|
1
|
Borriello L, Jarray R, Rignault-Bricard R, Montes M, Lopez N, Maciel TT, Hermine O, Raynaud F, Demange L, Lepelletier Y. Neuropilin Antagonists (NRPas) Block the Phosphorylation of the Cancer Therapeutic Key Factor p38α Kinase Triggering Cell Death. Molecules 2025; 30:1494. [PMID: 40286084 PMCID: PMC11990468 DOI: 10.3390/molecules30071494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/11/2025] [Accepted: 03/20/2025] [Indexed: 04/29/2025] Open
Abstract
Neuropilin-1 is henceforth a relevant target in cancer treatment; however, its way of action remains partly elusive, and the development of small inhibitory molecules is therefore required for its study. Here, we report that two small-sized neuropilin antagonists (NRPa-47 and NRPa-48), VEGF-A165/NRP-1 binding inhibitors, are able to decrease VEGF-Rs phosphorylation and to modulate their downstream cascades in the triple-negative breast cancer cell line (MDA-MB-231). Nevertheless, NRPas exert a divergent pathway regulation of MAPK phosphorylation, such as JNK-1/-2/-3, ERK-1/-2, and p38β/γ/δ-kinases, as well as their respective downstream targets. However, NRPa-47 and NRPa-48 apply a common down-regulation of the p38α-kinase phosphorylation and their downstream targets, emphasising its central regulating role. More importantly, none of the 40 selected kinases, including SAPK2a/p38α, are affected in vitro by NRPas, strengthening their specificity. Taken together, NRPas induced cell death by the down-modulation of pro-apoptotic and anti-apoptotic proteins, cell death receptors and adaptors, heat shock proteins (HSP-27/-60/-70), cell cycle proteins (p21, p27, phospho-RAD17), and transcription factors (p53, HIF-1α). In conclusion, we showed for the first time how NRPas may alter tumour cell signalling and contribute to the down-modulation of the cancer therapeutic key factor p38α-kinase phosphorylation. Thus, the efficient association of NRPas and p38α-kinase inhibitor strengthened this hypothesis.
Collapse
Affiliation(s)
- Lucia Borriello
- Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA;
- Fox Chase Cancer Center, Cancer Signaling and Microenvironment Program, Philadelphia, PA 19140, USA
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 Rue des Saints Pères, 75270 Paris, CEDEX 06, France
| | - Rafika Jarray
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 Rue des Saints Pères, 75270 Paris, CEDEX 06, France
- Division of Prions and Related Diseases (SEPIA), CEA (Commissariat à l’Énergie Atomique), Institute of Emerging Diseases and Innovative Therapies (iMETI), 92265 Fontenay-aux-Roses, France
| | - Rachel Rignault-Bricard
- INSERM UMR 1163, Laboratory of Cellular and Molecular Basis of Normal Hematopoiesis and Hematological Disorders: Therapeutical Implications, 24 Boulevard Montparnasse, 75015 Paris, France (O.H.)
- Imagine Institute, Université Paris Cité, 24 Boulevard Montparnasse, 75015 Paris, France
| | - Matthieu Montes
- Laboratoire Génomique, Bioinformatique et Chimie Moléculaire, EA7528, Conservatoire National des Arts et Métiers, 292 Rue Saint Martin, 75003 Paris, France
| | - Nicolas Lopez
- W-MedPhys, 128 Rue la Boétie, 75008 Paris, France;
- ENOES/ENESIA, 62 Rue de Miromesnil, 75008 Paris, France
- Unité Mixte de Recherche “Institut de Physique Théorique (IPhT)” CEA-CNRS, UMR 3681, Route de l’Orme des Merisiers, 91191 St Aubin-Gif-sur-Yvette, France
| | - Thiago Trovati Maciel
- INSERM UMR 1163, Laboratory of Cellular and Molecular Basis of Normal Hematopoiesis and Hematological Disorders: Therapeutical Implications, 24 Boulevard Montparnasse, 75015 Paris, France (O.H.)
- Imagine Institute, Université Paris Cité, 24 Boulevard Montparnasse, 75015 Paris, France
| | - Olivier Hermine
- INSERM UMR 1163, Laboratory of Cellular and Molecular Basis of Normal Hematopoiesis and Hematological Disorders: Therapeutical Implications, 24 Boulevard Montparnasse, 75015 Paris, France (O.H.)
- Imagine Institute, Université Paris Cité, 24 Boulevard Montparnasse, 75015 Paris, France
| | - Françoise Raynaud
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (LCBPT), UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères, 45 Rue des Saints Pères, 75270 Paris, CEDEX 06, France
| | - Luc Demange
- UMR 8038 CNRS CiTCoM, Team PNAS, Faculté de Pharmacie, Université Paris Cité, 4 Avenue de l’Observatoire, 75006 Paris, France
| | - Yves Lepelletier
- INSERM UMR 1163, Laboratory of Cellular and Molecular Basis of Normal Hematopoiesis and Hematological Disorders: Therapeutical Implications, 24 Boulevard Montparnasse, 75015 Paris, France (O.H.)
- Imagine Institute, Université Paris Cité, 24 Boulevard Montparnasse, 75015 Paris, France
- W-MedPhys, 128 Rue la Boétie, 75008 Paris, France;
| |
Collapse
|
|
2
|
Ren J, Li R, Meng C, Xu Y, Li C. Identification of BCL3 as a biomarker for chondrocyte programmed cell death in osteoarthritis. Int J Exp Pathol 2025; 106:e12522. [PMID: 39676743 PMCID: PMC11731105 DOI: 10.1111/iep.12522] [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: 09/02/2024] [Revised: 10/23/2024] [Accepted: 11/19/2024] [Indexed: 12/17/2024] Open
Abstract
Osteoarthritis (OA) is a condition that is widely prevalent and causes joint pain and disability, with programmed cell death (PCD) playing a role in its pathogenesis. This study aimed to identify biomarkers associated with PCD in OA and explore their potential roles. Three RNA-sequencing datasets (GSE114007, GSE51588 and GSE220243) related to OA were analysed. Differential expression and weighted gene co-expression network identified key differentially expressed PCD-related genes (DE-PRMGs). Potential biomarkers were identified and validated through receiver operating characteristic (ROC) curves, correlation analyses, gene set enrichment analysis, single-cell expression and RT-qPCR. A total of 45 DE-PRMGs were identified, affecting pathways like TNF signalling and RNA degradation. BCL3, TREM2 and NRP2 were prioritized as potential OA biomarkers, which are associated with ribosome function and immune cell infiltration and potentially linked to PCD. The functional role of one of the molecules identified, BCL3, was explored further using a cell model of inflammation induced chondrocytes. BCL3 was significantly down regulated in OA samples from the public dataset and clinical samples analysed by RT-qPCR. BCL3 overexpression reduced apoptosis in chondrocytes stimulated with inflammatory cytokines. Thus the functional studies highlighted the anti-apoptotic role of BCL3 in chondrocytes and provide new insights into OA pathogenesis with potential for future therapeutic development.
Collapse
Affiliation(s)
- Junxiao Ren
- Yunnan University of Chinese MedicineKunmingYunnanChina
| | - Rui Li
- Yunnan University of Chinese MedicineKunmingYunnanChina
| | - Chen Meng
- Kunming Medical UniversityKunmingYunnanChina
| | - Yongqing Xu
- The 920th Hospital of Joint Logistics SupportForce of PLAKunmingYunnanChina
| | - Chuan Li
- Yunnan University of Chinese MedicineKunmingYunnanChina
- Engineering Laboratory of Peptides of Chinese Academy of SciencesKunmingYunnanChina
| |
Collapse
|
|
3
|
Fernández-Nogueira P, Linzoain-Agos P, Cueto-Remacha M, De la Guia-Lopez I, Recalde-Percaz L, Parcerisas A, Gascon P, Carbó N, Gutierrez-Uzquiza A, Fuster G, Bragado P. Role of semaphorins, neuropilins and plexins in cancer progression. Cancer Lett 2024; 606:217308. [PMID: 39490515 DOI: 10.1016/j.canlet.2024.217308] [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: 08/02/2024] [Revised: 10/23/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024]
Abstract
Progress in understanding nervous system-cancer interconnections has emphasized the functional role of semaphorins (SEMAs) and their receptors, neuropilins (NRPs) and plexins (PLXNs), in cancer progression. SEMAs are a conserved and extensive family of broadly expressed soluble and membrane-associated proteins that were first described as regulators of axon guidance and neural and vascular development. However, recent advances have shown that they can have a dual role in cancer progression, acting either as tumor promoters or suppressors. SEMAs effects result from their interaction with specific co-receptors/receptors NRPs/PLXNs, that have also been described to play a role in cancer progression. They can influence both cancer cells and tumor microenvironment components modulating various aspects of tumorigenesis such as oncogenesis, tumor growth, invasion and metastatic spread or treatment resistance. In this review we focus on the role of these axon guidance signals and their receptors and co-receptors in various aspects of cancer. Furthermore, we also highlight their potential application as novel approaches for cancer treatment in the future.
Collapse
Affiliation(s)
- P Fernández-Nogueira
- Department of Biomedicine, School of Medicine, Universitat de Barcelona, 08028, Barcelona, Spain; Biosciences Department, Faculty of Sciences, Technology and Engineering, University of Vic. Central University of Catalonia (UVic-UCC), 08500, Vic, Catalonia, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Institute of Biomedicine of the Universitat de Barcelona (IBUB), 08028, Barcelona, Spain
| | - P Linzoain-Agos
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040, Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040, Madrid, Spain
| | - M Cueto-Remacha
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040, Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040, Madrid, Spain
| | - I De la Guia-Lopez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040, Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040, Madrid, Spain
| | - L Recalde-Percaz
- Department of Biomedicine, School of Medicine, Universitat de Barcelona, 08028, Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Institute of Biomedicine of the Universitat de Barcelona (IBUB), 08028, Barcelona, Spain
| | - A Parcerisas
- Biosciences Department, Faculty of Sciences, Technology and Engineering, University of Vic. Central University of Catalonia (UVic-UCC), 08500, Vic, Catalonia, Spain; Tissue Repair and Regeneration Laboratory (TR2Lab), Institute of Research and Innovation of Life Sciences and Health, Catalunya Central (IRIS-CC), 08500, Vic, Catalonia, Spain
| | - P Gascon
- Department of Biomedicine, School of Medicine, Universitat de Barcelona, 08028, Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Institute of Biomedicine of the Universitat de Barcelona (IBUB), 08028, Barcelona, Spain
| | - N Carbó
- Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Institute of Biomedicine of the Universitat de Barcelona (IBUB), 08028, Barcelona, Spain
| | - A Gutierrez-Uzquiza
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040, Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040, Madrid, Spain
| | - G Fuster
- Department of Biomedicine, School of Medicine, Universitat de Barcelona, 08028, Barcelona, Spain; Biosciences Department, Faculty of Sciences, Technology and Engineering, University of Vic. Central University of Catalonia (UVic-UCC), 08500, Vic, Catalonia, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Institute of Biomedicine of the Universitat de Barcelona (IBUB), 08028, Barcelona, Spain; Tissue Repair and Regeneration Laboratory (TR2Lab), Institute of Research and Innovation of Life Sciences and Health, Catalunya Central (IRIS-CC), 08500, Vic, Catalonia, Spain.
| | - P Bragado
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040, Madrid, Spain; Health Research Institute of the Hospital Clínico San Carlos, 28040, Madrid, Spain.
| |
Collapse
|
|
4
|
Cheon I, Lee S, Oh S, Ahn YH. miR-200-mediated inactivation of cancer-associated fibroblasts via targeting of NRP2-VEGFR signaling attenuates lung cancer invasion and metastasis. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102194. [PMID: 38766528 PMCID: PMC11101731 DOI: 10.1016/j.omtn.2024.102194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 04/18/2024] [Indexed: 05/22/2024]
Abstract
Cancer-associated fibroblasts (CAFs) play a substantial role in promoting cancer cell motility, drug resistance, angiogenesis, and metastasis; therefore, extensive research has been conducted to determine their mode of activation. We aimed to identify whether miRNA-200 (miR-200), a widely recognized suppressor of epithelial-mesenchymal transition, prevents CAFs from promoting cancer progression. Overexpression of miR-200 prevented CAFs from promoting lung cancer cell migration, invasion, tumorigenicity, and metastasis. Additionally, miR-200 suppressed the ability of CAFs to recruit and polarize macrophages toward the M2 phenotype, as well as the migration and tube formation of vascular endothelial cells. NRP2, a co-receptor of vascular endothelial growth factor receptor (VEGFR), was confirmed to be a target of miR-200, which mediates the functional activity of miR-200 in CAFs. NRP2-VEGFR signaling facilitates the secretion of VEGF-D and pleiotrophin from CAFs, leading to the activation of cancer cell migration and invasion. These findings suggest that miR-200 remodels CAFs to impede cancer progression and metastasis and that miR-200 and NRP2 are potential therapeutic targets in the treatment of lung cancer.
Collapse
Affiliation(s)
- Inyoung Cheon
- Department of Molecular Medicine and Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul 07804, Korea
| | - Sieun Lee
- Department of Molecular Medicine and Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul 07804, Korea
| | - Seonyeong Oh
- Department of Molecular Medicine and Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul 07804, Korea
| | - Young-Ho Ahn
- Department of Molecular Medicine and Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul 07804, Korea
| |
Collapse
|
|
5
|
Chen T, Li S, Wang L. Semaphorins in tumor microenvironment: Biological mechanisms and therapeutic progress. Int Immunopharmacol 2024; 132:112035. [PMID: 38603857 DOI: 10.1016/j.intimp.2024.112035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/15/2024] [Accepted: 04/05/2024] [Indexed: 04/13/2024]
Abstract
Hallmark features of the tumor microenvironment include immune cells, stromal cells, blood vessels, and extracellular matrix (ECM), providing a conducive environment for the growth and survival of tumors. Recent advances in the understanding of cancer biology have highlighted the functional role of semaphorins (SEMAs). SEMAs are a large and diverse family of widely expressed secreted and membrane-binding proteins, which were initially implicated in axon guidance and neural development. However, it is now clear that they are widely expressed beyond the nervous system and participate in regulating immune responses and cancer progression. In fact, accumulating evidence disclosed that different SEMAs can either stimulate or restrict tumor progression, some of which act as important regulators of tumor angiogenesis. Conversely, limited information is known about the functional relevance of SEMA signals in TME. In this setting, we systematically elaborate the role SEMAs and their major receptors played in characterized components of TME. Furthermore, we provide a convergent view of current SEMAs pharmacological progress in clinical treatment and also put forward their potential application value and clinical prospects in the future.
Collapse
Affiliation(s)
- Tianyi Chen
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, PR China
| | - Shazhou Li
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, PR China
| | - Lufang Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, PR China.
| |
Collapse
|
|
6
|
Costanzo A, Clarke D, Holt M, Sharma S, Nagy K, Tan X, Kain L, Abe B, Luce S, Boitard C, Wyseure T, Mosnier LO, Su AI, Grimes C, Finn MG, Savage PB, Gottschalk M, Pettus J, Teyton L. Repositioning the Early Pathology of Type 1 Diabetes to the Extraislet Vasculature. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1094-1104. [PMID: 38426888 PMCID: PMC10944819 DOI: 10.4049/jimmunol.2300769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 01/29/2024] [Indexed: 03/02/2024]
Abstract
Type 1 diabetes (T1D) is a prototypic T cell-mediated autoimmune disease. Because the islets of Langerhans are insulated from blood vessels by a double basement membrane and lack detectable lymphatic drainage, interactions between endocrine and circulating T cells are not permitted. Thus, we hypothesized that initiation and progression of anti-islet immunity required islet neolymphangiogenesis to allow T cell access to the islet. Combining microscopy and single cell approaches, the timing of this phenomenon in mice was situated between 5 and 8 wk of age when activated anti-insulin CD4 T cells became detectable in peripheral blood while peri-islet pathology developed. This "peri-insulitis," dominated by CD4 T cells, respected the islet basement membrane and was limited on the outside by lymphatic endothelial cells that gave it the attributes of a tertiary lymphoid structure. As in most tissues, lymphangiogenesis seemed to be secondary to local segmental endothelial inflammation at the collecting postcapillary venule. In addition to classic markers of inflammation such as CD29, V-CAM, and NOS, MHC class II molecules were expressed by nonhematopoietic cells in the same location both in mouse and human islets. This CD45- MHC class II+ cell population was capable of spontaneously presenting islet Ags to CD4 T cells. Altogether, these observations favor an alternative model for the initiation of T1D, outside of the islet, in which a vascular-associated cell appears to be an important MHC class II-expressing and -presenting cell.
Collapse
Affiliation(s)
- Anne Costanzo
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Don Clarke
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Marie Holt
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Siddhartha Sharma
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Kenna Nagy
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Xuqian Tan
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA
| | - Lisa Kain
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Brian Abe
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | | | | | - Tine Wyseure
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA
| | - Laurent O. Mosnier
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA
| | - Andrew I. Su
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA
| | - Catherine Grimes
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE
| | - M. G. Finn
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA
| | - Paul B. Savage
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT
| | - Michael Gottschalk
- Rady Children’s Hospital, University of California San Diego, San Diego, CA
| | - Jeremy Pettus
- UC San Diego School of Medicine, University of California San Diego, San Diego, CA
| | - Luc Teyton
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| |
Collapse
|
|
7
|
Gundogan AO, Oltulu R, Belviranli S, Oltulu P. Expression of placental growth factor, neuropilin-1, and neuropilin-2 in primary pterygium tissue. Graefes Arch Clin Exp Ophthalmol 2024; 262:957-965. [PMID: 37878035 DOI: 10.1007/s00417-023-06280-1] [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: 05/09/2023] [Revised: 09/26/2023] [Accepted: 10/12/2023] [Indexed: 10/26/2023] Open
Abstract
PURPOSE The aim of this study was to evaluate the expression of placental growth factor (PLGF), neuropilin-1 (NP-1), and neuropilin-2 (NP-2) molecules in primary pterygium tissue compared with normal conjunctival tissue. METHODS The records of 42 patients who underwent excision surgery with autografts for primary pterygium (pterygium group) and 20 patients who underwent conjunctival nevus excision surgery (control group) in the same period were reviewed retrospectively. The samples obtained from the pterygium tissues in the pterygium group and the clean conjunctival tissues adjacent to the nevus in the control group were collected from the archive. Immunohistochemical stains of the primary antibodies-1/100 diluted PLGF, NP-1, and NP-2 (Abcam Cambridge Science Park, UK)-were applied to all groups. Staining intensities and the percentage of positive cells in epithelial, endothelial, stromal, and inflammatory cells were analyzed by an experienced pathologist. RESULTS The positivity rates of PLGF and NP-2 expression in epithelial, endothelial, stromal, and inflammatory cells were found to be higher in the pterygium group than in the control group (PLGF: p < 0.001, p < 0.001, p = 0.001, and p < 0.001, respectively; NP-2: p < 0.001 for all). Staining intensities for PLGF and NP-2 were higher in the pterygium group than in the control group (PLGF: p < 0.001, p < 0.001, p = 0.005, and p < 0.001, respectively; NP-2: p < 0.001, p < 0.001, p = 0.001, and p < 0.001, respectively). However, no significant differences were found in any cell type in terms of NP-1 expression positivity rates (p = 0.730, p = 0.121, p = 0.524, and p = 0.624, respectively) or staining intensity (p = 0.716, p = 0.147, p = 0.147, and p = 0.780, respectively). CONCLUSION PLGF and NP-2 levels were found to be higher in pterygium tissue, while there was no difference in NP-1. These results indicate the possible roles of NP-2 and PLGF in primary pterygium.
Collapse
Affiliation(s)
| | - Refik Oltulu
- Department of Ophthalmology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Selman Belviranli
- Department of Ophthalmology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Pembe Oltulu
- Department of Pathology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| |
Collapse
|
|
8
|
Dhupar R, Powers AA, Eisenberg SH, Gemmill RM, Bardawil CE, Udoh HM, Cubitt A, Nangle LA, Soloff AC. Orchestrating Resilience: How Neuropilin-2 and Macrophages Contribute to Cardiothoracic Disease. J Clin Med 2024; 13:1446. [PMID: 38592275 PMCID: PMC10934188 DOI: 10.3390/jcm13051446] [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: 01/16/2024] [Revised: 02/21/2024] [Accepted: 02/24/2024] [Indexed: 04/10/2024] Open
Abstract
Immunity has evolved to balance the destructive nature of inflammation with wound healing to overcome trauma, infection, environmental insults, and rogue malignant cells. The inflammatory response is marked by overlapping phases of initiation, resolution, and post-resolution remodeling. However, the disruption of these events can lead to prolonged tissue damage and organ dysfunction, resulting long-term disease states. Macrophages are the archetypic phagocytes present within all tissues and are important contributors to these processes. Pleiotropic and highly plastic in their responses, macrophages support tissue homeostasis, repair, and regeneration, all while balancing immunologic self-tolerance with the clearance of noxious stimuli, pathogens, and malignant threats. Neuropilin-2 (Nrp2), a promiscuous co-receptor for growth factors, semaphorins, and integrins, has increasingly been recognized for its unique role in tissue homeostasis and immune regulation. Notably, recent studies have begun to elucidate the role of Nrp2 in both non-hematopoietic cells and macrophages with cardiothoracic disease. Herein, we describe the unique role of Nrp2 in diseases of the heart and lung, with an emphasis on Nrp2 in macrophages, and explore the potential to target Nrp2 as a therapeutic intervention.
Collapse
Affiliation(s)
- Rajeev Dhupar
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (R.D.); (H.M.U.)
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Surgical and Research Services, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA
| | - Amy A. Powers
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (R.D.); (H.M.U.)
| | - Seth H. Eisenberg
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (R.D.); (H.M.U.)
| | - Robert M. Gemmill
- Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA;
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Charles E. Bardawil
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (R.D.); (H.M.U.)
| | - Hannah M. Udoh
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (R.D.); (H.M.U.)
| | - Andrea Cubitt
- aTyr Pharma, San Diego, CA 92121, USA; (A.C.); (L.A.N.)
| | | | - Adam C. Soloff
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (R.D.); (H.M.U.)
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Surgical and Research Services, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA
| |
Collapse
|
|
9
|
Li T, Ran J, Miao Z, Yang M, Mou D, Jiang Y, Xu X, Xie Q, Jin K. Deficiency of inflammation-sensing protein neuropilin-2 in myeloid-derived macrophages exacerbates colitis via NF-κB activation. J Pathol 2024; 262:175-188. [PMID: 37946610 DOI: 10.1002/path.6221] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 09/05/2023] [Accepted: 09/22/2023] [Indexed: 11/12/2023]
Abstract
Neuropilin-2 (NRP2) is a multifunctional protein engaged in the regulation of angiogenesis, lymphangiogenesis, axon guidance, and tumor metastasis, but its function in colitis remains unclear. Here, we found that NRP2 was an inflammation-sensing protein rapidly and dramatically induced in myeloid cells, especially in macrophages, under inflammatory contexts. NRP2 deficiency in myeloid cells exacerbated dextran sulfate sodium salt-induced experimental colitis by promoting polarization of M1 macrophages and colon injury. Mechanistically, NRP2 could be induced via NF-κB activation by TNF-α in macrophages, but exerted an inhibitory effect on NF-κB signaling, forming a negative feedback loop with NF-κB to sense and alleviate inflammation. Deletion of NRP2 in macrophages broke this negative feedback circuit, leading to NF-κB overactivation, inflammatory exacerbation, and more severe colitis. Collectively, these findings reveal inflammation restriction as a role for NRP2 in macrophages under inflammation contexts and suggest that NRP2 in macrophages may relieve inflammation in inflammatory bowel disease. © 2023 The Pathological Society of Great Britain and Ireland.
Collapse
Affiliation(s)
- Tong Li
- Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu, PR China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, PR China
- West China Medical Publishers, West China Hospital of Sichuan University, Chengdu, PR China
| | - Jingjing Ran
- Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu, PR China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China
| | - Zhiyong Miao
- Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu, PR China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China
| | - Min Yang
- Department of Rheumatology and Immunology, West China Hospital of Sichuan University, Chengdu, PR China
| | - Dachao Mou
- Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu, PR China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China
| | - Yunhan Jiang
- Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu, PR China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China
| | - Xiaoqiu Xu
- Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu, PR China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China
| | - Qibing Xie
- Department of Rheumatology and Immunology, West China Hospital of Sichuan University, Chengdu, PR China
| | - Ke Jin
- Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu, PR China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China
| |
Collapse
|
|
10
|
Clahsen T, Hadrian K, Notara M, Schlereth SL, Howaldt A, Prokosch V, Volatier T, Hos D, Schroedl F, Kaser-Eichberger A, Heindl LM, Steven P, Bosch JJ, Steinkasserer A, Rokohl AC, Liu H, Mestanoglu M, Kashkar H, Schumacher B, Kiefer F, Schulte-Merker S, Matthaei M, Hou Y, Fassbender S, Jantsch J, Zhang W, Enders P, Bachmann B, Bock F, Cursiefen C. The novel role of lymphatic vessels in the pathogenesis of ocular diseases. Prog Retin Eye Res 2023; 96:101157. [PMID: 36759312 DOI: 10.1016/j.preteyeres.2022.101157] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/13/2022] [Accepted: 12/17/2022] [Indexed: 02/10/2023]
Abstract
Historically, the eye has been considered as an organ free of lymphatic vessels. In recent years, however, it became evident, that lymphatic vessels or lymphatic-like vessels contribute to several ocular pathologies at various peri- and intraocular locations. The aim of this review is to outline the pathogenetic role of ocular lymphatics, the respective molecular mechanisms and to discuss current and future therapeutic options based thereon. We will give an overview on the vascular anatomy of the healthy ocular surface and the molecular mechanisms contributing to corneal (lymph)angiogenic privilege. In addition, we present (i) current insights into the cellular and molecular mechanisms occurring during pathological neovascularization of the cornea triggered e.g. by inflammation or trauma, (ii) the role of lymphatic vessels in different ocular surface pathologies such as dry eye disease, corneal graft rejection, ocular graft versus host disease, allergy, and pterygium, (iii) the involvement of lymphatic vessels in ocular tumors and metastasis, and (iv) the novel role of the lymphatic-like structure of Schlemm's canal in glaucoma. Identification of the underlying molecular mechanisms and of novel modulators of lymphangiogenesis will contribute to the development of new therapeutic targets for the treatment of ocular diseases associated with pathological lymphangiogenesis in the future. The preclinical data presented here outline novel therapeutic concepts for promoting transplant survival, inhibiting metastasis of ocular tumors, reducing inflammation of the ocular surface, and treating glaucoma. Initial data from clinical trials suggest first success of novel treatment strategies to promote transplant survival based on pretransplant corneal lymphangioregression.
Collapse
Affiliation(s)
- Thomas Clahsen
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Karina Hadrian
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Maria Notara
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Simona L Schlereth
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Antonia Howaldt
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Verena Prokosch
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Thomas Volatier
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Deniz Hos
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Falk Schroedl
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Alexandra Kaser-Eichberger
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Ludwig M Heindl
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Philipp Steven
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Cluster of Excellence: Cellular Stress Responses in Ageing-Associated Diseases, CECAD, University of Cologne, Cologne, Germany
| | - Jacobus J Bosch
- Centre for Human Drug Research and Leiden University Medical Center, Leiden, the Netherlands
| | | | - Alexander C Rokohl
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Hanhan Liu
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Mert Mestanoglu
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Hamid Kashkar
- Institute for Molecular Immunology, Center for Molecular Medicine Cologne (CMMC), CECAD Research Center, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Björn Schumacher
- Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany; Cluster of Excellence: Cellular Stress Responses in Ageing-Associated Diseases, CECAD, University of Cologne, Cologne, Germany
| | - Friedemann Kiefer
- European Institute for Molecular Imaging (EIMI), University of Münster, 48149, Münster, Germany
| | - Stefan Schulte-Merker
- Institute for Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, Münster, Germany
| | - Mario Matthaei
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Yanhong Hou
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Xuhui District, Shanghai, China
| | - Sonja Fassbender
- IUF‒Leibniz Research Institute for Environmental Medicine, Duesseldorf, Germany; Immunology and Environment, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Jonathan Jantsch
- Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Wei Zhang
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Philip Enders
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Björn Bachmann
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Felix Bock
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany; Cluster of Excellence: Cellular Stress Responses in Ageing-Associated Diseases, CECAD, University of Cologne, Cologne, Germany.
| |
Collapse
|
|
11
|
Xu Z, Goel HL, Burkart C, Burman L, Chong YE, Barber AG, Geng Y, Zhai L, Wang M, Kumar A, Menefee A, Polizzi C, Eide L, Rauch K, Rahman J, Hamel K, Fogassy Z, Klopp-Savino S, Paz S, Zhang M, Cubitt A, Nangle LA, Mercurio AM. Inhibition of VEGF binding to neuropilin-2 enhances chemosensitivity and inhibits metastasis in triple-negative breast cancer. Sci Transl Med 2023; 15:eadf1128. [PMID: 37134152 PMCID: PMC10583499 DOI: 10.1126/scitranslmed.adf1128] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 04/10/2023] [Indexed: 05/05/2023]
Abstract
Although blocking the binding of vascular endothelial growth factor (VEGF) to neuropilin-2 (NRP2) on tumor cells is a potential strategy to treat aggressive carcinomas, a lack of effective reagents that can be used clinically has hampered this potential therapy. Here, we describe the generation of a fully humanized, high-affinity monoclonal antibody (aNRP2-10) that specifically inhibits the binding of VEGF to NRP2, conferring antitumor activity without causing toxicity. Using triple-negative breast cancer as a model, we demonstrated that aNRP2-10 could be used to isolate cancer stem cells (CSCs) from heterogeneous tumor populations and inhibit CSC function and epithelial-to-mesenchymal transition. aNRP2-10 sensitized cell lines, organoids, and xenografts to chemotherapy and inhibited metastasis by promoting the differentiation of CSCs to a state that is more responsive to chemotherapy and less prone to metastasis. These data provide justification for the initiation of clinical trials designed to improve the response of patients with aggressive tumors to chemotherapy using this monoclonal antibody.
Collapse
Affiliation(s)
- Zhiwen Xu
- aTyr Pharma, San Diego, CA 92121, USA
| | - Hira Lal Goel
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | | | | | | | | | - Yanyan Geng
- IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
- Pangu Biopharma, 26th Floor, Three Exchange Square, 8 Connaught Place, Central, Hong Kong, China
| | - Liting Zhai
- IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
- Pangu Biopharma, 26th Floor, Three Exchange Square, 8 Connaught Place, Central, Hong Kong, China
| | - Mengdie Wang
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Ayush Kumar
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | | | | | - Lisa Eide
- aTyr Pharma, San Diego, CA 92121, USA
| | | | | | | | | | | | | | - Mingjie Zhang
- IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
| | | | | | - Arthur M. Mercurio
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| |
Collapse
|
|
12
|
Lan YL, Wang H, Chen A, Zhang J. Update on the current knowledge of lymphatic drainage system and its emerging roles in glioma management. Immunology 2023; 168:233-247. [PMID: 35719015 DOI: 10.1111/imm.13517] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/22/2022] [Indexed: 01/17/2023] Open
Abstract
The draining of brain interstitial fluid (ISF) to cerebrospinal fluid (CSF) and the subsequent draining of CSF to meningeal lymphatics is well-known. Nonetheless, its role in the development of glioma is a remarkable finding that has to be extensively understood. The glymphatic system (GS) collects CSF from the subarachnoid space and brain ISF through aquaporin-4 (AQP4) water channels. The glial limiting membrane and the perivascular astrocyte-end-feet membrane both have elevated levels of AQP4. CSF is thought to drain through the nerve sheaths of the olfactory and other cranial nerves as well as spinal meningeal lymphatics via dorsal or basal lymphatic vessels. Meningeal lymphatic vessels (MLVs) exist below the skull in the dorsal and basal regions. In this view, MLVs offer a pathway to drain macromolecules and traffic immunological cells from the CNS into cervical lymph nodes (CLNs), and thus can be used as a candidate curing strategy against glioma and other associated complications, such as neuro-inflammation. Taken together, the lymphatic drainage system could provide a route or approach for drug targeting of glioma and other neurological conditions. Nevertheless, its pathophysiological role in glioma remains elusive, which needs extensive research. The current review aims to explore the lymphatic drainage system, its role in glioma progression, and possible therapeutic techniques that target MLVs in the CNS.
Collapse
Affiliation(s)
- Yu-Long Lan
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hongjin Wang
- Department of Neurology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Aiqin Chen
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianmin Zhang
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| |
Collapse
|
|
13
|
Patnam M, Dommaraju SR, Masood F, Herbst P, Chang JH, Hu WY, Rosenblatt MI, Azar DT. Lymphangiogenesis Guidance Mechanisms and Therapeutic Implications in Pathological States of the Cornea. Cells 2023; 12:319. [PMID: 36672254 PMCID: PMC9856498 DOI: 10.3390/cells12020319] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/22/2022] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
Corneal lymphangiogenesis is one component of the neovascularization observed in several inflammatory pathologies of the cornea including dry eye disease and corneal graft rejection. Following injury, corneal (lymph)angiogenic privilege is impaired, allowing ingrowth of blood and lymphatic vessels into the previously avascular cornea. While the mechanisms underlying pathological corneal hemangiogenesis have been well described, knowledge of the lymphangiogenesis guidance mechanisms in the cornea is relatively scarce. Various signaling pathways are involved in lymphangiogenesis guidance in general, each influencing one or multiple stages of lymphatic vessel development. Most endogenous factors that guide corneal lymphatic vessel growth or regression act via the vascular endothelial growth factor C signaling pathway, a central regulator of lymphangiogenesis. Several exogenous factors have recently been repurposed and shown to regulate corneal lymphangiogenesis, uncovering unique signaling pathways not previously known to influence lymphatic vessel guidance. A strong understanding of the relevant lymphangiogenesis guidance mechanisms can facilitate the development of targeted anti-lymphangiogenic therapeutics for corneal pathologies. In this review, we examine the current knowledge of lymphatic guidance cues, their regulation of inflammatory states in the cornea, and recently discovered anti-lymphangiogenic therapeutic modalities.
Collapse
Affiliation(s)
- Mehul Patnam
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Sunil R. Dommaraju
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Faisal Masood
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Paula Herbst
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Jin-Hong Chang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Wen-Yang Hu
- Department of Urology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Mark I. Rosenblatt
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Dimitri T. Azar
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| |
Collapse
|
|
14
|
Benwell CJ, Johnson RT, Taylor JA, Price CA, Robinson SD. Endothelial VEGFR Coreceptors Neuropilin-1 and Neuropilin-2 Are Essential for Tumor Angiogenesis. CANCER RESEARCH COMMUNICATIONS 2022; 2:1626-1640. [PMID: 36970722 PMCID: PMC10036134 DOI: 10.1158/2767-9764.crc-22-0250] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 10/16/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022]
Abstract
Neuropilin (NRP) expression is highly correlated with poor outcome in multiple cancer subtypes. As known coreceptors for VEGFRs, core drivers of angiogenesis, past investigations have alluded to their functional roles in facilitating tumorigenesis by promoting invasive vessel growth. Despite this, it remains unclear as to whether NRP1 and NRP2 act in a synergistic manner to enhance pathologic angiogenesis. Here we demonstrate, using NRP1 ECKO , NRP2 ECKO , and NRP1/NRP2 ECKO mouse models, that maximum inhibition of primary tumor development and angiogenesis is achieved when both endothelial NRP1 and NRP2 are targeted simultaneously. Metastasis and secondary site angiogenesis were also significantly inhibited in NRP1/NRP2 ECKO animals. Mechanistic studies revealed that codepleting NRP1 and NRP2 in mouse-microvascular endothelial cells stimulates rapid shuttling of VEGFR-2 to Rab7+ endosomes for proteosomal degradation. Our results highlight the importance of targeting both NRP1 and NRP2 to modulate tumor angiogenesis. Significance The findings presented in this study demonstrate that tumor angiogenesis and growth can be arrested completely by cotargeting endothelial NRP1 and NRP2. We provide new insight into the mechanisms of action regulating NRP-dependent tumor angiogenesis and signpost a novel approach to halt tumor progression.
Collapse
Affiliation(s)
- Christopher J. Benwell
- Gut Microbes and Health Programme, Quadram Institute Bioscience, Norwich, United Kingdom
| | - Robert T. Johnson
- School of Pharmacy, University of East Anglia, Norwich, United Kingdom
| | - James A.G.E. Taylor
- Gut Microbes and Health Programme, Quadram Institute Bioscience, Norwich, United Kingdom
| | - Christopher A. Price
- Gut Microbes and Health Programme, Quadram Institute Bioscience, Norwich, United Kingdom
| | - Stephen D. Robinson
- Gut Microbes and Health Programme, Quadram Institute Bioscience, Norwich, United Kingdom
- School of Biological Sciences, University of East Anglia, Norwich, United Kingdom
| |
Collapse
|
|
15
|
An Overview of the Molecular Cues and Their Intracellular Signaling Shared by Cancer and the Nervous System: From Neurotransmitters to Synaptic Proteins, Anatomy of an All-Inclusive Cooperation. Int J Mol Sci 2022; 23:ijms232314695. [PMID: 36499024 PMCID: PMC9739679 DOI: 10.3390/ijms232314695] [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: 10/18/2022] [Revised: 11/18/2022] [Accepted: 11/18/2022] [Indexed: 11/27/2022] Open
Abstract
We propose an overview of the molecular cues and their intracellular signaling involved in the crosstalk between cancer and the nervous system. While "cancer neuroscience" as a field is still in its infancy, the relation between cancer and the nervous system has been known for a long time, and a huge body of experimental data provides evidence that tumor-nervous system connections are widespread. They encompass different mechanisms at different tumor progression steps, are multifaceted, and display some intriguing analogies with the nervous system's physiological processes. Overall, we can say that many of the paradigmatic "hallmarks of cancer" depicted by Weinberg and Hanahan are affected by the nervous system in a variety of manners.
Collapse
|
|
16
|
Tian XM, Xiang B, Jin LM, Mi T, Wang JK, Zhanghuang C, Zhang ZX, Chen ML, Shi QL, Liu F, Lin T, Wei GH. Immune-related gene signature associates with immune landscape and predicts prognosis accurately in patients with Wilms tumour. Front Immunol 2022; 13:920666. [PMID: 36172369 PMCID: PMC9510599 DOI: 10.3389/fimmu.2022.920666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
Wilms tumour (WT) is the most common kidney malignancy in children. Chemoresistance is the leading cause of tumour recurrence and poses a substantial therapeutic challenge. Increasing evidence has underscored the role of the tumour immune microenvironment (TIM) in cancers and the potential for immunotherapy to improve prognosis. There remain no reliable molecular markers for reflecting the immune landscape and predicting patient survival in WT. Here, we examine differences in gene expression by high-throughput RNA sequencing, focused on differentially expressed immune-related genes (IRGs) based on the ImmPort database. Via univariate Cox regression analysis and Lasso-penalized Cox regression analysis, IRGs were screened out to establish an immune signature. Kaplan-Meier curves, time-related ROC analysis, univariate and multivariate Cox regression studies, and nomograms were used to evaluate the accuracy and prognostic significance of this signature. Furthermore, we found that the immune signature could reflect the immune status and the immune cell infiltration character played in the tumour microenvironment (TME) and showed significant association with immune checkpoint molecules, suggesting that the poor outcome may be partially explained by its immunosuppressive TME. Remarkably, TIDE, a computational method to model tumour immune evasion mechanisms, showed that this signature holds great potential for predicting immunotherapy responses in the TARGET-wt cohort. To decipher the underlying mechanism, GSEA was applied to explore enriched pathways and biological processes associated with immunophenotyping and Connectivity map (CMap) along with DeSigN analysis for drug exploration. Finally, four candidate immune genes were selected, and their expression levels in WT cell lines were monitored via qRT-PCR. Meanwhile, we validated the function of a critical gene, NRP2. Taken together, we established a novel immune signature that may serve as an effective prognostic signature and predictive biomarker for immunotherapy response in WT patients. This study may give light on therapeutic strategies for WT patients from an immunological viewpoint.
Collapse
Affiliation(s)
- Xiao-Mao Tian
- Department of Urology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| | - Bin Xiang
- Department of Urology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| | - Li-Ming Jin
- Department of Urology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| | - Tao Mi
- Department of Urology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| | - Jin-Kui Wang
- Department of Urology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| | - Chenghao Zhanghuang
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| | - Zhao-Xia Zhang
- Department of Urology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| | - Mei-Ling Chen
- Department of Urology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| | - Qin-Lin Shi
- Department of Urology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| | - Feng Liu
- Department of Urology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
- *Correspondence: Feng Liu,
| | - Tao Lin
- Department of Urology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Guang-Hui Wei
- Department of Urology, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, China
| |
Collapse
|
|
17
|
Cao J, Xu Y, Liu X, Cai Y, Luo B. Innovative signature establishment using lymphangiogenesis-related lncRNA pairs to predict prognosis of hepatocellular carcinoma. Heliyon 2022; 8:e10215. [PMID: 36033263 PMCID: PMC9403397 DOI: 10.1016/j.heliyon.2022.e10215] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 05/17/2022] [Accepted: 08/02/2022] [Indexed: 11/27/2022] Open
Abstract
Aims Hepatocellular carcinoma (HCC) remains a major tumoral burden globally, and its heterogeneity encumbers prognostic prediction. The lymphangiogenesis-related long non-coding RNAs (lrlncRNAs) reported to be implicated in immune response regulation show potential importance in predicting the prognostic and therapeutic outcome. Hence, this study aims to establish a lrlncRNA pairs-based signature not requiring specific expression levels of transcripts, which displays promising clinical practicality and satisfactory predictive capability. Main methods Transcriptomic and clinical information of the Liver Hepatocellular Carcinoma (LIHC) project retrieved from the TCGA portal were used to find differently expressed lrlncRNA (DElrlncRNA) via analysis performed between lymphangiogenesis-related genes (lr-genes) and lncRNAs(lrlncRNA), and to ultimately construct the signature based on lrlncRNA pairs screened out via Lasso and Cox regression analyses. Akaike information criterion (AIC) values were computed to find the cut-off point optimum for high-risk and low-risk group allocation. The signature then underwent trials in terms of its predictive value for survival, clinicopathological features, immune cells infiltration in tumoral microenvironment, selected checkpoint biomarkers and chemosensitivity. Key findings A novel lymphangiogenesis-related lncRNA pair signature was established using nine lrlncRNA pairs identified and significantly related to overall survival, clinicopathological features, immune cells infiltration and susceptibility to chemotherapy. Moreover, the signature efficacy was verified in acknowledged clinicopathological subgroups and partially validated by qRT-PCR assay in various human HCC cell lines. Significance The novel lrlncRNA-pairs based signature was shown to effectively and independently estimate HCC prognosis and help screen patients suitable for anti-tumor immunotherapy and chemotherapy.
Collapse
Affiliation(s)
- Jincheng Cao
- Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Yanni Xu
- Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Xiaodi Liu
- Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Yan Cai
- Department of Ultrasound, Central People's Hospital of Zhanjiang, 236 Yuanzhu Road, Zhanjiang, Guangdong 524045, China
| | - Baoming Luo
- Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| |
Collapse
|
|
18
|
Neuropilin (NRPs) Related Pathological Conditions and Their Modulators. Int J Mol Sci 2022; 23:ijms23158402. [PMID: 35955539 PMCID: PMC9368954 DOI: 10.3390/ijms23158402] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/20/2022] [Accepted: 07/27/2022] [Indexed: 01/08/2023] Open
Abstract
Neuropilin 1 (NRP1) represents one of the two homologous neuropilins (NRP, splice variants of neuropilin 2 are the other) found in all vertebrates. It forms a transmembrane glycoprotein distributed in many human body tissues as a (co)receptor for a variety of different ligands. In addition to its physiological role, it is also associated with various pathological conditions. Recently, NRP1 has been discovered as a coreceptor for the SARS-CoV-2 viral entry, along with ACE2, and has thus become one of the COVID-19 research foci. However, in addition to COVID-19, the current review also summarises its other pathological roles and its involvement in clinical diseases like cancer and neuropathic pain. We also discuss the diversity of native NRP ligands and perform a joint analysis. Last but not least, we review the therapeutic roles of NRP1 and introduce a series of NRP1 modulators, which are typical peptidomimetics or other small molecule antagonists, to provide the medicinal chemistry community with a state-of-the-art overview of neuropilin modulator design and NRP1 druggability assessment.
Collapse
|
|
19
|
Saikia Q, Reeve H, Alzahrani A, Critchley WR, Zeqiraj E, Divan A, Harrison MA, Ponnambalam S. VEGFR endocytosis: Implications for angiogenesis. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2022; 194:109-139. [PMID: 36631189 DOI: 10.1016/bs.pmbts.2022.06.021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The binding of vascular endothelial growth factor (VEGF) superfamily to VEGF receptor tyrosine kinases (VEGFRs) and co-receptors regulates vasculogenesis, angiogenesis and lymphangiogenesis. A recurring theme is that dysfunction in VEGF signaling promotes pathological angiogenesis, an important feature of cancer and pro-inflammatory disease states. Endocytosis of basal (resting) or activated VEGFRs facilitates signal attenuation and endothelial quiescence. However, increasing evidence suggest that activated VEGFRs can continue to signal from intracellular compartments such as endosomes. In this chapter, we focus on the evolving link between VEGFR endocytosis, signaling and turnover and the implications for angiogenesis. There is much interest in how such understanding of VEGFR dynamics can be harnessed therapeutically for a wide range of human disease states.
Collapse
Affiliation(s)
- Queen Saikia
- School of Molecular & Cellular Biology, University of Leeds, Leeds, United Kingdom
| | - Hannah Reeve
- School of Molecular & Cellular Biology, University of Leeds, Leeds, United Kingdom
| | - Areej Alzahrani
- School of Molecular & Cellular Biology, University of Leeds, Leeds, United Kingdom
| | - William R Critchley
- School of Molecular & Cellular Biology, University of Leeds, Leeds, United Kingdom
| | - Elton Zeqiraj
- School of Molecular & Cellular Biology, University of Leeds, Leeds, United Kingdom
| | - Aysha Divan
- School of Molecular & Cellular Biology, University of Leeds, Leeds, United Kingdom
| | - Michael A Harrison
- School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom
| | | |
Collapse
|
|
20
|
Islam R, Mishra J, Bodas S, Bhattacharya S, Batra SK, Dutta S, Datta K. Role of Neuropilin-2-mediated signaling axis in cancer progression and therapy resistance. Cancer Metastasis Rev 2022; 41:771-787. [PMID: 35776228 PMCID: PMC9247951 DOI: 10.1007/s10555-022-10048-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 06/16/2022] [Indexed: 12/12/2022]
Abstract
Neuropilins (NRPs) are transmembrane proteins involved in vascular and nervous system development by regulating angiogenesis and axon guidance cues. Several published reports have established their role in tumorigenesis. NRPs are detectable in tumor cells of several cancer types and participate in cancer progression. NRP2 is also expressed in endothelial and immune cells in the tumor microenvironment and promotes functions such as lymphangiogenesis and immune suppression important for cancer progression. In this review, we have taken a comprehensive approach to discussing various aspects of NRP2-signaling in cancer, including its regulation, functional significance in cancer progression, and how we could utilize our current knowledge to advance the studies and target NRP2 to develop effective cancer therapies.
Collapse
Affiliation(s)
- Ridwan Islam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Juhi Mishra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sanika Bodas
- Department of Molecular Genetics and Cell Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Sreyashi Bhattacharya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Samikshan Dutta
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Kaustubh Datta
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
| |
Collapse
|
|
21
|
Abstract
The lymphatic system, composed of initial and collecting lymphatic vessels as well as lymph nodes that are present in almost every tissue of the human body, acts as an essential transport system for fluids, biomolecules and cells between peripheral tissues and the central circulation. Consequently, it is required for normal body physiology but is also involved in the pathogenesis of various diseases, most notably cancer. The important role of tumor-associated lymphatic vessels and lymphangiogenesis in the formation of lymph node metastasis has been elucidated during the last two decades, whereas the underlying mechanisms and the relation between lymphatic and peripheral organ dissemination of cancer cells are incompletely understood. Lymphatic vessels are also important for tumor-host communication, relaying molecular information from a primary or metastatic tumor to regional lymph nodes and the circulatory system. Beyond antigen transport, lymphatic endothelial cells, particularly those residing in lymph node sinuses, have recently been recognized as direct regulators of tumor immunity and immunotherapy responsiveness, presenting tumor antigens and expressing several immune-modulatory signals including PD-L1. In this review, we summarize recent discoveries in this rapidly evolving field and highlight strategies and challenges of therapeutic targeting of lymphatic vessels or specific lymphatic functions in cancer patients.
Collapse
Affiliation(s)
- Lothar C Dieterich
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Carlotta Tacconi
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.,Department of Biosciences, University of Milan, Milan, Italy
| | - Luca Ducoli
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Michael Detmar
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| |
Collapse
|
|
22
|
Hypoxia orchestrates the lymphovascular–immune ensemble in cancer. Trends Cancer 2022; 8:771-784. [DOI: 10.1016/j.trecan.2022.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/31/2022] [Accepted: 04/25/2022] [Indexed: 11/18/2022]
|
|
23
|
Bekisz S, Baudin L, Buntinx F, Noël A, Geris L. In Vitro, In Vivo, and In Silico Models of Lymphangiogenesis in Solid Malignancies. Cancers (Basel) 2022; 14:1525. [PMID: 35326676 PMCID: PMC8946816 DOI: 10.3390/cancers14061525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/24/2022] [Accepted: 03/08/2022] [Indexed: 12/04/2022] Open
Abstract
Lymphangiogenesis (LA) is the formation of new lymphatic vessels by lymphatic endothelial cells (LECs) sprouting from pre-existing lymphatic vessels. It is increasingly recognized as being involved in many diseases, such as in cancer and secondary lymphedema, which most often results from cancer treatments. For some cancers, excessive LA is associated with cancer progression and metastatic dissemination to the lymph nodes (LNs) through lymphatic vessels. The study of LA through in vitro, in vivo, and, more recently, in silico models is of paramount importance in providing novel insights and identifying the key molecular actors in the biological dysregulation of this process under pathological conditions. In this review, the different biological (in vitro and in vivo) models of LA, especially in a cancer context, are explained and discussed, highlighting their principal modeled features as well as their advantages and drawbacks. Imaging techniques of the lymphatics, complementary or even essential to in vivo models, are also clarified and allow the establishment of the link with computational approaches. In silico models are introduced, theoretically described, and illustrated with examples specific to the lymphatic system and the LA. Together, these models constitute a toolbox allowing the LA research to be brought to the next level.
Collapse
Affiliation(s)
- Sophie Bekisz
- Biomechanics Research Unit, GIGA In silico Medicine, ULiège, 4000 Liège, Belgium;
| | - Louis Baudin
- Laboratory of Biology of Tumor and Development, GIGA Cancer, ULiège, 4000 Liège, Belgium; (L.B.); (F.B.); (A.N.)
| | - Florence Buntinx
- Laboratory of Biology of Tumor and Development, GIGA Cancer, ULiège, 4000 Liège, Belgium; (L.B.); (F.B.); (A.N.)
| | - Agnès Noël
- Laboratory of Biology of Tumor and Development, GIGA Cancer, ULiège, 4000 Liège, Belgium; (L.B.); (F.B.); (A.N.)
| | - Liesbet Geris
- Biomechanics Research Unit, GIGA In silico Medicine, ULiège, 4000 Liège, Belgium;
- Biomechanics Section, KU Leuven, 3000 Leuven, Belgium
- Skeletal Biology and Engineering Research Center, KU Leuven, 3000 Leuven, Belgium
| |
Collapse
|
|
24
|
Chen F, Xie X, Wang L. Research Progress on Intracranial Lymphatic Circulation and Its Involvement in Disorders. Front Neurol 2022; 13:865714. [PMID: 35359624 PMCID: PMC8963982 DOI: 10.3389/fneur.2022.865714] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 02/14/2022] [Indexed: 12/14/2022] Open
Abstract
The lymphatic system is an important part of the circulatory system, as an auxiliary system of the vein, which has the functions of immune defense, maintaining the stability of the internal environment, and regulating the pressure of the tissue. It has long been thought that there are no typical lymphatic vessels consisting of endothelial cells in the central nervous system (CNS). In recent years, studies have confirmed the presence of lymphatic vessels lined with endothelial cells in the meninges. The periventricular meninges of the CNS host different populations of immune cells that affect the immune response associated with the CNS, and the continuous drainage of interstitial and cerebrospinal fluid produced in the CNS also proceeds mainly by the lymphatic system. This fluid process mobilizes to a large extent the transfer of antigens produced by the CNS to the meningeal immune cells and subsequently to the peripheral immune system through the lymphatic network, with clinically important implications for infectious diseases, autoimmunity, and tumor immunology. In our review, we discussed recent research advances in intracranial lymphatic circulation and the pathogenesis of its associated diseases, especially the discovery of meningeal lymphatic vessels, which has led to new therapeutic targets for the treatment of diseases associated with the intracranial lymphatic system.
Collapse
|
|
25
|
Poghosyan S, Frenkel N, Lentzas A, Laoukili J, Rinkes IB, Kranenburg O, Hagendoorn J. Loss of Neuropilin-2 in Murine Mesenchymal-like Colon Cancer Organoids Causes Mesenchymal-to-Epithelial Transition and an Acquired Dependency on Insulin-Receptor Signaling and Autophagy. Cancers (Basel) 2022; 14:cancers14030671. [PMID: 35158941 PMCID: PMC8833430 DOI: 10.3390/cancers14030671] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/24/2022] [Accepted: 01/27/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Many cancer types are reported to have high lymphangiogenic receptor Neuropilin-2 (Nrp2) expression, including colorectal cancer (CRC). Nrp2 is shown to be associated with tumor progression in vivo and poor prognosis in CRC patients. Although the role of Nrp2 is well established in lymphangiogenesis, the tumor cell-intrinsic role of Nrp2 remains elusive. Here, we employed murine CRC tumor-derived mesenchymal-like organoids to induce Nrp2 depletion. We demonstrate that Nrp2 deletion in CRC organoids results in a drastically altered phenotype that is characterized by mesenchymal-to-epithelial transition (MET), and an acquired dependency on IR signaling and autophagy. This phenotype is preserved in subcutaneous tumors generated by CRC organoids. We conclude that there is a complex interaction between Nrp2 and alternative pro-survival mechanisms in aggressive CRC, which could be therapeutically exploited. Abstract Neuropilin-2 (Nrp2), an important regulator of lymphangiogenesis and lymphatic metastasis, has been associated with progression in colorectal cancer (CRC). However, the tumor cell-intrinsic role of Nrp2 in cancer progression is incompletely understood. To address this question, we employed CRISPR-Cas9 technology to generate Nrp2-knockout organoids derived from murine CRC tumors with a mesenchymal phenotype. Transcriptome profiling and tumor tissue analysis showed that Nrp2 loss resulted in mesenchymal-to-epithelial transition (MET), which was accompanied with restored polarity and tight junction stabilization. Signaling pathway analysis revealed that Nrp2-knockout organoids acquire de novo dependency on insulin receptor (IR) signaling and autophagy as alternative survival mechanisms. Combined inhibition of IR signaling and autophagy prevented the stabilization of cell-cell junctions, reduced metabolic activity, and caused profound cell death in Nrp2-knockout organoids. Collectively, the data demonstrate a key role for Nrp2 in maintaining the aggressive phenotype and survival of tumor-derived CRC organoids. The identified connection between Nrp2, insulin receptor signaling and autophagy may guide the development of novel combination-treatment strategies for aggressive CRC.
Collapse
|
|
26
|
Yang Y, Ma Y, Yan S, Wang P, Hu J, Chen S, Zhu J, Wang J, Chen G, Liu Y. CAF promotes chemoresistance through NRP2 in gastric cancer. Gastric Cancer 2022; 25:503-514. [PMID: 34826008 PMCID: PMC9013334 DOI: 10.1007/s10120-021-01270-w] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 11/19/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Fibroblasts are the predominant cell type in the stroma of tumor, and cancer-associated fibroblasts (CAFs) promote cancer chemoresistance by secreting various bioactive molecules. However, the differential expression between CAFs and normal fibroblasts (NFs) and how can CAFs uniquely impact cancer cells are still unexplored. METHODS Primary CAFs and NFs were cultured from gastric cancer specimens, and their variant expression was analyzed by RNA-sequencing. Chemoresistance was evaluated by measuring cell viability, apoptosis, and 3D-coculture techniques. RESULTS CAFs were isolated from gastric cancers and defined by specific cell-surface markers. CAFs decreased the sensitivity of gastric cancer cells to 5-FU. RNA-sequencing showed that CAFs expressed a higher level of NRP2 than NFs. And the high expression of NRP2 was correlated with worse oncological outcomes in gastric cancer patients. Further study showed that the knockdown of NRP2 eradicated the resistance to 5-FU. And the secretion of stromal cell-derived factor-1 (SDF-1) was reduced following NRP2 knockdown. Furthermore, we found that the increased sensitivity to 5-FU was induced by DNA damage. And this process was mediated by predominant effectors of the Hippo pathway, YAP/TAZ. CONCLUSIONS The present study indicated that CAFs within gastric cancers promote chemoresistance through the expression of NRP2. The secretion of SDF-1 that mediated by VEGF/NRP2 signaling in CAFs and the activation of Hippo pathway in cancer cells in large part participated in this project.
Collapse
Affiliation(s)
- Yanpeng Yang
- Department of Gastroenterology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China
| | - Yongchen Ma
- Department of Endoscopic Center, Peking University First Hospital, Beijing, China
| | - Shen Yan
- Department of Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, China
| | - Pengyuan Wang
- Department of Gastroenterology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China
| | - Jianwen Hu
- Department of Gastroenterology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China
| | - Shanwen Chen
- Department of Gastroenterology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China
| | - Jing Zhu
- Department of Gastroenterology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China
| | - Jingui Wang
- Department of Gastroenterology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China
| | - Guowei Chen
- Department of Gastroenterology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China
| | - Yucun Liu
- Department of Gastroenterology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, China
| |
Collapse
|
|
27
|
Roy S, Banerjee P, Ekser B, Bayless K, Zawieja D, Alpini G, Glaser SS, Chakraborty S. Targeting Lymphangiogenesis and Lymph Node Metastasis in Liver Cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:2052-2063. [PMID: 34509441 PMCID: PMC8647434 DOI: 10.1016/j.ajpath.2021.08.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/21/2021] [Accepted: 08/26/2021] [Indexed: 12/17/2022]
Abstract
Increased lymphangiogenesis and lymph node metastasis, the important prognostic indicators of aggressive hepatobiliary malignancies such as hepatocellular cancer and cholangiocarcinoma, are associated with poor patient outcome. The liver produces 25% to 50% of total lymphatic fluid in the body and has a dense network of lymphatic vessels. The lymphatic system plays critical roles in fluid homeostasis and inflammation and immune response. Yet, lymphatic vessel alterations and function are grossly understudied in the context of liver pathology. Expansion of the lymphatic network has been documented in clinical samples of liver cancer; and although largely overlooked in the liver, tumor-induced lymphangiogenesis is an important player, increasing tumor metastasis in several cancers. This review aims to provide a detailed perspective on the current knowledge of alterations in the hepatic lymphatic system during liver malignancies, as well as various molecular signaling mechanisms and growth factors that may provide future targets for therapeutic intervention. In addition, the review also addresses current mechanisms and bottlenecks for effective therapeutic targeting of tumor-associated lymphangiogenesis.
Collapse
Affiliation(s)
- Sukanya Roy
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Priyanka Banerjee
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Kayla Bayless
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - David Zawieja
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, Indiana; Richard L Roudebush VA Medical Center, Indianapolis, Indiana
| | - Shannon S Glaser
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Sanjukta Chakraborty
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas.
| |
Collapse
|
|
28
|
Jarahian M, Marofi F, Maashi MS, Ghaebi M, Khezri A, Berger MR. Re-Expression of Poly/Oligo-Sialylated Adhesion Molecules on the Surface of Tumor Cells Disrupts Their Interaction with Immune-Effector Cells and Contributes to Pathophysiological Immune Escape. Cancers (Basel) 2021; 13:5203. [PMID: 34680351 PMCID: PMC8534074 DOI: 10.3390/cancers13205203] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/28/2022] Open
Abstract
Glycans linked to surface proteins are the most complex biological macromolecules that play an active role in various cellular mechanisms. This diversity is the basis of cell-cell interaction and communication, cell growth, cell migration, as well as co-stimulatory or inhibitory signaling. Our review describes the importance of neuraminic acid and its derivatives as recognition elements, which are located at the outermost positions of carbohydrate chains linked to specific glycoproteins or glycolipids. Tumor cells, especially from solid tumors, mask themselves by re-expression of hypersialylated neural cell adhesion molecule (NCAM), neuropilin-2 (NRP-2), or synaptic cell adhesion molecule 1 (SynCAM 1) in order to protect themselves against the cytotoxic attack of the also highly sialylated immune effector cells. More particularly, we focus on α-2,8-linked polysialic acid chains, which characterize carrier glycoproteins such as NCAM, NRP-2, or SynCam-1. This characteristic property correlates with an aggressive clinical phenotype and endows them with multiple roles in biological processes that underlie all steps of cancer progression, including regulation of cell-cell and/or cell-extracellular matrix interactions, as well as increased proliferation, migration, reduced apoptosis rate of tumor cells, angiogenesis, and metastasis. Specifically, re-expression of poly/oligo-sialylated adhesion molecules on the surface of tumor cells disrupts their interaction with immune-effector cells and contributes to pathophysiological immune escape. Further, sialylated glycoproteins induce immunoregulatory cytokines and growth factors through interactions with sialic acid-binding immunoglobulin-like lectins. We describe the processes, which modulate the interaction between sialylated carrier glycoproteins and their ligands, and illustrate that sialic acids could be targets of novel therapeutic strategies for treatment of cancer and immune diseases.
Collapse
Affiliation(s)
- Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy Unit Heidelberg, 69120 Heidelberg, Germany;
| | - Faroogh Marofi
- Department of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5165665931, Iran;
| | - Marwah Suliman Maashi
- Stem Cells and Regenerative Medicine Unit at King Fahad Medical Research Centre, Jeddah 11211, Saudi Arabia;
| | - Mahnaz Ghaebi
- Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan 4513956184, Iran;
| | - Abdolrahman Khezri
- Department of Biotechnology, Inland Norway University of Applied Sciences, 2418 Hamar, Norway;
| | - Martin R. Berger
- German Cancer Research Center, Toxicology and Chemotherapy Unit Heidelberg, 69120 Heidelberg, Germany;
| |
Collapse
|
|
29
|
Cai B, Hou M, Zhang S, Xin Z, Huang J, Yang J, Wang Y, Cai X, Xie S, Zhang C, Huang Y. Dual Targeting of Endoplasmic Reticulum by Redox-Deubiquitination Regulation for Cancer Therapy. Int J Nanomedicine 2021; 16:5193-5209. [PMID: 34354353 PMCID: PMC8331122 DOI: 10.2147/ijn.s321612] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/22/2021] [Indexed: 12/15/2022] Open
Abstract
Background Recently, nanocatalyst-induced endoplasmic reticulum (ER) stress for cancer therapy has been attracting considerable attention. However, cancer cells are often able to overcome ER stress-induced death by activating the unfolded protein response (UPR), making nanocatalytic monotherapy a poor defense against cancer progression. Purpose In this study, to improve the nanocatalytic treatment efficacy, a phase change material (PCM) was used to encapsulate the upstream ER stress initiator, iron oxide nanoparticles (Fe3O4 NPs), and the downstream UPR modulator, PR-619. Subsequently, the tumor-homing peptide tLyP-1 was coupled to it to form tLyP-1/PR-619/Fe3O4@PCM (tPF@PCM) theranostic platform. Materials and Methods tPF@PCM was synthesized using nanoprecipitation and resolidification methods followed by the EDC/NHS cross-linking method. The targeting capacity of tPF@PCM was evaluated in vitro and in vivo using flow cytometry and magnetic resonance imaging, respectively. The therapeutic efficacy of tPF@PCM was investigated in a renal cell carcinoma mouse model. Moreover, we explored the synergistic anti-tumor mechanism by examining the intracellular reactive oxygen species (ROS), aggregated proteins, ER stress response levels, and type of cell death. Results tPF@PCM had excellent tumor-targeting properties and exhibited satisfactory photothermal-enhanced tumor inhibition efficacy both in vitro and in vivo. Specifically, the phase transition temperature (45 °C) maintained using 808 nm laser irradiation significantly increased the release and catalytic activity of the peroxidase mimic Fe3O4 NPs. This strongly catalyzed the generation of hydroxyl radicals (•OH) via the Fenton reaction in the acidic tumor microenvironment. The redox imbalance subsequently resulted in an increase in the level of damaged proteins in the ER and initiated ER stress. Moreover, the pan-deubiquitinase inhibitor PR-619 blocked the “adaptive” UPR-mediated degradation of these damaged proteins, exacerbating the ER burden. Consequently, irremediable ER stress activated the “terminal” UPR, leading to apoptosis in cancer cells. Conclusion This ER stress-exacerbating strategy effectively suppresses tumorigenesis, offering novel directions for advances in the treatment of conventional therapy-resistant cancers.
Collapse
Affiliation(s)
- Biao Cai
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Mengfei Hou
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China
| | - Shijun Zhang
- Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Zhixiang Xin
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Jiwei Huang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Jingxing Yang
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China
| | - Yueming Wang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Xingyun Cai
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Shaowei Xie
- Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| | - Chunfu Zhang
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China
| | - Yiran Huang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, People's Republic of China
| |
Collapse
|
|
30
|
Wang L, Wang L, Wang S, Zhou Z, Liu Z, Xu P, Luo X, Wu T, Luo F, Yan J. N2E4, a Monoclonal Antibody Targeting Neuropilin-2, Inhibits Tumor Growth and Metastasis in Pancreatic Ductal Adenocarcinoma via Suppressing FAK/Erk/HIF-1α Signaling. Front Oncol 2021; 11:657008. [PMID: 34336654 PMCID: PMC8319910 DOI: 10.3389/fonc.2021.657008] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 05/24/2021] [Indexed: 01/20/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with extremely limited treatment; the effective targeting strategy stays an urgent unmet need. Neuropilin-2 (NRP2), a multifunctional transmembrane non-tyrosine-kinase glycoprotein, enhances various signal transduction pathways to modulate cancer progression. However, the application value of NRP2 as a therapeutic target in pancreatic cancer is still unclear. Here, we detected the elevated NRP2 was associated with the poor prognosis of pancreas carcinoma. The mouse monoclonal antibody targeting NRP2 (N2E4) that could specifically bind to PDAC cells was developed. Moreover, N2E4 inhibits PDAC proliferation, migration, and invasion in vitro, and repressed growth and metastasis in vivo. Mechanistically, the effect of N2E4 was mainly related to the blocking of interaction between NRP2 with integrinβ1 to inhibit FAK/Erk/HIF-1a/VEGF signaling. Therefore, N2E4 has the potential for targeting therapy of PDAC. This study lays a foundation for the future development of NRP2-based targeted therapy for PDAC.
Collapse
Affiliation(s)
- Li Wang
- Cancer Research Center, Medical College, Xiamen University, Xiamen, China
| | - Lanlan Wang
- Cancer Research Center, Medical College, Xiamen University, Xiamen, China
| | - Shengyu Wang
- Cancer Research Center, Medical College, Xiamen University, Xiamen, China
| | - Zonglang Zhou
- The 174th Clinical College of People’s Liberation Army, Anhui Medical University, Hefei, China
| | - Zongjunlin Liu
- Cancer Research Center, Medical College, Xiamen University, Xiamen, China
| | - Peilan Xu
- Cancer Research Center, Medical College, Xiamen University, Xiamen, China
| | - Xian Luo
- Cancer Research Center, Medical College, Xiamen University, Xiamen, China
| | - Ting Wu
- Cancer Research Center, Medical College, Xiamen University, Xiamen, China
| | - Fanghong Luo
- Cancer Research Center, Medical College, Xiamen University, Xiamen, China
| | - Jianghua Yan
- Cancer Research Center, Medical College, Xiamen University, Xiamen, China
| |
Collapse
|
|
31
|
He M, He Q, Cai X, Chen Z, Lao S, Deng H, Liu X, Zheng Y, Liu X, Liu J, Xie Z, Yao M, Liang W, He J. Role of lymphatic endothelial cells in the tumor microenvironment-a narrative review of recent advances. Transl Lung Cancer Res 2021; 10:2252-2277. [PMID: 34164274 PMCID: PMC8182726 DOI: 10.21037/tlcr-21-40] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background As lymphatic vessel is a major route for solid tumor metastasis, they are considered an essential part of tumor drainage conduits. Apart from forming the walls of lymphatic vessels, lymphatic endothelial cells (LECs) have been found to play multiple other roles in the tumor microenvironment, calling for a more in-depth review. We hope that this review may help researchers gain a detailed understanding of this fast-developing field and shed some light upon future research. Methods To achieve an informative review of recent advance, we carefully searched the Medline database for English literature that are openly published from the January 1995 to December 2020 and covered the topic of LEC or lymphangiogenesis in tumor progression and therapies. Two different authors independently examined the literature abstracts to exclude possible unqualified ones, and 310 papers with full texts were finally retrieved. Results In this paper, we discussed the structural and molecular basis of tumor-associated LECs, together with their roles in tumor metastasis and drug therapy. We then focused on their impacts on tumor cells, tumor stroma, and anti-tumor immunity, and the molecular and cellular mechanisms involved. Special emphasis on lung cancer and possible therapeutic targets based on LECs were also discussed. Conclusions LECs can play a much more complex role than simply forming conduits for tumor cell dissemination. Therapies targeting tumor-associated lymphatics for lung cancer and other tumors are promising, but more research is needed to clarify the mechanisms involved.
Collapse
Affiliation(s)
- Miao He
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qihua He
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiuyu Cai
- Department of VIP Region, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zisheng Chen
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Respiratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, China
| | - Shen Lao
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Hongsheng Deng
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiwen Liu
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yongmei Zheng
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaoyan Liu
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jun Liu
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhanhong Xie
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Maojin Yao
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenhua Liang
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,The First People Hospital of Zhaoqing, Zhaoqing, China
| | - Jianxing He
- Department of Thoracic Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
|
32
|
Cui S, Wu Q, Liu M, Su M, Liu S, Shao L, Han X, He H. EphA2 super-enhancer promotes tumor progression by recruiting FOSL2 and TCF7L2 to activate the target gene EphA2. Cell Death Dis 2021; 12:264. [PMID: 33712565 PMCID: PMC7955082 DOI: 10.1038/s41419-021-03538-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 02/17/2021] [Accepted: 02/18/2021] [Indexed: 01/11/2023]
Abstract
Super-enhancers or stretch enhancers (SEs) consist of large clusters of active transcription enhancers which promote the expression of critical genes that define cell identity during development and disease. However, the role of many super-enhancers in tumor cells remains unclear. This study aims to explore the function and mechanism of a new super-enhancer in various tumor cells. A new super-enhancer that exists in a variety of tumors named EphA2-Super-enhancer (EphA2-SE) was found using multiple databases and further identified. CRISPR/Cas9-mediated deletion of EphA2-SE results in the significant downregulation of its target gene EphA2. Mechanistically, we revealed that the core active region of EphA2-SE comprises E1 component enhancer, which recruits TCF7L2 and FOSL2 transcription factors to drive the expression of EphA2, induce cell proliferation and metastasis. Bioinformatics analysis of RNA-seq data and functional experiments in vitro illustrated that EphA2-SE deletion inhibited cell growth and metastasis by blocking PI3K/AKT and Wnt/β-catenin pathway in HeLa, HCT-116 and MCF-7 cells. Overexpression of EphA2 in EphA2-SE-/- clones rescued the effect of EphA2-SE deletion on proliferation and metastasis. Subsequent xenograft animal model revealed that EphA2-SE deletion suppressed tumor proliferation and survival in vivo. Taken together, these findings demonstrate that EphA2-SE plays an oncogenic role and promotes tumor progression in various tumors by recruiting FOSL2 and TCF7L2 to drive the expression of oncogene EphA2.
Collapse
Affiliation(s)
- Shuang Cui
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China
| | - Qiong Wu
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China.
| | - Ming Liu
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China
| | - Mu Su
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China
| | - ShiYou Liu
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China
| | - Lan Shao
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China
| | - Xiao Han
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China
| | - Hongjuan He
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China.
| |
Collapse
|
|
33
|
Lymphatic metastasis of bladder cancer: Molecular mechanisms, diagnosis and targeted therapy. Cancer Lett 2021; 505:13-23. [PMID: 33610730 DOI: 10.1016/j.canlet.2021.02.010] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 02/05/2021] [Accepted: 02/11/2021] [Indexed: 12/24/2022]
Abstract
Bladder cancer is the most common and lethal cancer of the urinary system. Lymphatic metastasis is the primary and main metastatic type of bladder cancer, leading to an extremely poor prognosis in patients. Therefore, a better understanding of molecular mechanisms may provide potential targets for the diagnosis and treatment of lymphatic metastasis in bladder cancer. Herein, we summarize the current knowledge of molecular mechanisms of the lymphatic metastasis in bladder cancer, including lymphangiogenesis and its regulators, noncoding RNAs, and microenvironment-associated molecules. Novel radiomics and genomics approaches have substantially improved the preoperative diagnostic accuracy of lymph node metastasis in patients with bladder cancer. Newly discovered targets may lead to promising therapeutic strategies for clinical intervention in lymphatic metastasis of bladder cancer. More basic and translational studies need to be conducted to further clarify the molecular mechanisms, and identify predictive markers and therapeutic targets of lymphatic metastasis for bladder cancer patients.
Collapse
|
|
34
|
Daly JL, Simonetti B, Klein K, Chen KE, Williamson MK, Antón-Plágaro C, Shoemark DK, Simón-Gracia L, Bauer M, Hollandi R, Greber UF, Horvath P, Sessions RB, Helenius A, Hiscox JA, Teesalu T, Matthews DA, Davidson AD, Collins BM, Cullen PJ, Yamauchi Y. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science 2020; 370:861-865. [PMID: 33082294 DOI: 10.1101/2020.06.05.134114] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 10/12/2020] [Indexed: 05/20/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), uses the viral spike (S) protein for host cell attachment and entry. The host protease furin cleaves the full-length precursor S glycoprotein into two associated polypeptides: S1 and S2. Cleavage of S generates a polybasic Arg-Arg-Ala-Arg carboxyl-terminal sequence on S1, which conforms to a C-end rule (CendR) motif that binds to cell surface neuropilin-1 (NRP1) and NRP2 receptors. We used x-ray crystallography and biochemical approaches to show that the S1 CendR motif directly bound NRP1. Blocking this interaction by RNA interference or selective inhibitors reduced SARS-CoV-2 entry and infectivity in cell culture. NRP1 thus serves as a host factor for SARS-CoV-2 infection and may potentially provide a therapeutic target for COVID-19.
Collapse
Affiliation(s)
- James L Daly
- School of Biochemistry, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK
| | - Boris Simonetti
- School of Biochemistry, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
| | - Katja Klein
- School of Cellular and Molecular Medicine, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK
| | - Kai-En Chen
- Institute for Molecular Bioscience, the University of Queensland, St. Lucia, QLD 4072, Australia
| | - Maia Kavanagh Williamson
- School of Cellular and Molecular Medicine, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK
| | - Carlos Antón-Plágaro
- School of Biochemistry, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK
| | - Deborah K Shoemark
- School of Biochemistry and BrisSynBio Centre, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK
| | - Lorena Simón-Gracia
- Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Michael Bauer
- Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland
| | - Reka Hollandi
- Synthetic and Systems Biology Unit, Biological Research Centre (BRC), Szeged, Hungary
| | - Urs F Greber
- Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland
| | - Peter Horvath
- Synthetic and Systems Biology Unit, Biological Research Centre (BRC), Szeged, Hungary
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Richard B Sessions
- School of Biochemistry, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK
| | - Ari Helenius
- Institute of Biochemistry, ETH Zurich, Zurich, Switzerland
| | - Julian A Hiscox
- Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
- Singapore Immunology Network, Agency for Science, Technology, and Research, 138648, Singapore
| | - Tambet Teesalu
- Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - David A Matthews
- School of Cellular and Molecular Medicine, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK
| | - Andrew D Davidson
- School of Cellular and Molecular Medicine, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK
| | - Brett M Collins
- Institute for Molecular Bioscience, the University of Queensland, St. Lucia, QLD 4072, Australia
| | - Peter J Cullen
- School of Biochemistry, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
| | - Yohei Yamauchi
- School of Cellular and Molecular Medicine, Faculty of Life Sciences, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
- Division of Biological Science, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan
| |
Collapse
|
|
35
|
VEGFC negatively regulates the growth and aggressiveness of medulloblastoma cells. Commun Biol 2020; 3:579. [PMID: 33067561 PMCID: PMC7568583 DOI: 10.1038/s42003-020-01306-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 09/17/2020] [Indexed: 02/08/2023] Open
Abstract
Medulloblastoma (MB), the most common brain pediatric tumor, is a pathology composed of four molecular subgroups. Despite a multimodal treatment, 30% of the patients eventually relapse, with the fatal appearance of metastases within 5 years. The major actors of metastatic dissemination are the lymphatic vessel growth factor, VEGFC, and its receptors/co-receptors. Here, we show that VEGFC is inversely correlated to cell aggressiveness. Indeed, VEGFC decreases MB cell proliferation and migration, and their ability to form pseudo-vessel in vitro. Irradiation resistant-cells, which present high levels of VEGFC, lose the ability to migrate and to form vessel-like structures. Thus, irradiation reduces MB cell aggressiveness via a VEGFC-dependent process. Cells intrinsically or ectopically overexpressing VEGFC and irradiation-resistant cells form smaller experimental tumors in nude mice. Opposite to the common dogma, our results give strong arguments in favor of VEGFC as a negative regulator of MB growth. Manon Penco-Campillo, Yannick Comoglio et al. show that VEGFC decreases the proliferation and migration of medulloblastoma cells, as well as their ability to form pseudo vessels. Cells expressing high levels of VEGFC also form smaller tumors when subcutaneously injected into the flank of nude mice, thus highlighting a negative regulatory role for VEGFC on tumor growth.
Collapse
|
|
36
|
Poursheikhani A, Abbaszadegan MR, Kerachian MA. Mechanisms of long non-coding RNA function in colorectal cancer tumorigenesis. Asia Pac J Clin Oncol 2020; 17:7-23. [PMID: 32970938 DOI: 10.1111/ajco.13452] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 08/03/2020] [Indexed: 12/14/2022]
Abstract
Colorectal cancer (CRC) is one of the most common cancers globally. Although a variety of CRC screening methods have been developed, many patients are diagnosed at advanced stages of CRC with tumor invasion and distance metastasis. Several studies have suggested the long noncoding RNAs (lncRNAs) as one of the main contributors in CRC tumorigenesis, although the exact underlying mechanism of lncRNAs in CRC is still unknown. Numerous studies have indicated aberrant expression of lncRNAs in CRC through different modes of action such as cell proliferation, apoptosis, cell cycle, DNA repair response, drug-resistance, migration, and metastasis. Furthermore, lncRNA polymorphisms can influence the risk of CRC development. Accordingly, lncRNAs can be served as promising diagnostic or prognostic biomarkers and also desired therapeutic targets affecting the outcome of patients with CRC. In this review, we summarized the updated and novel evidence that identifies different roles of lncRNAs in the tumorigenesis of CRC.
Collapse
Affiliation(s)
- Arash Poursheikhani
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Abbaszadegan
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Amin Kerachian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Cancer Genetics Research Unit, Reza Radiotherapy, and Oncology Center, Mashhad, Iran
| |
Collapse
|
|
37
|
Zhao L, Chen H, Lu L, Wang L, Zhang X, Guo X. New insights into the role of co-receptor neuropilins in tumour angiogenesis and lymphangiogenesis and targeted therapy strategies. J Drug Target 2020; 29:155-167. [PMID: 32838575 DOI: 10.1080/1061186x.2020.1815210] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Local tumour sites lead to pathological angiogenesis and lymphangiogenesis due to malignant conditions such as hypoxia. Although VEGF and VEGFR are considered to be the main anti-tumour treatment targets, the problems of limited efficacy and observable side effects of some drugs relevant to this target still remain to be solved. Therefore, it is necessary to identify new therapeutic targets for angiogenesis or lymphangiogenesis. The neuropilin family is a class of single transmembrane glycoprotein receptors, including neuropilin1 (NRP1) and neuropilin2 (NRP2), which could act as co-receptors of VEGFA-165 and VEGFC and play a key role in promoting tumour proliferation, invasion and metastasis. In this review, we introduced the schematic diagram to visually reveal the function of NRP1 and NRP2 in enhancing the binding affinity of VEGFR2 to VEGFA-165 and VEGFR3 to VEGFC, respectively. We also discussed the signalling pathways that depend on the co-receptors NRP1 and NRP2 and some existing targeted therapeutic strategies, such as monoclonal antibodies, targeted peptides, microRNAs and small molecule inhibitors. It will contribute a vital foundation for the future research and development of new drugs targeting NRPs. HIGHLIGHTS NRP1 acts as a co-receptor with VEGFR2 and the pro-angiogenic factor VEGFA-165 to up-regulate tumour angiogenesis by promoting endothelial cells proliferation, survival, migration, invasion and by preventing of apoptosis. NRP2 acts as a co-receptor with VEGFR3 and the pro-lymphogenic factor VEGFC to facilitate tumour metastasis by promoting lymphangiogenesis. Although NRP1 and NRP2 do not have enzymatic signalling activity, the affinity of VEGFR2 for VEGFA-165 and VEGFR3 for VEGFC can increase in a co-receptor manner, as detailed in the schematic. The exclusive roles of NRP1 and NRP2 in signalling pathways are specifically described to emphasise the molecular regulatory mechanisms involved in co-receptors. Various studies have shown that the co-receptors NRP1 and NRP2 can be directly or indirectly targeted by different methods to prevent tumour angiogenesis and lymphangiogenesis. Therapeutic strategies targeting NRPs look promising soon as evidenced by preclinical and clinical studies.
Collapse
Affiliation(s)
- Lin Zhao
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Hongyuan Chen
- Department of General Surgery, Shandong University Affiliated Shandong Provincial Hospital, Jinan, China
| | - Lu Lu
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Lei Wang
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Xinke Zhang
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Xiuli Guo
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| |
Collapse
|
|
38
|
Harman JL, Sayers J, Chapman C, Pellet-Many C. Emerging Roles for Neuropilin-2 in Cardiovascular Disease. Int J Mol Sci 2020; 21:E5154. [PMID: 32708258 PMCID: PMC7404143 DOI: 10.3390/ijms21145154] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/16/2020] [Accepted: 07/17/2020] [Indexed: 12/26/2022] Open
Abstract
Cardiovascular disease, the leading cause of death worldwide, is predominantly associated with atherosclerosis. Atherosclerosis is a chronic inflammatory disease characterised by the narrowing of large to medium-sized arteries due to a build-up of plaque. Atherosclerotic plaque is comprised of lipids, extracellular matrix, and several cell types, including endothelial, immune, and vascular smooth muscle cells. Such narrowing of the blood vessels can itself restrict blood flow to vital organs but most severe clinical complications, including heart attacks and strokes, occur when lesions rupture, triggering the blood to clot and obstructing blood flow further down the vascular tree. To circumvent such obstructions, percutaneous coronary intervention or bypass grafts are often required; however, re-occlusion of the treated artery frequently occurs. Neuropilins (NRPs), a multifunctional family of cell surface co-receptors, are expressed by endothelial, immune, and vascular smooth muscle cells and are regulators of numerous signalling pathways within the vasculature. Here, we review recent studies implicating NRP2 in the development of occlusive vascular diseases and discuss how NRP2 could be targeted for therapeutic intervention.
Collapse
Affiliation(s)
- Jennifer L Harman
- Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK
| | - Jacob Sayers
- University College London, Division of Medicine, Rayne Building, University Street, London WC1E 6JF, UK
| | - Chey Chapman
- Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK
| | - Caroline Pellet-Many
- Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK
| |
Collapse
|
|
39
|
Alghamdi AAA, Benwell CJ, Atkinson SJ, Lambert J, Johnson RT, Robinson SD. NRP2 as an Emerging Angiogenic Player; Promoting Endothelial Cell Adhesion and Migration by Regulating Recycling of α5 Integrin. Front Cell Dev Biol 2020; 8:395. [PMID: 32528960 PMCID: PMC7264094 DOI: 10.3389/fcell.2020.00395] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 04/29/2020] [Indexed: 01/01/2023] Open
Abstract
Angiogenesis relies on the ability of endothelial cells (ECs) to migrate over the extracellular matrix via integrin receptors to respond to an angiogenic stimulus. Of the two neuropilin (NRP) orthologs to be identified, both have been reported to be expressed on normal blood and lymphatic ECs, and to play roles in the formation of blood and lymphatic vascular networks during angiogenesis. Whilst the role of NRP1 and its interactions with integrins during angiogenesis has been widely studied, the role of NRP2 in ECs is poorly understood. Here we demonstrate that NRP2 promotes Rac-1 mediated EC adhesion and migration over fibronectin (FN) matrices in a mechanistically distinct fashion to NRP1, showing no dependence on β3 integrin (ITGB3) expression, or VEGF stimulation. Furthermore, we highlight evidence of a regulatory crosstalk between NRP2 and α5 integrin (ITGA5) in ECs, with NRP2 depletion eliciting an upregulation of ITGA5 expression and disruptions in ITGA5 cellular organization. Finally, we propose a mechanism whereby NRP2 promotes ITGA5 recycling in ECs; NRP2 depleted ECs were found to exhibit reduced levels of total ITGA5 subunit recycling compared to wild-type (WT) ECs. Our findings expose NRP2 as a novel angiogenic player by promoting ITGA5-mediated EC adhesion and migration on FN.
Collapse
Affiliation(s)
- Abdullah A A Alghamdi
- School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
| | - Christopher J Benwell
- Gut Microbes and Health, Quadram Institute Bioscience, Norwich Research Park, Norwich, United Kingdom
| | - Samuel J Atkinson
- School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
| | - Jordi Lambert
- Faculty of Medicine and Health Sciences, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
| | - Robert T Johnson
- School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
| | - Stephen D Robinson
- School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.,Gut Microbes and Health, Quadram Institute Bioscience, Norwich Research Park, Norwich, United Kingdom
| |
Collapse
|
|
40
|
Dimou A, Nasarre C, Peterson YK, Pagano R, Gooz M, Nasarre P, Drabkin HA, Armeson KE, Gibney BC, Gemmill RM, Denlinger CE. Neuropilin-2b facilitates resistance to tyrosine kinase inhibitors in non-small cell lung cancer. J Thorac Cardiovasc Surg 2020; 162:463-473. [PMID: 32653291 DOI: 10.1016/j.jtcvs.2020.03.166] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Revised: 03/22/2020] [Accepted: 03/24/2020] [Indexed: 12/27/2022]
Abstract
OBJECTIVE Innate and acquired resistance is the principle factor limiting the efficacy of tyrosine kinase inhibitors in lung cancer. We have observed a dramatic upregulation of the cell surface co-receptor neuropilin-2b in lung cancers clinically treated with tyrosine kinase inhibitors correlating with acquired resistance. We hypothesize that neuropilin-2b plays a functional role in acquired tyrosine kinase inhibitor resistance. METHODS Non-small cell lung cancer proliferation and survival were determined during chronic tyrosine kinase inhibitor exposure in the presence or absence of neuropilin-2b knock-down. Interactions of neuropilin-2a and neuropilin-2b isoforms with PTEN and GSK3β were assessed by immunoprecipitation. Neuropilin-2a and neuropilin-2b mutants deleted for their cytoplasmic domains were used to identify regions responsible for neuropilin-2b-GSK3β interaction. Because GSK3β is known to phosphorylate and degrade PTEN, phospho-PTEN and total PTEN levels were assessed after transfection of neuropilin-2a and neuropilin-2b wild-type and mutant constructs. RESULTS Non-small cell lung cancer cells chronically treated with gefitinib or osimertinib developed drug resistance and exhibited logarithmic growth in the presence of endothelial growth factor receptor tyrosine kinase inhibitors. However, neuropilin-2b knockdown cells remained sensitive to gefitinib. Likewise, neuropilin-2b knockdown suppressed and neuropilin-2a knockdown enhanced cellular migration. Acquired drug resistance and cell migration correlated with neuropilin-2b-dependent AKT activation with the intermediate step of GSK3β-dependent PTEN degradation. A specific binding site for GSK3β on the cytoplasmic domain of neuropilin-2b was identified with truncated protein constructs and computer modeling. CONCLUSIONS Neuropilin-2b facilitates non-small cell lung cancer resistance to tyrosine kinase inhibitors, and this biological effect relates to AKT activation. Neuropilin-2b GSK3β interactions appear to be essential for PTEN degradation and AKT activation in lung cancer cells. Disruption of the neuropilin-2b GSK3β interaction may represent a novel treatment strategy to preserve sensitivity to tyrosine kinase inhibitors in non-small cell lung cancer.
Collapse
Affiliation(s)
- Anastasios Dimou
- Division of Medical Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC
| | - Cecile Nasarre
- Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, SC
| | - Yuri K Peterson
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC
| | - Rose Pagano
- Division of Medical Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC
| | - Monika Gooz
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC
| | - Patrick Nasarre
- Department of Surgery, Medical University of South Carolina, Charleston, SC
| | - Harry A Drabkin
- Division of Medical Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC
| | - Kent E Armeson
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC
| | - Barry C Gibney
- Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, SC
| | - Robert M Gemmill
- Division of Medical Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC
| | - Chadrick E Denlinger
- Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, Charleston, SC.
| |
Collapse
|
|
41
|
Said AM, Parker MW, Vander Kooi CW. Design, synthesis, and evaluation of a novel benzamidine-based inhibitor of VEGF-C binding to Neuropilin-2. Bioorg Chem 2020; 100:103856. [PMID: 32344185 DOI: 10.1016/j.bioorg.2020.103856] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 03/11/2020] [Accepted: 04/14/2020] [Indexed: 12/11/2022]
Abstract
The Neuropilin (Nrp) family of cell surface receptors have key physiological and pathological functions. Nrp2 is of particular interest due to its involvement in tumor metastasis. Currently, peptide and small molecule inhibitors that target Nrp utilize arginine-based molecules which have limitations due to high inherent flexibility and issues related to stability. Further, there are no known small molecule inhibitors specific for Nrp2. Recent molecular insights identify a key ligand binding region in the b1 domain of Nrp2 responsible for binding the C-terminus of its cognate ligand VEGF-C. Based on this, we report the discovery of a novel benzamidine-based inhibitor that functions through competitive inhibition of VEGF-C binding to Nrp2. Further, we have explored inhibitor functionality and selectivity by defining its structure-activity relationship (SAR) providing valuable insights on this benzamidine-based family of Nrp2 inhibitors. This study provides the basis for further development of a potent and specific small molecule inhibitor that competitively targets pathological Nrp2 function.
Collapse
Affiliation(s)
- Ahmed M Said
- Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, 14260, United States; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Helwan, Cairo 11795, Egypt.
| | - Matthew W Parker
- Department of Molecular and Cellular Biochemistry, Center for Structural Biology, University of Kentucky, Lexington, KY 40536, United States
| | - Craig W Vander Kooi
- Department of Molecular and Cellular Biochemistry, Center for Structural Biology, University of Kentucky, Lexington, KY 40536, United States.
| |
Collapse
|
|
42
|
Peng K, Li Y, Bai Y, Jiang T, Sun H, Zhu Q, Xu Y. Discovery of novel nonpeptide small-molecule NRP1 antagonists: Virtual screening, molecular simulation and structural modification. Bioorg Med Chem 2020; 28:115183. [DOI: 10.1016/j.bmc.2019.115183] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 10/05/2019] [Accepted: 10/25/2019] [Indexed: 12/27/2022]
|
|
43
|
Zhang H, Wang R, Wang M. miR-331-3p suppresses cell invasion and migration in colorectal carcinoma by directly targeting NRP2. Oncol Lett 2019; 18:6501-6508. [PMID: 31807170 PMCID: PMC6876315 DOI: 10.3892/ol.2019.11029] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 07/30/2019] [Indexed: 12/21/2022] Open
Abstract
Colorectal carcinoma (CRC) is a common tumor of the digestive system with poor prognosis. Studies have shown that aberrant microRNA (miRNA) expression can affect CRC progression by regulating target genes. In the present study, we investigated the functional roles and potential mechanisms of miR-331-3p in CRC. The expression of miR-331-3p and neuropilin-2 (NRP2) in CRC was detected by RT-qPCR. Then, Transwell assays were conducted to investigate the influence of miR-331-3p on CRC cell invasion and migration abilities. Luciferase reporter assays were performed to determine the target gene of miR-331-3p. It was found that miR-331-3p expression was notably declined in CRC and inversely correlated with the NRP2 expression. miR-331-3p upregulation significantly inhibited CRC cell invasion and migration. Additionally, western blot analysis demonstrated that miR-331-3p restoration evidently suppressed CRC cell EMT. Moreover, NRP2 was conformed to be a novel target of miR-331-3p and knockdown of NRP2 partially inversed the effects of the miR-331-3p inhibitor on cell invasion and migration. These results suggested that miR-331-3p exerted tumor suppressive roles in CRC by targeting NRP2 and miR-331-3p/NRP2 may serve as a potential therapy for CRC.
Collapse
Affiliation(s)
- Hongye Zhang
- Department of Oncology, Linyi Central Hospital, Linyi, Shandong 276400, P.R. China
| | - Ruiyu Wang
- Department of Oncology, Linyi Central Hospital, Linyi, Shandong 276400, P.R. China
| | - Mingxia Wang
- Department of Oncology, Linyi Central Hospital, Linyi, Shandong 276400, P.R. China
| |
Collapse
|
|
44
|
Wu ZS, Ding W, Cai J, Bashir G, Li YQ, Wu S. Communication Of Cancer Cells And Lymphatic Vessels In Cancer: Focus On Bladder Cancer. Onco Targets Ther 2019; 12:8161-8177. [PMID: 31632067 PMCID: PMC6781639 DOI: 10.2147/ott.s219111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 08/07/2019] [Indexed: 12/16/2022] Open
Abstract
Bladder cancer is one of the most commonly diagnosed cancers worldwide and causes the highest lifetime treatment costs per patient. Bladder cancer is most likely to metastasize through lymphatic ducts, and once the lymph nodes are involved, the prognosis is poorly and finitely improved by current modalities. The underlying metastatic mechanism for bladder cancer is thus becoming a research focus to date. To identify relevant published data, an online search of the PubMed/Medline archives was performed to locate original articles and review articles regarding lymphangiogenesis and lymphatic metastasis in urinary bladder cancer (UBC), and was limited to articles in English published between 1998 and 2018. A further search of the clinical trials.gov search engine was conducted to identify both trials with results available and those with results not yet available. Herein, we summarized the unique mechanisms and biomarkers involved in the malignant progression of bladder cancer as well as their emerging roles in therapeutics, and that current data suggests that lymphangiogenesis and lymph node invasion are important prognostic factors for UBC. The growing knowledge about their roles in bladder cancers provides the basis for novel therapeutic strategies. In addition, more basic and clinical research needs to be conducted in order to identify further accurate predictive molecules and relevant mechanisms.
Collapse
Affiliation(s)
- Zhang-song Wu
- Medical College, Shenzhen University, Shenzhen518000, People’s Republic of China
- Department of Urological Surgery, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen518000, People’s Republic of China
- Shenzhen following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen518000, People’s Republic of China
| | - Wa Ding
- Medical College, Shenzhen University, Shenzhen518000, People’s Republic of China
- Shenzhen following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen518000, People’s Republic of China
| | - Jiajia Cai
- Shenzhen following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen518000, People’s Republic of China
- Medical College, Anhui University of Science and Technology, Huainan232001, People’s Republic of China
| | - Ghassan Bashir
- Shenzhen following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen518000, People’s Republic of China
| | - Yu-qing Li
- Department of Urological Surgery, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen518000, People’s Republic of China
- Shenzhen following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen518000, People’s Republic of China
| | - Song Wu
- Medical College, Shenzhen University, Shenzhen518000, People’s Republic of China
- Department of Urological Surgery, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen518000, People’s Republic of China
- Shenzhen following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen518000, People’s Republic of China
- Medical College, Anhui University of Science and Technology, Huainan232001, People’s Republic of China
| |
Collapse
|
|
45
|
Sestito LF, Thomas SN. Biomaterials for Modulating Lymphatic Function in Immunoengineering. ACS Pharmacol Transl Sci 2019; 2:293-310. [PMID: 32259064 DOI: 10.1021/acsptsci.9b00047] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Indexed: 12/13/2022]
Abstract
Immunoengineering is a rapidly growing and interdisciplinary field focused on developing tools to study and understand the immune system, then employing that knowledge to modulate immune response for the treatment of disease. Because of its roles in housing a substantial fraction of the body's lymphocytes, in facilitating immune cell trafficking, and direct immune modulatory functions, among others, the lymphatic system plays multifaceted roles in immune regulation. In this review, the potential for biomaterials to be applied to regulate the lymphatic system and its functions to achieve immunomodulation and the treatment of disease are described. Three related processes-lymphangiogenesis, lymphatic vessel contraction, and lymph node remodeling-are specifically explored. The molecular regulation of each process and their roles in pathologies are briefly outlined, with putative therapeutic targets and the lymphatic remodeling that can result from disease highlighted. Applications of biomaterials that harness these pathways for the treatment of disease via immunomodulation are discussed.
Collapse
Affiliation(s)
- Lauren F Sestito
- Wallace H. Coulter Department of Biomedical Engineering, George W. Woodruff School of Mechanical Engineering, and Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive NW, Atlanta, Georgia 30332, United States.,Department of Biomedical Engineering, Emory University, 201 Dowman Drive, Atlanta, Georgia 30322, United States
| | - Susan N Thomas
- Wallace H. Coulter Department of Biomedical Engineering, George W. Woodruff School of Mechanical Engineering, and Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive NW, Atlanta, Georgia 30332, United States.,Department of Biomedical Engineering, Emory University, 201 Dowman Drive, Atlanta, Georgia 30322, United States.,Wallace H. Coulter Department of Biomedical Engineering, George W. Woodruff School of Mechanical Engineering, and Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive NW, Atlanta, Georgia 30332, United States.,Wallace H. Coulter Department of Biomedical Engineering, George W. Woodruff School of Mechanical Engineering, and Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive NW, Atlanta, Georgia 30332, United States.,Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road NW, Atlanta, Georgia 30322, United States
| |
Collapse
|
|
46
|
Bollard J, Patte C, Radkova K, Massoma P, Chardon L, Valantin J, Gadot N, Goddard I, Vercherat C, Hervieu V, Gouysse G, Poncet G, Scoazec JY, Walter T, Roche C. Neuropilin-2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors. J Pathol 2019; 249:343-355. [PMID: 31257576 DOI: 10.1002/path.5321] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 05/21/2019] [Accepted: 06/21/2019] [Indexed: 12/19/2022]
Abstract
The identification of novel regulators of tumor progression is a key challenge to gain knowledge on the biology of small intestinal neuroendocrine tumors (SI-NETs). We recently identified the loss of the axon guidance protein semaphorin 3F as a protumoral event in SI-NETs. Interestingly the expression of its receptor neuropilin-2 (NRP-2) was still maintained. This study aimed at deciphering the potential role of NRP-2 as a contributor to SI-NET progression. The role of NRP-2 in SI-NET progression was addressed using an approach integrating human tissue and serum samples, cell lines and in vivo models. Data obtained from human SI-NET tissues showed that membranous NRP-2 expression is present in a majority of tumors, and is correlated with invasion, metastatic abilities, and neovascularization. In addition, NRP-2 soluble isoform was found elevated in serum samples from metastatic patients. In preclinical mouse models of NET progression, NRP-2 silencing led to a sustained antitumor effect, partly driven by the downregulation of VEGFR2. In contrast, its ectopic expression conferred a gain of aggressiveness, driven by the activation of various oncogenic signaling pathways. Lastly, NRP-2 inhibition led to a decrease of tumor cell viability, and sensitized to therapeutic agents. Overall, our results point out NRP-2 as a potential therapeutic target for SI-NETs, and will foster the development of innovative strategies targeting this receptor. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Julien Bollard
- Neuroendocrine Tumors Group, Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France.,INSERM U1052/CNRS UMR5286/University of Lyon, Cancer Research Center of Lyon, Lyon, France
| | - Céline Patte
- Neuroendocrine Tumors Group, Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France.,INSERM U1052/CNRS UMR5286/University of Lyon, Cancer Research Center of Lyon, Lyon, France
| | - Kristina Radkova
- Neuroendocrine Tumors Group, Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France.,INSERM U1052/CNRS UMR5286/University of Lyon, Cancer Research Center of Lyon, Lyon, France
| | - Patrick Massoma
- INSERM U1052/CNRS UMR5286/University of Lyon, Cancer Research Center of Lyon, Lyon, France
| | - Laurence Chardon
- Department of Biology and Hormonology, Lyon-Est Hospital, Bron, France
| | - Julie Valantin
- Pathology-Research Platform, Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France
| | - Nicolas Gadot
- Pathology-Research Platform, Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France
| | - Isabelle Goddard
- Laboratoire des Modèles Tumoraux, Lyon Synergie Cancer, Lyon, France
| | - Cécile Vercherat
- Neuroendocrine Tumors Group, Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France.,INSERM U1052/CNRS UMR5286/University of Lyon, Cancer Research Center of Lyon, Lyon, France
| | - Valérie Hervieu
- Neuroendocrine Tumors Group, Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France.,INSERM U1052/CNRS UMR5286/University of Lyon, Cancer Research Center of Lyon, Lyon, France.,Department of Pathology, Lyon-Est Hospital, Bron, France
| | | | - Gilles Poncet
- Neuroendocrine Tumors Group, Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France.,INSERM U1052/CNRS UMR5286/University of Lyon, Cancer Research Center of Lyon, Lyon, France.,Department of Medical Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Jean-Yves Scoazec
- Department of Pathology, Gustave-Roussy Cancer Campus, Villejuif, France
| | - Thomas Walter
- Neuroendocrine Tumors Group, Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France.,INSERM U1052/CNRS UMR5286/University of Lyon, Cancer Research Center of Lyon, Lyon, France.,Department of Medical Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Colette Roche
- Neuroendocrine Tumors Group, Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France.,INSERM U1052/CNRS UMR5286/University of Lyon, Cancer Research Center of Lyon, Lyon, France
| |
Collapse
|
|
47
|
Elaimy AL, Amante JJ, Zhu LJ, Wang M, Walmsley CS, FitzGerald TJ, Goel HL, Mercurio AM. The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression. Proc Natl Acad Sci U S A 2019; 116:14174-14180. [PMID: 31235595 PMCID: PMC6628806 DOI: 10.1073/pnas.1821194116] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Vascular endothelial growth factor (VEGF) signaling in tumor cells mediated by neuropilins (NRPs) contributes to the aggressive nature of several cancers, including triple-negative breast cancer (TNBC), independently of its role in angiogenesis. Understanding the mechanisms by which VEGF-NRP signaling contributes to the phenotype of such cancers is a significant and timely problem. We report that VEGF-NRP2 promote homologous recombination (HR) in BRCA1 wild-type TNBC cells by contributing to the expression and function of Rad51, an essential enzyme in the HR pathway that mediates efficient DNA double-strand break repair. Mechanistically, we provide evidence that VEGF-NRP2 stimulates YAP/TAZ-dependent Rad51 expression and that Rad51 is a direct YAP/TAZ-TEAD transcriptional target. We also discovered that VEGF-NRP2-YAP/TAZ signaling contributes to the resistance of TNBC cells to cisplatin and that Rad51 rescues the defects in DNA repair upon inhibition of either VEGF-NRP2 or YAP/TAZ. These findings reveal roles for VEGF-NRP2 and YAP/TAZ in DNA repair, and they indicate a unified mechanism involving VEGF-NRP2, YAP/TAZ, and Rad51 that contributes to resistance to platinum chemotherapy.
Collapse
Affiliation(s)
- Ameer L Elaimy
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605
- Medical Scientist Training Program, University of Massachusetts Medical School, Worcester, MA 01605
| | - John J Amante
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605
| | - Lihua Julie Zhu
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605
- Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
- Department of Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605
| | - Mengdie Wang
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605
| | - Charlotte S Walmsley
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605
| | - Thomas J FitzGerald
- Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, MA 01605
| | - Hira Lal Goel
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605
| | - Arthur M Mercurio
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605;
| |
Collapse
|
|
48
|
Tamura R, Yoshida K, Toda M. Current understanding of lymphatic vessels in the central nervous system. Neurosurg Rev 2019; 43:1055-1064. [PMID: 31209659 DOI: 10.1007/s10143-019-01133-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 04/29/2019] [Accepted: 06/05/2019] [Indexed: 12/18/2022]
Abstract
Lymphangiogenesis is associated with some pathological conditions such as inflammation, tissue repair, and tumor growth. Recently, a paradigm shift occurred following the discovery of meningeal lymphatic structures in the human central nervous system (CNS); these structures may be a key drainage route for cerebrospinal fluid (CSF) into the peripheral blood and may also contribute to inflammatory reaction and immune surveillance of the CNS. Lymphatic vessels located along the dural sinuses absorb CSF from the adjacent subarachnoid space and brain interstitial fluid via the glymphatic system, which is composed of aquaporin-4 water channels expressed on perivascular astrocytic end-feet membranes. Magnetic resonance imaging (MRI) clearly visualized these lymphatic vessels in the human dura mater. The conception of some neurological disorders, such as multiple sclerosis and Alzheimer's disease, has been changed by this paradigm shift. Meningeal lymphatic vessels could be a promising therapeutic target for the prevention of neurological disorders. However, the involvement of meningeal lymphatic vessels in the pathophysiology has not been fully elucidated and is the subject of future investigations. In this article, to understand the involvement of meningeal lymphatic vessels in neurological disorders, we review the differences between lymphangiogenesis in the CNS and in other tissues during both developmental and adulthood stages, and pathological conditions that may be associated with meningeal lymphatic vessels in the CNS.
Collapse
Affiliation(s)
- Ryota Tamura
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Kazunari Yoshida
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Masahiro Toda
- Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| |
Collapse
|
|
49
|
Chang X, Yang Q, Zhang C, Zhang Y, Liang X, Liu Y, Xu G. Roles for VEGF-C/NRP-2 axis in regulating renal tubular epithelial cell survival and autophagy during serum deprivation. Cell Biochem Funct 2019; 37:290-300. [PMID: 31211440 PMCID: PMC6618243 DOI: 10.1002/cbf.3402] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 04/01/2019] [Indexed: 12/18/2022]
Abstract
Vascular endothelial growth factor C (VEGF-C) is an angiogenic and lymphangiogenic growth factor. Recent research has revealed the role for VEGF-C in regulating autophagy by interacting with a nontyrosine kinase receptor, neuropilin-2 (NRP-2). However, whether VEGF-C participates in regulating cell survival and autophagy in renal proximal tubular cells is unknown. To address this question, we employed a cell modal of serum deprivation to verify the role of VEGF-C and its receptor NRP-2 in regulating cell survival and autophagy in NRK52E cell lines. The results show that VEGF-C rescued the loss of cell viability induced by serum deprivation in a concentration-dependent manner. Furthermore, endogenous VEGF-C was knocked down in NRK52E cells by using specific small-interfering RNAs (siRNA), cells were more sensitive to serum deprivation-induced cell death. A similar increase in cell death rate was observed following NRP-2 depletion in serum-starved NRK52E cells. Autophagy activity in serum-starved NRK52E cells was confirmed by western blot analysis of microtubule-associated protein-1 chain 3 (LC3), immunofluorescence staining of endogenous LC3, and the formation of autophagosomes by electron microscopy. VEGF-C or NRP-2 depletion further increased LC3 expression induced by serum deprivation, suggesting that VEGF-C and NRP-2 were involved in controlling autophagy in NRK52E cells. We further performed autophagic flux experiments to identify that VEGF-C promotes the activation of autophagy in serum-starved NRK52E cells. Together, these results suggest for the first time that VEGF-C/NRP-2 axis promotes survival and autophagy in NRK52E cells under serum deprivation condition. SIGNIFICANCE OF THE STUDY: More researchers had focused on the regulation of autophagy in kidney disease. The effect of VEGF-C on cell death and autophagy in renal epithelial cells has not been examined. We first identified the VEGF-C as a regulator of cell survival and autophagy in NRK52E cell lines. And VEGF-C/NRP-2 may mediate autophagy by regulating the phosphorylation of 4EBP1 and P70S6K. VEGF-C treatment may be identified as a therapeutic target in renal injury repair due to its capacity to promote tubular cell survival in the future.
Collapse
Affiliation(s)
- Xiaoyan Chang
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Qian Yang
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Conghui Zhang
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Ying Zhang
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xinjun Liang
- Hubei Cancer Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yanyan Liu
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Gang Xu
- Department of Nephrology, Division of Internal Medicine, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| |
Collapse
|
|
50
|
Peixoto A, Relvas-Santos M, Azevedo R, Santos LL, Ferreira JA. Protein Glycosylation and Tumor Microenvironment Alterations Driving Cancer Hallmarks. Front Oncol 2019; 9:380. [PMID: 31157165 PMCID: PMC6530332 DOI: 10.3389/fonc.2019.00380] [Citation(s) in RCA: 223] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 04/23/2019] [Indexed: 12/12/2022] Open
Abstract
Decades of research have disclosed a plethora of alterations in protein glycosylation that decisively impact in all stages of disease and ultimately contribute to more aggressive cell phenotypes. The biosynthesis of cancer-associated glycans and its reflection in the glycoproteome is driven by microenvironmental cues and these events act synergistically toward disease evolution. Such intricate crosstalk provides the molecular foundations for the activation of relevant oncogenic pathways and leads to functional alterations driving invasion and disease dissemination. However, it also provides an important source of relevant glyco(neo)epitopes holding tremendous potential for clinical intervention. Therefore, we highlight the transversal nature of glycans throughout the currently accepted cancer hallmarks, with emphasis on the crosstalk between glycans and the tumor microenvironment stromal components. Focus is also set on the pressing need to include glycans and glycoconjugates in comprehensive panomics models envisaging molecular-based precision medicine capable of improving patient care. We foresee that this may provide the necessary rationale for more comprehensive studies and molecular-based intervention.
Collapse
Affiliation(s)
- Andreia Peixoto
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal.,Tumour and Microenvironment Interactions Group, INEB-Institute for Biomedical Engineering, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Marta Relvas-Santos
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal
| | - Rita Azevedo
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Department of Surgical Oncology, Portuguese Institute of Oncology, Porto, Portugal
| | - José Alexandre Ferreira
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal.,Porto Comprehensive Cancer Center, Porto, Portugal
| |
Collapse
|