbst P, Chang JH, Hu WY, Rosenblatt MI, Azar DT. Lymphangiogenesis Guidance Mechanisms and Therapeutic Implications in Pathological States of the Cornea. Cells 2023; 12:319. [PMID: 36672254 PMCID: PMC9856498 DOI: 10.3390/cells12020319] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/22/2022] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
Corneal lymphangiogenesis is one component of the neovascularization observed in several inflammatory pathologies of the cornea including dry eye disease and corneal graft rejection. Following injury, corneal (lymph)angiogenic privilege is impaired, allowing ingrowth of blood and lymphatic vessels into the previously avascular cornea. While the mechanisms underlying pathological corneal hemangiogenesis have been well described, knowledge of the lymphangiogenesis guidance mechanisms in the cornea is relatively scarce. Various signaling pathways are involved in lymphangiogenesis guidance in general, each influencing one or multiple stages of lymphatic vessel development. Most endogenous factors that guide corneal lymphatic vessel growth or regression act via the vascular endothelial growth factor C signaling pathway, a central regulator of lymphangiogenesis. Several exogenous factors have recently been repurposed and shown to regulate corneal lymphangiogenesis, uncovering unique signaling pathways not previously known to influence lymphatic vessel guidance. A strong understanding of the relevant lymphangiogenesis guidance mechanisms can facilitate the development of targeted anti-lymphangiogenic therapeutics for corneal pathologies. In this review, we examine the current knowledge of lymphatic guidance cues, their regulation of inflammatory states in the cornea, and recently discovered anti-lymphangiogenic therapeutic modalities.
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Affiliation(s)
- Mehul Patnam
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Sunil R. Dommaraju
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Faisal Masood
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Paula Herbst
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Jin-Hong Chang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Wen-Yang Hu
- Department of Urology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Mark I. Rosenblatt
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Dimitri T. Azar
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
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12
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Extracellular Vesicles Are Important Mediators That Regulate Tumor Lymph Node Metastasis via the Immune System. Int J Mol Sci 2023; 24:ijms24021362. [PMID: 36674900 PMCID: PMC9865533 DOI: 10.3390/ijms24021362] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/27/2022] [Accepted: 01/05/2023] [Indexed: 01/13/2023] Open
Abstract
Extracellular vesicles (EVs) are particles with a lipid bilayer structure, and they are secreted by various cells in the body. EVs interact with and modulate the biological functions of recipient cells by transporting their cargoes, such as nucleic acids and proteins. EVs influence various biological phenomena, including disease progression. They also participate in tumor progression by stimulating a variety of signaling pathways and regulating immune system activation. EVs induce immune tolerance by suppressing CD8+ T-cell activation or polarizing macrophages toward the M2 phenotype, which results in tumor cell proliferation, migration, invasion, and metastasis. Moreover, immune checkpoint molecules are also expressed on the surface of EVs that are secreted by tumors that express these molecules, allowing tumor cells to not only evade immune cell attack but also acquire resistance to immune checkpoint inhibitors. During tumor metastasis, EVs contribute to microenvironmental changes in distant organs before metastatic lesions appear; thus, EVs establish a premetastatic niche. In particular, lymph nodes are adjacent organs that are connected to tumor lesions via lymph vessels, so that tumor cells metastasize to draining lymph nodes at first, such as sentinel lymph nodes. When EVs influence the microenvironment of lymph nodes, which are secondary lymphoid tissues, the immune response against tumor cells is weakened; subsequently, tumor cells spread throughout the body. In this review, we will discuss the association between EVs and tumor progression via the immune system as well as the clinical application of EVs as biomarkers and therapeutic agents.
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13
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Sung C, Jiao W, Park SY, Cooper M, Bouz A, Choi D, Jung E, Kim G, Hong YK, Wong AK. Lymphatic endothelial cell RXRα is critical for 9-cis-retinoic acid-mediated lymphangiogenesis and prevention of secondary lymphedema. FASEB J 2023; 37:e22674. [PMID: 36520015 DOI: 10.1096/fj.202200146rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 11/11/2022] [Accepted: 11/16/2022] [Indexed: 12/23/2022]
Abstract
Secondary lymphedema is a debilitating disease characterized by abnormal soft tissue swelling and caused by lymphatic system dysfunction. Despite a high prevalence of secondary lymphedema after cancer treatments, current management is supportive and there are no approved therapeutic agents that can thwart disease progression. We have previously demonstrated that 9-cis-retinoic acid (9-cisRA) has the potential to be repurposed for lymphedema as it mitigates disease by promoting lymphangiogenesis at the site of lymphatic injury. Although the efficacy of 9-cisRA has been demonstrated in previous studies, the mechanism of action is not completely understood. In this study, we demonstrate that when RXRα is specifically deleted in lymphatic endothelial cells, 9-cisRA fails to induce lymphangiogenesis in vitro and prevent pathologic progression of postsurgical lymphedema in vivo. These findings demonstrate that downstream nuclear receptor RXRα plays a critical role in the therapeutic efficacy of 9-cisRA in postsurgical lymphedema.
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Affiliation(s)
- Cynthia Sung
- Division of Plastic Surgery, City of Hope National Medical Center, Duarte, California, USA.,Keck School of Medicine of USC, Los Angeles, California, USA
| | - Wan Jiao
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Sun Young Park
- Division of Plastic Surgery, City of Hope National Medical Center, Duarte, California, USA.,Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Michael Cooper
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Antoun Bouz
- Herbert Wertheim College of Medicine of FIU, Miami, Florida, USA
| | - Dahae Choi
- Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Los Angeles, California, USA
| | - Eunson Jung
- Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Los Angeles, California, USA
| | - Gene Kim
- Keck School of Medicine of USC, Los Angeles, California, USA
| | - Young Kwon Hong
- Keck School of Medicine of USC, Los Angeles, California, USA.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Los Angeles, California, USA
| | - Alex K Wong
- Division of Plastic Surgery, City of Hope National Medical Center, Duarte, California, USA.,Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA
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14
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The natural FGF-trap long pentraxin 3 inhibits lymphangiogenesis and lymphatic dissemination. Exp Hematol Oncol 2022; 11:84. [PMID: 36320051 PMCID: PMC9623950 DOI: 10.1186/s40164-022-00330-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 09/30/2022] [Indexed: 11/14/2022] Open
Abstract
The lymphatic vascular system represents a major route for dissemination of several solid tumors, including melanoma. Even though the members of the Vascular Endothelial Growth Factor family VEGF-C and VEGF-A have been shown to drive tumor lymphangiogenesis, experimental evidence indicates that also the pro-angiogenic factor Fibroblast Growth Factor-2 (FGF2) may play a role in the lymphangiogenic switch by triggering the activation of lymphatic endothelial cells (LECs) in cooperation with VEGFs.The soluble pattern recognition receptor Long Pentraxin 3 (PTX3) acts as a natural FGF trap, thus exerting an oncosuppressive role in FGF-dependent tumors. Here, the capacity of PTX3 to modulate lymphangiogenesis was assessed in vitro and in vivo. The results demonstrate that recombinant human PTX3 inhibits the lymphangiogenic activity exerted by the VEGF-A/FGF2/sphingosine-1-phosphate (VFS) cocktail on human and murine LECs. In keeping with in vitro data, a reduced lymphangiogenic response was observed in a lymphangiogenic Matrigel plug assay following the subcutaneous injection of the VFS cocktail in PTX3-overexpressing transgenic TgN(Tie2-hPTX3) mice when compared to wild-type or Ptx3 null animals. Accordingly, the capacity of B16F10-VEGFC-luc melanoma cells to colonize the primary tumor-draining lymph node after grafting into the foot pad was dramatically impaired in PTX3-overexpressing mice.Together with the observation that both the VFS cocktail and melanoma cell conditioned media caused a significant downregulation of PTX3 expression in LECs, these data indicate that the FGF trap activity of PTX3 may exert a key effect in the modulation of lymphangiogenesis and tumor metastatic dissemination.
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15
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The Role of PROX1 in Neoplasia: A Key Player Often Overlooked. Diagnostics (Basel) 2022; 12:diagnostics12071624. [PMID: 35885529 PMCID: PMC9320018 DOI: 10.3390/diagnostics12071624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/29/2022] [Accepted: 07/02/2022] [Indexed: 12/02/2022] Open
Abstract
The human PROX1 gene (Prospero homeobox gene 1) is a member of the homeobox transcription factor family. PROX1 plays a key role in the development of the lymphatic system and is primarily used as a lymphatic vessel marker. However, as the accumulating evidence indicates that PROX1 is also implicated in the tumorigenesis of various cancer types, the scientific community has attempted to elucidate its complicated function in neoplasia pathogenesis, as well as its utility in cancer diagnosis, prognosis, and therapy. PROX1 has been shown to participate in the complex molecular mechanisms affecting tumorigenesis and has been associated with a plethora of clinicopathological parameters, including tumor stage and patients’ overall survival. Depending on the specific organ affected, PROX1 has exhibited both tumor-promoting and tumor-suppressing properties, with its inhibition and reactivation representing possible novel therapeutic interventions, respectively. Moreover, researchers have reported PROX1 as a useful tool in the fields of diagnosis and prognosis assessment. The current study aims to summarize and present the existing data that render PROX1 a novel and useful diagnostic and prognostic biomarker, as well as a possible therapeutic target.
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16
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Lymphatic Tissue Bioengineering for the Treatment of Postsurgical Lymphedema. BIOENGINEERING (BASEL, SWITZERLAND) 2022; 9:bioengineering9040162. [PMID: 35447722 PMCID: PMC9025804 DOI: 10.3390/bioengineering9040162] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/17/2022] [Accepted: 03/20/2022] [Indexed: 01/28/2023]
Abstract
Lymphedema is characterized by progressive and chronic tissue swelling and inflammation from local accumulation of interstitial fluid due to lymphatic injury or dysfunction. It is a debilitating condition that significantly impacts a patient's quality of life, and has limited treatment options. With better understanding of the molecular mechanisms and pathophysiology of lymphedema and advances in tissue engineering technologies, lymphatic tissue bioengineering and regeneration have emerged as a potential therapeutic option for postsurgical lymphedema. Various strategies involving stem cells, lymphangiogenic factors, bioengineered matrices and mechanical stimuli allow more precisely controlled regeneration of lymphatic tissue at the site of lymphedema without subjecting patients to complications or iatrogenic injuries associated with surgeries. This review provides an overview of current innovative approaches of lymphatic tissue bioengineering that represent a promising treatment option for postsurgical lymphedema.
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17
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Chennakesavalu M, Somala SRR, Dommaraju SR, Peesapati MP, Guo K, Rosenblatt MI, Chang JH, Azar DT. Corneal lymphangiogenesis as a potential target in dry eye disease - a systematic review. Surv Ophthalmol 2021; 66:960-976. [PMID: 33811911 PMCID: PMC9991079 DOI: 10.1016/j.survophthal.2021.03.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 03/17/2021] [Accepted: 03/22/2021] [Indexed: 02/03/2023]
Abstract
Dry eye disease (DED) is a common ocular surface condition causing symptoms of significant discomfort, visual disturbance, and pain. With recent advancements, DED has become recognized as a chronic self-perpetuating inflammatory condition triggered by various internal and environmental factors. DED has been shown to arise from the activation of both the innate and adaptive immune systems, leading to corneal epithelium and lacrimal gland dysfunction. While the cornea is normally avascular and thus imbued with angiogenic and lymphangiogenic privilege, various DED models have revealed activated corneal antigen-presenting cells in regional lymph nodes, suggesting the formation of new corneal lymphatic vessels in DED. The recent availability of reliable lymphatic cell surface markers such as LYVE-1 has made it possible to study lymphangiogenesis. Accordingly, numerous studies have been published within the last decade discussing the role of lymphangiogenesis in DED pathology. We systematically review the literature to identify and evaluate studies presenting data on corneal lymphangiogenesis in DED. There is considerable evidence supporting corneal lymphangiogenesis as a central mediator of DED pathogenesis. These findings suggest that anti-lymphangiogenic therapeutic strategies may be a viable option for the treatment of DED, a conclusion supported by the limited number of reported clinical trials examining anti-lymphangiogenic modalities in DED.
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Affiliation(s)
- Mohansrinivas Chennakesavalu
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Sri Raghurama R Somala
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Sunil R Dommaraju
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Meghna Priyanka Peesapati
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Kai Guo
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Mark I Rosenblatt
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Jin-Hong Chang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL.
| | - Dimitri T Azar
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL
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18
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Rezzola S, Sigmund EC, Halin C, Ronca R. The lymphatic vasculature: An active and dynamic player in cancer progression. Med Res Rev 2021; 42:576-614. [PMID: 34486138 PMCID: PMC9291933 DOI: 10.1002/med.21855] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 04/29/2021] [Accepted: 08/26/2021] [Indexed: 12/16/2022]
Abstract
The lymphatic vasculature has been widely described and explored for its key functions in fluid homeostasis and in the organization and modulation of the immune response. Besides transporting immune cells, lymphatic vessels play relevant roles in tumor growth and tumor cell dissemination. Cancer cells that have invaded into afferent lymphatics are propagated to tumor‐draining lymph nodes (LNs), which represent an important hub for metastatic cell arrest and growth, immune modulation, and secondary dissemination to distant sites. In recent years many studies have reported new mechanisms by which the lymphatic vasculature affects cancer progression, ranging from induction of lymphangiogenesis to metastatic niche preconditioning or immune modulation. In this review, we provide an up‐to‐date description of lymphatic organization and function in peripheral tissues and in LNs and the changes induced to this system by tumor growth and progression. We will specifically focus on the reported interactions that occur between tumor cells and lymphatic endothelial cells (LECs), as well as on interactions between immune cells and LECs, both in the tumor microenvironment and in tumor‐draining LNs. Moreover, the most recent prognostic and therapeutic implications of lymphatics in cancer will be reported and discussed in light of the new immune‐modulatory roles that have been ascribed to LECs.
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Affiliation(s)
- Sara Rezzola
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Elena C Sigmund
- Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland
| | - Cornelia Halin
- Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland
| | - Roberto Ronca
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
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19
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Song H, Zhu J, Li P, Han F, Fang L, Yu P. Metabolic flexibility maintains proliferation and migration of FGFR signaling-deficient lymphatic endothelial cells. J Biol Chem 2021; 297:101149. [PMID: 34473994 PMCID: PMC8498002 DOI: 10.1016/j.jbc.2021.101149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/24/2021] [Accepted: 08/30/2021] [Indexed: 01/01/2023] Open
Abstract
Metabolic flexibility is the capacity of cells to alter fuel metabolism in response to changes in metabolic demand or nutrient availability. It is critical for maintaining cellular bioenergetics and is involved in the pathogenesis of cardiovascular disease and metabolic disorders. However, the regulation and function of metabolic flexibility in lymphatic endothelial cells (LECs) remain unclear. We have previously shown that glycolysis is the predominant metabolic pathway to generate ATP in LECs and that fibroblast growth factor receptor (FGFR) signaling controls lymphatic vessel formation by promoting glycolysis. Here, we found that chemical inhibition of FGFR activity or knockdown of FGFR1 induces substantial upregulation of fatty acid β-oxidation (FAO) while reducing glycolysis and cellular ATP generation in LECs. Interestingly, such compensatory elevation was not observed in glucose oxidation and glutamine oxidation. Mechanistic studies show that FGFR blockade promotes the expression of carnitine palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme of FAO; this is achieved by dampened extracellular signal–regulated protein kinase activation, which in turn upregulates the expression of the peroxisome proliferator–activated receptor alpha. Metabolic analysis further demonstrates that CPT1A depletion decreases total cellular ATP levels in FGFR1-deficient rather than wildtype LECs. This result suggests that FAO, which makes a negligible contribution to cellular energy under normal conditions, can partially compensate for energy deficiency caused by FGFR inhibition. Consequently, CPT1A silencing potentiates the effect of FGFR1 knockdown on impeding LEC proliferation and migration. Collectively, our study identified a key role of metabolic flexibility in modulating the effect of FGFR signaling on LEC growth.
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Affiliation(s)
- Hongyuan Song
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Jie Zhu
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Ping Li
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Fei Han
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Longhou Fang
- Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas, USA; Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Institute for Academic Medicine, Houston Methodist Research Institute, Houston, Texas, USA; Department of Cardiothoracic Surgeries, Weill Cornell Medical College, Cornell University, New York City, New York, USA
| | - Pengchun Yu
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
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20
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Woo KV, Shen IY, Weinheimer CJ, Kovacs A, Nigro J, Lin CY, Chakinala M, Byers DE, Ornitz DM. Endothelial FGF signaling is protective in hypoxia-induced pulmonary hypertension. J Clin Invest 2021; 131:141467. [PMID: 34623323 DOI: 10.1172/jci141467] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 06/25/2021] [Indexed: 01/08/2023] Open
Abstract
Hypoxia-induced pulmonary hypertension (PH) is one of the most common and deadliest forms of PH. Fibroblast growth factor receptors 1 and 2 (FGFR1/2) are elevated in patients with PH and in mice exposed to chronic hypoxia. Endothelial FGFR1/2 signaling is important for the adaptive response to several injury types and we hypothesized that endothelial FGFR1/2 signaling would protect against hypoxia-induced PH. Mice lacking endothelial FGFR1/2, mice with activated endothelial FGFR signaling, and human pulmonary artery endothelial cells (HPAECs) were challenged with hypoxia. We assessed the effect of FGFR activation and inhibition on right ventricular pressure, vascular remodeling, and endothelial-mesenchymal transition (EndMT), a known pathologic change seen in patients with PH. Hypoxia-exposed mice lacking endothelial FGFRs developed increased PH, while mice overexpressing a constitutively active FGFR in endothelial cells did not develop PH. Mechanistically, lack of endothelial FGFRs or inhibition of FGFRs in HPAECs led to increased TGF-β signaling and increased EndMT in response to hypoxia. These phenotypes were reversed in mice with activated endothelial FGFR signaling, suggesting that FGFR signaling inhibits TGF-β pathway-mediated EndMT during chronic hypoxia. Consistent with these observations, lung tissue from patients with PH showed activation of FGFR and TGF-β signaling. Collectively, these data suggest that activation of endothelial FGFR signaling could be therapeutic for hypoxia-induced PH.
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Affiliation(s)
- Kel Vin Woo
- Division of Cardiology, Department of Pediatrics.,Department of Developmental Biology
| | | | | | | | | | | | - Murali Chakinala
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Derek E Byers
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
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21
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Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway. Nat Commun 2021; 12:4391. [PMID: 34282140 PMCID: PMC8289847 DOI: 10.1038/s41467-021-24643-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 05/20/2021] [Indexed: 12/30/2022] Open
Abstract
Acquired heterotopic ossification (HO) is the extraskeletal bone formation after trauma. Various mesenchymal progenitors are reported to participate in ectopic bone formation. Here we induce acquired HO in mice by Achilles tenotomy and observe that conditional knockout (cKO) of fibroblast growth factor receptor 3 (FGFR3) in Col2+ cells promote acquired HO development. Lineage tracing studies reveal that Col2+ cells adopt fate of lymphatic endothelial cells (LECs) instead of chondrocytes or osteoblasts during HO development. FGFR3 cKO in Prox1+ LECs causes even more aggravated HO formation. We further demonstrate that FGFR3 deficiency in LECs leads to decreased local lymphatic formation in a BMPR1a-pSmad1/5-dependent manner, which exacerbates inflammatory levels in the repaired tendon. Local administration of FGF9 in Matrigel inhibits heterotopic bone formation, which is dependent on FGFR3 expression in LECs. Here we uncover Col2+ lineage cells as an origin of lymphatic endothelium, which regulates local inflammatory microenvironment after trauma and thus influences HO development via FGFR3-BMPR1a pathway. Activation of FGFR3 in LECs may be a therapeutic strategy to inhibit acquired HO formation via increasing local lymphangiogenesis. Different types of mesenchymal progenitors participate in ectopic bone formation. Here, the authors show Col2+ lineage cells adopt a lymphatic endothelium cell fate, which regulates local inflammatory microenvironment after trauma, thus influencing heterotopic ossification (HO) development via a FGFR3-BMPR1a pathway.
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22
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He M, He Q, Cai X, Chen Z, Lao S, Deng H, Liu X, Zheng Y, Liu X, Liu J, Xie Z, Yao M, Liang W, He J. Role of lymphatic endothelial cells in the tumor microenvironment-a narrative review of recent advances. Transl Lung Cancer Res 2021; 10:2252-2277. [PMID: 34164274 PMCID: PMC8182726 DOI: 10.21037/tlcr-21-40] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background As lymphatic vessel is a major route for solid tumor metastasis, they are considered an essential part of tumor drainage conduits. Apart from forming the walls of lymphatic vessels, lymphatic endothelial cells (LECs) have been found to play multiple other roles in the tumor microenvironment, calling for a more in-depth review. We hope that this review may help researchers gain a detailed understanding of this fast-developing field and shed some light upon future research. Methods To achieve an informative review of recent advance, we carefully searched the Medline database for English literature that are openly published from the January 1995 to December 2020 and covered the topic of LEC or lymphangiogenesis in tumor progression and therapies. Two different authors independently examined the literature abstracts to exclude possible unqualified ones, and 310 papers with full texts were finally retrieved. Results In this paper, we discussed the structural and molecular basis of tumor-associated LECs, together with their roles in tumor metastasis and drug therapy. We then focused on their impacts on tumor cells, tumor stroma, and anti-tumor immunity, and the molecular and cellular mechanisms involved. Special emphasis on lung cancer and possible therapeutic targets based on LECs were also discussed. Conclusions LECs can play a much more complex role than simply forming conduits for tumor cell dissemination. Therapies targeting tumor-associated lymphatics for lung cancer and other tumors are promising, but more research is needed to clarify the mechanisms involved.
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Affiliation(s)
- Miao He
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qihua He
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiuyu Cai
- Department of VIP Region, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zisheng Chen
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Respiratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, China
| | - Shen Lao
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Hongsheng Deng
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiwen Liu
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yongmei Zheng
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaoyan Liu
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jun Liu
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhanhong Xie
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Maojin Yao
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenhua Liang
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,The First People Hospital of Zhaoqing, Zhaoqing, China
| | - Jianxing He
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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23
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Grant D, Wanner N, Frimel M, Erzurum S, Asosingh K. Comprehensive phenotyping of endothelial cells using flow cytometry 1: Murine. Cytometry A 2020; 99:251-256. [PMID: 33345421 DOI: 10.1002/cyto.a.24292] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 12/03/2020] [Accepted: 12/04/2020] [Indexed: 12/21/2022]
Abstract
The endothelium forms a selective barrier between circulating blood or lymph and surrounding tissue. Endothelial cells play an essential role in vessel homeostasis, and identification of these cells is critical in vascular biology research. However, characteristics of endothelial cells differ depending on the location and type of blood or lymph vessel. Endothelial cell subsets are numerous and often identified using different flow cytometric markers, making immunophenotyping these cells complex. In part 1 of this two part review series, we present a comprehensive overview of markers for the flow cytometric identification and phenotyping of murine endothelial subsets. These subsets can be distinguished using a panel of cell surface and intracellular markers shared by all endothelial cells in combination with additional markers of specialized endothelial cell types. This review can be used to determine the best markers for identifying and phenotyping desired murine endothelial cell subsets.
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Affiliation(s)
- Dillon Grant
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - Nicholas Wanner
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - Matthew Frimel
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - Serpil Erzurum
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA
| | - Kewal Asosingh
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA.,Flow Cytometry Core Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
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24
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Bui K, Hong YK. Ras Pathways on Prox1 and Lymphangiogenesis: Insights for Therapeutics. Front Cardiovasc Med 2020; 7:597374. [PMID: 33263009 PMCID: PMC7688453 DOI: 10.3389/fcvm.2020.597374] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 10/12/2020] [Indexed: 12/12/2022] Open
Abstract
Over the past couple of decades, lymphatics research has accelerated and gained a much-needed recognition in pathophysiology. As the lymphatic system plays heavy roles in interstitial fluid drainage, immune surveillance and lipid absorption, the ablation or excessive growth of this vasculature could be associated with many complications, from lymphedema to metastasis. Despite their growing importance in cancer, few anti-lymphangiogenic therapies exist today, as they have yet to pass phase 3 clinical trials and acquire FDA approval. As such, many studies are being done to better define the signaling pathways that govern lymphangiogenesis, in hopes of developing new therapeutic approaches to inhibit or stimulate this process. This review will cover our current understanding of the Ras signaling pathways and their interactions with Prox1, the master transcriptional switch involved in specifying lymphatic endothelial cell fate and lymphangiogenesis, in hopes of providing insights to lymphangiogenesis-based therapies.
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Affiliation(s)
| | - Young-Kwon Hong
- Department of Surgery, Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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25
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Xie Y, Su N, Yang J, Tan Q, Huang S, Jin M, Ni Z, Zhang B, Zhang D, Luo F, Chen H, Sun X, Feng JQ, Qi H, Chen L. FGF/FGFR signaling in health and disease. Signal Transduct Target Ther 2020; 5:181. [PMID: 32879300 PMCID: PMC7468161 DOI: 10.1038/s41392-020-00222-7] [Citation(s) in RCA: 467] [Impact Index Per Article: 93.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/28/2020] [Accepted: 06/15/2020] [Indexed: 12/13/2022] Open
Abstract
Growing evidences suggest that the fibroblast growth factor/FGF receptor (FGF/FGFR) signaling has crucial roles in a multitude of processes during embryonic development and adult homeostasis by regulating cellular lineage commitment, differentiation, proliferation, and apoptosis of various types of cells. In this review, we provide a comprehensive overview of the current understanding of FGF signaling and its roles in organ development, injury repair, and the pathophysiology of spectrum of diseases, which is a consequence of FGF signaling dysregulation, including cancers and chronic kidney disease (CKD). In this context, the agonists and antagonists for FGF-FGFRs might have therapeutic benefits in multiple systems.
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Affiliation(s)
- Yangli Xie
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
| | - Nan Su
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Jing Yang
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Qiaoyan Tan
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Shuo Huang
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Min Jin
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Zhenhong Ni
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Bin Zhang
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Dali Zhang
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Fengtao Luo
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Hangang Chen
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Xianding Sun
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Jian Q Feng
- Department of Biomedical Sciences, Texas A&M University College of Dentistry, Dallas, TX, 75246, USA
| | - Huabing Qi
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
| | - Lin Chen
- Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
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26
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Chao CM, Chong L, Chu X, Shrestha A, Behnke J, Ehrhardt H, Zhang J, Chen C, Bellusci S. Targeting Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension (BPD-PH): Potential Role of the FGF Signaling Pathway in the Development of the Pulmonary Vascular System. Cells 2020; 9:cells9081875. [PMID: 32796770 PMCID: PMC7464452 DOI: 10.3390/cells9081875] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/07/2020] [Accepted: 08/07/2020] [Indexed: 12/11/2022] Open
Abstract
More than 50 years after the first description of Bronchopulmonary dysplasia (BPD) by Northway, this chronic lung disease affecting many preterm infants is still poorly understood. Additonally, approximately 40% of preterm infants suffering from severe BPD also suffer from Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH), leading to a significant increase in total morbidity and mortality. Until today, there is no curative therapy for both BPD and BPD-PH available. It has become increasingly evident that growth factors are playing a central role in normal and pathologic development of the pulmonary vasculature. Thus, this review aims to summarize the recent evidence in our understanding of BPD-PH from a basic scientific point of view, focusing on the potential role of Fibroblast Growth Factor (FGF)/FGF10 signaling pathway contributing to disease development, progression and resolution.
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Affiliation(s)
- Cho-Ming Chao
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; (J.Z.); (C.C.)
- Cardio-Pulmonary Institute, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany; (X.C.); (A.S.)
- Department of General Pediatrics and Neonatology, Justus-Liebig-University, Feulgenstrasse 12, D-35392 Gießen, Universities of Gießen and Marburg Lung Center, German Center for Lung Research, 35392 Giessen, Germany; (J.B.); (H.E.)
- Correspondence: (C.-M.C.); (S.B.)
| | - Lei Chong
- Institute of Pediatrics, National Key Clinical Specialty of Pediatric Respiratory Medicine, Discipline of Pediatric Respiratory Medicine, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China;
| | - Xuran Chu
- Cardio-Pulmonary Institute, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany; (X.C.); (A.S.)
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Amit Shrestha
- Cardio-Pulmonary Institute, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany; (X.C.); (A.S.)
| | - Judith Behnke
- Department of General Pediatrics and Neonatology, Justus-Liebig-University, Feulgenstrasse 12, D-35392 Gießen, Universities of Gießen and Marburg Lung Center, German Center for Lung Research, 35392 Giessen, Germany; (J.B.); (H.E.)
| | - Harald Ehrhardt
- Department of General Pediatrics and Neonatology, Justus-Liebig-University, Feulgenstrasse 12, D-35392 Gießen, Universities of Gießen and Marburg Lung Center, German Center for Lung Research, 35392 Giessen, Germany; (J.B.); (H.E.)
| | - Jinsan Zhang
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; (J.Z.); (C.C.)
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
- International Collaborative Center on Growth Factor Research, Life Science Institute, Wenzhou University, Wenzhou 325035, China
| | - Chengshui Chen
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; (J.Z.); (C.C.)
| | - Saverio Bellusci
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; (J.Z.); (C.C.)
- Cardio-Pulmonary Institute, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany; (X.C.); (A.S.)
- Correspondence: (C.-M.C.); (S.B.)
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27
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Choi D, Park E, Kim KE, Jung E, Seong YJ, Zhao L, Madhavan S, Daghlian G, Lee HH, Daghlian PT, Daghlian S, Bui K, Koh CJ, Wong AK, Cho IT, Hong YK. The Lymphatic Cell Environment Promotes Kaposi Sarcoma Development by Prox1-Enhanced Productive Lytic Replication of Kaposi Sarcoma Herpes Virus. Cancer Res 2020; 80:3130-3144. [PMID: 32518204 DOI: 10.1158/0008-5472.can-19-3105] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 03/13/2020] [Accepted: 06/04/2020] [Indexed: 12/17/2022]
Abstract
Kaposi sarcoma is the most common cancer in human immunodeficiency virus-positive individuals and is caused by Kaposi sarcoma-associated herpesvirus (KSHV). It is believed that a small number of latently infected Kaposi sarcoma tumor cells undergo spontaneous lytic reactivation to produce viral progeny for infection of new cells. Here, we use matched donor-derived human dermal blood and lymphatic endothelial cells (BEC and LEC, respectively) to show that KSHV-infected BECs progressively lose viral genome as they proliferate. In sharp contrast, KSHV-infected LECs predominantly entered lytic replication, underwent cell lysis, and released new virus. Continuous lytic cell lysis and de novo infection allowed LEC culture to remain infected for a prolonged time. Because of the strong propensity of LECs toward lytic replication, LECs maintained virus as a population, despite the death of individual host cells from lytic lysis. The master regulator of lymphatic development, Prox1, bound the promoter of the RTA gene to upregulate its expression and physically interacted with RTA protein to coregulate lytic genes. Thus, LECs may serve as a proficient viral reservoir that provides viral progeny for continuous de novo infection of tumor origin cells, and potentially BECs and mesenchymal stem cells, which give rise to Kaposi sarcoma tumors. Our study reveals drastically different host cell behaviors between BEC and LEC and defines the underlying mechanisms of the lymphatic cell environment supporting persistent infection in Kaposi sarcoma tumors. SIGNIFICANCE: This study defines the mechanism by which Kaposi's sarcoma could be maintained by virus constantly produced by lymphatic cells in HIV-positive individuals.
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Affiliation(s)
- Dongwon Choi
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Eunkyung Park
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Kyu Eui Kim
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Eunson Jung
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Young Jin Seong
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Luping Zhao
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Shrimika Madhavan
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - George Daghlian
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Hansuh H Lee
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Patill T Daghlian
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Saren Daghlian
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Khoa Bui
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Chester J Koh
- Division of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas
| | - Alex K Wong
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Il-Taeg Cho
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Young-Kwon Hong
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California. .,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
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28
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Patterson KC, Queval CJ, Gutierrez MG. Granulomatous Inflammation in Tuberculosis and Sarcoidosis: Does the Lymphatic System Contribute to Disease? Bioessays 2019; 41:e1900086. [PMID: 31588585 DOI: 10.1002/bies.201900086] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 08/09/2019] [Indexed: 12/22/2022]
Abstract
A striking and unexplained feature of granulomatous inflammation is its anatomical association with the lymphatic system. Accumulating evidence suggests that lymphatic tracks and granulomas may alter the function of each other. The formation of new lymphatics, or lymphangiogenesis, is an adaptive response to tumor formation, infection, and wound healing. Granulomas also may induce lymphangiogenesis which, through a variety of mechanisms, could contribute to disease outcomes in tuberculosis and sarcoidosis. On the other hand, alterations in lymph node function and lymphatic draining may be primary events which attenuate the risk and severity of granulomatous inflammation. This review begins with an introduction of granulomatous inflammation and the lymphatic system. A role of the lymphatic system in tuberculosis and sarcoidosis is then hypothesized. With a focus on lymphangiogenesis in these diseases, and on the potential for this process to promote dissemination, parallels are established with the well-established role of lymphangiogenesis in tumor biology.
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Affiliation(s)
- Karen C Patterson
- Brighton and Sussex Medical School, 94N-SRd, Falmer, Brighton, BN1 9PX, UK.,Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Christophe J Queval
- Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
| | - Maximiliano G Gutierrez
- Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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29
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Cao MX, Tang YL, Zhang WL, Tang YJ, Liang XH. Non-coding RNAs as Regulators of Lymphangiogenesis in Lymphatic Development, Inflammation, and Cancer Metastasis. Front Oncol 2019; 9:916. [PMID: 31616631 PMCID: PMC6763613 DOI: 10.3389/fonc.2019.00916] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 09/03/2019] [Indexed: 02/05/2023] Open
Abstract
Non-coding RNAs (ncRNAs), which do not encode proteins, have pivotal roles in manipulating gene expression in development, physiology, and pathology. Emerging data have shown that ncRNAs can regulate lymphangiogenesis, which refers to lymphatics deriving from preexisting vessels, becomes established during embryogenesis, and has a close relationship with pathological conditions such as lymphatic developmental diseases, inflammation, and cancer. This review summarizes the molecular mechanisms of lymphangiogenesis in lymphatic development, inflammation and cancer metastasis, and discusses ncRNAs' regulatory effects on them. Therapeutic targets with regard to lymphangiogenesis are also discussed.
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Affiliation(s)
- Ming-Xin Cao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Wei-Long Zhang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Jie Tang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China.,Hubei Key Laboratory of Industrial Microbiology, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Hubei University of Technology, Wuhan, China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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30
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Tamura R, Yoshida K, Toda M. Current understanding of lymphatic vessels in the central nervous system. Neurosurg Rev 2019; 43:1055-1064. [PMID: 31209659 DOI: 10.1007/s10143-019-01133-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 04/29/2019] [Accepted: 06/05/2019] [Indexed: 12/18/2022]
Abstract
Lymphangiogenesis is associated with some pathological conditions such as inflammation, tissue repair, and tumor growth. Recently, a paradigm shift occurred following the discovery of meningeal lymphatic structures in the human central nervous system (CNS); these structures may be a key drainage route for cerebrospinal fluid (CSF) into the peripheral blood and may also contribute to inflammatory reaction and immune surveillance of the CNS. Lymphatic vessels located along the dural sinuses absorb CSF from the adjacent subarachnoid space and brain interstitial fluid via the glymphatic system, which is composed of aquaporin-4 water channels expressed on perivascular astrocytic end-feet membranes. Magnetic resonance imaging (MRI) clearly visualized these lymphatic vessels in the human dura mater. The conception of some neurological disorders, such as multiple sclerosis and Alzheimer's disease, has been changed by this paradigm shift. Meningeal lymphatic vessels could be a promising therapeutic target for the prevention of neurological disorders. However, the involvement of meningeal lymphatic vessels in the pathophysiology has not been fully elucidated and is the subject of future investigations. In this article, to understand the involvement of meningeal lymphatic vessels in neurological disorders, we review the differences between lymphangiogenesis in the CNS and in other tissues during both developmental and adulthood stages, and pathological conditions that may be associated with meningeal lymphatic vessels in the CNS.
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Affiliation(s)
- Ryota Tamura
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Kazunari Yoshida
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Masahiro Toda
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
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31
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Norman TA, Gower AC, Chen F, Fine A. Transcriptional landscape of pulmonary lymphatic endothelial cells during fetal gestation. PLoS One 2019; 14:e0216795. [PMID: 31083674 PMCID: PMC6513083 DOI: 10.1371/journal.pone.0216795] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 04/29/2019] [Indexed: 02/06/2023] Open
Abstract
The genetic programs responsible for pulmonary lymphatic maturation prior to birth are not known. To address this gap in knowledge, we developed a novel cell sorting strategy to collect fetal pulmonary lymphatic endothelial cells (PLECs) for global transcriptional profiling. We identified PLECs based on their unique cell surface immunophenotype (CD31+/Vegfr3+/Lyve1+/Pdpn+) and isolated them from murine lungs during late gestation (E16.5, E17.5, E18.5). Gene expression profiling was performed using whole-genome microarrays, and 1,281 genes were significantly differentially expressed with respect to time (FDR q < 0.05) and grouped into six clusters. Two clusters containing a total of 493 genes strongly upregulated at E18.5 were significantly enriched in genes with functional annotations corresponding to innate immune response, positive regulation of angiogenesis, complement & coagulation cascade, ECM/cell-adhesion, and lipid metabolism. Gene Set Enrichment Analysis identified several pathways coordinately upregulated during late gestation, the strongest of which was the type-I IFN-α/β signaling pathway. Upregulation of canonical interferon target genes was confirmed by qRT-PCR and in situ hybridization in E18.5 PLECs. We also identified transcriptional events consistent with a prenatal PLEC maturation program. This PLEC-specific program included individual genes (Ch25h, Itpkc, Pcdhac2 and S1pr3) as well as a set of chemokines and genes containing an NF-κB binding site in their promoter. Overall, this work reveals transcriptional insights into the genes, signaling pathways and biological processes associated with pulmonary lymphatic maturation in the fetal lung.
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Affiliation(s)
- Timothy A Norman
- Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, United States of America
- Pathology & Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Adam C Gower
- Clinical and Translational Science Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Felicia Chen
- Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Alan Fine
- Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, United States of America
- Boston Veteran's Hospital, West Roxbury, Massachusetts, United States of America
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32
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Choi D, Park E, Jung E, Cha B, Lee S, Yu J, Kim PM, Lee S, Hong YJ, Koh CJ, Cho CW, Wu Y, Li Jeon N, Wong AK, Shin L, Kumar SR, Bermejo-Moreno I, Srinivasan RS, Cho IT, Hong YK. Piezo1 incorporates mechanical force signals into the genetic program that governs lymphatic valve development and maintenance. JCI Insight 2019; 4:125068. [PMID: 30676326 DOI: 10.1172/jci.insight.125068] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 01/17/2019] [Indexed: 01/05/2023] Open
Abstract
The lymphatic system plays crucial roles in tissue homeostasis, lipid absorption, and immune cell trafficking. Although lymphatic valves ensure unidirectional lymph flows, the flow itself controls lymphatic valve formation. Here, we demonstrate that a mechanically activated ion channel Piezo1 senses oscillating shear stress (OSS) and incorporates the signal into the genetic program controlling lymphatic valve development and maintenance. Time-controlled deletion of Piezo1 using a pan-endothelial Cre driver (Cdh5[PAC]-CreERT2) or lymphatic-specific Cre driver (Prox1-CreERT2) equally inhibited lymphatic valve formation in newborn mice. Furthermore, Piezo1 deletion in adult lymphatics caused substantial lymphatic valve degeneration. Piezo1 knockdown in cultured lymphatic endothelial cells (LECs) largely abrogated the OSS-induced upregulation of the lymphatic valve signature genes. Conversely, ectopic Piezo1 overexpression upregulated the lymphatic valve genes in the absence of OSS. Remarkably, activation of Piezo1 using chemical agonist Yoda1 not only accelerated lymphatic valve formation in animals, but also triggered upregulation of some lymphatic valve genes in cultured LECs without exposure to OSS. In summary, our studies together demonstrate that Piezo1 is the force sensor in the mechanotransduction pathway controlling lymphatic valve development and maintenance, and Piezo1 activation is a potentially novel therapeutic strategy for congenital and surgery-associated lymphedema.
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Affiliation(s)
- Dongwon Choi
- Department of Surgery, and.,Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA
| | - Eunkyung Park
- Department of Surgery, and.,Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA
| | - Eunson Jung
- Department of Surgery, and.,Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA
| | - Boksik Cha
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Somin Lee
- Department of Mechanical and Aerospace Engineering, Seoul National University, Seoul, South Korea
| | - James Yu
- Department of Mechanical and Aerospace Engineering, Seoul National University, Seoul, South Korea
| | - Paul M Kim
- Department of Surgery, and.,Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA
| | - Sunju Lee
- Department of Surgery, and.,Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA
| | - Yeo Jin Hong
- Department of Surgery, and.,Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA
| | - Chester J Koh
- Division of Pediatric Urology, Texas Children's Hospital, Baylor Collexge of Medicine, Houston, Texas, USA
| | - Chang-Won Cho
- Department of Surgery, and.,Traditional Food Research Group, Korea Food Research Institute, Wanju-gun, Jeollabuk-do, South Korea
| | - Yifan Wu
- Department of Surgery, and.,Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA
| | - Noo Li Jeon
- Department of Mechanical and Aerospace Engineering, Seoul National University, Seoul, South Korea
| | | | | | | | - Ivan Bermejo-Moreno
- Department of Aerospace and Mechanical Engineering, University of Southern California, Los Angeles, California, USA
| | - R Sathish Srinivasan
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | | | - Young-Kwon Hong
- Department of Surgery, and.,Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA
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Teuwen LA, Geldhof V, Carmeliet P. How glucose, glutamine and fatty acid metabolism shape blood and lymph vessel development. Dev Biol 2019; 447:90-102. [DOI: 10.1016/j.ydbio.2017.12.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 10/26/2017] [Accepted: 12/01/2017] [Indexed: 12/18/2022]
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Perrault DP, Lee GK, Park SY, Lee S, Choi D, Jung E, Seong YJ, Park EK, Sung C, Yu R, Bouz A, Pourmoussa A, Kim SJ, Hong YK, Wong AK. Small Peptide Modulation of Fibroblast Growth Factor Receptor 3-Dependent Postnatal Lymphangiogenesis. Lymphat Res Biol 2019; 17:19-29. [PMID: 30648916 DOI: 10.1089/lrb.2018.0035] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The fibroblast growth factor receptor (FGFR) family includes transmembrane receptors involved in a wide range of developmental and postdevelopmental biologic processes as well as a wide range of human diseases. In particular, FGFR3 has been implicated in the mechanism by which 9-cis retinoic acid (9-cisRA) induces lymphangiogenesis and improves lymphedema. The purpose of this study was to validate the efficacy of a novel small peptide FGFR3 inhibitor, peptide P3 (VSPPLTLGQLLS), and to elucidate the role of FGFR3 in 9-cisRA-induced lymphangiogenesis using this peptide. METHODS AND RESULTS Peptide P3 effectively inhibited FGFR3 phosphorylation. In vitro, peptide P3-mediated FGFR3 inhibition did not decrease lymphatic endothelial cell (LEC) proliferation, migration, or tubule formation. However, peptide P3-mediated FGFR3 inhibition did block 9-cisRA-stimulated LEC proliferation, migration, and tubule formation. In vivo, peptide P3-mediated FGFR3 inhibition was sufficient to inhibit 9-cisRA-induced tracheal lymphangiogenesis. CONCLUSION FGFR3 does not appear to be essential to nonpromoted LEC proliferation, migration, and tubule formation. However, FGFR3 may play a key role in LEC proliferation, migration, tubule formation, and postnatal in vivo lymphangiogenesis when pharmacologically induced by 9-cisRA. P3 may have the potential to be used as a precise regulatory control element for 9-cisRA-mediated lymphangiogenesis.
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Affiliation(s)
- David P Perrault
- 1 Division of Plastic and Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Gene K Lee
- 1 Division of Plastic and Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Sun Young Park
- 1 Division of Plastic and Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Sunju Lee
- 2 Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Dongwon Choi
- 2 Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Eunson Jung
- 2 Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Young Jin Seong
- 2 Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Eun Kyung Park
- 2 Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Cynthia Sung
- 1 Division of Plastic and Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Roy Yu
- 1 Division of Plastic and Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Antoun Bouz
- 1 Division of Plastic and Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Austin Pourmoussa
- 1 Division of Plastic and Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Soo Jung Kim
- 1 Division of Plastic and Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Young-Kwon Hong
- 2 Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Alex K Wong
- 1 Division of Plastic and Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California
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Presta M, Foglio E, Churruca Schuind A, Ronca R. Long Pentraxin-3 Modulates the Angiogenic Activity of Fibroblast Growth Factor-2. Front Immunol 2018; 9:2327. [PMID: 30349543 PMCID: PMC6187966 DOI: 10.3389/fimmu.2018.02327] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 09/19/2018] [Indexed: 12/15/2022] Open
Abstract
Angiogenesis, the process of new blood vessel formation from pre-existing ones, plays a key role in various physiological and pathological conditions. Alteration of the angiogenic balance, consequent to the deranged production of angiogenic growth factors and/or natural angiogenic inhibitors, is responsible for angiogenesis-dependent diseases, including cancer. Fibroblast growth factor-2 (FGF2) represents the prototypic member of the FGF family, able to induce a complex “angiogenic phenotype” in endothelial cells in vitro and a potent neovascular response in vivo as the consequence of a tight cross talk between pro-inflammatory and angiogenic signals. The soluble pattern recognition receptor long pentraxin-3 (PTX3) is a member of the pentraxin family produced locally in response to inflammatory stimuli. Besides binding features related to its role in innate immunity, PTX3 interacts with FGF2 and other members of the FGF family via its N-terminal extension, thus inhibiting FGF-mediated angiogenic responses in vitro and in vivo. Accordingly, PTX3 inhibits the growth and vascularization of FGF-dependent tumors and FGF2-mediated smooth muscle cell proliferation and artery restenosis. Recently, the characterization of the molecular bases of FGF2/PTX3 interaction has allowed the identification of NSC12, the first low molecular weight pan-FGF trap able to inhibit FGF-dependent tumor growth and neovascularization. The aim of this review is to provide an overview of the impact of PTX3 and PTX3-derived molecules on the angiogenic, inflammatory, and tumorigenic activity of FGF2 and their potential implications for the development of more efficacious anti-FGF therapeutic agents to be used in those clinical settings in which FGFs play a pathogenic role.
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Affiliation(s)
- Marco Presta
- Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy
| | - Eleonora Foglio
- Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy
| | - Ander Churruca Schuind
- Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy
| | - Roberto Ronca
- Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy
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Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, Contarino C, Onengut-Gumuscu S, Farber E, Raper D, Viar KE, Powell RD, Baker W, Dabhi N, Bai R, Cao R, Hu S, Rich SS, Munson JM, Lopes MB, Overall CC, Acton ST, Kipnis J. Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature 2018; 560:185-191. [PMID: 30046111 PMCID: PMC6085146 DOI: 10.1038/s41586-018-0368-8] [Citation(s) in RCA: 905] [Impact Index Per Article: 129.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 06/15/2018] [Indexed: 01/26/2023]
Abstract
Ageing is a major risk factor for many neurological pathologies, but its mechanisms remain unclear. Unlike other tissues, the parenchyma of the central nervous system (CNS) lacks lymphatic vasculature and waste products are removed partly through a paravascular route. (Re)discovery and characterization of meningeal lymphatic vessels has prompted an assessment of their role in waste clearance from the CNS. Here we show that meningeal lymphatic vessels drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes in mice. Impairment of meningeal lymphatic function slows paravascular influx of macromolecules into the brain and efflux of macromolecules from the interstitial fluid, and induces cognitive impairment in mice. Treatment of aged mice with vascular endothelial growth factor C enhances meningeal lymphatic drainage of macromolecules from the cerebrospinal fluid, improving brain perfusion and learning and memory performance. Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer's disease promotes amyloid-β deposition in the meninges, which resembles human meningeal pathology, and aggravates parenchymal amyloid-β accumulation. Meningeal lymphatic dysfunction may be an aggravating factor in Alzheimer's disease pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.
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Affiliation(s)
- Sandro Da Mesquita
- Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA.
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.
| | - Antoine Louveau
- Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
| | - Andrea Vaccari
- Virginia Image and Video Analysis Laboratory, Department of Electrical and Computer Engineering, University of Virginia, Charlottesville, VA, USA
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Igor Smirnov
- Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
| | - R Chase Cornelison
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Kathryn M Kingsmore
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Christian Contarino
- Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
- Department of Mathematics, University of Trento, Povo, Italy
| | - Suna Onengut-Gumuscu
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Emily Farber
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Daniel Raper
- Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
- Department of Neurosurgery, University of Virginia Health System, Charlottesville, VA, USA
| | - Kenneth E Viar
- Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
| | - Romie D Powell
- Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
| | - Wendy Baker
- Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
| | - Nisha Dabhi
- Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
| | - Robin Bai
- Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
| | - Rui Cao
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Song Hu
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Jennifer M Munson
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
- Department of Biomedical Engineering and Mechanics, College of Engineering, Virginia Tech, Blacksburg, VA, USA
| | - M Beatriz Lopes
- Department of Pathology, University of Virginia, Charlottesville, VA, USA
| | - Christopher C Overall
- Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
| | - Scott T Acton
- Virginia Image and Video Analysis Laboratory, Department of Electrical and Computer Engineering, University of Virginia, Charlottesville, VA, USA
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
| | - Jonathan Kipnis
- Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA.
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.
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Abstract
The blood and lymphatic vasculatures are vital to the maintenance of homeostasis. The interaction between two vascular networks throughout the body is precisely controlled to enable oxygen and nutrient delivery, removal of carbon dioxide and metabolic waste, drainage of interstitial fluid, transport of immune cells, and other key activities. Recent years have seen an explosion of information dealing with the development and function of the lymphatic system. The growth of lymphatic vessels, termed lymphangiogenesis, is a high-energy requirement process that involves sprouting, proliferation, migration, and remodeling of lymphatic endothelial cells and capillaries. Although there has been substantial progress in identifying growth factors and their downstream signaling pathways that control lymphangiogenesis, the role of metabolic processes during lymphangiogenesis and their links to growth factor signaling are poorly understood. In this review, we will discuss recent work that has provided new insights into lymphatic metabolism and its role in lymphangiogenesis.
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Affiliation(s)
- Heon-Woo Lee
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Pengchun Yu
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Michael Simons
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
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Abstract
The transcription factor PROX1 is essential for development and cell fate specification. Its function in cancer is context-dependent since PROX1 has been shown to play both oncogenic and tumour suppressive roles. Here, we show that PROX1 suppresses the transcription of MMP14, a metalloprotease involved in angiogenesis and cancer invasion, by binding and suppressing the activity of MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels in vivo and in human LECs increased MMP14 expression. In a hepatocellular carcinoma cell line expressing high endogenous levels of PROX1, its silencing increased both MMP14 expression and MMP14-dependent invasion in 3D. Moreover, PROX1 ectopic expression reduced the MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells in conjunction with MMP14 suppression. Our study uncovers a new transcriptional regulatory mechanism of cancer cell invasion and endothelial cell specification.
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Osaki T, Serrano JC, Kamm RD. Cooperative Effects of Vascular Angiogenesis and Lymphangiogenesis. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2018; 4:120-132. [PMID: 30417074 DOI: 10.1007/s40883-018-0054-2] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
In this study, we modeled lymphangiogenesis and vascular angiogenesis in a microdevice using a tissue engineering approach. Lymphatic vessels (LV) and blood vessels (BV) were fabricated by sacrificial molding with seeding human lymphatic endothelial cells and human umbilical vein endothelial cells into molded microchannels (600 μm diameter). During subsequent perfusion culture, lymphangiogenesis and vascular angiogenesis were induced by addition of phorbol 12-myristate 13-acetate (PMA) and VEGF-C or VEGF-A characterized by podoplanin and Prox-1 expression. The lymphatic capillaries formed button-like junctions treated with dexamethasone. To test the potential for screening anti-angiogenic (vascular and lymphatic) factors, antagonists of VEGF were introduced. We found that an inhibitor of VEGF-R3 did not completely suppress lymphatic angiogenesis with BVs present, although lymphatic angiogenesis was selectively prevented by addition of a VEGF-R3 inhibitor without BVs. To probe the mechanism of action, we focus on matrix metalloproteinase (MMP) secretion by vascular endothelial cells and lymphatic endothelial cells under monoculture or co-culture conditions. We found that vascular angiogenesis facilitated lymphangiogenesis via remodeling of the local microenvironment by the increased secretion of MMP, mainly by endothelial cells. Applications of this model include a drug screening assay for corneal disease and models for tumorigenesis including lymphatic angiogenesis and vascular angiogenesis.
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Affiliation(s)
- Tatsuya Osaki
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Jean C Serrano
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Roger D Kamm
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.,Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.,BioSystems and Micromechanics (BioSyM), Singapore-MIT Alliance for Research and Technology, Singapore, Singapore
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Sáinz-Jaspeado M, Claesson-Welsh L. Cytokines regulating lymphangiogenesis. Curr Opin Immunol 2018; 53:58-63. [PMID: 29680577 DOI: 10.1016/j.coi.2018.04.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 03/24/2018] [Accepted: 04/03/2018] [Indexed: 12/15/2022]
Abstract
Lymphatic vessels are established by differentiation of lymphendothelial progenitors during embryogenesis. Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing ones is rare in the healthy adult but takes place during pathological conditions such as inflammation, tissue repair and tumor growth. Conditions of dysfunctional lymphatics exist after surgical interventions or in certain genetic diseases. A key lymphangiogenic stimulator is vascular endothelial growth factor-C (VEGFC) acting on VEGF receptor-3 (VEGFR3) expressed on lymphendothelial cells. Other cytokines may act directly to regulate lymphangiogenesis positively or negatively, or indirectly by inducing expression of VEGFC. This review describes different known lymphangiogenic cytokines, their mechanism of action and role in lymphangiogenesis in health and disease.
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Affiliation(s)
- Miguel Sáinz-Jaspeado
- Uppsala University, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Dag Hammarskjöldsv. 20, 751 85 Uppsala, Sweden
| | - Lena Claesson-Welsh
- Uppsala University, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Dag Hammarskjöldsv. 20, 751 85 Uppsala, Sweden.
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Li J, Chen H, Li X, Wang L, Gao A, Zhang P, Lin W, Gao W, Yang D, Guo X, Liu J, Dang Q, Sun Y. Co-expression of podoplanin and fibroblast growth factor 1 predicts poor prognosis in patients with lung squamous cell carcinoma. Mol Med Rep 2017; 16:1643-1652. [PMID: 28656229 PMCID: PMC5562063 DOI: 10.3892/mmr.2017.6830] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 02/09/2017] [Indexed: 01/08/2023] Open
Abstract
Podoplanin and fibroblast growth factor (FGF) 1 have been detected more frequently in lung squamous cell carcinoma (SQCC) compared with lung adenocarcinoma. Furthermore, it has been previous demonstrated that FGF1 is located on the edge of tumor nests in certain lung SQCC sections, which resembles the characteristic expression pattern of podoplanin. Podoplanin and FGF1 have roles in lymphangiogenesis and angiogenesis. Based on their consistently specific expression in lung SQCC and similar localization patterns, the present study aimed to investigate whether the expression of podoplanin in tumor cells is correlated with FGF1 expression in lung SQCC and whether their co-expression has clinicopathological significance, particularly for lymphangiogenesis/angiogenesis. The correlation between podoplanin and FGF1 expression in tumor cells of 82 lung SQCC cases was investigated by immunohistochemical staining and the association between the co-expression of podoplanin and FGF1, and clinicopathological factors such as microvessel density (MVD), was examined in these samples. In addition, the prognostic value of co-expression of podoplanin and FGF1 in tumor cells was determined, and the regulation of FGF1 expression and angiogenesis by podoplanin was examined in vitro in a human lung SQCC cell line. Immunohistochemical analysis demonstrated that there was a significant correlation between podoplanin and FGF1 expression in lung SQCC tumor cells (R=0.591; P<0.0001). Co-expression of podoplanin and FGF1 was significantly associated with larger primary tumor size, advanced TNM stage and higher intratumoral MVD. Survival analysis demonstrated that cases with podoplanin and FGF1 double-positive staining had a significantly lower survival rate compared with cases with double-negative staining. In vitro experiments revealed that podoplanin regulated FGF1 expression and affected tube formation of human umbilical vein endothelial cells. Combined, the results demonstrated that podoplanin was co-expressed with FGF1 in lung SQCC and this co-expression was correlated with poor prognosis.
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Affiliation(s)
- Juan Li
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, P.R. China
| | - Han Chen
- Soochow University College of Medicine, Suzhou, Jiangsu 215000, P.R. China
| | - Xiaoqing Li
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, P.R. China
| | - Linlin Wang
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, P.R. China
| | - Aiqin Gao
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, P.R. China
| | - Pei Zhang
- Department of Oncology, Nan Lou Division, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Wenli Lin
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, P.R. China
| | - Wei Gao
- Department of Pathology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, P.R. China
| | - Dong Yang
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, P.R. China
| | - Xiaosun Guo
- Department of Pathophysiology, School of Medicine, Shandong University, Jinan, Shandong 250013, P.R. China
| | - Jie Liu
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, P.R. China
| | - Qi Dang
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, P.R. China
| | - Yuping Sun
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, P.R. China
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Choi D, Park E, Jung E, Seong YJ, Hong M, Lee S, Burford J, Gyarmati G, Peti-Peterdi J, Srikanth S, Gwack Y, Koh CJ, Boriushkin E, Hamik A, Wong AK, Hong YK. ORAI1 Activates Proliferation of Lymphatic Endothelial Cells in Response to Laminar Flow Through Krüppel-Like Factors 2 and 4. Circ Res 2017; 120:1426-1439. [PMID: 28167653 PMCID: PMC6300148 DOI: 10.1161/circresaha.116.309548] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 02/01/2017] [Accepted: 02/06/2017] [Indexed: 11/16/2022]
Abstract
RATIONALE Lymphatic vessels function to drain interstitial fluid from a variety of tissues. Although shear stress generated by fluid flow is known to trigger lymphatic expansion and remodeling, the molecular basis underlying flow-induced lymphatic growth is unknown. OBJECTIVE We aimed to gain a better understanding of the mechanism by which laminar shear stress activates lymphatic proliferation. METHODS AND RESULTS Primary endothelial cells from dermal blood and lymphatic vessels (blood vascular endothelial cells and lymphatic endothelial cells [LECs]) were exposed to low-rate steady laminar flow. Shear stress-induced molecular and cellular responses were defined and verified using various mutant mouse models. Steady laminar flow induced the classic shear stress responses commonly in blood vascular endothelial cells and LECs. Surprisingly, however, only LECs showed enhanced cell proliferation by regulating the vascular endothelial growth factor (VEGF)-A, VEGF-C, FGFR3, and p57/CDKN1C genes. As an early signal mediator, ORAI1, a pore subunit of the calcium release-activated calcium channel, was identified to induce the shear stress phenotypes and cell proliferation in LECs responding to the fluid flow. Mechanistically, ORAI1 induced upregulation of Krüppel-like factor (KLF)-2 and KLF4 in the flow-activated LECs, and the 2 KLF proteins cooperate to regulate VEGF-A, VEGF-C, FGFR3, and p57 by binding to the regulatory regions of the genes. Consistently, freshly isolated LECs from Orai1 knockout embryos displayed reduced expression of KLF2, KLF4, VEGF-A, VEGF-C, and FGFR3 and elevated expression of p57. Accordingly, mouse embryos deficient in Orai1, Klf2, or Klf4 showed a significantly reduced lymphatic density and impaired lymphatic development. CONCLUSIONS Our study identified a molecular mechanism for laminar flow-activated LEC proliferation.
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MESH Headings
- Animals
- Cell Proliferation
- Cyclin-Dependent Kinase Inhibitor p57/genetics
- Cyclin-Dependent Kinase Inhibitor p57/metabolism
- Endothelial Cells/metabolism
- Endothelium, Lymphatic/metabolism
- Endothelium, Lymphatic/pathology
- Endothelium, Lymphatic/physiopathology
- Endothelium, Vascular/metabolism
- Gene Expression Regulation
- Genotype
- Human Umbilical Vein Endothelial Cells/metabolism
- Humans
- Kruppel-Like Factor 4
- Kruppel-Like Transcription Factors/deficiency
- Kruppel-Like Transcription Factors/genetics
- Kruppel-Like Transcription Factors/metabolism
- Lymphangiogenesis
- Mechanotransduction, Cellular
- Mice, Knockout
- ORAI1 Protein/deficiency
- ORAI1 Protein/genetics
- ORAI1 Protein/metabolism
- Phenotype
- Receptor, Fibroblast Growth Factor, Type 3/genetics
- Receptor, Fibroblast Growth Factor, Type 3/metabolism
- Stress, Mechanical
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Vascular Endothelial Growth Factor C/genetics
- Vascular Endothelial Growth Factor C/metabolism
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Affiliation(s)
- Dongwon Choi
- Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
- Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Eunkyung Park
- Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
- Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Eunson Jung
- Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
- Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Young Jin Seong
- Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
- Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Mingu Hong
- Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
- Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Sunju Lee
- Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
- Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - James Burford
- Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Georgina Gyarmati
- Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Janos Peti-Peterdi
- Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Sonal Srikanth
- Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Yousang Gwack
- Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Chester J. Koh
- Pediatric Urology, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas
| | - Evgenii Boriushkin
- Cardiovascular Medicine, Department of Medicine, Stony Brook University, Stony Brook, New York, 11794
| | - Anne Hamik
- Cardiovascular Medicine, Department of Medicine, Stony Brook University, Stony Brook, New York, 11794
- Northport Veterans Affairs Medical Center, Northport, New York
| | - Alex K. Wong
- Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Young-Kwon Hong
- Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
- Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
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Venero Galanternik M, Castranova D, Gore AV, Blewett NH, Jung HM, Stratman AN, Kirby MR, Iben J, Miller MF, Kawakami K, Maraia RJ, Weinstein BM. A novel perivascular cell population in the zebrafish brain. eLife 2017; 6. [PMID: 28395729 PMCID: PMC5423774 DOI: 10.7554/elife.24369] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 03/28/2017] [Indexed: 12/12/2022] Open
Abstract
The blood-brain barrier is essential for the proper homeostasis and function of the CNS, but its mechanism of function is poorly understood. Perivascular cells surrounding brain blood vessels are thought to be important for blood-brain barrier establishment, but their roles are not well defined. Here, we describe a novel perivascular cell population closely associated with blood vessels on the zebrafish brain. Based on similarities in their morphology, location, and scavenger behavior, these cells appear to be the zebrafish equivalent of cells variably characterized as Fluorescent Granular Perithelial cells (FGPs), perivascular macrophages, or 'Mato Cells' in mammals. Despite their macrophage-like morphology and perivascular location, zebrafish FGPs appear molecularly most similar to lymphatic endothelium, and our imaging studies suggest that these cells emerge by differentiation from endothelium of the optic choroidal vascular plexus. Our findings provide the first report of a perivascular cell population in the brain derived from vascular endothelium.
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Affiliation(s)
- Marina Venero Galanternik
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - Daniel Castranova
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - Aniket V Gore
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - Nathan H Blewett
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - Hyun Min Jung
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - Amber N Stratman
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - Martha R Kirby
- Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, United States
| | - James Iben
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - Mayumi F Miller
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - Koichi Kawakami
- Division of Molecular and Developmental Biology, National Institute of Genetics, Mishima, Japan.,Department of Genetics, SOKENDAI (The Graduate University for Advanced Studies), Mishima, Japan
| | - Richard J Maraia
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
| | - Brant M Weinstein
- Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
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45
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Choi D, Park E, Jung E, Seong YJ, Yoo J, Lee E, Hong M, Lee S, Ishida H, Burford J, Peti-Peterdi J, Adams RH, Srikanth S, Gwack Y, Chen CS, Vogel HJ, Koh CJ, Wong AK, Hong YK. Laminar flow downregulates Notch activity to promote lymphatic sprouting. J Clin Invest 2017; 127:1225-1240. [PMID: 28263185 DOI: 10.1172/jci87442] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 01/11/2017] [Indexed: 01/01/2023] Open
Abstract
The major function of the lymphatic system is to drain interstitial fluid from tissue. Functional drainage causes increased fluid flow that triggers lymphatic expansion, which is conceptually similar to hypoxia-triggered angiogenesis. Here, we have identified a mechanotransduction pathway that translates laminar flow-induced shear stress to activation of lymphatic sprouting. While low-rate laminar flow commonly induces the classic shear stress responses in blood endothelial cells and lymphatic endothelial cells (LECs), only LECs display reduced Notch activity and increased sprouting capacity. In response to flow, the plasma membrane calcium channel ORAI1 mediates calcium influx in LECs and activates calmodulin to facilitate a physical interaction between Krüppel-like factor 2 (KLF2), the major regulator of shear responses, and PROX1, the master regulator of lymphatic development. The PROX1/KLF2 complex upregulates the expression of DTX1 and DTX3L. DTX1 and DTX3L, functioning as a heterodimeric Notch E3 ligase, concertedly downregulate NOTCH1 activity and enhance lymphatic sprouting. Notably, overexpression of the calcium reporter GCaMP3 unexpectedly inhibited lymphatic sprouting, presumably by disturbing calcium signaling. Endothelial-specific knockouts of Orai1 and Klf2 also markedly impaired lymphatic sprouting. Moreover, Dtx3l loss of function led to defective lymphatic sprouting, while Dtx3l gain of function rescued impaired sprouting in Orai1 KO embryos. Together, the data reveal a molecular mechanism underlying laminar flow-induced lymphatic sprouting.
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46
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Gambino TJ, Williams SP, Caesar C, Resnick D, Nowell CJ, Farnsworth RH, Achen MG, Stacker SA, Karnezis T. A Three-Dimensional Lymphatic Endothelial Cell Tube Formation Assay to Identify Novel Kinases Involved in Lymphatic Vessel Remodeling. Assay Drug Dev Technol 2017; 15:30-43. [DOI: 10.1089/adt.2016.764] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- T. Jessica Gambino
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Steven P. Williams
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Carol Caesar
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Daniel Resnick
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Cameron J. Nowell
- Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Rae H. Farnsworth
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Marc G. Achen
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
- Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
| | - Steven A. Stacker
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
- Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
| | - Tara Karnezis
- Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
- O'Brien Institute, a Department of St. Vincent's Institute, Fitzroy, Victoria, Australia
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47
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Borges VF, Elder AM, Lyons TR. Deciphering Pro-Lymphangiogenic Programs during Mammary Involution and Postpartum Breast Cancer. Front Oncol 2016; 6:227. [PMID: 27853703 PMCID: PMC5090124 DOI: 10.3389/fonc.2016.00227] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 10/10/2016] [Indexed: 12/12/2022] Open
Abstract
Postpartum breast cancers are a highly metastatic subset of young women’s breast cancers defined as breast cancers diagnosed in the postpartum period or within 5 years of last child birth. Women diagnosed with postpartum breast cancer are nearly twice as likely to develop metastasis and to die from breast cancer when compared with nulliparous women. Additionally, epidemiological studies utilizing multiple cohorts also suggest that nearly half of all breast cancers in women aged <45 qualify as postpartum cases. Understanding the biology that underlies this increased risk for metastasis and death may lead to identification of targeted interventions that will benefit the large number of young women with breast cancer who fall into this subset. Preclinical mouse models of postpartum breast cancer have revealed that breast tumor cells become more aggressive if they are present during the normal physiologic process of postpartum mammary gland involution in mice. As involution appears to be a period of lymphatic growth and remodeling, and human postpartum breast cancers have high peritumor lymphatic vessel density (LVD) and increased incidence of lymph node metastasis (1, 2), we propose that novel insight into is to be gained through the study of the biological mechanisms driving normal postpartum mammary lymphangiogenesis as well as in the microenvironment of postpartum tumors.
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Affiliation(s)
- Virginia F Borges
- Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, CO, USA; Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Alan M Elder
- Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, CO, USA; Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Traci R Lyons
- Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, CO, USA; Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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48
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Venero Galanternik M, Stratman AN, Jung HM, Butler MG, Weinstein BM. Building the drains: the lymphatic vasculature in health and disease. WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY 2016; 5:689-710. [PMID: 27576003 DOI: 10.1002/wdev.246] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 06/30/2016] [Accepted: 07/01/2016] [Indexed: 02/06/2023]
Abstract
The lymphatic vasculature is comprised of a network of endothelial vessels found in close proximity to but separated from the blood vasculature. An essential tissue component of all vertebrates, lymphatics are responsible for the maintenance of fluid homeostasis, dissemination of immune cells, and lipid reabsorption under healthy conditions. When lymphatic vessels are impaired due to invasive surgery, genetic disorders, or parasitic infections, severe fluid build-up accumulates in the affected tissues causing a condition known as lymphedema. Malignant tumors can also directly activate lymphangiogenesis and use these vessels to promote the spread of metastatic cells. Although their first description goes back to the times of Hippocrates, with subsequent anatomical characterization at the beginning of the 20th-century, the lack of identifying molecular markers and tools to visualize these translucent vessels meant that investigation of lymphatic vessels fell well behind research of blood vessels. However, after years under the shadow of the blood vasculature, recent advances in imaging technologies and new genetic and molecular tools have accelerated the pace of research on lymphatic vessel development. These new tools have facilitated both work in classical mammalian models and the emergence of new powerful vertebrate models like zebrafish, quickly driving the field of lymphatic development back into the spotlight. In this review, we summarize the highlights of recent research on the development and function of the lymphatic vascular network in health and disease. WIREs Dev Biol 2016, 5:689-710. doi: 10.1002/wdev.246 For further resources related to this article, please visit the WIREs website.
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Affiliation(s)
- Marina Venero Galanternik
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Amber N Stratman
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Hyun Min Jung
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Matthew G Butler
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Brant M Weinstein
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
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49
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Klein S, Dieterich LC, Mathelier A, Chong C, Sliwa-Primorac A, Hong YK, Shin JW, Lizio M, Itoh M, Kawaji H, Lassmann T, Daub CO, Arner E, Carninci P, Hayashizaki Y, Forrest ARR, Wasserman WW, Detmar M. DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C. J Cell Sci 2016; 129:2573-85. [PMID: 27199372 DOI: 10.1242/jcs.186767] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 05/11/2016] [Indexed: 01/15/2023] Open
Abstract
Lymphangiogenesis plays a crucial role during development, in cancer metastasis and in inflammation. Activation of VEGFR-3 (also known as FLT4) by VEGF-C is one of the main drivers of lymphangiogenesis, but the transcriptional events downstream of VEGFR-3 activation are largely unknown. Recently, we identified a wave of immediate early transcription factors that are upregulated in human lymphatic endothelial cells (LECs) within the first 30 to 80 min after VEGFR-3 activation. Expression of these transcription factors must be regulated by additional pre-existing transcription factors that are rapidly activated by VEGFR-3 signaling. Using transcription factor activity analysis, we identified the homeobox transcription factor HOXD10 to be specifically activated at early time points after VEGFR-3 stimulation, and to regulate expression of immediate early transcription factors, including NR4A1. Gain- and loss-of-function studies revealed that HOXD10 is involved in LECs migration and formation of cord-like structures. Furthermore, HOXD10 regulates expression of VE-cadherin, claudin-5 and NOS3 (also known as e-NOS), and promotes lymphatic endothelial permeability. Taken together, these results reveal an important and unanticipated role of HOXD10 in the regulation of VEGFR-3 signaling in lymphatic endothelial cells, and in the control of lymphangiogenesis and permeability.
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Affiliation(s)
- Sarah Klein
- Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland
| | - Lothar C Dieterich
- Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland
| | - Anthony Mathelier
- Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University British Columbia, Vancouver, British Columbia, Canada V5Z 4H4
| | - Chloé Chong
- Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland
| | - Adriana Sliwa-Primorac
- Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland
| | - Young-Kwon Hong
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA
| | - Jay W Shin
- RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan
| | - Marina Lizio
- RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan
| | - Masayoshi Itoh
- RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan
| | - Hideya Kawaji
- RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan
| | - Timo Lassmann
- RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia 6008, Australia
| | - Carsten O Daub
- RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan
| | - Erik Arner
- RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan
| | | | - Piero Carninci
- RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan
| | - Yoshihide Hayashizaki
- RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama 351-0198, Japan
| | - Alistair R R Forrest
- RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan Cancer and Cell Biology Division, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, Western Australia 6009, Australia
| | - Wyeth W Wasserman
- Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University British Columbia, Vancouver, British Columbia, Canada V5Z 4H4
| | - Michael Detmar
- Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland
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50
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Regenfuß B, Dreisow ML, Hos D, Masli S, Bock F, Cursiefen C. The Naïve Murine Cornea as a Model System to Identify Novel Endogenous Regulators of Lymphangiogenesis: TRAIL and rtPA. Lymphat Res Biol 2016; 13:76-84. [PMID: 26091403 DOI: 10.1089/lrb.2015.0004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND In the murine cornea, which is an established model for analyzing pathologic lymphatic vessel growth, phenotypic heterogeneity of the endogenous lymphatic vessels in the limbus of the cornea was previously described. In this study, the cornea of BALB/c, C57BL/6, and FVB mice with different limbal lymphangiogenic phenotypes was analyzed to identify novel candidates potentially influencing lymphatic vessel growth. METHODS AND RESULTS Pathway specific expression analysis of the cornea was performed to identify novel candidate genes. Corneal protein expression of the respective candidates was analyzed by fluorescent immunohistochemistry. The effect of the candidates on proliferation of human dermal lymphatic endothelial cells (HDLECs) was analyzed by BrdU proliferation ELISA. Thirteen genes were differentially regulated in corneas of mouse strains with more endogenous limbal lymphatic vessels (high-lymphangiogenic) (C57BL/6) compared to mouse strains with less endogenous limbal lymphatic vessels (low-lymphangiogenic) (BALB/c, FVB). Two candidates, Tumor necrosis factor (ligand) superfamily member 10 (Tnfsf10/Trail) and Plasminogen activator, tissue (Plat/tPA) were expressed in the cornea of BALB/c and C57BL/6 mice on the protein level. In vitro, Trail and recombinant tPA inhibited the proliferation of human dermal lymphatic endothelial cells. CONCLUSION Molecular analysis of the naive cornea in mouse strains with different limbal lymphatic phenotypes is a valuable model to identify novel endogenous regulators of lymphangiogenesis.
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Affiliation(s)
- Birgit Regenfuß
- 1 Department of Ophthalmology, University of Cologne , Germany
| | | | - Deniz Hos
- 1 Department of Ophthalmology, University of Cologne , Germany
| | - Sharmila Masli
- 2 Department of Ophthalmology, Boston University School of Medicine , Boston, Massachusetts
| | - Felix Bock
- 1 Department of Ophthalmology, University of Cologne , Germany
| | - Claus Cursiefen
- 1 Department of Ophthalmology, University of Cologne , Germany
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