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1
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Cong B, Cao X, Jiang WG, Ye L. Molecular and Cellular Machinery of Lymphatic Metastasis in Breast Cancer. Onco Targets Ther 2025; 18:199-209. [PMID: 39926374 PMCID: PMC11806925 DOI: 10.2147/ott.s503272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/23/2025] [Indexed: 02/11/2025] Open
Abstract
Breast cancer is one of the most common malignant tumours in women worldwide. A primary route for breast cancer cells to disseminate is through regional lymphatic vessels and nodes. Cancer cell-induced lymphangiogenesis plays a crucial role in lymphatic metastasis and is associated with poor survival of breast cancer. Advances in molecular biology have led to the identification of biomarkers associated with lymphangiogenesis and lymphatic metastasis, including lymphatic vessel endothelial cell (LVEC) markers and tumour microenvironment markers, such as vascular endothelial growth factor receptor 3 (VEGFR3), podoplanin (PDPN), and lymphatic endothelial hyaluronan receptor-1 (LYVE1). LVEC molecular markers play a profound role in both the formation of new lymphatic vessels and the invasive expansion of primary tumour. Abnormal expression of LVEC markers may contribute to lymphatic vessel disease and/or metastasis of cancer cells through the lymphatic system. These molecular markers may present a potential for targeted therapies and precision diagnostics for managing lymphatic metastasis in breast cancer. This review aims to provide a comprehensive summary of the current understanding of the molecular and cellular machinery underlying lymphatic metastasis in breast cancer, with a particular focus on the lymphangiogenic markers and their role in the lymphatic dissemination.
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Affiliation(s)
- Binbin Cong
- Cardiff China Medical Research Collaborative, Division of Cancer & Genetics, Cardiff University School of Medicine, Academic Avenue, Cardiff, UK
- Breast Cancer Centre, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China
| | - Xiaoshan Cao
- Cardiff China Medical Research Collaborative, Division of Cancer & Genetics, Cardiff University School of Medicine, Academic Avenue, Cardiff, UK
- Breast Cancer Centre, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China
| | - Wen G Jiang
- Cardiff China Medical Research Collaborative, Division of Cancer & Genetics, Cardiff University School of Medicine, Academic Avenue, Cardiff, UK
| | - Lin Ye
- Cardiff China Medical Research Collaborative, Division of Cancer & Genetics, Cardiff University School of Medicine, Academic Avenue, Cardiff, UK
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2
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Kanai T, Osawa K, Kajiwara K, Sato Y, Sawa Y. Study of Podoplanin-Deficient Mouse Bone with Mechanical Stress. Dent J (Basel) 2025; 13:61. [PMID: 39996935 PMCID: PMC11854086 DOI: 10.3390/dj13020061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 12/20/2024] [Accepted: 01/23/2025] [Indexed: 02/26/2025] Open
Abstract
Objective: We investigated morphological differences in osteocyte processes between aged mice and our original podoplanin-conditional knockout (cKO) mice in which the floxed exon 3 of podoplanin was deleted by Dmp-1-driven Cre (Dmp1-Cre;PdpnΔ/Δ). Methods: SEM observation on osteocyte cell process, histochemistry for bone remodeling with mechanostress, and RT-PCR for RANKL and M-CSF in podoplanin cKO mouse bone with mechanostress was investigated. Results: SEM observations showed fewer and thinner osteocyte processes in femurs from 23-week-old Dmp1-Cre;PdpnΔ/Δ mice than from 23-week-old wild-type mice, while the numbers of osteocyte processes in femurs and calvarias were similar in 23-week-old Dmp1-Cre;PdpnΔ/Δ mice and 48-week-old wild-type mice. Furthermore, cell process numbers in femurs and calvarias were significantly smaller in 23-week-old Dmp1-Cre;PdpnΔ/Δ mice than in 48-week-old wild-type mice. In the test for differences in alveolar bone resorption under mechanical stress between Dmp1-Cre;PdpnΔ/Δ and wild-type mice, the area of TRAP-positive resorption pits was larger in wild-type mice than in Dmp1-Cre;PdpnΔ/Δ mice. In a quantitative tissue PCR analysis, the mRNA expression levels of RANKL and M-CSF in alveolar bone under mechanical stress were significantly lower in Dmp1-Cre;PdpnΔ/Δ mice than in wild-type mice. These results suggest that a reduction in cell process formation in osteocytes with podoplanin cKO affected the absorption of alveolar bone under mechanical stress in Dmp1-Cre;PdpnΔ/Δ mice. Conclusions: In podoplanin-deficient bone, the deformation of osteocyte processes by mechanical stimuli is not recognized as a stress due to the lower number of cell processes with podoplanin deficiency; therefore, the production of osteoclast migration/differentiation factors by activated osteocytes is not fully induced and macrophage migration to alveolar bone with mechanical stress appeared to be suppressed. These results indicate that podoplanin-dependent osteocyte process formation indirectly plays a key role in sensing mechanical stress in bone.
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Affiliation(s)
- Takenori Kanai
- Department of Orthodontics, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Kita 13 Nishi 7, Kita-ku, Sapporo 060-8586, Japan; (T.K.); (K.O.); (Y.S.)
| | - Kyoko Osawa
- Department of Orthodontics, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Kita 13 Nishi 7, Kita-ku, Sapporo 060-8586, Japan; (T.K.); (K.O.); (Y.S.)
| | - Koichiro Kajiwara
- Department of Oral Growth & Development, Hokkaido University, Kita 13 Nishi 7, Kita-ku, Sapporo 060-8586, Japan;
| | - Yoshiaki Sato
- Department of Orthodontics, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Kita 13 Nishi 7, Kita-ku, Sapporo 060-8586, Japan; (T.K.); (K.O.); (Y.S.)
| | - Yoshihiko Sawa
- Department of Oral Function & Anatomy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-0914, Japan
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3
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Cao Z, Quazi S, Arora S, Osellame LD, Burvenich IJ, Janes PW, Scott AM. Cancer-associated fibroblasts as therapeutic targets for cancer: advances, challenges, and future prospects. J Biomed Sci 2025; 32:7. [PMID: 39780187 PMCID: PMC11715488 DOI: 10.1186/s12929-024-01099-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 11/09/2024] [Indexed: 01/11/2025] Open
Abstract
Research into cancer treatment has been mainly focused on developing therapies to directly target cancer cells. Over the past decade, extensive studies have revealed critical roles of the tumour microenvironment (TME) in cancer initiation, progression, and drug resistance. Notably, cancer-associated fibroblasts (CAFs) have emerged as one of the primary contributors in shaping TME, creating a favourable environment for cancer development. Many preclinical studies have identified promising targets on CAFs, demonstrating remarkable efficacy of some CAF-targeted treatments in preclinical models. Encouraged by these compelling findings, therapeutic strategies have now advanced into clinical evaluation. We aim to provide a comprehensive review of relevant subjects on CAFs, including CAF-related markers and targets, their multifaceted roles, and current landscape of ongoing clinical trials. This knowledge can guide future research on CAFs and advocate for clinical investigations targeting CAFs.
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Affiliation(s)
- Zhipeng Cao
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC, 3084, Australia.
- School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia.
- Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, 3084, Australia.
| | - Sadia Quazi
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC, 3084, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia
| | - Sakshi Arora
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC, 3084, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia
| | - Laura D Osellame
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC, 3084, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia
| | - Ingrid J Burvenich
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC, 3084, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia
| | - Peter W Janes
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC, 3084, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia
- Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia
| | - Andrew M Scott
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC, 3084, Australia.
- School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia.
- Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, 3084, Australia.
- Department of Medicine, University of Melbourne, Melbourne, VIC, 3010, Australia.
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4
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Chan HW, Kuo DY, Shueng PW, Chuang HY. Visualizing the Tumor Microenvironment: Molecular Imaging Probes Target Extracellular Matrix, Vascular Networks, and Immunosuppressive Cells. Pharmaceuticals (Basel) 2024; 17:1663. [PMID: 39770505 PMCID: PMC11676442 DOI: 10.3390/ph17121663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/08/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
The tumor microenvironment (TME) is a critical factor in cancer progression, driving tumor growth, immune evasion, therapeutic resistance, and metastasis. Understanding the dynamic interactions within the TME is essential for advancing cancer management. Molecular imaging provides a non-invasive, real-time, and longitudinal approach to studying the TME, with techniques such as positron emission tomography (PET), magnetic resonance imaging (MRI), and fluorescence imaging offering complementary strengths, including high sensitivity, spatial resolution, and intraoperative precision. Recent advances in imaging probe development have enhanced the ability to target and monitor specific components of the TME, facilitating early cancer diagnosis, therapeutic monitoring, and deeper insights into tumor biology. By integrating these innovations, molecular imaging offers transformative potential for precision oncology, improving diagnostic accuracy and treatment outcomes through a comprehensive assessment of TME dynamics.
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Affiliation(s)
- Hui-Wen Chan
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Li-Nong St., Beitou Dist., Taipei City 112, Taiwan;
| | - Deng-Yu Kuo
- Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
| | - Pei-Wei Shueng
- Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei City 112, Taiwan
| | - Hui-Yen Chuang
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Li-Nong St., Beitou Dist., Taipei City 112, Taiwan;
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5
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Cheok YY, Tan GMY, Chan YT, Abdullah S, Looi CY, Wong WF. Podoplanin and its multifaceted roles in mammalian developmental program. Cells Dev 2024; 180:203943. [PMID: 39111713 DOI: 10.1016/j.cdev.2024.203943] [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: 05/25/2023] [Revised: 06/01/2024] [Accepted: 08/04/2024] [Indexed: 08/18/2024]
Abstract
Podoplanin is a vital molecule which plays an integral part in the regulation of development, immunity, and cancer. Expression of Podoplanin is detected at different early developmental stages of mammalian embryo, and it functions to modulate morphogenesis of various organ systems. In experimental animal models of different genetic backgrounds, absence of Podoplanin results in either embryonic lethality or immediate death upon birth, suggesting the importance of the gene in early developmental processes. This review discusses the gene and protein structure of Podoplanin; and elucidates various functions of Podoplanin in different systems, including central nervous system as well as respiratory, lymphatic, and cardiovascular systems.
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Affiliation(s)
- Yi Ying Cheok
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Grace Min Yi Tan
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Yee Teng Chan
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Suhailah Abdullah
- Department of Medicine, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Chung Yeng Looi
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, 47500 Subang Jaya, Selangor, Malaysia
| | - Won Fen Wong
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia.
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6
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Tomero-Sanz H, Jiménez-Heffernan JA, Fernández-Chacón MC, Cristóbal-García I, Sainz de la Cuesta R, González-Cortijo L, López-Cabrera M, Sandoval P. Detection of Carcinoma-Associated Fibroblasts Derived from Mesothelial Cells via Mesothelial-to-Mesenchymal Transition in Primary Ovarian Carcinomas. Cancers (Basel) 2024; 16:2697. [PMID: 39123425 PMCID: PMC11311419 DOI: 10.3390/cancers16152697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/23/2024] [Accepted: 07/27/2024] [Indexed: 08/12/2024] Open
Abstract
Carcinoma-associated fibroblasts (CAFs) are highly accumulated in the tumor-surrounding stroma of primary epithelial ovarian cancer (OC). CAFs exert important functions for the vascularization, growth, and progression of OC cells. However, the origin of CAFs in primary OC had not yet been studied, and they were assumed to arise from the activation of resident fibroblasts. Here, we compared CAFs in the ovary to CAFs found in peritoneal metastases from patients with advanced OC. Our findings show that CAFs from primary tumors and peritoneal metastases share the expression of mesothelial markers. Therefore, similar to peritoneal carcinomatosis, CAFs in primary ovarian carcinomas may originate from mesothelial cells via a mesothelial-to-mesenchymal transition. The detection of mesothelial-derived CAFs in tumors confined to the ovary and identification of biomarkers could be the key to the early detection of OC and peritoneal spread.
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Affiliation(s)
- Henar Tomero-Sanz
- Tissue and Organ Homeostasis Program, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, 28049 Madrid, Spain;
| | | | | | | | - Ricardo Sainz de la Cuesta
- Hospital Universitario QuirónSalud Madrid, 28223 Madrid, Spain; (R.S.d.l.C.); (L.G.-C.)
- Department of de Medicine, Facultad de Biomédica y Ciencias de la Salud, Universidad Europea de Madrid, 28670 Madrid, Spain
| | - Lucía González-Cortijo
- Hospital Universitario QuirónSalud Madrid, 28223 Madrid, Spain; (R.S.d.l.C.); (L.G.-C.)
- Department of de Medicine, Facultad de Biomédica y Ciencias de la Salud, Universidad Europea de Madrid, 28670 Madrid, Spain
| | - Manuel López-Cabrera
- Tissue and Organ Homeostasis Program, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, 28049 Madrid, Spain;
| | - Pilar Sandoval
- Tissue and Organ Homeostasis Program, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, 28049 Madrid, Spain;
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7
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Mondal DK, Xie C, Pascal GJ, Buraschi S, Iozzo RV. Decorin suppresses tumor lymphangiogenesis: A mechanism to curtail cancer progression. Proc Natl Acad Sci U S A 2024; 121:e2317760121. [PMID: 38652741 PMCID: PMC11067011 DOI: 10.1073/pnas.2317760121] [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: 10/12/2023] [Accepted: 03/25/2024] [Indexed: 04/25/2024] Open
Abstract
The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we identified that decorin down-regulated a cluster of tumor-associated genes involved in lymphatic vessel (LV) development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of LVs, were markedly suppressed at both the mRNA and protein levels, and this suppression correlated with a significant reduction in tumor LVs. We further identified that soluble decorin, but not its homologous proteoglycan biglycan, inhibited LV sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with vascular endothelial growth factor receptor 3 (VEGFR3), the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we identified that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a biological factor with antilymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.
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Affiliation(s)
- Dipon K. Mondal
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA19107
| | - Christopher Xie
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA19107
| | - Gabriel J. Pascal
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA19107
| | - Simone Buraschi
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA19107
| | - Renato V. Iozzo
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA19107
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8
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Reis E Sousa C, Yamasaki S, Brown GD. Myeloid C-type lectin receptors in innate immune recognition. Immunity 2024; 57:700-717. [PMID: 38599166 DOI: 10.1016/j.immuni.2024.03.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/01/2024] [Accepted: 03/05/2024] [Indexed: 04/12/2024]
Abstract
C-type lectin receptors (CLRs) expressed by myeloid cells constitute a versatile family of receptors that play a key role in innate immune recognition. Myeloid CLRs exhibit a remarkable ability to recognize an extensive array of ligands, from carbohydrates and beyond, and encompass pattern-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and markers of altered self. These receptors, classified into distinct subgroups, play pivotal roles in immune recognition and modulation of immune responses. Their intricate signaling pathways orchestrate a spectrum of cellular responses, influencing processes such as phagocytosis, cytokine production, and antigen presentation. Beyond their contributions to host defense in viral, bacterial, fungal, and parasitic infections, myeloid CLRs have been implicated in non-infectious diseases such as cancer, allergies, and autoimmunity. A nuanced understanding of myeloid CLR interactions with endogenous and microbial triggers is starting to uncover the context-dependent nature of their roles in innate immunity, with implications for therapeutic intervention.
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Affiliation(s)
- Caetano Reis E Sousa
- Immunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
| | - Sho Yamasaki
- Molecular Immunology, Research Institute for Microbial Diseases, Immunology Frontier Research Center (IFReC), Osaka University, Suita 565-0871, Japan.
| | - Gordon D Brown
- MRC Centre for Medical Mycology at the University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK.
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9
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Dahms P, Lyons TR. Toward Characterizing Lymphatic Vasculature in the Mammary Gland During Normal Development and Tumor-Associated Remodeling. J Mammary Gland Biol Neoplasia 2024; 29:1. [PMID: 38218743 PMCID: PMC10787674 DOI: 10.1007/s10911-023-09554-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 12/24/2023] [Indexed: 01/15/2024] Open
Abstract
Lymphatic vasculature has been shown to promote metastatic spread of breast cancer. Lymphatic vasculature, which is made up of larger collecting vessels and smaller capillaries, has specialized cell junctions that facilitate cell intravasation. Normally, these junctions are designed to collect immune cells and other cellular components for immune surveillance by lymph nodes, but they are also utilized by cancer cells to facilitate metastasis. Although lymphatic development overall in the body has been well-characterized, there has been little focus on how the lymphatic network changes in the mammary gland during stages of remodeling such as pregnancy, lactation, and postpartum involution. In this review, we aim to define the currently known lymphangiogenic factors and lymphatic remodeling events during mammary gland morphogenesis. Furthermore, we juxtapose mammary gland pubertal development and postpartum involution to show similarities of pro-lymphangiogenic signaling as well as other molecular signals for epithelial cell survival that are critical in these morphogenic stages. The similar mechanisms include involvement of M2-polarized macrophages that contribute to matrix remodeling and vasculogenesis; signal transducer and activator of transcription (STAT) survival and proliferation signaling; and cyclooxygenase 2 (COX2)/Prostaglandin E2 (PGE2) signaling to promote ductal and lymphatic expansion. Investigation and characterization of lymphangiogenesis in the normal mammary gland can provide insight to targetable mechanisms for lymphangiogenesis and lymphatic spread of tumor cells in breast cancer.
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Affiliation(s)
- Petra Dahms
- Division of Medical Oncology Senior Scientist, Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, 12801 E 17th Ave, RC1 South, Mailstop 8117, 80045, Aurora, CO, USA
- Division of Medical Oncology, Anschutz Medical Center, University of Colorado, Aurora, CO, USA
- Anschutz Medical Campus Graduate Program in Cancer Biology, University of Colorado, Aurora, USA
| | - Traci R Lyons
- Division of Medical Oncology Senior Scientist, Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, 12801 E 17th Ave, RC1 South, Mailstop 8117, 80045, Aurora, CO, USA.
- Division of Medical Oncology, Anschutz Medical Center, University of Colorado, Aurora, CO, USA.
- Anschutz Medical Campus Graduate Program in Cancer Biology, University of Colorado, Aurora, USA.
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10
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Fan F, Su B, Kolodychak A, Ekwueme E, Alderfer L, Saha S, Webber MJ, Hanjaya-Putra D. Hyaluronic Acid Hydrogels with Phototunable Supramolecular Cross-Linking for Spatially Controlled Lymphatic Tube Formation. ACS APPLIED MATERIALS & INTERFACES 2023; 15:58181-58195. [PMID: 38065571 PMCID: PMC10739586 DOI: 10.1021/acsami.3c12514] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 11/23/2023] [Accepted: 11/27/2023] [Indexed: 12/22/2023]
Abstract
The dynamics of the extracellular matrix (ECM) influences stem cell differentiation and morphogenesis into complex lymphatic networks. While dynamic hydrogels with stress relaxation properties have been developed, many require detailed chemical processing to tune viscoelasticity, offering a limited opportunity for in situ and spatiotemporal control. Here, a hyaluronic acid (HA) hydrogel is reported with viscoelasticity that is controlled and spatially tunable using UV light to direct the extent of supramolecular and covalent cross-linking interactions. This is achieved using UV-mediated photodimerization of a supramolecular ternary complex of pendant trans-Brooker's Merocyanine (BM) guests and a cucurbit[8]uril (CB[8]) macrocycle. The UV-mediated conversion of this supramolecular complex to its covalent photodimerized form is catalyzed by CB[8], offering a user-directed route to spatially control hydrogel dynamics in combination with orthogonal photopatterning by UV irradiation through photomasks. This material thus achieves spatial heterogeneity of substrate dynamics, recreating features of native ECM without the need for additional chemical reagents. Moreover, these dynamic hydrogels afford spatial control of substrate mechanics to direct human lymphatic endothelial cells (LECs) to form lymphatic cord-like structures (CLS). Specifically, cells cultured on viscoelastic supramolecular hydrogels have enhanced formation of CLS, arising from increased expression of key lymphatic markers, such as LYVE-1, Podoplanin, and Prox1, compared to static elastic hydrogels prepared from fully covalent cross-linking. Viscoelastic hydrogels promote lymphatic CLS formation through the expression of Nrp2, VEGFR2, and VEGFR3 to enhance the VEGF-C stimulation. Overall, viscoelastic supramolecular hydrogels offer a facile route to spatially control lymphatic CLS formation, providing a tool for future studies of basic lymphatic biology and tissue engineering applications.
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Affiliation(s)
- Fei Fan
- Bioengineering
Graduate Program, Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Bo Su
- Chemical
and Biomolecular Engineering, University
of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Alexander Kolodychak
- Chemical
and Biomolecular Engineering, University
of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Ephraim Ekwueme
- Bioengineering
Graduate Program, Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Laura Alderfer
- Bioengineering
Graduate Program, Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Sanjoy Saha
- Bioengineering
Graduate Program, Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Matthew J. Webber
- Chemical
and Biomolecular Engineering, University
of Notre Dame, Notre Dame, Indiana 46556, United States
| | - Donny Hanjaya-Putra
- Bioengineering
Graduate Program, Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
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11
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Ouchida T, Tanaka T, Suzuki H, Uchida K, Nakagawa T, Li G, Nakamura T, Yanaka M, Handa S, Kaneko MK, Kato Y. PMab-301: An Anti-Giraffe Podoplanin Monoclonal Antibody for Immunohistochemistry. Monoclon Antib Immunodiagn Immunother 2023; 42:209-215. [PMID: 38150189 DOI: 10.1089/mab.2023.0020] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2023] Open
Abstract
Immunohistochemistry staining is an essential method in pathological diagnoses. Podoplanin (PDPN) is a specific maker of alveolar epithelium, lymphatic vessels, and glomeruli. In this study, we established a novel anti-giraffe PDPN (girPDPN) mAb, PMab-301, using the Cell-Based Immunization and Screening (CBIS) method. PMab-301 (mouse IgG1, kappa) detected girPDPN in various applications, such as flow cytometry, western blot, and immunohistochemistry. PMab-301 specifically stained type-I alveolar cells using formalin-fixed paraffin-embedded giraffe lung tissues. Our findings suggest the potential usefulness of PMab-301 for the pathophysiological analyses of giraffe tissues.
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Affiliation(s)
- Tsunenori Ouchida
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroyuki Suzuki
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuyuki Uchida
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Takayuki Nakagawa
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Guanjie Li
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takuro Nakamura
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Miyuki Yanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Saori Handa
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
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12
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Sato-Nishiuchi R, Doiguchi M, Morooka N, Sekiguchi K. Polydom/SVEP1 binds to Tie1 and promotes migration of lymphatic endothelial cells. J Cell Biol 2023; 222:e202208047. [PMID: 37338522 PMCID: PMC10281526 DOI: 10.1083/jcb.202208047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 04/13/2023] [Accepted: 06/05/2023] [Indexed: 06/21/2023] Open
Abstract
Polydom is an extracellular matrix protein involved in lymphatic vessel development. Polydom-deficient mice die immediately after birth due to defects in lymphatic vessel remodeling, but the mechanism involved is poorly understood. Here, we report that Polydom directly binds to Tie1, an orphan receptor in the Angiopoietin-Tie axis, and facilitates migration of lymphatic endothelial cells (LECs) in a Tie1-dependent manner. Polydom-induced LEC migration is diminished by PI3K inhibitors but not by an ERK inhibitor, suggesting that the PI3K/Akt signaling pathway is involved in Polydom-induced LEC migration. In line with this possibility, Akt phosphorylation in LECs is enhanced by Polydom although no significant Tie1 phosphorylation is induced by Polydom. LECs also exhibited nuclear exclusion of Foxo1, a signaling event downstream of Akt activation, which was impaired in Polydom-deficient mice. These findings indicate that Polydom is a physiological ligand for Tie1 and participates in lymphatic vessel development through activation of the PI3K/Akt pathway.
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Affiliation(s)
- Ryoko Sato-Nishiuchi
- Division of Matrixome Research and Application, Institute for Protein Research, Osaka University , Suita, Japan
| | - Masamichi Doiguchi
- Division of Matrixome Research and Application, Institute for Protein Research, Osaka University , Suita, Japan
| | - Nanami Morooka
- Division of Matrixome Research and Application, Institute for Protein Research, Osaka University , Suita, Japan
- Department of Medical Physiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kiyotoshi Sekiguchi
- Division of Matrixome Research and Application, Institute for Protein Research, Osaka University , Suita, Japan
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13
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Cazzola A, Calzón Lozano D, Menne DH, Dávila Pedrera R, Liu J, Peña-Jiménez D, Fontenete S, Halin C, Perez-Moreno M. Lymph Vessels Associate with Cancer Stem Cells from Initiation to Malignant Stages of Squamous Cell Carcinoma. Int J Mol Sci 2023; 24:13615. [PMID: 37686421 PMCID: PMC10488284 DOI: 10.3390/ijms241713615] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 08/28/2023] [Accepted: 09/01/2023] [Indexed: 09/10/2023] Open
Abstract
Tumor-associated lymph vessels and lymph node involvement are critical staging criteria in several cancers. In skin squamous cell carcinoma, lymph vessels play a role in cancer development and metastatic spread. However, their relationship with the cancer stem cell niche at early tumor stages remains unclear. To address this gap, we studied the lymph vessel localization at the cancer stem cell niche and observed an association from benign skin lesions to malignant stages of skin squamous cell carcinoma. By co-culturing lymphatic endothelial cells with cancer cell lines representing the initiation and promotion stages, and conducting RNA profiling, we observed a reciprocal induction of cell adhesion, immunity regulation, and vessel remodeling genes, suggesting dynamic interactions between lymphatic and cancer cells. Additionally, imaging analyses of the cultured cells revealed the establishment of heterotypic contacts between cancer cells and lymph endothelial cells, potentially contributing to the observed distribution and maintenance at the cancer stem cell niche, inducing downstream cellular responses. Our data provide evidence for an association of lymph vessels from the early stages of skin squamous cell carcinoma development, opening new avenues for better comprehending their involvement in cancer progression.
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Affiliation(s)
- Anna Cazzola
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - David Calzón Lozano
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Dennis Hirsch Menne
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Raquel Dávila Pedrera
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Jingcheng Liu
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Daniel Peña-Jiménez
- Unidad de Investigación Biomédica, Universidad Alfonso X el Sabio (UAX), Avenida de la Universidad 1, Villanueva de la Cañada, 28691 Madrid, Spain
| | - Silvia Fontenete
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Cornelia Halin
- Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland;
| | - Mirna Perez-Moreno
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
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14
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Mondal DK, Xie C, Buraschi S, Iozzo RV. Decorin suppresses tumor lymphangiogenesis: A mechanism to curtail cancer progression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.28.555187. [PMID: 37693608 PMCID: PMC10491239 DOI: 10.1101/2023.08.28.555187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a pro-survival program and to sustain a pro-angiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we discovered that decorin downregulated a cluster of tumor-associated genes involved in lymphatic vessel development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of lymphatic vessels, were markedly suppressed at both the mRNA and protein levels and this suppression correlated with a significant reduction in tumor lymphatic vessels. We further discovered that soluble decorin, but not its homologous proteoglycan biglycan, inhibited lymphatic vessel sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with VEGFR3, the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we discovered that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a new biological factor with anti-lymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.
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15
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Fuseya S, Izumi H, Hamano A, Murakami Y, Suzuki R, Koiwai R, Hayashi T, Kuno A, Takahashi S, Kudo T. Reduction in disialyl-T antigen levels in mice deficient for both St6galnac3 and St6galnac4 results in blood filling of lymph nodes. Sci Rep 2023; 13:10582. [PMID: 37386100 PMCID: PMC10310836 DOI: 10.1038/s41598-023-37363-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 06/20/2023] [Indexed: 07/01/2023] Open
Abstract
Sialic acid (SA) is present at the terminal ends of carbohydrate chains in glycoproteins and glycolipids and is involved in various biological phenomena. The biological function of the disialyl-T (SAα2-3Galβ1-3(SAα2-6)GalNAcα1-O-Ser/Thr) structure is largely unknown. To elucidate the role of disialyl-T structure and determine the key enzyme from the N-acetylgalactosaminide α2,6-sialyltransferase (St6galnac) family involved in its in vivo synthesis, we generated St6galnac3- and St6galnac4-deficient mice. Both single-knockout mice developed normally without any prominent phenotypic abnormalities. However, the St6galnac3::St6galnact4 double knockout (DKO) mice showed spontaneous hemorrhage of the lymph nodes (LN). To identify the cause of bleeding in the LN, we examined podoplanin, which modifies the disialyl-T structures. The protein expression of podoplanin in the LN of DKO mice was similar to that in wild-type mice. However, the reactivity of MALII lectin, which recognizes disialyl-T, in podoplanin immunoprecipitated from DKO LN was completely abolished. Moreover, the expression of vascular endothelial cadherin was reduced on the cell surface of high endothelial venule (HEV) in the LN, suggesting that hemorrhage was caused by the structural disruption of HEV. These results suggest that podoplanin possesses disialyl-T structure in mice LN and that both St6galnac3 and St6galnac4 are required for disialyl-T synthesis.
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Affiliation(s)
- Sayaka Fuseya
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Ibaraki, 305-8565, Japan
| | - Hiroyuki Izumi
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Ayane Hamano
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Yuka Murakami
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
- School of Integrative and Global Majors, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Riku Suzuki
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Rikako Koiwai
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Takuto Hayashi
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Atsushi Kuno
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Ibaraki, 305-8565, Japan
| | - Satoru Takahashi
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
| | - Takashi Kudo
- Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
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16
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Freise L, Behncke RY, Allerkamp HH, Sandermann TH, Chu NH, Funk EM, Hondrich LJ, Riedel A, Witzel C, Hansmeier NR, Danyel M, Gellhaus A, Dechend R, Hägerling R. Three-Dimensional Histological Characterization of the Placental Vasculature Using Light Sheet Microscopy. Biomolecules 2023; 13:1009. [PMID: 37371590 DOI: 10.3390/biom13061009] [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: 03/20/2023] [Revised: 05/20/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
The placenta is the first embryonic organ, representing the connection between the embryo and the mother, and is therefore necessary for the embryo's growth and survival. To meet the ever-growing need for nutrient and gas exchange, the maternal spiral arteries undergo extensive remodeling, thus increasing the uteroplacental blood flow by 16-fold. However, the insufficient remodeling of the spiral arteries can lead to severe pregnancy-associated disorders, including but not limited to pre-eclampsia. Insufficient endovascular trophoblast invasion plays a key role in the manifestation of pre-eclampsia; however, the underlying processes are complex and still unknown. Classical histopathology is based on two-dimensional section microscopy, which lacks a volumetric representation of the vascular remodeling process. To further characterize the uteroplacental vascularization, a detailed, non-destructive, and subcellular visualization is beneficial. In this study, we use light sheet microscopy for optical sectioning, thus establishing a method to obtain a three-dimensional visualization of the vascular system in the placenta. By introducing a volumetric visualization method of the placenta, we could establish a powerful tool to deeply investigate the heterogeneity of the spiral arteries during the remodeling process, evaluate the state-of-the-art treatment options, effects on vascularization, and, ultimately, reveal new insights into the underlying pathology of pre-eclampsia.
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Affiliation(s)
- Lennart Freise
- Research Group 'Lymphovascular Medicine and Translational 3D-Histopathology', Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health, Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Rose Yinghan Behncke
- Research Group 'Lymphovascular Medicine and Translational 3D-Histopathology', Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health, Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Hanna Helene Allerkamp
- Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria
| | - Tim Henrik Sandermann
- Research Group 'Lymphovascular Medicine and Translational 3D-Histopathology', Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health, Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Ngoc Hai Chu
- Research Group 'Lymphovascular Medicine and Translational 3D-Histopathology', Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health, Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Eva Maria Funk
- Research Group 'Lymphovascular Medicine and Translational 3D-Histopathology', Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health, Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Lukas Jonathan Hondrich
- Research Group 'Lymphovascular Medicine and Translational 3D-Histopathology', Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health, Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Alina Riedel
- Department of Gynecology and Obstetrics, University Hospital Essen, 45147 Essen, Germany
| | - Christian Witzel
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
| | - Nils Rouven Hansmeier
- Research Group 'Lymphovascular Medicine and Translational 3D-Histopathology', Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health, Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
- Research Group 'Development and Disease', Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany
| | - Magdalena Danyel
- Research Group 'Lymphovascular Medicine and Translational 3D-Histopathology', Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health, Charité - Universitätsmedizin Berlin, BIH Academy, Clinician Scientist Program, Charitéplatz 1, 10117 Berlin, Germany
| | - Alexandra Gellhaus
- Department of Gynecology and Obstetrics, University Hospital Essen, 45147 Essen, Germany
| | - Ralf Dechend
- Experimental and Clinical Research Center (ECRC), a Cooperation of Charité - Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine (MDC), Lindenbergerweg 80, 13125 Berlin, Germany
- HELIOS Klinikum, 13125 Berlin, Germany
| | - René Hägerling
- Research Group 'Lymphovascular Medicine and Translational 3D-Histopathology', Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health, Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
- Research Group 'Development and Disease', Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany
- Berlin Institute of Health, Charité - Universitätsmedizin Berlin, BIH Academy, Clinician Scientist Program, Charitéplatz 1, 10117 Berlin, Germany
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17
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Jeong DP, Montes D, Chang HC, Hanjaya-Putra D. Fractal dimension to characterize interactions between blood and lymphatic endothelial cells. Phys Biol 2023; 20:045004. [PMID: 37224822 PMCID: PMC10258918 DOI: 10.1088/1478-3975/acd898] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 05/02/2023] [Accepted: 05/24/2023] [Indexed: 05/26/2023]
Abstract
Spatial patterning of different cell types is crucial for tissue engineering and is characterized by the formation of sharp boundary between segregated groups of cells of different lineages. The cell-cell boundary layers, depending on the relative adhesion forces, can result in kinks in the border, similar to fingering patterns between two viscous partially miscible fluids which can be characterized by its fractal dimension. This suggests that mathematical models used to analyze the fingering patterns can be applied to cell migration data as a metric for intercellular adhesion forces. In this study, we develop a novel computational analysis method to characterize the interactions between blood endothelial cells (BECs) and lymphatic endothelial cells (LECs), which form segregated vasculature by recognizing each other through podoplanin. We observed indiscriminate mixing with LEC-LEC and BEC-BEC pairs and a sharp boundary between LEC-BEC pair, and fingering-like patterns with pseudo-LEC-BEC pairs. We found that the box counting method yields fractal dimension between 1 for sharp boundaries and 1.3 for indiscriminate mixing, and intermediate values for fingering-like boundaries. We further verify that these results are due to differential affinity by performing random walk simulations with differential attraction to nearby cells and generate similar migration pattern, confirming that higher differential attraction between different cell types result in lower fractal dimensions. We estimate the characteristic velocity and interfacial tension for our simulated and experimental data to show that the fractal dimension negatively correlates with capillary number (Ca), further indicating that the mathematical models used to study viscous fingering pattern can be used to characterize cell-cell mixing. Taken together, these results indicate that the fractal analysis of segregation boundaries can be used as a simple metric to estimate relative cell-cell adhesion forces between different cell types.
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Affiliation(s)
- Donghyun Paul Jeong
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, United States of America
| | - Daniel Montes
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, United States of America
| | - Hsueh-Chia Chang
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Center for Stem Cell and Regenerative Medicine, University of Notre Dame, Notre Dame, IN 46556, United States of America
| | - Donny Hanjaya-Putra
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, United States of America
- Center for Stem Cell and Regenerative Medicine, University of Notre Dame, Notre Dame, IN 46556, United States of America
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18
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Bonente D, Bianchi L, De Salvo R, Nicoletti C, De Benedetto E, Bacci T, Bini L, Inzalaco G, Franci L, Chiariello M, Tosi GM, Bertelli E, Barone V. Co-Expression of Podoplanin and CD44 in Proliferative Vitreoretinopathy Epiretinal Membranes. Int J Mol Sci 2023; 24:ijms24119728. [PMID: 37298679 DOI: 10.3390/ijms24119728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 05/30/2023] [Accepted: 06/01/2023] [Indexed: 06/12/2023] Open
Abstract
Epiretinal membranes (ERMs) are sheets of tissue that pathologically develop in the vitreoretinal interface leading to progressive vision loss. They are formed by different cell types and by an exuberant deposition of extracellular matrix proteins. Recently, we reviewed ERMs' extracellular matrix components to better understand molecular dysfunctions that trigger and fuel the onset and development of this disease. The bioinformatics approach we applied delineated a comprehensive overview on this fibrocellular tissue and on critical proteins that could really impact ERM physiopathology. Our interactomic analysis proposed the hyaluronic-acid-receptor cluster of differentiation 44 (CD44) as a central regulator of ERM aberrant dynamics and progression. Interestingly, the interaction between CD44 and podoplanin (PDPN) was shown to promote directional migration in epithelial cells. PDPN is a glycoprotein overexpressed in various cancers and a growing body of evidence indicates its relevant function in several fibrotic and inflammatory pathologies. The binding of PDPN to partner proteins and/or its ligand results in the modulation of signaling pathways regulating proliferation, contractility, migration, epithelial-mesenchymal transition, and extracellular matrix remodeling, all processes that are vital in ERM formation. In this context, the understanding of the PDPN role can help to modulate signaling during fibrosis, hence opening a new line of therapy.
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Affiliation(s)
- Denise Bonente
- Department of Life Sciences, University of Siena, Via A. Moro 2, 53100 Siena, Italy
- Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy
| | - Laura Bianchi
- Section of Functional Proteomics, Department of Life Sciences, University of Siena, Via A. Moro 2, 53100 Siena, Italy
| | - Rossana De Salvo
- Section of Functional Proteomics, Department of Life Sciences, University of Siena, Via A. Moro 2, 53100 Siena, Italy
| | - Claudio Nicoletti
- Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy
| | - Elena De Benedetto
- Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Tommaso Bacci
- Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Luca Bini
- Section of Functional Proteomics, Department of Life Sciences, University of Siena, Via A. Moro 2, 53100 Siena, Italy
| | - Giovanni Inzalaco
- Core Research Laboratory (CRL), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Via Fiorentina 1, 53100 Siena, Italy
- Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale delle Ricerche (CNR), Via Fiorentina 1, 53100 Siena, Italy
- Department of Medical Biotechnologies, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Lorenzo Franci
- Core Research Laboratory (CRL), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Via Fiorentina 1, 53100 Siena, Italy
- Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale delle Ricerche (CNR), Via Fiorentina 1, 53100 Siena, Italy
| | - Mario Chiariello
- Core Research Laboratory (CRL), Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Via Fiorentina 1, 53100 Siena, Italy
- Istituto di Fisiologia Clinica (IFC), Consiglio Nazionale delle Ricerche (CNR), Via Fiorentina 1, 53100 Siena, Italy
| | - Gian Marco Tosi
- Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Eugenio Bertelli
- Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy
| | - Virginia Barone
- Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy
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19
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Mukenge S, Negrini D, Alfieri O. Secondary Lymphedema: Clinical Interdisciplinary Tricks to Overcome an Intriguing Disease. BIOLOGY 2023; 12:biology12050646. [PMID: 37237460 DOI: 10.3390/biology12050646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/11/2023] [Accepted: 04/22/2023] [Indexed: 05/28/2023]
Abstract
Secondary lymphedema is a complex pathology which is very impairing to the patient, consisting of fluid accumulation in the tissue, accompanied by alteration of the interstitial fibrous tissue matrix, deposition of cellular debris and local inflammation. It develops mostly in limbs and/or external genitals because of demolishing oncological surgery with excision of local lymph nodes, or it may depend upon inflammatory or infective diseases, trauma, or congenital vascular malformation. Its treatment foresees various approaches, from simple postural attitude to physical therapy, to minimally invasive lymphatic microsurgery. This review focuses on the different types of evolving peripheral lymphedema and describes potential solutions to single objective symptoms. Particular attention is paid to the newest lymphatic microsurgical approaches, such as lymphatic grafting and lympho-venous shunt application, to successfully heal, in the long term, serious cases of secondary lymphedema of limbs or external genitals. The presented data also emphasize the potential role of minimally invasive microsurgery in enhancing the development of newly formed lymphatic meshes, focusing on the need for further accurate research in the development of microsurgical approaches to the lymphatic vascular system.
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Affiliation(s)
- Sylvain Mukenge
- Department of Cardiothoracic-Vascular Surgery, Vita-Salute San Raffaele University, 20132 Milano, Italy
| | - Daniela Negrini
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy
| | - Ottavio Alfieri
- Department of Cardiothoracic-Vascular Surgery, Vita-Salute San Raffaele University, 20132 Milano, Italy
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20
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Calcific aortic valve disease: mechanisms, prevention and treatment. Nat Rev Cardiol 2023:10.1038/s41569-023-00845-7. [PMID: 36829083 DOI: 10.1038/s41569-023-00845-7] [Citation(s) in RCA: 70] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/01/2023] [Indexed: 02/26/2023]
Abstract
Calcific aortic valve disease (CAVD) is the most common disorder affecting heart valves and is characterized by thickening, fibrosis and mineralization of the aortic valve leaflets. Analyses of surgically explanted aortic valve leaflets have shown that dystrophic mineralization and osteogenic transition of valve interstitial cells co-occur with neovascularization, microhaemorrhage and abnormal production of extracellular matrix. Age and congenital bicuspid aortic valve morphology are important and unalterable risk factors for CAVD, whereas additional risk is conferred by elevated blood pressure and plasma lipoprotein(a) levels and the presence of obesity and diabetes mellitus, which are modifiable factors. Genetic and molecular studies have identified that the NOTCH, WNT-β-catenin and myocardin signalling pathways are involved in the control and commitment of valvular cells to a fibrocalcific lineage. Complex interactions between valve endothelial and interstitial cells and immune cells promote the remodelling of aortic valve leaflets and the development of CAVD. Although no medical therapy is effective for reducing or preventing the progression of CAVD, studies have started to identify actionable targets.
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21
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SARS-CoV-2 Infection: A Clinical and Histopathological Study in Pregnancy. BIOLOGY 2023; 12:biology12020174. [PMID: 36829453 PMCID: PMC9953179 DOI: 10.3390/biology12020174] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/14/2023] [Accepted: 01/19/2023] [Indexed: 01/24/2023]
Abstract
During pregnancy, SARS-CoV-2 infection is associated with several adverse outcomes, including an increased risk of pre-eclampsia, preterm delivery, hypertensive disorders, gestational diabetes, and fetal growth restriction related to the development of placenta vascular abnormalities. We analyzed human placenta from full-term, uncomplicated pregnancies with SARS-CoV-2 infection during the first, second, or third trimesters of gestation. We studied, by the immunohistochemistry technique, the expression of CD34 and podoplanin (PDPN) as markers of vasculogenesis to find any differences. As secondary outcomes, we correlated maternal symptoms with placental histological alterations, including fibrin deposits, lymphocyte infiltration in the villi, edema, and thrombi. Our results showed a PDPN expression around the villous stroma as a plexiform network around the villous nucleus of fetal vessels; significant down-regulation was observed in the villous stroma of women infected during the third trimester. CD34 showed no changes in expression levels. During SARS-CoV-2 infection, the most common maternal symptoms were fever, anosmia, ageusia and asthenia, and the majority were treated with paracetamol, corticosteroids and azithromycin. Patients that required multiple symptomatic treatments evidenced a large amount of fibrin deposition in the villi. Certainly, PDPN plays a key role in healthy placental vasculogenesis and thus in its proper physiology, and SARS-CoV-2 surely alters its normal expression. Further studies are necessary to understand what mechanisms are being altered to try to avoid possible complications for both the mother and fetus in terms of the contagions that will still occur.
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22
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Kato T, Furusawa A, Okada R, Inagaki F, Wakiyama H, Furumoto H, Fukushima H, Okuyama S, Choyke PL, Kobayashi H. Near-Infrared Photoimmunotherapy Targeting Podoplanin-Expressing Cancer Cells and Cancer-Associated Fibroblasts. Mol Cancer Ther 2023; 22:75-88. [PMID: 36223542 PMCID: PMC9812859 DOI: 10.1158/1535-7163.mct-22-0313] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 07/07/2022] [Accepted: 10/05/2022] [Indexed: 02/03/2023]
Abstract
Near-infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that uses an antibody-IRDye700DX (IR700) conjugate that binds to a target followed by the application of NIR light that results in dramatic changes in solubility of the conjugate leading to rapid cell membrane damage and highly immunogenic cell death. NIR-PIT has been used clinically in treating advanced head and neck cancers using an anti-EGFR antibody-IR700 conjugate and has been conditionally approved for clinical use in Japan. NIR-PIT can be employed using a wide range of targeting antibodies. Podoplanin (PDPN), also known as gp38, is a 38 kDa type-1 transmembrane protein associated with lymphatic vessels. In cancer cells and cancer-associated fibroblasts (CAFs), PDPN expression has been widely reported and correlates with poor outcomes in several cancer types. In this study, we evaluated the efficacy of PDPN-targeted NIR-PIT in syngenetic mouse models of cancer. PDPN-targeted NIR-PIT destroyed PDPN-expressing cancer cells and CAFs selectively, suppressing tumor progression and prolonging survival with minimal damage to lymphatic vessels compared with the control group. Interestingly, PDPN-targeted NIR-PIT also exerted a therapeutic effect by targeting CAFs in tumor models which do not express in cancer cells. Furthermore, increased cytotoxic T cells in the tumor bed after PDPN-targeted NIR-PIT were observed, suggesting enhanced host antitumor immunity. Thus, PDPN-targeted NIR-PIT is a promising new cancer therapy strategy for PDPN-expressing cancer cells and CAFs.
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Affiliation(s)
- Takuya Kato
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1088, United States
| | - Aki Furusawa
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1088, United States
| | - Ryuhei Okada
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1088, United States
| | - Fuyuki Inagaki
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1088, United States
| | - Hiroaki Wakiyama
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1088, United States
| | - Hideyuki Furumoto
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1088, United States
| | - Hiroshi Fukushima
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1088, United States
| | - Shuhei Okuyama
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1088, United States
| | - Peter L. Choyke
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1088, United States
| | - Hisataka Kobayashi
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1088, United States
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23
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Abstract
The formation of new blood and lymphatic vessels is essential for both the development of multicellular organisms and (patho)physiological processes like wound repair and tumor growth. In the 1990s, circulating blood platelets were first postulated to regulate tumor angiogenesis by interacting with the endothelium and releasing angiogenic regulators from specialized α granules. Since then, many studies have validated the contributions of platelets to tumor angiogenesis, while uncovering novel roles for platelets in other angiogenic processes like wound resolution and retinal vascular disease. Although the majority of (lymph)angiogenesis occurs during development, platelets appear necessary for lymphatic but not vascular growth, implying their particular importance in pathological cases of adult angiogenesis. Future work is required to determine whether drugs targeting platelet production or function offer a clinically relevant tool to limit detrimental angiogenesis.
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Affiliation(s)
- Harvey G Roweth
- Hematology Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Elisabeth M Battinelli
- Hematology Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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24
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Wang YC, Meng WT, Zhang HF, Zhu J, Wang QL, Mou FF, Guo HD. Lymphangiogenesis, a potential treatment target for myocardial injury. Microvasc Res 2023; 145:104442. [PMID: 36206847 DOI: 10.1016/j.mvr.2022.104442] [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: 03/11/2022] [Revised: 07/26/2022] [Accepted: 09/29/2022] [Indexed: 11/07/2022]
Abstract
The lymphatic vascular system is crucial for the regulation of tissue fluid homeostasis, lipid metabolism, and immune function. Cardiac injury quickly leads to myocardial edema, cardiac lymphatic dysfunction, which ultimately results in myocardial fluid imbalance and cardiac dysfunction. Therefore, lymphangiogenesis-targeted therapy may improve the recovery of myocardial function post cardiac ischemia as observed in myocardial infarction (MI). Indeed, a promising strategy for the clinical treatment of MI relies on vascular endothelial growth factor-C (VEGF-C)-targeted therapy, which promotes lymphangiogenesis. However, much effort is needed to identify the mechanisms of lymphatic transport in response to heart disease. This article reviews regulatory factors of lymphangiogenesis, and discusses the effects of lymphangiogenesis on cardiac function after cardiac injury and its regulatory mechanisms. The involvement of stem cells on lymphangiogenesis was also discussed as stem cells could differentiate into lymphatic endothelial cells (LECs) and stimulate phenotype of LECs.
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Affiliation(s)
- Ya-Chao Wang
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wan-Ting Meng
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hai-Feng Zhang
- Department of Human Anatomy, Xuzhou Medical University, Xuzhou 221004, China
| | - Jing Zhu
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qiang-Li Wang
- School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Fang-Fang Mou
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Hai-Dong Guo
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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25
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Liu X, Cui K, Wu H, Li KS, Peng Q, Wang D, Cowan DB, Dixon JB, Sathish Srinivasan R, Bielenberg DR, Chen K, Wang DZ, Chen Y, Chen H. Promoting Lymphangiogenesis and Lymphatic Growth and Remodeling to Treat Cardiovascular and Metabolic Diseases. Arterioscler Thromb Vasc Biol 2023; 43:e1-e10. [PMID: 36453280 PMCID: PMC9780193 DOI: 10.1161/atvbaha.122.318406] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 11/15/2022] [Indexed: 12/03/2022]
Abstract
Lymphatic vessels are low-pressure, blind-ended tubular structures that play a crucial role in the maintenance of tissue fluid homeostasis, immune cell trafficking, and dietary lipid uptake and transport. Emerging research has indicated that the promotion of lymphatic vascular growth, remodeling, and function can reduce inflammation and diminish disease severity in several pathophysiologic conditions. In particular, recent groundbreaking studies have shown that lymphangiogenesis, which describes the formation of new lymphatic vessels from the existing lymphatic vasculature, can be beneficial for the alleviation and resolution of metabolic and cardiovascular diseases. Therefore, promoting lymphangiogenesis represents a promising therapeutic approach. This brief review summarizes the most recent findings related to the modulation of lymphatic function to treat metabolic and cardiovascular diseases such as obesity, myocardial infarction, atherosclerosis, and hypertension. We also discuss experimental and therapeutic approaches to enforce lymphatic growth and remodeling as well as efforts to define the molecular and cellular mechanisms underlying these processes.
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Affiliation(s)
- Xiaolei Liu
- Lemole Center for Integrated Lymphatics Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA (X.L.)
| | - Kui Cui
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, MA (K.C., K.S.L., Q.P., D.W., D.B.C., D.R.B., H.C.)
| | | | - Kathryn S Li
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, MA (K.C., K.S.L., Q.P., D.W., D.B.C., D.R.B., H.C.)
| | - Qianman Peng
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, MA (K.C., K.S.L., Q.P., D.W., D.B.C., D.R.B., H.C.)
| | - Donghai Wang
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, MA (K.C., K.S.L., Q.P., D.W., D.B.C., D.R.B., H.C.)
| | - Douglas B Cowan
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, MA (K.C., K.S.L., Q.P., D.W., D.B.C., D.R.B., H.C.)
| | - J Brandon Dixon
- George W. Woodruff School of Mechanical Engineering, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta (J.B.D.)
| | - R Sathish Srinivasan
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City (R.S.S.)
| | - Diane R Bielenberg
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, MA (K.C., K.S.L., Q.P., D.W., D.B.C., D.R.B., H.C.)
| | - Kaifu Chen
- Department of Cardiology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, MA (K.C.)
| | - Da-Zhi Wang
- USF Heart Institute, Center for Regenerative Medicine, College of Medicine Internal Medicine, University of South Florida, Tampa (D.Z.W.)
| | - Yabing Chen
- Department of Pathology, Birmingham Veterans Affairs Medical Center, University of Alabama at Birmingham (Y.C.)
| | - Hong Chen
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, MA (K.C., K.S.L., Q.P., D.W., D.B.C., D.R.B., H.C.)
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26
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Harris NR, Bálint L, Dy DM, Nielsen NR, Méndez HG, Aghajanian A, Caron KM. The ebb and flow of cardiac lymphatics: a tidal wave of new discoveries. Physiol Rev 2023; 103:391-432. [PMID: 35953269 PMCID: PMC9576179 DOI: 10.1152/physrev.00052.2021] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 06/16/2022] [Accepted: 07/18/2022] [Indexed: 12/16/2022] Open
Abstract
The heart is imbued with a vast lymphatic network that is responsible for fluid homeostasis and immune cell trafficking. Disturbances in the forces that regulate microvascular fluid movement can result in myocardial edema, which has profibrotic and proinflammatory consequences and contributes to cardiovascular dysfunction. This review explores the complex relationship between cardiac lymphatics, myocardial edema, and cardiac disease. It covers the revised paradigm of microvascular forces and fluid movement around the capillary as well as the arsenal of preclinical tools and animal models used to model myocardial edema and cardiac disease. Clinical studies of myocardial edema and their prognostic significance are examined in parallel to the recent elegant animal studies discerning the pathophysiological role and therapeutic potential of cardiac lymphatics in different cardiovascular disease models. This review highlights the outstanding questions of interest to both basic scientists and clinicians regarding the roles of cardiac lymphatics in health and disease.
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Affiliation(s)
- Natalie R Harris
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - László Bálint
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Danielle M Dy
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Natalie R Nielsen
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Hernán G Méndez
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Amir Aghajanian
- Division of Cardiology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Kathleen M Caron
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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27
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Nanamiya R, Suzuki H, Takei J, Li G, Goto N, Harada H, Saito M, Tanaka T, Asano T, Kaneko MK, Kato Y. Development of Monoclonal Antibody 281-mG 2a-f Against Golden Hamster Podoplanin. Monoclon Antib Immunodiagn Immunother 2022; 41:311-319. [PMID: 35483059 DOI: 10.1089/mab.2021.0058] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Golden (Syrian) hamster (Mesocricetus auratus) is a small animal model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Pathological analyses of the tissues are required to understand the pathogenesis of SARS-CoV-2 and the evaluation of therapeutic modalities, including neutralizing monoclonal antibodies (mAbs). However, mAbs that recognize the golden hamster-derived antigens and distinguish specific cell types, such as the pneumocytes, are limited. Podoplanin (PDPN) is an essential marker of lung type I alveolar epithelial cells, kidney podocytes, and lymphatic endothelial cells. In this study, an anti-Chinese hamster (Cricetulus griseus) PDPN mAb PMab-281 (IgG3, kappa) was established using the Cell-Based Immunization and Screening (CBIS) method. A defucosylated mouse IgG2a version of PMab-281 (281-mG2a-f) was also developed. The 281-mG2a-f strongly recognized both the Chinese hamster and the golden hamster PDPN using flow cytometry and could detect lung type I alveolar epithelial cells, lymphatic endothelial cells, and Bowman's capsules in the kidney from the golden hamster using immunohistochemistry. These results suggest the usefulness of 281-mG2a-f for analyzing the golden hamster-derived tissues and cells for SARS-CoV-2 research.
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Affiliation(s)
- Ren Nanamiya
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Junko Takei
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Japan
| | - Guanjie Li
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Nohara Goto
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Hiroyuki Harada
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Japan
| | - Masaki Saito
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Teizo Asano
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
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28
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Inhaled particulate accumulation with age impairs immune function and architecture in human lung lymph nodes. Nat Med 2022; 28:2622-2632. [PMID: 36411343 PMCID: PMC9835154 DOI: 10.1038/s41591-022-02073-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 10/03/2022] [Indexed: 11/22/2022]
Abstract
Older people are particularly susceptible to infectious and neoplastic diseases of the lung and it is unclear how lifelong exposure to environmental pollutants affects respiratory immune function. In an analysis of human lymph nodes (LNs) from 84 organ donors aged 11-93 years, we found a specific age-related decline in lung-associated, but not gut-associated, LN immune function linked to the accumulation of inhaled atmospheric particulate matter. Increasing densities of particulates were found in lung-associated LNs with age, but not in the corresponding gut-associated LNs. Particulates were specifically contained within CD68+CD169- macrophages, which exhibited decreased activation, phagocytic capacity, and altered cytokine production compared with non-particulate-containing macrophages. The structures of B cell follicles and lymphatic drainage were also disrupted in lung-associated LNs with particulates. Our results reveal that the cumulative effects of environmental exposure and age may compromise immune surveillance of the lung via direct effects on immune cell function and lymphoid architecture.
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29
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Poojari A, Dev K, Rabiee A. Lipedema: Insights into Morphology, Pathophysiology, and Challenges. Biomedicines 2022; 10:biomedicines10123081. [PMID: 36551837 PMCID: PMC9775665 DOI: 10.3390/biomedicines10123081] [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: 10/26/2022] [Revised: 11/26/2022] [Accepted: 11/28/2022] [Indexed: 12/02/2022] Open
Abstract
Lipedema is an adipofascial disorder that almost exclusively affects women. Lipedema leads to chronic pain, swelling, and other discomforts due to the bilateral and asymmetrical expansion of subcutaneous adipose tissue. Although various distinctive morphological characteristics, such as the hyperproliferation of fat cells, fibrosis, and inflammation, have been characterized in the progression of lipedema, the mechanisms underlying these changes have not yet been fully investigated. In addition, it is challenging to reduce the excessive fat in lipedema patients using conventional weight-loss techniques, such as lifestyle (diet and exercise) changes, bariatric surgery, and pharmacological interventions. Therefore, lipedema patients also go through additional psychosocial distress in the absence of permanent treatment. Research to understand the pathology of lipedema is still in its infancy, but promising markers derived from exosome, cytokine, lipidomic, and metabolomic profiling studies suggest a condition distinct from obesity and lymphedema. Although genetics seems to be a substantial cause of lipedema, due to the small number of patients involved in such studies, the extrapolation of data at a broader scale is challenging. With the current lack of etiology-guided treatments for lipedema, the discovery of new promising biomarkers could provide potential solutions to combat this complex disease. This review aims to address the morphological phenotype of lipedema fat, as well as its unclear pathophysiology, with a primary emphasis on excessive interstitial fluid, extracellular matrix remodeling, and lymphatic and vasculature dysfunction. The potential mechanisms, genetic implications, and proposed biomarkers for lipedema are further discussed in detail. Finally, we mention the challenges related to lipedema and emphasize the prospects of technological interventions to benefit the lipedema community in the future.
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30
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Xu Y, Cheng L, Yuan L, Yi Q, Xiao L, Chen H. Progress on Brain and Ocular Lymphatic System. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6413553. [PMID: 36425338 PMCID: PMC9681545 DOI: 10.1155/2022/6413553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/11/2022] [Accepted: 10/26/2022] [Indexed: 02/06/2024]
Abstract
In recent years, 2 major discoveries have modified the traditional understanding of the brain. First, meningeal lymphatic vessels (MLV) were found in the dural sinus, which may absorb and drain cerebrospinal fluid (CSF). Second, the glymphatic system was discovered, composed of para-arterial CSF influx channel, paravenous interstitial fluid (ISF) efflux channel, and the water channel aquaporin-4 (AQP4) in astrocytes connecting the 2 channels. Accumulating evidence demonstrates that the lymphatic system of the brain plays a vital role within the circulation of CSF and, therefore, in the removal of metabolites. Therefore, it is involved in the incidence and development of some central nervous system (CNS) diseases. The optic nerve and retina are the extension of the CNS in the orbit. Whether they have a lymphatic system and how they clear the metabolites of the optic nerve and retina are still unclear. Recent studies have found that the ocular lymphatic system has a crucial impact on bounding eye diseases, like disorders of the optic nerve and retina. Therefore, here we review the recent research progress concerning the structure and function of MLV and glymphatic system. We also discuss the biomarkers for identification of lymphatic vessels, the composition of ocular lymphatic systems, and the possible association with diseases.
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Affiliation(s)
- Yang Xu
- Eye School of Chengdu University of TCM, Chengdu, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection, China
| | - Lu Cheng
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China
- National Clinical Research Center for Eye Diseases, Shanghai, China
| | - Lu Yuan
- Eye School of Chengdu University of TCM, Chengdu, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection, China
| | - Qianya Yi
- Eye School of Chengdu University of TCM, Chengdu, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection, China
| | - Liuyi Xiao
- University of Electronic Science and Technology of China, Chengdu, China
| | - Hui Chen
- Eye School of Chengdu University of TCM, Chengdu, China
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China
- National Clinical Research Center for Eye Diseases, Shanghai, China
- University of Electronic Science and Technology of China, Chengdu, China
- University of Shanghai for Science and Technology, Shanghai, China
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31
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Jeong DP, Hall E, Neu E, Hanjaya-Putra D. Podoplanin is Responsible for the Distinct Blood and Lymphatic Capillaries. Cell Mol Bioeng 2022; 15:467-478. [PMID: 36444348 PMCID: PMC9700554 DOI: 10.1007/s12195-022-00730-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 07/21/2022] [Indexed: 11/03/2022] Open
Abstract
Abstract
Introduction
Controlling the formation of blood and lymphatic vasculatures is crucial for engineered tissues. Although the lymphatic vessels originate from embryonic blood vessels, the two retain functional and physiological differences even as they develop in the vicinity of each other. This suggests that there is a previously unknown molecular mechanism by which blood (BECs) and lymphatic endothelial cells (LECs) recognize each other and coordinate to generate distinct capillary networks.
Methods
We utilized Matrigel and fibrin assays to determine how cord-like structures (CLS) can be controlled by altering LEC and BEC identity through podoplanin (PDPN) and folliculin (FLCN) expressions. We generated BECΔFLCN and LECΔPDPN, and observed cell migration to characterize loss lymphatic and blood characteristics due to respective knockouts.
Results
We observed that LECs and BECs form distinct CLS in Matrigel and fibrin gels despite being cultured in close proximity with each other. We confirmed that the LECs and BECs do not recognize each other through paracrine signaling, as proliferation and migration of both cells were unaffected by paracrine signals. On the other hand, we found PDPN to be the key surface protein that is responsible for LEC-BEC recognition, and LECs lacking PDPN became pseudo-BECs and vice versa. We also found that FLCN maintains BEC identity through downregulation of PDPN.
Conclusions
Overall, these observations reveal a new molecular pathway through which LECs and BECs form distinct CLS through physical contact by PDPN which in turn is regulated by FLCN, which has important implications toward designing functional engineered tissues.
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Okada Y, Suzuki H, Kaneko MK, Kato Y. Epitope Mapping of an Anti-elephant Podoplanin Monoclonal Antibody (PMab-295) Using Enzyme-Linked Immunosorbent Assay. Monoclon Antib Immunodiagn Immunother 2022; 41:221-227. [PMID: 35917553 DOI: 10.1089/mab.2022.0017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Podoplanin (PDPN) is a marker of lung type I alveolar cells, kidney podocytes, and lymphatic endothelial cells. The overexpression of PDPN contributes to the malignant progression of tumors. Therefore, the development of anti-PDPN monoclonal antibodies (mAbs) to animals is essential to evaluate the pathogenesis and cellular functions. Using peptide immunization, we previously developed an anti-elephant PDPN (elePDPN) mAb, PMab-295, which is useful for flow cytometry, Western blotting, and immunohistochemistry. In this study, we determined the critical epitope of PMab-295 by enzyme-linked immunosorbent assay (ELISA). We performed ELISA with the alanine-substituted peptides of elePDPN extracellular domain (amino acids 38-51), and found that PMab-295 did not recognize the alanine-substituted peptides of M41A, P44A, and E47A. Furthermore, these peptides could not inhibit the recognition of PMab-295 to elePDPN-expressing cells by flow cytometry and immunohistochemistry. The results indicate that the binding epitope of PMab-295 includes Met41, Pro44, and Glu47 of elePDPN.
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Affiliation(s)
- Yuki Okada
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
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Immunomodulatory Responses of Subcapsular Sinus Floor Lymphatic Endothelial Cells in Tumor-Draining Lymph Nodes. Cancers (Basel) 2022; 14:cancers14153602. [PMID: 35892863 PMCID: PMC9330828 DOI: 10.3390/cancers14153602] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 07/20/2022] [Indexed: 11/17/2022] Open
Abstract
Tumor-draining lymph nodes (LNs), composed of lymphocytes, antigen-presenting cells, and stromal cells, are highly relevant for tumor immunity and the efficacy of immunotherapies. Lymphatic endothelial cells (LECs) represent an important stromal cell type within LNs, and several distinct subsets of LECs that interact with various immune cells and regulate immune responses have been identified. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize LECs from LNs draining B16F10 melanomas compared to non-tumor-draining LNs. Several upregulated genes with immune-regulatory potential, especially in LECs lining the subcapsular sinus floor (fLECs), were identified and validated. Interestingly, some of these genes, namely, podoplanin, CD200, and BST2, affected the adhesion of macrophages to LN LECs in vitro. Congruently, lymphatic-specific podoplanin deletion led to a decrease in medullary sinus macrophages in tumor-draining LNs in vivo. In summary, our data show that tumor-derived factors induce transcriptional changes in LECs of the draining LNs, especially the fLECs, and that these changes may affect tumor immunity. We also identified a new function of podoplanin, which is expressed on all LECs, in mediating macrophage adhesion to LECs and their correct localization in LN sinuses.
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Near-Infrared Photoimmunotherapy for Thoracic Cancers: A Translational Perspective. Biomedicines 2022; 10:biomedicines10071662. [PMID: 35884975 PMCID: PMC9312913 DOI: 10.3390/biomedicines10071662] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/23/2022] [Accepted: 07/07/2022] [Indexed: 12/18/2022] Open
Abstract
The conventional treatment of thoracic tumors includes surgery, anticancer drugs, radiation, and cancer immunotherapy. Light therapy for thoracic tumors has long been used as an alternative; conventional light therapy also called photodynamic therapy (PDT) has been used mainly for early-stage lung cancer. Recently, near-infrared photoimmunotherapy (NIR-PIT), which is a completely different concept from conventional PDT, has been developed and approved in Japan for the treatment of recurrent and previously treated head and neck cancer because of its specificity and effectiveness. NIR-PIT can apply to any target by changing to different antigens. In recent years, it has become clear that various specific and promising targets are highly expressed in thoracic tumors. In combination with these various specific targets, NIR-PIT is expected to be an ideal therapeutic approach for thoracic tumors. Additionally, techniques are being developed to further develop NIR-PIT for clinical practice. In this review, NIR-PIT is introduced, and its potential therapeutic applications for thoracic cancers are described.
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35
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Bonetti G, Paolacci S, Samaja M, Maltese PE, Michelini S, Michelini S, Michelini S, Ricci M, Cestari M, Dautaj A, Medori MC, Bertelli M. Low Efficacy of Genetic Tests for the Diagnosis of Primary Lymphedema Prompts Novel Insights into the Underlying Molecular Pathways. Int J Mol Sci 2022; 23:ijms23137414. [PMID: 35806420 PMCID: PMC9267137 DOI: 10.3390/ijms23137414] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/16/2022] [Accepted: 06/29/2022] [Indexed: 02/07/2023] Open
Abstract
Lymphedema is a chronic inflammatory disorder caused by ineffective fluid uptake by the lymphatic system, with effects mainly on the lower limbs. Lymphedema is either primary, when caused by genetic mutations, or secondary, when it follows injury, infection, or surgery. In this study, we aim to assess to what extent the current genetic tests detect genetic variants of lymphedema, and to identify the major molecular pathways that underlie this rather unknown disease. We recruited 147 individuals with a clinical diagnosis of primary lymphedema and used established genetic tests on their blood or saliva specimens. Only 11 of these were positive, while other probands were either negative (63) or inconclusive (73). The low efficacy of such tests calls for greater insight into the underlying mechanisms to increase accuracy. For this purpose, we built a molecular pathways diagram based on a literature analysis (OMIM, Kegg, PubMed, Scopus) of candidate and diagnostic genes. The PI3K/AKT and the RAS/MAPK pathways emerged as primary candidates responsible for lymphedema diagnosis, while the Rho/ROCK pathway appeared less critical. The results of this study suggest the most important pathways involved in the pathogenesis of lymphedema, and outline the most promising diagnostic and candidate genes to diagnose this disease.
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Affiliation(s)
- Gabriele Bonetti
- MAGI’s LAB, 38068 Rovereto, Italy; (S.P.); (P.E.M.); (A.D.); (M.C.M.); (M.B.)
- Correspondence: ; Tel.: +39-0365-62-061
| | - Stefano Paolacci
- MAGI’s LAB, 38068 Rovereto, Italy; (S.P.); (P.E.M.); (A.D.); (M.C.M.); (M.B.)
| | | | | | - Sandro Michelini
- Vascular Diagnostics and Rehabilitation Service, Marino Hospital, ASL Roma 6, 00047 Marino, Italy;
| | - Serena Michelini
- Unit of Physical Medicine, “Sapienza” University of Rome, 00185 Rome, Italy;
| | | | - Maurizio Ricci
- Division of Rehabilitation Medicine, Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, 60126 Ancona, Italy;
| | - Marina Cestari
- Study Centre Pianeta Linfedema, 05100 Terni, Italy;
- Lymphology Sector of the Rehabilitation Service, USLUmbria2, 05100 Terni, Italy
| | - Astrit Dautaj
- MAGI’s LAB, 38068 Rovereto, Italy; (S.P.); (P.E.M.); (A.D.); (M.C.M.); (M.B.)
| | - Maria Chiara Medori
- MAGI’s LAB, 38068 Rovereto, Italy; (S.P.); (P.E.M.); (A.D.); (M.C.M.); (M.B.)
| | - Matteo Bertelli
- MAGI’s LAB, 38068 Rovereto, Italy; (S.P.); (P.E.M.); (A.D.); (M.C.M.); (M.B.)
- MAGI Group, 25010 San Felice del Benaco, Italy;
- MAGI Euregio, 39100 Bolzano, Italy
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Zhang Z, Zhang N, Yu J, Xu W, Gao J, Lv X, Wen Z. The Role of Podoplanin in the Immune System and Inflammation. J Inflamm Res 2022; 15:3561-3572. [PMID: 35747250 PMCID: PMC9212786 DOI: 10.2147/jir.s366620] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 06/08/2022] [Indexed: 11/23/2022] Open
Abstract
Podoplanin is a small cell-surface mucin-like glycoprotein that participates in multiple physiological and pathological processes. Podoplanin exerts an important function in the immune response and is upregulated in fibroblasts, macrophages, T helper cells, and epithelial cells during inflammation. Herein, we summarize the latest knowledge on the functional expression of podoplanin in the immune system and review the contribution of podoplanin to several inflammatory diseases. Furthermore, we discuss podoplanin as a novel therapeutic target for various inflammatory diseases.
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Affiliation(s)
- Zhiyuan Zhang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Nan Zhang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Jing Yu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Wenting Xu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Jiameng Gao
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Xin Lv
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Zongmei Wen
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
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Goto N, Suzuki H, Tanaka T, Asano T, Kaneko MK, Kato Y. Epitope Mapping of an Anti-Chinese/Golden Hamster Podoplanin Monoclonal Antibody. Monoclon Antib Immunodiagn Immunother 2022; 41:163-169. [PMID: 35666546 DOI: 10.1089/mab.2022.0014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Chinese hamster (Cricetulus griseus) and golden hamster (Mesocricetus auratus) are important animal models of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, which affect several organs, including respiratory tract, lung, and kidney. Podoplanin (PDPN) is a marker of lung type I alveolar cells, kidney podocytes, and lymphatic endothelial cells. The development of anti-PDPN monoclonal antibodies (mAbs) for these animals is essential to evaluate the pathogenesis by SARS-CoV-2 infections. Using the Cell-Based Immunization and Screening method, we previously developed an anti-Chinese hamster PDPN (ChamPDPN) mAb, PMab-281 (mouse IgG3, kappa), and further changed its subclass into IgG2a (281-mG2a-f), both of which can recognize not only ChamPDPN but also golden hamster PDPN (GhamPDPN) by flow cytometry and immunohistochemistry. In this study, we examined the critical epitope of 281-mG2a-f, using enzyme-linked immunosorbent assay (ELISA) with synthesized peptides. First, we performed ELISA with peptides derived from ChamPDPN and GhamPDPN extracellular domain, and found that 281-mG2a-f reacted with the peptides, which commonly possess the KIPFEELxT sequence. Next, we analyzed the reaction with the alanine-substituted mutants, and revealed that 281-mG2a-f did not recognize the alanine-substituted peptides of I75A, F77A, and E79A of ChamPDPN. Furthermore, these peptides could not inhibit the recognition of 281-mG2a-f to ChamPDPN-expressing cells by flow cytometry. The results indicate that the binding epitope of 281-mG2a-f includes Ile75, Phe77, and Glu79 of ChamPDPN, which are shared with GhamPDPN.
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Affiliation(s)
- Nohara Goto
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Teizo Asano
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
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Gonzales GB, Njunge JM, Gichuki BM, Wen B, Ngari M, Potani I, Thitiri J, Laukens D, Voskuijl W, Bandsma R, Vanmassenhove J, Berkley JA. The role of albumin and the extracellular matrix on the pathophysiology of oedema formation in severe malnutrition. EBioMedicine 2022; 79:103991. [PMID: 35398787 PMCID: PMC9014367 DOI: 10.1016/j.ebiom.2022.103991] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/21/2022] [Accepted: 03/24/2022] [Indexed: 02/09/2023] Open
Abstract
BACKGROUND While fluid flows in a steady state from plasma, through interstitium, and into the lymph compartment, altered fluid distribution and oedema can result from abnormal Starling's forces, increased endothelial permeability or impaired lymphatic drainage. The mechanism of oedema formation, especially the primary role of hypoalbuminaemia, remains controversial. Here, we explored the roles of albumin and albumin-independent mechanisms in oedema formation among children with severe malnutrition (SM). METHODS We performed secondary analysis of data obtained from two independent clinical trials in Malawi and Kenya (NCT02246296 and NCT00934492). We then used an unconventional strategy of comparing children with kwashiorkor and marasmus by matching (discovery cohort, n = 144) and normalising (validation cohort, n = 98, 2 time points) for serum albumin. Untargeted proteomics was used in the discovery cohort to determine plausible albumin-independent mechanisms associated with oedema, which was validated using enzyme-linked immunosorbent assay and multiplex assays in the validation cohort. FINDINGS We demonstrated that low serum albumin is necessary but not sufficient to develop oedema in SM. We further found that markers of extracellular matrix (ECM) degradation rather than markers of EG degradation distinguished oedematous and non-oedematous children with SM. INTERPRETATION Our results show that oedema formation has both albumin-dependent and independent mechanisms. ECM integrity appears to have a greater role in oedema formation than EG shedding in SM. FUNDING Research Foundation Flanders (FWO), Thrasher Foundation (15122 and 9403), VLIR-UOS-Ghent University Global Minds Fund, Bill & Melinda Gates Foundation (OPP1131320), MRC/DfID/Wellcome Trust Global Health Trials Scheme (MR/M007367/1), Canadian Institutes of Health Research (156307), Wellcome Trust (WT083579MA).
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Affiliation(s)
- Gerard Bryan Gonzales
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, the Netherland,Department of Internal Medicine and Paediatrics, Laboratory of Gastroenterology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium,VIB-UGent Center for Inflammation Research, Ghent, Belgium,Corresponding author at: Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, the Netherland.
| | - James M. Njunge
- The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya,KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya,Corresponding author at: The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya.
| | - Bonface M Gichuki
- The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya,KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya
| | - Bijun Wen
- Centre for Global Child Health, The Hospital for Sick Children, Toronto, Ontario, Canada,Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Moses Ngari
- The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya,KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya
| | - Isabel Potani
- The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya,Centre for Global Child Health, The Hospital for Sick Children, Toronto, Ontario, Canada,Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada,Kamuzu University of Health Sciences (Former College of Medicine), Blantyre, Malawi
| | - Johnstone Thitiri
- The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya,KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya
| | - Debby Laukens
- Department of Internal Medicine and Paediatrics, Laboratory of Gastroenterology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium,VIB-UGent Center for Inflammation Research, Ghent, Belgium
| | - Wieger Voskuijl
- The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya,Kamuzu University of Health Sciences (Former College of Medicine), Blantyre, Malawi,Amsterdam Centre for Global Child Health, Emma Children's Hospital, Amsterdam University Medical Centres, Amsterdam, the Netherland,Department of Global Health, Amsterdam Institute for Global Health and Development, Amsterdam University Medical Centres, Amsterdam, the Netherland
| | - Robert Bandsma
- The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya,Centre for Global Child Health, The Hospital for Sick Children, Toronto, Ontario, Canada,Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada,Kamuzu University of Health Sciences (Former College of Medicine), Blantyre, Malawi
| | - Jill Vanmassenhove
- Department of Internal Medicine and Paediatrics, Renal Division, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - James A Berkley
- The Childhood Acute Illness & Nutrition (CHAIN) Network, Nairobi, Kenya,KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya,Nuffield Department of Medicine, Centre for Tropical Medicine & Global Health, University of Oxford, Oxford, UK
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Abstract
The brain harbors a unique ability to, figuratively speaking, shift its gears. During wakefulness, the brain is geared fully toward processing information and behaving, while homeostatic functions predominate during sleep. The blood-brain barrier establishes a stable environment that is optimal for neuronal function, yet the barrier imposes a physiological problem; transcapillary filtration that forms extracellular fluid in other organs is reduced to a minimum in brain. Consequently, the brain depends on a special fluid [the cerebrospinal fluid (CSF)] that is flushed into brain along the unique perivascular spaces created by astrocytic vascular endfeet. We describe this pathway, coined the term glymphatic system, based on its dependency on astrocytic vascular endfeet and their adluminal expression of aquaporin-4 water channels facing toward CSF-filled perivascular spaces. Glymphatic clearance of potentially harmful metabolic or protein waste products, such as amyloid-β, is primarily active during sleep, when its physiological drivers, the cardiac cycle, respiration, and slow vasomotion, together efficiently propel CSF inflow along periarterial spaces. The brain's extracellular space contains an abundance of proteoglycans and hyaluronan, which provide a low-resistance hydraulic conduit that rapidly can expand and shrink during the sleep-wake cycle. We describe this unique fluid system of the brain, which meets the brain's requisites to maintain homeostasis similar to peripheral organs, considering the blood-brain-barrier and the paths for formation and egress of the CSF.
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Affiliation(s)
- Martin Kaag Rasmussen
- Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Humberto Mestre
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York
| | - Maiken Nedergaard
- Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York
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40
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Solari E, Marcozzi C, Ottaviani C, Negrini D, Moriondo A. Draining the Pleural Space: Lymphatic Vessels Facing the Most Challenging Task. BIOLOGY 2022; 11:419. [PMID: 35336793 PMCID: PMC8945018 DOI: 10.3390/biology11030419] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/25/2022] [Accepted: 03/08/2022] [Indexed: 01/06/2023]
Abstract
Lymphatic vessels exploit the mechanical stresses of their surroundings together with intrinsic rhythmic contractions to drain lymph from interstitial spaces and serosal cavities to eventually empty into the blood venous stream. This task is more difficult when the liquid to be drained has a very subatmospheric pressure, as it occurs in the pleural cavity. This peculiar space must maintain a very low fluid volume at negative hydraulic pressure in order to guarantee a proper mechanical coupling between the chest wall and lungs. To better understand the potential for liquid drainage, the key parameter to be considered is the difference in hydraulic pressure between the pleural space and the lymphatic lumen. In this review we collected old and new findings from in vivo direct measurements of hydraulic pressures in anaesthetized animals with the aim to better frame the complex physiology of diaphragmatic and intercostal lymphatics which drain liquid from the pleural cavity.
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Affiliation(s)
| | | | | | | | - Andrea Moriondo
- Department of Medicine and Surgery, School of Medicine, University of Insubria, 21100 Varese, Italy; (E.S.); (C.M.); (C.O.); (D.N.)
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41
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Suzuki H, Kaneko MK, Kato Y. Roles of Podoplanin in Malignant Progression of Tumor. Cells 2022; 11:575. [PMID: 35159384 PMCID: PMC8834262 DOI: 10.3390/cells11030575] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/02/2022] [Accepted: 02/05/2022] [Indexed: 02/07/2023] Open
Abstract
Podoplanin (PDPN) is a cell-surface mucin-like glycoprotein that plays a critical role in tumor development and normal development of the lung, kidney, and lymphatic vascular systems. PDPN is overexpressed in several tumors and is involved in their malignancy. PDPN induces platelet aggregation through binding to platelet receptor C-type lectin-like receptor 2. Furthermore, PDPN modulates signal transductions that regulate cell proliferation, differentiation, migration, invasion, epithelial-to-mesenchymal transition, and stemness, all of which are crucial for the malignant progression of tumor. In the tumor microenvironment (TME), PDPN expression is upregulated in the tumor stroma, including cancer-associated fibroblasts (CAFs) and immune cells. CAFs play significant roles in the extracellular matrix remodeling and the development of immunosuppressive TME. Additionally, PDPN functions as a co-inhibitory molecule on T cells, indicating its involvement with immune evasion. In this review, we describe the mechanistic basis and diverse roles of PDPN in the malignant progression of tumors and discuss the possibility of the clinical application of PDPN-targeted cancer therapy, including cancer-specific monoclonal antibodies, and chimeric antigen receptor T technologies.
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Affiliation(s)
- Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Mika K. Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan;
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan;
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The Role of Podoplanin in Skin Diseases. Int J Mol Sci 2022; 23:ijms23031310. [PMID: 35163233 PMCID: PMC8836045 DOI: 10.3390/ijms23031310] [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: 12/16/2021] [Revised: 01/22/2022] [Accepted: 01/23/2022] [Indexed: 02/05/2023] Open
Abstract
Podoplanin is a sialomucin-like type I transmembrane receptor glycoprotein that is expressed specifically in lymphatic vessels, sebaceous glands, and hair follicles in normal skin. However, under pathological conditions podoplanin expression is upregulated in various cells, such as keratinocytes, fibroblasts, tumor cells, and inflammatory cells, and plays pivotal roles in different diseases. In psoriasis, podoplanin expression is induced in basal keratinocytes via the JAK-STAT pathway and contributes toward epidermal hyperproliferation. Podoplanin expression on keratinocytes can also promote IL-17 secretion from lymphocytes, promoting chronic inflammation. During wound healing, the podoplanin/CLEC-2 interaction between keratinocytes and platelets regulates re-epithelialization at the wound edge. In skin cancers, podoplanin expresses on tumor cells and promotes their migration and epithelial-mesenchymal transition, thereby accelerating invasion and metastasis. Podoplanin is also expressed in normal peritumoral cells, such as cancer-associated fibroblasts in melanoma and keratinocytes in extramammary Paget's disease, which promote tumor progression and predict aggressive behavior and poor prognosis. This review provides an overview of our current understanding of the mechanisms via which podoplanin mediates these pathological skin conditions.
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Hwang BO, Park SY, Cho ES, Zhang X, Lee SK, Ahn HJ, Chun KS, Chung WY, Song NY. Platelet CLEC2-Podoplanin Axis as a Promising Target for Oral Cancer Treatment. Front Immunol 2022; 12:807600. [PMID: 34987523 PMCID: PMC8721674 DOI: 10.3389/fimmu.2021.807600] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/26/2021] [Indexed: 12/21/2022] Open
Abstract
Cancer tissues are not just simple masses of malignant cells, but rather complex and heterogeneous collections of cellular and even non-cellular components, such as endothelial cells, stromal cells, immune cells, and collagens, referred to as tumor microenvironment (TME). These multiple players in the TME develop dynamic interactions with each other, which determines the characteristics of the tumor. Platelets are the smallest cells in the bloodstream and primarily regulate blood coagulation and hemostasis. Notably, cancer patients often show thrombocytosis, a status of an increased platelet number in the bloodstream, as well as the platelet infiltration into the tumor stroma, which contributes to cancer promotion and progression. Thus, platelets function as one of the important stromal components in the TME, emerging as a promising chemotherapeutic target. However, the use of traditional antiplatelet agents, such as aspirin, has limitations mainly due to increased bleeding complications. This requires to implement new strategies to target platelets for anti-cancer effects. In oral squamous cell carcinoma (OSCC) patients, both high platelet counts and low tumor-stromal ratio (high stroma) are strongly correlated with increased metastasis and poor prognosis. OSCC tends to invade adjacent tissues and bones and spread to the lymph nodes for distant metastasis, which is a huge hurdle for OSCC treatment in spite of relatively easy access for visual examination of precancerous lesions in the oral cavity. Therefore, locoregional control of the primary tumor is crucial for OSCC treatment. Similar to thrombocytosis, higher expression of podoplanin (PDPN) has been suggested as a predictive marker for higher frequency of lymph node metastasis of OSCC. Cumulative evidence supports that platelets can directly interact with PDPN-expressing cancer cells via C-type lectin-like receptor 2 (CLEC2), contributing to cancer cell invasion and metastasis. Thus, the platelet CLEC2-PDPN axis could be a pinpoint target to inhibit interaction between platelets and OSCC, avoiding undesirable side effects. Here, we will review the role of platelets in cancer, particularly focusing on CLEC2-PDPN interaction, and will assess their potentials as therapeutic targets for OSCC treatment.
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Affiliation(s)
- Byeong-Oh Hwang
- Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, South Korea.,BK21 Four Project, Yonsei University College of Dentistry, Seoul, South Korea.,Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea
| | - Se-Young Park
- Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, South Korea.,BK21 Four Project, Yonsei University College of Dentistry, Seoul, South Korea.,Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea
| | - Eunae Sandra Cho
- BK21 Four Project, Yonsei University College of Dentistry, Seoul, South Korea.,Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, South Korea.,Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, South Korea
| | - Xianglan Zhang
- Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, South Korea.,Department of Pathology, Yanbian University Hospital, Yanji City, China
| | - Sun Kyoung Lee
- Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea
| | - Hyung-Joon Ahn
- Department of Orofacial Pain and Oral Medicine, Dental Hospital, Yonsei University College of Dentistry, Seoul, South Korea
| | - Kyung-Soo Chun
- College of Pharmacy, Keimyung University, Daegu, South Korea
| | - Won-Yoon Chung
- Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, South Korea.,BK21 Four Project, Yonsei University College of Dentistry, Seoul, South Korea.,Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea.,Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, South Korea
| | - Na-Young Song
- Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, South Korea.,BK21 Four Project, Yonsei University College of Dentistry, Seoul, South Korea.,Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea
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44
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Straker RJ, Taylor LA, Neuwirth MG, Sinnamon AJ, Shannon AB, Abbott J, Miura JT, Chu EY, Xu X, Karakousis GC. Optimizing Detection of Lymphatic Invasion in Primary Cutaneous Melanoma With the Use of D2-40 and a Paired Melanocytic Marker. Am J Dermatopathol 2022; 44:21-27. [PMID: 34231497 PMCID: PMC8671172 DOI: 10.1097/dad.0000000000002018] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
ABSTRACT Dual immunohistochemical (IHC) staining with D2-40 and S100 improves detection of lymphatic invasion (LI) in primary cutaneous melanoma. However, limited data exist evaluating this technique using other melanocytic markers, and thus, the optimal marker for detection of LI is unestablished. To address this knowledge gap, a case-control study was performed comparing melanoma specimens from 22 patients with known lymphatic spread (LS) with a control group of 11 patients without LS. Specimens underwent dual IHC staining with D2-40 and MART-1, SOX-10, and S100 to evaluate for LI. Receiver operating characteristic analysis was used to estimate each stain's accuracy for detection of LI. The LS group was more likely to be ≥65 years (P = 0.04), have a tumor thickness of ≥1 mm (P < 0.01), and have ulcerated tumors (P = 0.02). Detection of LI with D2-40/MART-1 significantly correlated with LS (P = 0.03), and the D2-40/MART-1 stain was most accurate for LI based on receiver operating characteristic curve analysis (area under the curve [AUC] 0.705) in comparison with D2-40/SOX-10 (AUC 0.575) and D2-40/S100 (AUC 0.633). These findings suggest that MART-1 may be the optimal melanocytic marker to combine with D2-40 for detection of LI in melanoma. Further studies are needed to determine the utility of routinely performing these stains for histopathologic analysis of melanoma.
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Affiliation(s)
- Richard J. Straker
- Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA
| | - Laura A. Taylor
- Department of Dermatology, University of Louisville, Louisville, KY
| | | | | | - Adrienne B. Shannon
- Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA
| | - James Abbott
- Department of Dermatology, University of Utah, Salt Lake City, UT
| | - John T. Miura
- Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA
| | - Emily Y. Chu
- Department of Dermatology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA
| | - Xiaowei Xu
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA
| | - Giorgos C. Karakousis
- Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA
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45
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Advances in 3D Vascularized Tumor-on-a-Chip Technology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1379:231-256. [DOI: 10.1007/978-3-031-04039-9_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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46
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Haji S, Ito T, Guenther C, Nakano M, Shimizu T, Mori D, Chiba Y, Tanaka M, Mishra SK, Willment JA, Brown GD, Nagae M, Yamasaki S. Human Dectin-1 is O-glycosylated and serves as a ligand for C-type lectin receptor CLEC-2. eLife 2022; 11:83037. [PMID: 36479973 PMCID: PMC9788829 DOI: 10.7554/elife.83037] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 12/07/2022] [Indexed: 12/13/2022] Open
Abstract
C-type lectin receptors (CLRs) elicit immune responses upon recognition of glycoconjugates present on pathogens and self-components. While Dectin-1 is the best-characterized CLR recognizing β-glucan on pathogens, the endogenous targets of Dectin-1 are not fully understood. Herein, we report that human Dectin-1 is a ligand for CLEC-2, another CLR expressed on platelets. Biochemical analyses revealed that Dectin-1 is a mucin-like protein as its stalk region is highly O-glycosylated. A sialylated core 1 glycan attached to the EDxxT motif of human Dectin-1, which is absent in mouse Dectin-1, provides a ligand moiety for CLEC-2. Strikingly, the expression of human Dectin-1 in mice rescued the lethality and lymphatic defect resulting from a deficiency of Podoplanin, a known CLEC-2 ligand. This finding is the first example of an innate immune receptor also functioning as a physiological ligand to regulate ontogeny upon glycosylation.
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Affiliation(s)
- Shojiro Haji
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka UniversityOsakaJapan,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka UniversityOsakaJapan
| | - Taiki Ito
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka UniversityOsakaJapan,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka UniversityOsakaJapan
| | - Carla Guenther
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka UniversityOsakaJapan,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka UniversityOsakaJapan
| | - Miyako Nakano
- Graduate School of Integrated Sciences for Life, Hiroshima UniversityHiroshimaJapan
| | - Takashi Shimizu
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka UniversityOsakaJapan,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka UniversityOsakaJapan
| | - Daiki Mori
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka UniversityOsakaJapan,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka UniversityOsakaJapan
| | - Yasunori Chiba
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)TsukubaJapan
| | - Masato Tanaka
- Laboratory of Immune Regulation School of Life Sciences, Tokyo University of Pharmacy and Life SciencesHachiojiJapan
| | - Sushil K Mishra
- The Glycoscience Group, National University of Ireland, GalwayGalwayIreland
| | - Janet A Willment
- Medical Research Council Centre for Medical Mycology, University of ExeterExeterUnited Kingdom
| | - Gordon D Brown
- Medical Research Council Centre for Medical Mycology, University of ExeterExeterUnited Kingdom
| | - Masamichi Nagae
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka UniversityOsakaJapan,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka UniversityOsakaJapan
| | - Sho Yamasaki
- Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka UniversityOsakaJapan,Laboratory of Molecular Immunology, Immunology Frontier Research Center (IFReC), Osaka UniversityOsakaJapan,Center for Infectious Disease Education and Research (CiDER), Osaka UniversityOsakaJapan,Division of Molecular Design, Research Center for Systems Immunology, Medical Institute of Bioregulation, Kyushu UniversityFukuokaJapan
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47
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Chen JM, Luo B, Ma R, Luo XX, Chen YS, Li Y. Lymphatic Endothelial Markers and Tumor Lymphangiogenesis Assessment in Human Breast Cancer. Diagnostics (Basel) 2021; 12:diagnostics12010004. [PMID: 35054174 PMCID: PMC8774380 DOI: 10.3390/diagnostics12010004] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/09/2021] [Accepted: 12/17/2021] [Indexed: 12/11/2022] Open
Abstract
Metastasis via lymphatic vessels or blood vessels is the leading cause of death for breast cancer, and lymphangiogenesis and angiogenesis are critical prerequisites for the tumor invasion–metastasis cascade. The research progress for tumor lymphangiogenesis has tended to lag behind that for angiogenesis due to the lack of specific markers. With the discovery of lymphatic endothelial cell (LEC) markers, growing evidence demonstrates that the LEC plays an active role in lymphatic formation and remodeling, tumor cell growth, invasion and intravasation, tumor–microenvironment remodeling, and antitumor immunity. However, some studies have drawn controversial conclusions due to the variation in the LEC markers and lymphangiogenesis assessments used. In this study, we review recent findings on tumor lymphangiogenesis, the most commonly used LEC markers, and parameters for lymphangiogenesis assessments, such as the lymphatic vessel density and lymphatic vessel invasion in human breast cancer. An in-depth understanding of tumor lymphangiogenesis and LEC markers can help to illustrate the mechanisms and distinct roles of lymphangiogenesis in breast cancer progression, which will help in exploring novel potential predictive biomarkers and therapeutic targets for breast cancer.
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Affiliation(s)
- Jia-Mei Chen
- Center of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (J.-M.C.); (X.-X.L.)
| | - Bo Luo
- Department of Pathology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China;
| | - Ru Ma
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital of Capital Medical University, Beijing 100038, China;
| | - Xi-Xi Luo
- Center of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (J.-M.C.); (X.-X.L.)
| | - Yong-Shun Chen
- Center of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (J.-M.C.); (X.-X.L.)
- Correspondence: (Y.-S.C.); (Y.L.); Tel.: +86-027-88048911 (Y.-S.C.); +86-010-63926525 (Y.L.)
| | - Yan Li
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital of Capital Medical University, Beijing 100038, China;
- Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Correspondence: (Y.-S.C.); (Y.L.); Tel.: +86-027-88048911 (Y.-S.C.); +86-010-63926525 (Y.L.)
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48
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Du J, He Z, Cui J, Li H, Xu M, Zhang S, Zhang S, Yan M, Qu X, Yu Z. Osteocyte Apoptosis Contributes to Cold Exposure-induced Bone Loss. Front Bioeng Biotechnol 2021; 9:733582. [PMID: 34858954 PMCID: PMC8632005 DOI: 10.3389/fbioe.2021.733582] [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: 06/30/2021] [Accepted: 09/27/2021] [Indexed: 12/19/2022] Open
Abstract
Emerging evidence indicates that bone mass is regulated by systemic energy balance. Temperature variations have profound effects on energy metabolism in animals, which will affect bone remodeling. But the mechanism remains unclear. 2-month-old C57BL/6J male mice were exposed to cold (4°C) and normal (23°C) temperatures for 28 days and the effects of cold exposure on bone mass was investigated. Micro-computed tomography results showed that bone volume fraction was significantly reduced after 14 days of exposure to cold temperature, and it was recovered after 28 days. Ploton silver staining and immunohistochemical results further revealed that exposure to cold decreased canalicular length, number of E11-and MMP13-positive osteocytes after 14 days, but they returned to the baseline levels after 28 days, different from the normal temperature control group. In addition, change of Caspase-3 indicated that exposure to cold temperature augmented apoptosis of osteocytes. In vitro results confirmed the positive effect of brown adipocytes on osteocyte‘s dendrites and E11 expression. In conclusion, our findings indicate that cold exposure can influence bone mass in a time-dependent manner, with bone mass decreasing and recovering at 2 and 4 weeks respectively. The change of bone mass may be caused by the apoptosis osteocytes. Brown adipocyte tissue could influence bone remodeling through affecting osteocyte.
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Affiliation(s)
- Jingke Du
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zihao He
- Arthritis Clinic and Research Center, Peking University People's Hospital, Peking University, Beijing, China
| | - Junqi Cui
- Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hanjun Li
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingming Xu
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuhong Zhang
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuangyan Zhang
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mengning Yan
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinhua Qu
- Department of Bone and Joint Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhifeng Yu
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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49
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Cheok YY, Tan GMY, Fernandez KC, Chan YT, Lee CYQ, Cheong HC, Looi CY, Vadivelu J, Abdullah S, Wong WF. Podoplanin Drives Motility of Active Macrophage via Regulating Filamin C During Helicobacter pylori Infection. Front Immunol 2021; 12:702156. [PMID: 34707599 PMCID: PMC8543000 DOI: 10.3389/fimmu.2021.702156] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 09/10/2021] [Indexed: 01/12/2023] Open
Abstract
Podoplanin (Pdpn) is a mucin-type transmembrane protein that has been implicated in multiple physiological settings including lymphangiogenesis, platelet aggregation, and cancer metastasis. Here, we reported an absence of Pdpn transcript expression in the resting mouse monocytic macrophages, RAW264.7 cells; intriguingly, a substantial upregulation of Pdpn was observed in activated macrophages following Helicobacter pylori or lipopolysaccharide stimulation. Pdpn-knockout macrophages demonstrated intact phagocytic and intracellular bactericidal activities comparable to wild type but exhibited impaired migration due to attenuated filopodia formation. In contrast, an ectopic expression of Pdpn augmented filopodia protrusion in activated macrophages. NanoString analysis uncovered a close dependency of Filamin C gene on the presence of Pdpn, highlighting an involvement of Filamin C in modulation of actin polymerization activity, which controls cell filopodia formation and migration. In addition, interleukin-1β production was significantly declined in the absence of Pdpn, suggesting a role of Pdpn in orchestrating inflammation during H. pylori infection besides cellular migration. Together, our findings unravel the Pdpn network that modulates movement of active macrophages.
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Affiliation(s)
- Yi Ying Cheok
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Grace Min Yi Tan
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Keith Conrad Fernandez
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Yee Teng Chan
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Chalystha Yie Qin Lee
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Heng Choon Cheong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Chung Yeng Looi
- School of Bioscience, Taylor's University, Subang Jaya, Selangor, Malaysia
| | - Jamuna Vadivelu
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Suhailah Abdullah
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Won Fen Wong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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50
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Lee HK, Lee SM, Lee DI. Corneal Lymphangiogenesis: Current Pathophysiological Understandings and Its Functional Role in Ocular Surface Disease. Int J Mol Sci 2021; 22:ijms222111628. [PMID: 34769057 PMCID: PMC8583961 DOI: 10.3390/ijms222111628] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/19/2021] [Accepted: 10/23/2021] [Indexed: 12/23/2022] Open
Abstract
The cornea is a transparent and avascular tissue that plays a central role in light refraction and provides a physical barrier to the external environment. Corneal avascularity is a unique histological feature that distinguishes it from the other parts of the body. Functionally, corneal immune privilege critically relies on corneal avascularity. Corneal lymphangiogenesis is now recognized as a general pathological feature in many pathologies, including dry eye disease (DED), corneal allograft rejection, ocular allergy, bacterial and viral keratitis, and transient corneal edema. Currently, sizable data from clinical and basic research have accumulated on the pathogenesis and functional role of ocular lymphangiogenesis. However, because of the invisibility of lymphatic vessels, ocular lymphangiogenesis has not been studied as much as hemangiogenesis. We reviewed the basic mechanisms of lymphangiogenesis and summarized recent advances in the pathogenesis of ocular lymphangiogenesis, focusing on corneal allograft rejection and DED. In addition, we discuss future directions for lymphangiogenesis research.
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Affiliation(s)
- Hyung-Keun Lee
- Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, Seoul 06273, Korea
- Correspondence: ; Tel.: +82-2-2019-3444
| | - Sang-Mok Lee
- Department of Ophthalmology, HanGil Eye Hospital, Catholic Kwandong University College of Medicine, Incheon 21388, Korea;
| | - Dong-Ihll Lee
- Medical School, Capital Medical University, Beijing 100069, China;
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