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1
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Toyofuku T, Ishikawa T, Kumanogoh A. Deletion of the plexin-D1 ectodomain leads to anoikis by suppressing integrin inside-out signaling. Mol Biol Cell 2025; 36:ar71. [PMID: 40266804 DOI: 10.1091/mbc.e25-02-0075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2025] Open
Abstract
Plexin-D1, mainly expressed in endothelial and cancer cells, regulates diverse effects, suppresses endothelial cell growth, and induces cancer cell migration and proliferation. Here, we demonstrated that plexin-D1 was cleaved by proteinase on cancer cells. To examine the role of cleaved plexin-D1 in cells, Madin-Darby canine kidney (MDCK) cells overexpressing truncated plexin-D1 were cultured in Matrigel. MDCK cells expressing plexin-D1 lacking the ectodomain (plexin-D1 ΔEC) underwent apoptosis. An adhesion assay for extracellular matrix (ECM) molecules showed that plexin-D1 ΔEC-expressing MDCK cells lost their affinity for the ECM. These results suggest that plexin-D1 ΔEC blocks integrin inside-out signaling, leading to detachment from the ECM and apoptosis, so-called anoikis. By contrast, MDCK cells expressing full-length plexin-D1 or plexin-D1 lacking the cytoplasmic domain (plexin-D1 ΔIC) developed multicellular branching tubular structures in Matrigel. This morphological change was blocked in plexin-D1-expressing MDCK cells by the hepatocyte growth factor receptor (Met) loss of function or by Met inhibitors. These results suggest that plexin-D1 associates with Met through the plexin-D1 extracellular domain, and this activates Met cytoplasmic kinase activity. We therefore conclude that plexin-D1 contains distinct domains that determine the fate of cancer cells.
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Affiliation(s)
- Toshihiko Toyofuku
- Department of Immunology and Molecular Medicine, Graduate School of Medicine, The Center of Medical Innovation and Translational Research, Osaka University, Suita, Osaka 565-0871, Japan
| | - Takako Ishikawa
- Department of Immunology and Molecular Medicine, Graduate School of Medicine, The Center of Medical Innovation and Translational Research, Osaka University, Suita, Osaka 565-0871, Japan
| | - Atsushi Kumanogoh
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
- Laboratory of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka 565-0871, Japan
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Villari G, Gioelli N, Gino M, Zhang H, Hodge K, Cordero F, Zanivan S, Zhu J, Serini G. Luminescent sensing of conformational integrin activation in living cells. Cell Rep 2025; 44:115319. [PMID: 39964812 PMCID: PMC11861568 DOI: 10.1016/j.celrep.2025.115319] [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: 05/14/2024] [Revised: 11/29/2024] [Accepted: 01/27/2025] [Indexed: 02/20/2025] Open
Abstract
Integrins are major receptors for secreted extracellular matrix, playing crucial roles in physiological and pathological contexts, such as angiogenesis and cancer. Regulation of the transition between inactive and active conformation is key for integrins to fulfill their functions, and pharmacological control of those dynamics may have therapeutic applications. We create and validate a prototypic luminescent β1 integrin activation sensor (β1IAS) by introducing a split luciferase into an activation reporting site between the βI and the hybrid domains. As a recombinant protein in both solution and living cells, β1IAS accurately reports β1 integrin activation in response to (bio)chemical and physical stimuli. A short interfering RNA (siRNA) high-throughput screening on live β1IAS knockin endothelial cells unveils hitherto unknown regulators of β1 integrin activation, such as β1 integrin inhibitors E3 ligase Pja2 and vascular endothelial growth factor B (VEGF-B). This split-luciferase-based strategy provides an in situ label-free measurement of integrin activation and may be applicable to other β integrins and receptors.
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Affiliation(s)
- Giulia Villari
- Department of Oncology, University of Torino School of Medicine, Candiolo, TO, Italy; Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, TO, Italy
| | - Noemi Gioelli
- Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, TO, Italy
| | - Marta Gino
- Department of Oncology, University of Torino School of Medicine, Candiolo, TO, Italy; Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, TO, Italy
| | - Heng Zhang
- Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI, USA
| | - Kelly Hodge
- Cancer Research UK Scotland Institute, Glasgow, UK
| | | | - Sara Zanivan
- Cancer Research UK Scotland Institute, Glasgow, UK; School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Jieqing Zhu
- Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI, USA; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Guido Serini
- Department of Oncology, University of Torino School of Medicine, Candiolo, TO, Italy; Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, TO, Italy.
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3
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Borlak J, Ciribilli Y, Bisio A, Selvaraj S, Inga A, Oh JH, Spanel R. The Abl1 tyrosine kinase is a key player in doxorubicin-induced cardiomyopathy and its p53/p73 cell death mediated signaling differs in atrial and ventricular cardiomyocytes. J Transl Med 2024; 22:845. [PMID: 39285385 PMCID: PMC11403941 DOI: 10.1186/s12967-024-05623-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 08/16/2024] [Indexed: 09/20/2024] Open
Abstract
BACKGROUND Doxorubicin is an important anticancer drug, however, elicits dose-dependently cardiomyopathy. Given its mode of action, i.e. topoisomerase inhibition and DNA damage, we investigated genetic events associated with cardiomyopathy and searched for mechanism-based possibilities to alleviate cardiotoxicity. We treated rats at clinically relevant doses of doxorubicin. Histopathology and transmission electron microscopy (TEM) defined cardiac lesions, and transcriptomics unveiled cardiomyopathy-associated gene regulations. Genomic-footprints revealed critical components of Abl1-p53-signaling, and EMSA-assays evidenced Abl1 DNA-binding activity. Gene reporter assays confirmed Abl1 activity on p53-targets while immunohistochemistry/immunofluorescence microscopy demonstrated Abl1, p53&p73 signaling. RESULTS Doxorubicin treatment caused dose-dependently toxic cardiomyopathy, and TEM evidenced damaged mitochondria and myofibrillar disarray. Surviving cardiomyocytes repressed Parkin-1 and Bnip3-mediated mitophagy, stimulated dynamin-1-like dependent mitochondrial fission and induced anti-apoptotic Bag1 signaling. Thus, we observed induced mitochondrial biogenesis. Transcriptomics discovered heterogeneity in cellular responses with minimal overlap between treatments, and the data are highly suggestive for distinct cardiomyocyte (sub)populations which differed in their resilience and reparative capacity. Genome-wide footprints revealed Abl1 and p53 enriched binding sites in doxorubicin-regulated genes, and we confirmed Abl1 DNA-binding activity in EMSA-assays. Extraordinarily, Abl1 signaling differed in the heart with highly significant regulations of Abl1, p53 and p73 in atrial cardiomyocytes. Conversely, in ventricular cardiomyocytes, Abl1 solely-modulated p53-signaling that was BAX transcription-independent. Gene reporter assays established Abl1 cofactor activity for the p53-reporter PG13-luc, and ectopic Abl1 expression stimulated p53-mediated apoptosis. CONCLUSIONS The tyrosine kinase Abl1 is of critical importance in doxorubicin induced cardiomyopathy, and we propose its inhibition as means to diminish risk of cardiotoxicity.
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Affiliation(s)
- Jürgen Borlak
- Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
| | - Yari Ciribilli
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
| | - Alessandra Bisio
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
| | - Saravanakumar Selvaraj
- Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Alberto Inga
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
| | - Jung-Hwa Oh
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Reinhard Spanel
- Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
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Zhang Y, Shen X, Deng S, Chen Q, Xu B. Neural Regulation of Vascular Development: Molecular Mechanisms and Interactions. Biomolecules 2024; 14:966. [PMID: 39199354 PMCID: PMC11353022 DOI: 10.3390/biom14080966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/02/2024] [Accepted: 08/06/2024] [Indexed: 09/01/2024] Open
Abstract
As a critical part of the circulatory system, blood vessels transport oxygen and nutrients to every corner of the body, nourishing each cell, and also remove waste and toxins. Defects in vascular development and function are closely associated with many diseases, such as heart disease, stroke, and atherosclerosis. In the nervous system, the nervous and vascular systems are intricately connected in both development and function. First, peripheral blood vessels and nerves exhibit parallel distribution patterns. In the central nervous system (CNS), nerves and blood vessels form a complex interface known as the neurovascular unit. Second, the vascular system employs similar cellular and molecular mechanisms as the nervous system for its development. Third, the development and function of CNS vasculature are tightly regulated by CNS-specific signaling pathways and neural activity. Additionally, vascular endothelial cells within the CNS are tightly connected and interact with pericytes, astrocytes, neurons, and microglia to form the blood-brain barrier (BBB). The BBB strictly controls material exchanges between the blood and brain, maintaining the brain's microenvironmental homeostasis, which is crucial for the normal development and function of the CNS. Here, we comprehensively summarize research on neural regulation of vascular and BBB development and propose directions for future research.
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Affiliation(s)
- Yu Zhang
- School of Life Sciences, Nantong University, Nantong 226019, China
| | - Xinyu Shen
- School of Life Sciences, Nantong University, Nantong 226019, China
| | - Shunze Deng
- School of Life Sciences, Nantong University, Nantong 226019, China
| | - Qiurong Chen
- School of Life Sciences, Nantong University, Nantong 226019, China
| | - Bing Xu
- School of Life Sciences, Nantong University, Nantong 226019, China
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5
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Tsuboi E, Asakawa Y, Hirose N, Yanoshita M, Sumi C, Takano M, Onishi A, Nishiyama S, Kubo N, Kita D, Tanimoto K. The role of semaphorin 3A on chondrogenic differentiation. In Vitro Cell Dev Biol Anim 2024; 60:609-615. [PMID: 38727898 PMCID: PMC11286676 DOI: 10.1007/s11626-024-00909-z] [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: 12/22/2023] [Accepted: 04/03/2024] [Indexed: 07/31/2024]
Abstract
Osteoblast-derived semaphorin3A (Sema3A) has been reported to be involved in bone protection, and Sema3A knockout mice have been reported to exhibit chondrodysplasia. From these reports, Sema3A is considered to be involved in chondrogenic differentiation and skeletal formation, but there are many unclear points about its function and mechanism in chondrogenic differentiation. This study investigated the pharmacological effects of Sema3A in chondrogenic differentiation. The amount of Sema3A secreted into the culture supernatant was measured using an enzyme-linked immunosorbent assay. The expression of chondrogenic differentiation-related factors, such as Type II collagen (COL2A1), Aggrecan (ACAN), hyaluronan synthase 2 (HAS2), SRY-box transcription factor 9 (Sox9), Runt-related transcription factor 2 (Runx2), and Type X collagen (COL10A1) in ATDC5 cells treated with Sema3A (1,10 and 100 ng/mL) was examined using real-time reverse transcription polymerase chain reaction. Further, to assess the deposition of total glycosaminoglycans during chondrogenic differentiation, ATDC5 cells were stained with Alcian Blue. Moreover, the amount of hyaluronan in the culture supernatant was measured by enzyme-linked immunosorbent assay. The addition of Sema3A to cultured ATDC5 cells increased the expression of Sox9, Runx2, COL2A1, ACAN, HAS2, and COL10A1 during chondrogenic differentiation. Moreover, it enhanced total proteoglycan and hyaluronan synthesis. Further, Sema3A was upregulated in the early stages of chondrogenic differentiation, and its secretion decreased later. Sema3A increases extracellular matrix production and promotes chondrogenic differentiation. To the best of our knowledge, this is the first study to demonstrate the role of Sema3A on chondrogenic differentiation.
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Affiliation(s)
- Eri Tsuboi
- Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8553, Japan
| | - Yuki Asakawa
- Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8553, Japan
| | - Naoto Hirose
- Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8553, Japan.
| | - Makoto Yanoshita
- Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8553, Japan
| | - Chikako Sumi
- Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8553, Japan
| | - Mami Takano
- Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8553, Japan
| | - Azusa Onishi
- Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8553, Japan
| | - Sayuri Nishiyama
- Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8553, Japan
| | - Naoki Kubo
- Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8553, Japan
| | - Daiki Kita
- Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8553, Japan
| | - Kotaro Tanimoto
- Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8553, Japan
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6
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Wang J, Yang X, Xu M, Liu H, Liu L, Tan Z. Distinct cellular microenvironment with cytotypic effects regulates orderly regeneration of vascular tissues. Mater Today Bio 2024; 26:101033. [PMID: 38533377 PMCID: PMC10963652 DOI: 10.1016/j.mtbio.2024.101033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/26/2024] [Accepted: 03/15/2024] [Indexed: 03/28/2024] Open
Abstract
Regeneration of the architecturally complex blood vascular system requires precise temporal and spatial control of cell behaviours. Additional components must be integrated into the structure to achieve clinical success for in situ tissue engineering. Consequently, this study proposed a universal method for including any substrate type in vascular cell extracellular matrices (VCEM) via regulating selective adhesion to promote vascular tissue regeneration. The results uncovered that the VCEM worked as cell adhesion substrates, exhibited cell type specificity, and functioned as an address signal for recognition by vascular cells, which resulted in matching with the determined cells. The qPCR and immunofluorescence results revealed that a cell type-specific VCEM could be designed to promote or inhibit cell adhesion, consistenting with the expression patterns of eyes absent 3 (Eya3). In addition, a 3D vascular graft combined with VCEM which could recapitulate the vascular cell-like microenvironment was fabricated. The vascular graft revealed a prospective role for cellular microenvironment in the establishment of vascular cell distribution and tissue architecture, and potentiated the orderly regeneration and functional recovery of vascular tissues in vivo. The findings demonstrate that differential adhesion between cell types due to the cellular microenvironment is sufficient to drive the complex assembly of engineered blood vessel functional units, and underlies hierarchical organization during vascular regeneration.
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Affiliation(s)
- Jian Wang
- College of Biology, Hunan University, Changsha, 410082, China
- Institute of Shenzhen, Hunan University Shenzhen, 518000, China
| | - Xun Yang
- Department of Traumatic Orthopedics, Shenzhen Second People's Hospital (The First Affiliated Hospital, Shenzhen University), Shenzhen, 518028, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, 518060, China
| | - Miaomiao Xu
- College of Biology, Hunan University, Changsha, 410082, China
- Greater Bay Area Institute for Innovation, Hunan University, Guangzhou, 511300, China
| | - Hui Liu
- College of Biology, Hunan University, Changsha, 410082, China
- Greater Bay Area Institute for Innovation, Hunan University, Guangzhou, 511300, China
| | - Lijun Liu
- Department of Traumatic Orthopedics, Shenzhen Second People's Hospital (The First Affiliated Hospital, Shenzhen University), Shenzhen, 518028, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, 518060, China
| | - Zhikai Tan
- College of Biology, Hunan University, Changsha, 410082, China
- Institute of Shenzhen, Hunan University Shenzhen, 518000, China
- Greater Bay Area Institute for Innovation, Hunan University, Guangzhou, 511300, China
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7
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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.
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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.
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8
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Lai YJ, Chang SH, Tung YC, Chang GJ, Almeida CD, Chen WJ, Yeh YH, Tsai FC. Naringin activates semaphorin 3A to ameliorate TGF-β-induced endothelial-to-mesenchymal transition related to atrial fibrillation. J Cell Physiol 2024; 239:e31248. [PMID: 38501506 DOI: 10.1002/jcp.31248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 02/25/2024] [Accepted: 02/29/2024] [Indexed: 03/20/2024]
Abstract
The loss of semaphorin 3A (Sema3A), which is related to endothelial-to-mesenchymal transition (EndMT) in atrial fibrosis, is implicated in the pathogenesis of atrial fibrillation (AF). To explore the mechanisms by which EndMT affects atrial fibrosis and assess the potential of a Sema3A activator (naringin) to prevent atrial fibrosis by targeting transforming growth factor-beta (TGF-β)-induced EndMT, we used human atria, isolated human atrial endocardial endothelial cells (AEECs), and used transgenic mice expressing TGF-β specifically in cardiac tissues (TGF-β transgenic mice). We evaluated an EndMT marker (Twist), a proliferation marker (proliferating cell nuclear antigen; PCNA), and an endothelial cell (EC) marker (CD31) through triple immunohistochemistry and confirmed that both EndMT and EC proliferation contribute to atrial endocardial fibrosis during AF in TGF-β transgenic mice and AF patient tissue sections. Additionally, we investigated the impact of naringin on EndMT and EC proliferation in AEECs and atrial fibroblasts. Naringin exhibited an antiproliferative effect, to which AEECs were more responsive. Subsequently, we downregulated Sema3A in AEECs using small interfering RNA to clarify a correlation between the reduction in Sema3A and the elevation of EndMT markers. Naringin treatment induced the expression of Sema3A and a concurrent decrease in EndMT markers. Furthermore, naringin administration ameliorated AF and endocardial fibrosis in TGF-β transgenic mice by stimulating Sema3A expression, inhibiting EndMT markers, reducing atrial fibrosis, and lowering AF vulnerability. This suggests therapeutic potential for naringin in AF treatment.
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Affiliation(s)
- Ying-Ju Lai
- Cardiovascular Department, Chang-Gung Memorial Hospital, Tao-Yuan, Taiwan
- Department of Respiratory Therapy, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
- Department of Respiratory Care, Chang-Gung University of Science and Technology, Chia-Yi, Puzi, Taiwan
| | - Shang-Hung Chang
- Cardiovascular Department, Chang-Gung Memorial Hospital, Tao-Yuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University Tao-Yuan, Tao-Yuan, Taiwan
| | - Ying-Chang Tung
- Cardiovascular Department, Chang-Gung Memorial Hospital, Tao-Yuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University Tao-Yuan, Tao-Yuan, Taiwan
| | - Gwo-Jyh Chang
- Cardiovascular Department, Chang-Gung Memorial Hospital, Tao-Yuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang-Gung University Tao-Yuan, Tao-Yuan, Taiwan
| | - Celina De Almeida
- Department of Respiratory Therapy, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang-Gung University Tao-Yuan, Tao-Yuan, Taiwan
| | - Wei-Jan Chen
- Cardiovascular Department, Chang-Gung Memorial Hospital, Tao-Yuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University Tao-Yuan, Tao-Yuan, Taiwan
| | - Yung-Hsin Yeh
- Cardiovascular Department, Chang-Gung Memorial Hospital, Tao-Yuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University Tao-Yuan, Tao-Yuan, Taiwan
| | - Feng-Chun Tsai
- Department of Surgery, Division of Cardiovascular Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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9
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Barnkob MB, Michaels YS, André V, Macklin PS, Gileadi U, Valvo S, Rei M, Kulicke C, Chen JL, Jain V, Woodcock VK, Colin-York H, Hadjinicolaou AV, Kong Y, Mayya V, Mazet JM, Mead GJ, Bull JA, Rijal P, Pugh CW, Townsend AR, Gérard A, Olsen LR, Fritzsche M, Fulga TA, Dustin ML, Jones EY, Cerundolo V. Semmaphorin 3 A causes immune suppression by inducing cytoskeletal paralysis in tumour-specific CD8 + T cells. Nat Commun 2024; 15:3173. [PMID: 38609390 PMCID: PMC11017241 DOI: 10.1038/s41467-024-47424-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Semaphorin-3A (SEMA3A) functions as a chemorepulsive signal during development and can affect T cells by altering their filamentous actin (F-actin) cytoskeleton. The exact extent of these effects on tumour-specific T cells are not completely understood. Here we demonstrate that Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 are upregulated on stimulated CD8+ T cells, allowing tumour-derived SEMA3A to inhibit T cell migration and assembly of the immunological synapse. Deletion of NRP1 in both CD4+ and CD8+ T cells enhance CD8+ T-cell infiltration into tumours and restricted tumour growth in animal models. Conversely, over-expression of SEMA3A inhibit CD8+ T-cell infiltration. We further show that SEMA3A affects CD8+ T cell F-actin, leading to inhibition of immune synapse formation and motility. Examining a clear cell renal cell carcinoma patient cohort, we find that SEMA3A expression is associated with reduced survival, and that T-cells appear trapped in SEMA3A rich regions. Our study establishes SEMA3A as an inhibitor of effector CD8+ T cell tumour infiltration, suggesting that blocking NRP1 could improve T cell function in tumours.
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Affiliation(s)
- Mike B Barnkob
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK.
- Centre for Cellular Immunotherapy of Haematological Cancer Odense (CITCO), Department of Clinical Immunology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
| | - Yale S Michaels
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK
- Paul Albrechtsen Research Institute, CancerCare Manitoba, 675 Mcdermot Ave, Winnipeg, MB, R3E 0V9, Canada
- Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Bannatyne Ave, Winnipeg, MB, R3E 3N4, Canada
| | - Violaine André
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK
| | - Philip S Macklin
- Nuffield Department of Medicine, University of Oxford, Nuffield Department of Medicine Research Building, Roosevelt Drive, Oxford, OX3 7FZ, UK
| | - Uzi Gileadi
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK
| | - Salvatore Valvo
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Dr, Oxford, OX3 7FY, UK
| | - Margarida Rei
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Corinna Kulicke
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK
- Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, OR, US
| | - Ji-Li Chen
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK
| | - Vitul Jain
- Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Victoria K Woodcock
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK
| | - Huw Colin-York
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK
| | - Andreas V Hadjinicolaou
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK
- Division of Gastroenterology & Hepatology, Department of Medicine, Cambridge University Hospitals, University of Cambridge, Cambridge, England
- Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, England
| | - Youxin Kong
- Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Viveka Mayya
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Dr, Oxford, OX3 7FY, UK
| | - Julie M Mazet
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Dr, Oxford, OX3 7FY, UK
| | - Gracie-Jennah Mead
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Dr, Oxford, OX3 7FY, UK
| | - Joshua A Bull
- Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Radcliffe Observatory Quarter, Woodstock Road, Oxford, OX2 6GG, UK
| | - Pramila Rijal
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK
| | - Christopher W Pugh
- Nuffield Department of Medicine, University of Oxford, Nuffield Department of Medicine Research Building, Roosevelt Drive, Oxford, OX3 7FZ, UK
| | - Alain R Townsend
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK
| | - Audrey Gérard
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Dr, Oxford, OX3 7FY, UK
| | - Lars R Olsen
- Department of Health Technology, Technical University of Denmark, Ørsteds Plads, Building 345C, 2800 Kgs, Lyngby, Denmark
| | - Marco Fritzsche
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Dr, Oxford, OX3 7FY, UK
| | - Tudor A Fulga
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK
| | - Michael L Dustin
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Dr, Oxford, OX3 7FY, UK
| | - E Yvonne Jones
- Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
| | - Vincenzo Cerundolo
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 9DS, UK
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10
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da Silva Gonçalves CE, Fock RA. Semaphorins and the bone marrow microenvironment: New candidates that influence the hematopoietic system. Cytokine Growth Factor Rev 2024; 76:22-29. [PMID: 38472041 DOI: 10.1016/j.cytogfr.2024.02.002] [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: 02/13/2024] [Accepted: 02/23/2024] [Indexed: 03/14/2024]
Abstract
The bone marrow is a haven for hematopoietic and non-hematopoietic cells, creating complex micro-anatomical regions called niches. These distinct niches all participate in an intricate orchestra of cellular interactions that regulates the hematopoietic stem cell and its progenies. In this review, we provide a detailed description of the three most well-known bone marrow niches and their participation in hematopoiesis. We use pre-clinical data, including different in vitro and in vivo studies to discuss how a group of proteins called Semaphorins could potentially modulate both hematopoietic and non-hematopoietic cells, establishing links between the niches, semaphorins, and hematopoietic regulation. Thus, here we provide a deep dive into the inner functioning of the bone marrow and discuss the overarching implications that semaphorins might have on blood formation.
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Affiliation(s)
- Carlos E da Silva Gonçalves
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
| | - Ricardo A Fock
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
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11
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Singh S, Parthasarathi KTS, Bhat MY, Gopal C, Sharma J, Pandey A. Profiling Kinase Activities for Precision Oncology in Diffuse Gastric Cancer. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2024; 28:76-89. [PMID: 38271566 DOI: 10.1089/omi.2023.0173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2024]
Abstract
Gastric cancer (GC) remains a leading cause of cancer-related mortality globally. This is due to the fact that majority of the cases of GC are diagnosed at an advanced stage when the treatment options are limited and prognosis is poor. The diffuse subtype of gastric cancer (DGC) under Lauren's classification is more aggressive and usually occurs in younger patients than the intestinal subtype. The concept of personalized medicine is leading to the identification of multiple biomarkers in a large variety of cancers using different combinations of omics technologies. Proteomic changes including post-translational modifications are crucial in oncogenesis. We analyzed the phosphoproteome of DGC by using paired fresh frozen tumor and adjacent normal tissue from five patients diagnosed with DGC. We found proteins involved in the epithelial-to-mesenchymal transition (EMT), c-MYC pathway, and semaphorin pathways to be differentially phosphorylated in DGC tissues. We identified three kinases, namely, bromodomain adjacent to the zinc finger domain 1B (BAZ1B), WNK lysine-deficient protein kinase 1 (WNK1), and myosin light-chain kinase (MLCK) to be hyperphosphorylated, and one kinase, AP2-associated protein kinase 1 (AAK1), to be hypophosphorylated. LMNA hyperphosphorylation at serine 392 (S392) was demonstrated in DGC using immunohistochemistry. Importantly, we have detected heparin-binding growth factor (HDGF), heat shock protein 90 (HSP90), and FTH1 as potential therapeutic targets in DGC, as drugs targeting these proteins are currently under investigation in clinical trials. Although these new findings need to be replicated in larger study samples, they advance our understanding of signaling alterations in DGC, which could lead to potentially novel actionable targets in GC.
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Affiliation(s)
- Smrita Singh
- Manipal Academy of Higher Education (MAHE), Manipal, India
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Center for Molecular Medicine, National Institute of Mental Health and Neuro-Sciences (NIMHANS), Bangalore, India
| | - K T Shreya Parthasarathi
- Manipal Academy of Higher Education (MAHE), Manipal, India
- Institute of Bioinformatics, International Technology Park, Bangalore, India
| | - Mohd Younis Bhat
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Amrita School of Biotechnology, Amrita Vishwapeetham University, Kollam, India
| | - Champaka Gopal
- Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, India
| | - Jyoti Sharma
- Manipal Academy of Higher Education (MAHE), Manipal, India
- Institute of Bioinformatics, International Technology Park, Bangalore, India
| | - Akhilesh Pandey
- Manipal Academy of Higher Education (MAHE), Manipal, India
- Center for Molecular Medicine, National Institute of Mental Health and Neuro-Sciences (NIMHANS), Bangalore, India
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
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12
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Luo W, Wen T, Qu X. Tumor immune microenvironment-based therapies in pancreatic ductal adenocarcinoma: time to update the concept. J Exp Clin Cancer Res 2024; 43:8. [PMID: 38167055 PMCID: PMC10759657 DOI: 10.1186/s13046-023-02935-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 12/18/2023] [Indexed: 01/05/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. The tumor immune microenvironment (TIME) formed by interactions among cancer cells, immune cells, cancer-associated fibroblasts (CAF), and extracellular matrix (ECM) components drives PDAC in a more immunosuppressive direction: this is a major cause of therapy resistance and poor prognosis. In recent years, research has advanced our understanding of the signaling mechanism by which TIME components interact with the tumor and the evolution of immunophenotyping. Through revolutionary technologies such as single-cell sequencing, we have gone from simply classifying PDACs as "cold" and "hot" to a more comprehensive approach of immunophenotyping that considers all the cells and matrix components. This is key to improving the clinical efficacy of PDAC treatments. In this review, we elaborate on various TIME components in PDAC, the signaling mechanisms underlying their interactions, and the latest research into PDAC immunophenotyping. A deep understanding of these network interactions will contribute to the effective combination of TIME-based therapeutic approaches, such as immune checkpoint inhibitors (ICI), adoptive cell therapy, therapies targeting myeloid cells, CAF reprogramming, and stromal normalization. By selecting the appropriate integrated therapies based on precise immunophenotyping, significant advances in the future treatment of PDAC are possible.
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Affiliation(s)
- Wenyu Luo
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, 110001, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, 110001, Liaoning, China
| | - Ti Wen
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China.
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China.
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, 110001, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, 110001, Liaoning, China.
| | - Xiujuan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China.
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, 110001, Liaoning, China.
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, 110001, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, 110001, Liaoning, China.
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13
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Naito M, Kumanogoh A. The role of semaphorins in allergic diseases. Allergol Int 2024; 73:31-39. [PMID: 37635021 DOI: 10.1016/j.alit.2023.08.006] [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: 03/12/2023] [Revised: 07/17/2023] [Accepted: 07/19/2023] [Indexed: 08/29/2023] Open
Abstract
Semaphorins were originally identified as guidance molecules in neural development. However, accumulating evidence indicates that 'immune semaphorins' are critically involved in regulating immune cell activation, differentiation, mobility and migration. Semaphorins are also intimately associated with the pathogenesis of allergic diseases including asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, and eosinophilic chronic rhinosinusitis. Interestingly, reflecting their function in positive or negative regulation of immune cells, levels of some semaphorins are increased while others are decreased in patients with allergic diseases. This review presents the pathogenic functions of immune semaphorins in allergic inflammation and discusses the potential use of these molecules as therapeutic targets for allergic diseases.
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Affiliation(s)
- Maiko Naito
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan; Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
| | - Atsushi Kumanogoh
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan; Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan; Center for Infectious Diseases for Education and Research (CiDER), Osaka University, Osaka, Japan; Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Osaka University, Osaka, Japan; Center for Advanced Modalities and DDS (CAMaD), Osaka University, Osaka, Japan.
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14
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Ruggiero C, Baroni M, Xenos D, Parretti L, Macchione IG, Bubba V, Laudisio A, Pedone C, Ferracci M, Magierski R, Boccardi V, Antonelli-Incalzi R, Mecocci P. Dementia, osteoporosis and fragility fractures: Intricate epidemiological relationships, plausible biological connections, and twisted clinical practices. Ageing Res Rev 2024; 93:102130. [PMID: 38030092 DOI: 10.1016/j.arr.2023.102130] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/06/2023] [Accepted: 11/14/2023] [Indexed: 12/01/2023]
Abstract
Dementia, osteoporosis, and fragility fractures are chronic diseases, often co-existing in older adults. These conditions pose severe morbidity, long-term disability, and mortality, with relevant socioeconomic implications. While in the research arena, the discussion remains on whether dementia is the cause or the consequence of fragility fractures, healthcare professionals need a better understanding of the interplay between such conditions from epidemiological and physiological standpoints. With this review, we summarized the available literature surrounding the relationship between cognitive impairment, dementia, and both low bone mineral density (BMD) and fragility fractures. Given the strength of the bi-directional associations and their impact on the quality of life, we shed light on the biological connections between brain and bone systems, presenting the main mediators, including gut microbioma, and pathological pathways leading to the dysregulation of bone and brain metabolism. Ultimately, we synthesized the evidence about the impact of available pharmacological treatments for the prevention of fragility fractures on cognitive functions and individuals' outcomes when dementia coexists. Vice versa, the effects of symptomatic treatments for dementia on the risk of falls and fragility fractures are explored. Combining evidence alongside clinical practice, we discuss challenges and opportunities related to the management of older adults affected by cognitive impairment or dementia and at high risk for fragility fracture prevention, which leads to not only an improvement in patient health-related outcomes and survival but also a reduction in healthcare cost and socio-economic burden.
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Affiliation(s)
- C Ruggiero
- Department of Medicine, Section of Gerontology and Geriatrics, University of Perugia, Italy.
| | - M Baroni
- Department of Medicine, Section of Gerontology and Geriatrics, University of Perugia, Italy
| | - D Xenos
- Department of Medicine, Section of Gerontology and Geriatrics, University of Perugia, Italy
| | - L Parretti
- Department of Medicine, Section of Gerontology and Geriatrics, University of Perugia, Italy
| | - I G Macchione
- Department of Medicine, Section of Gerontology and Geriatrics, University of Perugia, Italy
| | - V Bubba
- Department of Medicine, Section of Gerontology and Geriatrics, University of Perugia, Italy
| | - A Laudisio
- Department of Medicine, Unit of Geriatrics, Campus Bio-Medico di Roma University, Rome, Italy
| | - C Pedone
- Department of Medicine, Unit of Geriatrics, Campus Bio-Medico di Roma University, Rome, Italy
| | - M Ferracci
- Department of Medicine, Section of Gerontology and Geriatrics, University of Perugia, Italy
| | - R Magierski
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland
| | - V Boccardi
- Department of Medicine, Section of Gerontology and Geriatrics, University of Perugia, Italy
| | - R Antonelli-Incalzi
- Department of Medicine, Unit of Geriatrics, Campus Bio-Medico di Roma University, Rome, Italy
| | - P Mecocci
- Department of Medicine, Section of Gerontology and Geriatrics, University of Perugia, Italy
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15
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Ansardamavandi A, Nikfarjam M, He H. PAK in Pancreatic Cancer-Associated Vasculature: Implications for Therapeutic Response. Cells 2023; 12:2692. [PMID: 38067120 PMCID: PMC10705971 DOI: 10.3390/cells12232692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 11/20/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
Angiogenesis has been associated with numbers of solid tumours. Anti-angiogenesis drugs starve tumours of nutrients and oxygen but also make it difficult for a chemo reagent to distribute into a tumour, leading to aggressive tumour growth. Anti-angiogenesis drugs do not appear to improve the overall survival rate of pancreatic cancer. Vessel normalisation is merging as one of the new approaches for halting tumour progression by facilitating the tumour infiltration of immune cells and the delivery of chemo reagents. Targeting p21-activated kinases (PAKs) in cancer has been shown to inhibit cancer cell growth and improve the efficacy of chemotherapy. Inhibition of PAK enhances anti-tumour immunity and stimulates the efficacy of immune checkpoint blockades. Inhibition of PAK also improves Car-T immunotherapy by reprogramming the vascular microenvironment. This review summarizes current research on PAK's role in tumour vasculature and therapeutical response, with a focus on pancreatic cancer.
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Affiliation(s)
- Arian Ansardamavandi
- Department of Surgery, Austin Precinct, The University of Melbourne, 145 Studley Rd, Heidelberg, VIC 3084, Australia; (A.A.); (M.N.)
| | - Mehrdad Nikfarjam
- Department of Surgery, Austin Precinct, The University of Melbourne, 145 Studley Rd, Heidelberg, VIC 3084, Australia; (A.A.); (M.N.)
- Department of Hepatopancreatic-Biliary Surgery, Austin Health, 145 Studley Rd, Heidelberg, VIC 3084, Australia
| | - Hong He
- Department of Surgery, Austin Precinct, The University of Melbourne, 145 Studley Rd, Heidelberg, VIC 3084, Australia; (A.A.); (M.N.)
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16
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Schnittman SR, Kolossváry M, Beck-Engeser G, Fitch KV, Ambayec GC, Nance RM, Zanni MV, Diggs M, Chan F, McCallum S, Toribio M, Bamford L, Fichtenbaum CJ, Eron JJ, Jacobson JM, Mayer KH, Malvestutto C, Bloomfield GS, Moore RD, Umbleja T, Saag MS, Aberg JA, Currier JS, Delaney JAC, Martin JN, Lu MT, Douglas PS, Ribaudo HJ, Crane HM, Hunt PW, Grinspoon SK. Biological and Clinical Implications of the Vascular Endothelial Growth Factor Coreceptor Neuropilin-1 in Human Immunodeficiency Virus. Open Forum Infect Dis 2023; 10:ofad467. [PMID: 37869406 PMCID: PMC10590105 DOI: 10.1093/ofid/ofad467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 09/06/2023] [Indexed: 10/24/2023] Open
Abstract
Plasma vascular endothelial growth factor (VEGF) coreceptor neuropilin-1 (NRP-1) had the largest association with coronary plaque in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) proteomics analysis. With little known about NRP-1 in people with human immunodeficiency virus (PWH), we explored its relation to other proteins in REPRIEVE and validated our findings through a Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) case-cohort study by assessing its relation to host factors and incident cardiovascular disease and cancer. Within REPRIEVE, NRP-1 was associated with proteins involved in angiogenesis, signal transduction, immunoregulation, and cell migration/adhesion. Within CNICS, NRP-1 was associated with key host factors, including older age and male sex. NRP-1 was associated with an increased hazard of multiple cancers but a decreased prostate cancer risk. Finally, NRP-1 was most strongly associated with mortality and type 2 myocardial infarction. These data suggest that NRP-1 is part of a clinically relevant immunoregulatory pathway related to multiple comorbidities in PWH. Clinical Trials Registration. NCT02344290.
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Affiliation(s)
- Samuel R Schnittman
- Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Márton Kolossváry
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Gabriele Beck-Engeser
- Division of Experimental Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Kathleen V Fitch
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Gabrielle C Ambayec
- Division of Experimental Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Robin M Nance
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Markella V Zanni
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Marissa Diggs
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Fay Chan
- Division of Experimental Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Sara McCallum
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Mabel Toribio
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Laura Bamford
- Division of Infectious Diseases and Global Public Health, University of California, San Diego, San Diego, California, USA
| | - Carl J Fichtenbaum
- Division of Infectious Diseases, University of Cincinnati, Cincinnati, Ohio, USA
| | - Joseph J Eron
- Division of Infectious Diseases, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Jeffrey M Jacobson
- Division of Infectious Diseases, Case Western Reserve University, Cleveland, Ohio, USA
| | - Kenneth H Mayer
- Fenway Health and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Carlos Malvestutto
- Division of Infectious Diseases, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Gerald S Bloomfield
- Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA
| | - Richard D Moore
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Triin Umbleja
- Harvard T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
| | - Michael S Saag
- Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Judith A Aberg
- Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Judith S Currier
- Division of Infectious Diseases, University of California, Los Angeles, Los Angeles, California, USA
| | - Joseph A C Delaney
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
- College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Jeffrey N Martin
- Department of Epidemiology and Biostatistics, University of California, San Francisco School of Medicine, San Francisco, California, USA
| | - Michael T Lu
- Cardiovascular Imaging Research Center, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Pamela S Douglas
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Heather J Ribaudo
- Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Heidi M Crane
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Peter W Hunt
- Division of Experimental Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Steven K Grinspoon
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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17
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Parab S, Setten E, Astanina E, Bussolino F, Doronzo G. The tissue-specific transcriptional landscape underlines the involvement of endothelial cells in health and disease. Pharmacol Ther 2023; 246:108418. [PMID: 37088448 DOI: 10.1016/j.pharmthera.2023.108418] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 03/23/2023] [Accepted: 04/17/2023] [Indexed: 04/25/2023]
Abstract
Endothelial cells (ECs) that line vascular and lymphatic vessels are being increasingly recognized as important to organ function in health and disease. ECs participate not only in the trafficking of gases, metabolites, and cells between the bloodstream and tissues but also in the angiocrine-based induction of heterogeneous parenchymal cells, which are unique to their specific tissue functions. The molecular mechanisms regulating EC heterogeneity between and within different tissues are modeled during embryogenesis and become fully established in adults. Any changes in adult tissue homeostasis induced by aging, stress conditions, and various noxae may reshape EC heterogeneity and induce specific transcriptional features that condition a functional phenotype. Heterogeneity is sustained via specific genetic programs organized through the combinatory effects of a discrete number of transcription factors (TFs) that, at the single tissue-level, constitute dynamic networks that are post-transcriptionally and epigenetically regulated. This review is focused on outlining the TF-based networks involved in EC specialization and physiological and pathological stressors thought to modify their architecture.
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Affiliation(s)
- Sushant Parab
- Department of Oncology, University of Torino, IT, Italy; Candiolo Cancer Institute-IRCCS-FPO, Candiolo, Torino, IT, Italy
| | - Elisa Setten
- Department of Oncology, University of Torino, IT, Italy; Candiolo Cancer Institute-IRCCS-FPO, Candiolo, Torino, IT, Italy
| | - Elena Astanina
- Candiolo Cancer Institute-IRCCS-FPO, Candiolo, Torino, IT, Italy
| | - Federico Bussolino
- Department of Oncology, University of Torino, IT, Italy; Candiolo Cancer Institute-IRCCS-FPO, Candiolo, Torino, IT, Italy.
| | - Gabriella Doronzo
- Department of Oncology, University of Torino, IT, Italy; Candiolo Cancer Institute-IRCCS-FPO, Candiolo, Torino, IT, Italy
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18
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Wälchli T, Bisschop J, Carmeliet P, Zadeh G, Monnier PP, De Bock K, Radovanovic I. Shaping the brain vasculature in development and disease in the single-cell era. Nat Rev Neurosci 2023; 24:271-298. [PMID: 36941369 PMCID: PMC10026800 DOI: 10.1038/s41583-023-00684-y] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2023] [Indexed: 03/23/2023]
Abstract
The CNS critically relies on the formation and proper function of its vasculature during development, adult homeostasis and disease. Angiogenesis - the formation of new blood vessels - is highly active during brain development, enters almost complete quiescence in the healthy adult brain and is reactivated in vascular-dependent brain pathologies such as brain vascular malformations and brain tumours. Despite major advances in the understanding of the cellular and molecular mechanisms driving angiogenesis in peripheral tissues, developmental signalling pathways orchestrating angiogenic processes in the healthy and the diseased CNS remain incompletely understood. Molecular signalling pathways of the 'neurovascular link' defining common mechanisms of nerve and vessel wiring have emerged as crucial regulators of peripheral vascular growth, but their relevance for angiogenesis in brain development and disease remains largely unexplored. Here we review the current knowledge of general and CNS-specific mechanisms of angiogenesis during brain development and in brain vascular malformations and brain tumours, including how key molecular signalling pathways are reactivated in vascular-dependent diseases. We also discuss how these topics can be studied in the single-cell multi-omics era.
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Affiliation(s)
- Thomas Wälchli
- Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, and Division of Neurosurgery, University and University Hospital Zurich, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
- Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
- Group of Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
- Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, Toronto, ON, Canada.
| | - Jeroen Bisschop
- Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, and Division of Neurosurgery, University and University Hospital Zurich, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
- Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland
- Group of Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
- Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, Toronto, ON, Canada
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB & Department of Oncology, KU Leuven, Leuven, Belgium
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, People's Republic of China
- Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Gelareh Zadeh
- Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Philippe P Monnier
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Donald K. Johnson Research Institute, Krembil Research Institute, Krembil Discovery Tower, Toronto, ON, Canada
- Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Katrien De Bock
- Laboratory of Exercise and Health, Department of Health Science and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Ivan Radovanovic
- Group of Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
- Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, Toronto, ON, Canada
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19
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Liu X, Iovanna J, Santofimia-Castaño P. Stroma-targeting strategies in pancreatic cancer: a double-edged sword. J Physiol Biochem 2023; 79:213-222. [PMID: 36580230 DOI: 10.1007/s13105-022-00941-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 12/19/2022] [Indexed: 12/30/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer with limited treatment options and terrible long-term survival, and it is expected to become the second leading cause of cancer-related death by 2030. One reason why this cancer is so aggressive and resistant is the formation of dense stroma that surrounds the neoplastic epithelium, which promotes tumor progression, invasion, metastasis, and resistance. The three major components of PDAC stroma are extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), and vasculature. The dense ECM acts as a natural physical barrier, impeding drug penetration to PDAC tumor cells. Consequently, the method that combines stroma-targeting with anticancer therapy may be a viable alternative for increasing drug penetration. Additionally, blood vessels are key entities of the tumor stroma, serving as a pathway for nutrition as well as the only way for chemical medicines and immune cells to act. Finally, PDAC CAFs and tumor cells have crosstalk effects in the tumor microenvironment, where they are responsible for enhanced matrix deposition. In this review, we aim to provide an overview of our current comprehension of the three key components of PDAC stroma and the new promising therapeutic targets for PDAC.
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Affiliation(s)
- Xi Liu
- Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258, INSERM U1068, CNRS, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique Et Technologique de Luminy, 163 Avenue de Luminy, 13288, Marseille, France
| | - Juan Iovanna
- Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258, INSERM U1068, CNRS, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique Et Technologique de Luminy, 163 Avenue de Luminy, 13288, Marseille, France
| | - Patricia Santofimia-Castaño
- Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 7258, INSERM U1068, CNRS, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique Et Technologique de Luminy, 163 Avenue de Luminy, 13288, Marseille, France.
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20
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Han X, Ma Y, Lu W, Yan J, Qin W, He J, Niu LN, Jiao K. Bioactive semaphorin 3A promotes sequential formation of sensory nerve and type H vessels during in situ osteogenesis. Front Bioeng Biotechnol 2023; 11:1138601. [PMID: 36949886 PMCID: PMC10025372 DOI: 10.3389/fbioe.2023.1138601] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 02/24/2023] [Indexed: 03/08/2023] Open
Abstract
Introduction: Sensory nerves and vessels are critical for skeletal development and regeneration, but crosstalk between neurovascular network and mineralization are not clear. The aim of this study was to explore neurovascular changes and identify bioactive regulators during in situ osteogenesis. Method: In situ osteogenesis model was performed in male rats following Achilles tenotomy. At 3, 6 and 9 weeks after surgery, mineralization, blood vessels, sensory innervation, and bioactive regulators expression were evaluated via micro-computed tomography, immunofluorescent staining, histology and reverse transcriptase-polymerase chain reaction analyses. Result: In the process of in situ osteogenesis, the mineral density increased with time, and the locations of minerals, nerves and blood vessels were highly correlated at each time point. The highest density of sensory nerve was observed in the experimental group at the 3rd week, and then gradually decreased with time, but still higher than that in the sham control group. Among many regulatory factors, semaphorin 3A (Sema3A) was highly expressed in experimental model and its expression was temporally sequential and spatially correlated sensory nerve. Conclusion: The present study showes that during in situ osteogenesis, innervation and angiogenesis are highly correlated, and Sema3A is associated with the position and expression of the sensory nerve.
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Affiliation(s)
- Xiaoxiao Han
- The College of Life Science, Northwest University, Xi’an, Shaanxi, China
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yuxuan Ma
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Weicheng Lu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Jianfei Yan
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Wenpin Qin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Jiaying He
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Li-Na Niu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Kai Jiao
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, China
- *Correspondence: Kai Jiao,
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21
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Wei B, Hao Z, Zheng H, Qin Y, Zhao F, Shi L. Brevilin A Inhibits VEGF-Induced Angiogenesis through ROS-Dependent Mitochondrial Dysfunction. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5888636. [PMID: 36567856 PMCID: PMC9771652 DOI: 10.1155/2022/5888636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/07/2022] [Accepted: 11/15/2022] [Indexed: 12/16/2022]
Abstract
Brevilin A (BA), a sesquiterpene lactone isolated from Centipeda minima herb, has been identified to exhibit potent anticancer activity. However, the potential pharmacological effect and mechanism of BA in regulating endothelial cell (EC) angiogenesis, a key event in tumor growth, is poorly understood. In this study, BA was shown to significantly prevent vascular endothelial growth factor (VEGF) induced EC angiogenic capacities in vitro, ex vivo, and in vivo. Subsequent functional assays revealed that BA dose dependently inhibited VEGF-stimulated survival, proliferation, migration, and triggered apoptosis activity in human umbilical vein endothelial cells (HUVECs), as well as suppressed the expression of antiapoptotic protein Bcl-2, increased the expression of proapoptotic protein caspase-3 and Bax, and suppressed PI3K/AKT pathway. Meanwhile, BA was also able to depolarize mitochondrial membranal permeability (MMP), accelerate mitochondrial superoxide accumulation, induce intracellular reactive oxygen species (ROS) production, and decreased intracellular glutathione (GSH) in HUVECs. Furthermore, both mitochondria-specific superoxide scavenger Mito-TEMPOL and broad-spectrum antioxidant N-acetyl-cysteine (NAC) dramatically abolished BA-induced mitochondrial dysfunction and mitochondrial ROS production, causing the reversion of PI3K/AKT pathway and repression of apoptosis, eventually correcting the impaired endothelial behavior in survival, growth, migration, and angiogenesis. Collectively, our data for the first time identified a new mechanism for antiangiogenic effect of BA in vascular EC, one that is based on the regulation of mitochondrial-dependent ROS overproduction.
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Affiliation(s)
- Bailing Wei
- College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China
| | - Zhen Hao
- College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China
| | - Hao Zheng
- College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China
| | - Yuanhua Qin
- College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China
| | - Feng Zhao
- College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China
| | - Lei Shi
- College of Basic Medical Sciences, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China
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22
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Computational Model Exploring Characteristic Pattern Regulation in Periventricular Vessels. LIFE (BASEL, SWITZERLAND) 2022; 12:life12122069. [PMID: 36556434 PMCID: PMC9788473 DOI: 10.3390/life12122069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/26/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022]
Abstract
The developing neocortical vasculature exhibits a distinctive pattern in each layer. In murine embryos, vessels in the cortical plate (CP) are vertically oriented, whereas those in the intermediate zone (IZ) and the subventricular zone (SVZ) form a honeycomb structure. The formation of tissue-specific vessels suggests that the behavior of endothelial cells is under a specific regulatory regime in each layer, although the mechanisms involved remain unknown. In the present study, we aimed to explore the conditions required to form these vessel patterns by conducting simulations using a computational model. We developed a novel model framework describing the collective migration of endothelial cells to represent the angiogenic process and performed a simulation using two-dimensional approximation. The attractive and repulsive guidance of tip cells was incorporated into the model based on the function and distribution of guidance molecules such as VEGF and Unc ligands. It is shown that an appropriate combination of guidance effects reproduces both the parallel straight pattern in the CP and meshwork patterns in the IZ/SVZ. Our model demonstrated how the guidance of the tip cell causes a variety of vessel patterns and predicted how tissue-specific vascular formation was regulated in the early development of neocortical vessels.
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23
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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: 17] [Impact Index Per Article: 5.7] [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.
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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
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24
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Yin Z, Zhang J, Xu S, Liu J, Xu Y, Yu J, Zhao M, Pan W, Wang M, Wan J. The role of semaphorins in cardiovascular diseases: Potential therapeutic targets and novel biomarkers. FASEB J 2022; 36:e22509. [PMID: 36063107 DOI: 10.1096/fj.202200844r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/24/2022] [Accepted: 08/09/2022] [Indexed: 12/17/2022]
Abstract
Semaphorins (Semas), which belongs to the axonal guidance molecules, include 8 classes and could affect axon growth in the nervous system. Recently, semaphorins were found to regulate other pathophysiological processes, such as immune response, oncogenesis, tumor angiogenesis, and bone homeostasis, through binding with their plexin and neuropilin receptors. In this review, we summarized the detailed role of semaphorins and their receptors in the pathological progression of various cardiovascular diseases (CVDs), highlighting that semaphorins may be potential therapeutic targets and novel biomarkers for CVDs.
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Affiliation(s)
- Zheng Yin
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Jishou Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Shuwan Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Jianfang Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Yao Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Junping Yu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Mengmeng Zhao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Wei Pan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Menglong Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Jun Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
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25
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Nojima S. Class IV semaphorins in disease pathogenesis. Pathol Int 2022; 72:471-487. [PMID: 36066011 DOI: 10.1111/pin.13270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/16/2022] [Indexed: 12/01/2022]
Abstract
Semaphorins are a large family of secreted and/or transmembrane proteins, originally identified as proteins that function in axon guidance during neuronal development. However, semaphorins play crucial roles in other physiological and pathological processes, including immune responses, angiogenesis, maintenance of tissue homeostasis, and cancer progression. Class IV semaphorins may be present as transmembrane and soluble forms and are implicated in the pathogenesis of various diseases. This review discusses recent progress on the roles of class IV semaphorins determined by clinical and experimental pathology studies.
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Affiliation(s)
- Satoshi Nojima
- Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.,Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka, Japan
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26
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Gioelli N, Neilson LJ, Wei N, Villari G, Chen W, Kuhle B, Ehling M, Maione F, Willox S, Brundu S, Avanzato D, Koulouras G, Mazzone M, Giraudo E, Yang XL, Valdembri D, Zanivan S, Serini G. Neuropilin 1 and its inhibitory ligand mini-tryptophanyl-tRNA synthetase inversely regulate VE-cadherin turnover and vascular permeability. Nat Commun 2022; 13:4188. [PMID: 35858913 PMCID: PMC9300702 DOI: 10.1038/s41467-022-31904-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 07/08/2022] [Indexed: 11/09/2022] Open
Abstract
The formation of a functional blood vessel network relies on the ability of endothelial cells (ECs) to dynamically rearrange their adhesive contacts in response to blood flow and guidance cues, such as vascular endothelial growth factor-A (VEGF-A) and class 3 semaphorins (SEMA3s). Neuropilin 1 (NRP1) is essential for blood vessel development, independently of its ligands VEGF-A and SEMA3, through poorly understood mechanisms. Grounding on unbiased proteomic analysis, we report here that NRP1 acts as an endocytic chaperone primarily for adhesion receptors on the surface of unstimulated ECs. NRP1 localizes at adherens junctions (AJs) where, interacting with VE-cadherin, promotes its basal internalization-dependent turnover and favors vascular permeability initiated by histamine in both cultured ECs and mice. We identify a splice variant of tryptophanyl-tRNA synthetase (mini-WARS) as an unconventionally secreted extracellular inhibitory ligand of NRP1 that, by stabilizing it at the AJs, slows down both VE-cadherin turnover and histamine-elicited endothelial leakage. Thus, our work shows a role for NRP1 as a major regulator of AJs plasticity and reveals how mini-WARS acts as a physiological NRP1 inhibitory ligand in the control of VE-cadherin endocytic turnover and vascular permeability.
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Affiliation(s)
- Noemi Gioelli
- Department of Oncology, University of Torino School of Medicine, Candiolo (TO), Italy
- Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo (TO), Italy
| | | | - Na Wei
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Giulia Villari
- Department of Oncology, University of Torino School of Medicine, Candiolo (TO), Italy
- Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo (TO), Italy
| | - Wenqian Chen
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Bernhard Kuhle
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Manuel Ehling
- Center for Cancer Biology, Department of Oncology, University of Leuven, Leuven, 3000, Belgium
- Center for Cancer Biology, VIB, Leuven, 3000, Belgium
| | - Federica Maione
- Department of Oncology, University of Torino School of Medicine, Candiolo (TO), Italy
- Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo (TO), Italy
| | - Sander Willox
- Center for Cancer Biology, Department of Oncology, University of Leuven, Leuven, 3000, Belgium
- Center for Cancer Biology, VIB, Leuven, 3000, Belgium
| | - Serena Brundu
- Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo (TO), Italy
- Department of Science and Drug Technology, University of Torino, Torino, Italy
| | - Daniele Avanzato
- Department of Oncology, University of Torino School of Medicine, Candiolo (TO), Italy
- Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo (TO), Italy
| | | | - Massimiliano Mazzone
- Center for Cancer Biology, Department of Oncology, University of Leuven, Leuven, 3000, Belgium
- Center for Cancer Biology, VIB, Leuven, 3000, Belgium
- Department of Science and Drug Technology, University of Torino, Torino, Italy
- Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Enrico Giraudo
- Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo (TO), Italy
- Department of Science and Drug Technology, University of Torino, Torino, Italy
| | - Xiang-Lei Yang
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Donatella Valdembri
- Department of Oncology, University of Torino School of Medicine, Candiolo (TO), Italy
- Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo (TO), Italy
| | - Sara Zanivan
- Cancer Research UK Beatson Institute, Glasgow, UK.
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
| | - Guido Serini
- Department of Oncology, University of Torino School of Medicine, Candiolo (TO), Italy.
- Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo (TO), Italy.
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27
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Lai YJ, Tsai FC, Chang GJ, Chang SH, Huang CC, Chen WJ, Yeh YH. miR-181b targets semaphorin 3A to mediate TGF-β-induced endothelial-mesenchymal transition related to atrial fibrillation. J Clin Invest 2022; 132:142548. [PMID: 35775491 PMCID: PMC9246393 DOI: 10.1172/jci142548] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 05/10/2022] [Indexed: 11/17/2022] Open
Abstract
Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition (EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-β-treated human AEECs, cardiac-specific TGF-β-transgenic mice, and heart failure rabbits to identify the underlying mechanism of EndMT in atrial fibrosis. Using isolated AEECs, we found that miR-181b was induced in TGF-β-treated AEECs, which decreased semaphorin 3A (Sema3A) and increased EndMT markers, and these effects could be reversed by a miR-181b antagomir. Experiments in which Sema3A was increased by a peptide or decreased by a siRNA in AEECs revealed a mechanistic link between Sema3A and LIM-kinase 1/phosphorylated cofilin (LIMK/p-cofilin) signaling and suggested that Sema3A is upstream of LIMK in regulating actin remodeling through p-cofilin. Administration of the miR-181b antagomir or recombinant Sema3A to TGF-β-transgenic mice evoked increased Sema3A, reduced EndMT markers, and significantly decreased atrial fibrosis and AF vulnerability. Our study provides a mechanistic link between the induction of EndMT by TGF-β via miR-181b/Sema3A/LIMK/p-cofilin signaling to atrial fibrosis. Blocking miR-181b and increasing Sema3A are potential strategies for AF therapeutic intervention.
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Affiliation(s)
- Ying-Ju Lai
- Cardiovascular Department, Chang Gung Memorial Hospital, Tao Yuan, Taiwan.,Department of Respiratory Therapy, Chang Gung University College of Medicine, Tao Yuan, Taiwan.,Department of Respiratory Care, Chang Gung University of Science and Technology, Chia Yi, Taiwan
| | - Feng-Chun Tsai
- Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Tao Yuan, Taiwan.,Department of Medicine and
| | - Gwo-Jyh Chang
- Cardiovascular Department, Chang Gung Memorial Hospital, Tao Yuan, Taiwan.,Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Tao Yuan, Taiwan
| | - Shang-Hung Chang
- Cardiovascular Department, Chang Gung Memorial Hospital, Tao Yuan, Taiwan.,Department of Medicine and
| | - Chung-Chi Huang
- Department of Respiratory Therapy, Chang Gung University College of Medicine, Tao Yuan, Taiwan.,Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Tao Yuan, Taiwan
| | - Wei-Jan Chen
- Cardiovascular Department, Chang Gung Memorial Hospital, Tao Yuan, Taiwan.,Department of Medicine and
| | - Yung-Hsin Yeh
- Cardiovascular Department, Chang Gung Memorial Hospital, Tao Yuan, Taiwan.,Department of Medicine and
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28
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Termini CM, Pang A, Fang T, Roos M, Chang VY, Zhang Y, Setiawan NJ, Signaevskaia L, Li M, Kim MM, Tabibi O, Lin PK, Sasine JP, Chatterjee A, Murali R, Himburg HA, Chute JP. Neuropilin 1 regulates bone marrow vascular regeneration and hematopoietic reconstitution. Nat Commun 2021; 12:6990. [PMID: 34848712 PMCID: PMC8635308 DOI: 10.1038/s41467-021-27263-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 11/07/2021] [Indexed: 12/27/2022] Open
Abstract
Ionizing radiation and chemotherapy deplete hematopoietic stem cells and damage the vascular niche wherein hematopoietic stem cells reside. Hematopoietic stem cell regeneration requires signaling from an intact bone marrow (BM) vascular niche, but the mechanisms that control BM vascular niche regeneration are poorly understood. We report that BM vascular endothelial cells secrete semaphorin 3 A (SEMA3A) in response to myeloablation and SEMA3A induces p53 - mediated apoptosis in BM endothelial cells via signaling through its receptor, Neuropilin 1 (NRP1), and activation of cyclin dependent kinase 5. Endothelial cell - specific deletion of Nrp1 or Sema3a or administration of anti-NRP1 antibody suppresses BM endothelial cell apoptosis, accelerates BM vascular regeneration and concordantly drives hematopoietic reconstitution in irradiated mice. In response to NRP1 inhibition, BM endothelial cells increase expression and secretion of the Wnt signal amplifying protein, R spondin 2. Systemic administration of anti - R spondin 2 blocks HSC regeneration and hematopoietic reconstitution which otherwise occurrs in response to NRP1 inhibition. SEMA3A - NRP1 signaling promotes BM vascular regression following myelosuppression and therapeutic blockade of SEMA3A - NRP1 signaling in BM endothelial cells accelerates vascular and hematopoietic regeneration in vivo.
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Affiliation(s)
- Christina M Termini
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA
- Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
- Department of Orthopedic Surgery, UCLA, Los Angeles, CA, USA
| | - Amara Pang
- Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Tiancheng Fang
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA
| | - Martina Roos
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA
- Eli and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
| | - Vivian Y Chang
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
- Pediatric Hematology/Oncology, UCLA, Los Angeles, CA, USA
| | - Yurun Zhang
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA
- Molecular Biology Institute, UCLA, Los Angeles, CA, USA
| | - Nicollette J Setiawan
- Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Lia Signaevskaia
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA
| | - Michelle Li
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA
| | - Mindy M Kim
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA
| | - Orel Tabibi
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA
| | - Paulina K Lin
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA
| | - Joshua P Sasine
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, CA, USA
- Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Avradip Chatterjee
- Department of Biomedical Sciences, Research Division of Immunology, Los Angeles, USA
| | - Ramachandran Murali
- Department of Biomedical Sciences, Research Division of Immunology, Los Angeles, USA
| | - Heather A Himburg
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - John P Chute
- Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA.
- Regenerative Medicine Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA.
- Samuel Oschin Cancer Center, Cedars Sinai Medical Center, Los Angeles, CA, USA.
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Silicified collagen scaffold induces semaphorin 3A secretion by sensory nerves to improve in-situ bone regeneration. Bioact Mater 2021; 9:475-490. [PMID: 34820584 PMCID: PMC8586786 DOI: 10.1016/j.bioactmat.2021.07.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 07/12/2021] [Accepted: 07/17/2021] [Indexed: 12/14/2022] Open
Abstract
Sensory nerves promote osteogenesis through the release of neuropeptides. However, the potential application and mechanism in which sensory nerves promote healing of bone defects in the presence of biomaterials remain elusive. The present study identified that new bone formation was more abundantly produced after implantation of silicified collagen scaffolds into defects created in the distal femur of rats. The wound sites were accompanied by extensive nerve innervation and angiogenesis. Sensory nerve dysfunction by capsaicin injection resulted in significant inhibition of silicon-induced osteogenesis in the aforementioned rodent model. Application of extracellular silicon in vitro induced axon outgrowth and increased expression of semaphorin 3 A (Sema3A) and semaphorin 4D (Sema4D) in the dorsal root ganglion (DRG), as detected by the upregulation of signaling molecules. Culture medium derived from silicon-stimulated DRG cells promoted proliferation and differentiation of bone marrow mesenchymal stem cells and endothelial progenitor cells. These effects were inhibited by the use of Sema3A neutralizing antibodies but not by Sema4D neutralizing antibodies. Knockdown of Sema3A in DRG blocked silicon-induced osteogenesis and angiogenesis almost completely in a femoral defect rat model, whereas overexpression of Sema3A promoted the silicon-induced phenomena. Activation of “mechanistic target of rapamycin” (mTOR) pathway and increase of Sema3A production were identified in the DRG of rats that were implanted with silicified collagen scaffolds. These findings support the role of silicon in inducing Sema3A production by sensory nerves, which, in turn, stimulates osteogenesis and angiogenesis. Taken together, silicon has therapeutic potential in orthopedic rehabilitation.
Nerve innervation, vascularization and tissue mineralization integrated into a single scaffold. Silicified collagen scaffolds has therapeutic potential in orthopedic rehabilitation. Silicified collagen scaffolds promote in-situ bone regeneration via sensory nerve innervation and semaphorin 3A production.
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Kart Bayram GS, Erden A, Bayram D, Özdemir B, Karakaş Ö, Apaydın H, Ateş O, Güven SC, Armağan B, Gök K, Maraş Y, Omma A, Küçükşahin O, Topçuoğlu C, Erten Ş. Semaphorin 3A Levels in Lupus With and Without Secondary Antiphospholipid Antibody Syndrome and Renal Involvement. Lab Med 2021; 53:285-289. [PMID: 34927690 DOI: 10.1093/labmed/lmab096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE The aim of this study is to evaluate semaphorin 3A levels in patients with systemic lupus erythematosus (SLE) with and without renal involvement and secondary antiphospholipid antibody syndrome (APS). METHODS Patients with SLE were grouped according to the presence of secondary APS or renal involvement. The control group consisted of age-matched, nonsmoking, healthy volunteers. Semaphorin 3A levels were compared among groups. All patients with SLE were regrouped according to the presence of thrombotic events, miscarriages, and proteinuria, and semaphorin 3A levels were investigated. Finally, semaphorin 3A levels of all patients with SLE as a single group were compared to those of the control patients. RESULTS The mean semaphorin 3A values were 16.16 ± 2.84 ng/mL in the control group, 9.05 ± 5.65 ng/mL in patients with SLE without nephritis and APS, 11.28 ± 5.23 ng/mL in the SLE with APS group, and 8.53 ± 5.11 ng/mL in the lupus nephritis group. When all 3 patient groups were examined as a single group, the mean semaphorin 3A value was significantly lower than that of the control group. Semaphorin 3A was reduced in patients with SLE with thromboembolism and/or history of miscarriage. CONCLUSION Semaphorin 3A levels were lower in all patient groups compared to the control group. Moreover, the reduced semaphorin 3A levels in patients with a history of thromboembolism and/or miscarriage suggest that semaphorin 3A may play an important role in the pathogenesis of vasculopathy.
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Affiliation(s)
| | | | - Doğan Bayram
- Ankara City Hospital, Internal Medicine, Üniversiteler Mahallesi, Ankara, Turkey
| | | | | | | | - Ortaç Ateş
- Ankara City Hospital, Biochemistry, Ankara, Turkey
| | | | | | - Kevser Gök
- Ankara City Hospital, Rheumatology, Ankara, Turkey
| | - Yüksel Maraş
- Ankara City Hospital, Rheumatology, Ankara, Turkey
| | - Ahmet Omma
- TC Saglik Bakanligi Ankara Numune Egitim ve Arastirma Hastanesi, Ankara, Turkey
| | - Orhan Küçükşahin
- Ankara Yildirim Beyazit University, Rheumatology, Ankara, Turkey
| | - Canan Topçuoğlu
- Ankara Numune Education and Research Hospital, Biochemistry Department, Ankara, Turkey
| | - Şükran Erten
- Ankara Yildirim Beyazit University, Rheumatology, Ankara, Turkey
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31
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Camillo C, Facchinello N, Villari G, Mana G, Gioelli N, Sandri C, Astone M, Tortarolo D, Clapero F, Gays D, Oberkersch RE, Arese M, Tamagnone L, Valdembri D, Santoro MM, Serini G. LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion. J Cell Biol 2021; 220:212665. [PMID: 34581723 PMCID: PMC8480966 DOI: 10.1083/jcb.202006033] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 03/22/2021] [Accepted: 09/02/2021] [Indexed: 01/20/2023] Open
Abstract
Dynamic modulation of endothelial cell-to-cell and cell–to–extracellular matrix (ECM) adhesion is essential for blood vessel patterning and functioning. Yet the molecular mechanisms involved in this process have not been completely deciphered. We identify the adhesion G protein–coupled receptor (ADGR) Latrophilin 2 (LPHN2) as a novel determinant of endothelial cell (EC) adhesion and barrier function. In cultured ECs, endogenous LPHN2 localizes at ECM contacts, signals through cAMP/Rap1, and inhibits focal adhesion (FA) formation and nuclear localization of YAP/TAZ transcriptional regulators, while promoting tight junction (TJ) assembly. ECs also express an endogenous LPHN2 ligand, fibronectin leucine-rich transmembrane 2 (FLRT2), that prevents ECM-elicited EC behaviors in an LPHN2-dependent manner. Vascular ECs of lphn2a knock-out zebrafish embryos become abnormally stretched, display a hyperactive YAP/TAZ pathway, and lack proper intercellular TJs. Consistently, blood vessels are hyperpermeable, and intravascularly injected cancer cells extravasate more easily in lphn2a null animals. Thus, LPHN2 ligands, such as FLRT2, may be therapeutically exploited to interfere with cancer metastatic dissemination.
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Affiliation(s)
- Chiara Camillo
- Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Italy.,Department of Oncology, University of Torino School of Medicine, Candiolo, Italy
| | - Nicola Facchinello
- Laboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padova, Padova, Italy
| | - Giulia Villari
- Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Italy.,Department of Oncology, University of Torino School of Medicine, Candiolo, Italy
| | - Giulia Mana
- Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Italy.,Department of Oncology, University of Torino School of Medicine, Candiolo, Italy
| | - Noemi Gioelli
- Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Italy.,Department of Oncology, University of Torino School of Medicine, Candiolo, Italy
| | - Chiara Sandri
- Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Italy.,Department of Oncology, University of Torino School of Medicine, Candiolo, Italy
| | - Matteo Astone
- Laboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padova, Padova, Italy
| | - Dora Tortarolo
- Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Italy.,Department of Oncology, University of Torino School of Medicine, Candiolo, Italy
| | - Fabiana Clapero
- Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Italy.,Department of Oncology, University of Torino School of Medicine, Candiolo, Italy
| | - Dafne Gays
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Roxana E Oberkersch
- Laboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padova, Padova, Italy
| | - Marco Arese
- Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Italy.,Department of Oncology, University of Torino School of Medicine, Candiolo, Italy
| | - Luca Tamagnone
- Institute of Histology and Embryology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.,"Agostino Gemelli" University Polyclinic Foundation, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Donatella Valdembri
- Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Italy.,Department of Oncology, University of Torino School of Medicine, Candiolo, Italy
| | - Massimo M Santoro
- Laboratory of Angiogenesis and Cancer Metabolism, Department of Biology, University of Padova, Padova, Italy
| | - Guido Serini
- Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Italy.,Department of Oncology, University of Torino School of Medicine, Candiolo, Italy
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Li Z, Ning F, Wang C, Yu H, Ma Q, Sun Y. Normalization of the tumor microvasculature based on targeting and modulation of the tumor microenvironment. NANOSCALE 2021; 13:17254-17271. [PMID: 34651623 DOI: 10.1039/d1nr03387e] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Angiogenesis is an essential process for tumor development. Owing to the imbalance between pro- and anti-angiogenic factors, the tumor vasculature possesses the characteristics of tortuous, hyperpermeable vessels and compressive force, resulting in a reduction in the effect of traditional chemotherapy and radiotherapy. Anti-angiogenesis has emerged as a promising strategy for cancer treatment. Tumor angiogenesis, however, has been proved to be a complex process in which the tumor microenvironment (TME) plays a vital role in the initiation and development of the tumor microvasculature. The host stromal cells in the TME, such as cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs) and Treg cells, contribute to angiogenesis. Furthermore, the abnormal metabolic environment, such as hypoxia and acidosis, leads to the up-regulated expression of angiogenic factors. Indeed, normalization of the tumor microvasculature via targeting and modulating the TME has become a promising strategy for anti-angiogenesis and anti-tumor therapy. In this review, we summarize the abnormalities of the tumor microvasculature, tumor angiogenesis induced by an abnormal metabolic environment and host stromal cells, as well as drug delivery therapies to restore the balance between pro- and anti-angiogenic factors by targeting and normalizing the tumor vasculature in the TME.
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Affiliation(s)
- Zhipeng Li
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China.
| | - Fang Ning
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China.
| | - Changduo Wang
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China.
| | - Hongli Yu
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China.
| | - Qingming Ma
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China.
| | - Yong Sun
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266021, China.
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Larionova I, Kazakova E, Gerashchenko T, Kzhyshkowska J. New Angiogenic Regulators Produced by TAMs: Perspective for Targeting Tumor Angiogenesis. Cancers (Basel) 2021; 13:cancers13133253. [PMID: 34209679 PMCID: PMC8268686 DOI: 10.3390/cancers13133253] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 06/15/2021] [Accepted: 06/22/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Since the targeting of a single pro-angiogenic factor fails to improve oncological disease outcome, significant efforts have been made to identify new pro-angiogenic factors that could compensate for the deficiency of current therapy or act independently as single drugs. Our review aims to present the state-of-the art for well-known and recently described factors produced by macrophages that induce and regulate angiogenesis. A number of positive and negative regulators of angiogenesis in the tumor microenvironment are produced by tumor-associated macrophages (TAMs). Accumulating evidence has indicated that, apart from the well-known angiogenic factors, there are plenty of novel angiogenesis-regulating proteins that belong to different classes. We summarize the data regarding the direct or indirect mechanisms of the interaction of these factors with endothelial cells during angiogenesis. We highlight the recent findings that explain the limitations in the efficiency of current anti-angiogenic therapy approaches. Abstract Angiogenesis is crucial to the supply of a growing tumor with nutrition and oxygen. Inhibition of angiogenesis is one of the main treatment strategies for colorectal, lung, breast, renal, and other solid cancers. However, currently applied drugs that target VEGF or receptor tyrosine kinases have limited efficiency, which raises a question concerning the mechanism of patient resistance to the already developed drugs. Tumor-associated macrophages (TAMs) were identified in the animal tumor models as a key inducer of the angiogenic switch. TAMs represent a potent source not only for VEGF, but also for a number of other pro-angiogenic factors. Our review provides information about the activity of secreted regulators of angiogenesis produced by TAMs. They include members of SEMA and S100A families, chitinase-like proteins, osteopontin, and SPARC. The COX-2, Tie2, and other factors that control the pro-angiogenic activity of TAMs are also discussed. We highlight how these recent findings explain the limitations in the efficiency of current anti-angiogenic therapy. Additionally, we describe genetic and posttranscriptional mechanisms that control the expression of factors regulating angiogenesis. Finally, we present prospects for the complex targeting of the pro-angiogenic activity of TAMs.
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Affiliation(s)
- Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia;
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia;
- Correspondence: (I.L.); (J.K.)
| | - Elena Kazakova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia;
| | - Tatiana Gerashchenko
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia;
| | - Julia Kzhyshkowska
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia;
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- German Red Cross Blood Service Baden-Württemberg—Hessen, 68167 Mannheim, Germany
- Correspondence: (I.L.); (J.K.)
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Chico TJA, Kugler EC. Cerebrovascular development: mechanisms and experimental approaches. Cell Mol Life Sci 2021; 78:4377-4398. [PMID: 33688979 PMCID: PMC8164590 DOI: 10.1007/s00018-021-03790-1] [Citation(s) in RCA: 5] [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: 06/22/2020] [Revised: 02/04/2021] [Accepted: 02/12/2021] [Indexed: 12/13/2022]
Abstract
The cerebral vasculature plays a central role in human health and disease and possesses several unique anatomic, functional and molecular characteristics. Despite their importance, the mechanisms that determine cerebrovascular development are less well studied than other vascular territories. This is in part due to limitations of existing models and techniques for visualisation and manipulation of the cerebral vasculature. In this review we summarise the experimental approaches used to study the cerebral vessels and the mechanisms that contribute to their development.
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Affiliation(s)
- Timothy J A Chico
- Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.
- The Bateson Centre, Firth Court, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
- Insigneo Institute for in Silico Medicine, The Pam Liversidge Building, Sheffield, S1 3JD, UK.
| | - Elisabeth C Kugler
- Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.
- The Bateson Centre, Firth Court, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
- Insigneo Institute for in Silico Medicine, The Pam Liversidge Building, Sheffield, S1 3JD, UK.
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35
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Functional and structural basis of extreme conservation in vertebrate 5' untranslated regions. Nat Genet 2021; 53:729-741. [PMID: 33821006 PMCID: PMC8825242 DOI: 10.1038/s41588-021-00830-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 02/26/2021] [Indexed: 01/07/2023]
Abstract
The lack of knowledge about extreme conservation in genomes remains a major gap in our understanding of the evolution of gene regulation. Here, we reveal an unexpected role of extremely conserved 5' untranslated regions (UTRs) in noncanonical translational regulation that is linked to the emergence of essential developmental features in vertebrate species. Endogenous deletion of conserved elements within these 5' UTRs decreased gene expression, and extremely conserved 5' UTRs possess cis-regulatory elements that promote cell-type-specific regulation of translation. We further developed in-cell mutate-and-map (icM2), a new methodology that maps RNA structure inside cells. Using icM2, we determined that an extremely conserved 5' UTR encodes multiple alternative structures and that each single nucleotide within the conserved element maintains the balance of alternative structures important to control the dynamic range of protein expression. These results explain how extreme sequence conservation can lead to RNA-level biological functions encoded in the untranslated regions of vertebrate genomes.
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36
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SH3BP4 promotes neuropilin-1 and α5-integrin endocytosis and is inhibited by Akt. Dev Cell 2021; 56:1164-1181.e12. [PMID: 33761321 DOI: 10.1016/j.devcel.2021.03.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 12/23/2020] [Accepted: 02/27/2021] [Indexed: 02/06/2023]
Abstract
Cells probe their surrounding matrix for attachment sites via integrins that are internalized by endocytosis. We find that SH3BP4 regulates integrin surface expression in a signaling-dependent manner via clathrin-coated pits (CCPs). Dephosphorylated SH3BP4 at S246 is efficiently recruited to CCPs, while upon Akt phosphorylation, SH3BP4 is sequestered by 14-3-3 adaptors and excluded from CCPs. In the absence of Akt activity, SH3BP4 binds GIPC1 and targets neuropilin-1 and α5/β1-integrin for endocytosis, leading to inhibition of cell spreading. Similarly, chemorepellent semaphorin-3a binds neuropilin-1 to activate PTEN, which antagonizes Akt and thus recruits SH3BP4 to CCPs to internalize both receptors and induce cell contraction. In PTEN mutant non-small cell lung cancer cells with high Akt activity, expression of non-phosphorylatable active SH3BP4-S246A restores semaphorin-3a induced cell contraction. Thus, SH3BP4 links Akt signaling to endocytosis of NRP1 and α5/β1-integrins to modulate cell-matrix interactions in response to intrinsic and extrinsic cues.
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37
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Chen M, Li Y, Huang X, Gu Y, Li S, Yin P, Zhang L, Tang P. Skeleton-vasculature chain reaction: a novel insight into the mystery of homeostasis. Bone Res 2021; 9:21. [PMID: 33753717 PMCID: PMC7985324 DOI: 10.1038/s41413-021-00138-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 11/18/2020] [Accepted: 12/16/2020] [Indexed: 02/01/2023] Open
Abstract
Angiogenesis and osteogenesis are coupled. However, the cellular and molecular regulation of these processes remains to be further investigated. Both tissues have recently been recognized as endocrine organs, which has stimulated research interest in the screening and functional identification of novel paracrine factors from both tissues. This review aims to elaborate on the novelty and significance of endocrine regulatory loops between bone and the vasculature. In addition, research progress related to the bone vasculature, vessel-related skeletal diseases, pathological conditions, and angiogenesis-targeted therapeutic strategies are also summarized. With respect to future perspectives, new techniques such as single-cell sequencing, which can be used to show the cellular diversity and plasticity of both tissues, are facilitating progress in this field. Moreover, extracellular vesicle-mediated nuclear acid communication deserves further investigation. In conclusion, a deeper understanding of the cellular and molecular regulation of angiogenesis and osteogenesis coupling may offer an opportunity to identify new therapeutic targets.
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Affiliation(s)
- Ming Chen
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China
| | - Yi Li
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China
| | - Xiang Huang
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China
| | - Ya Gu
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China
| | - Shang Li
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China
| | - Pengbin Yin
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China.
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China.
| | - Licheng Zhang
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China.
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China.
| | - Peifu Tang
- Department of Orthopedics, Chinese PLA General Hospital, Beijing, China.
- National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China.
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Zink J, Frye M, Frömel T, Carlantoni C, John D, Schreier D, Weigert A, Laban H, Salinas G, Stingl H, Günther L, Popp R, Hu J, Vanhollebeke B, Schmidt H, Acker-Palmer A, Renné T, Fleming I, Benz PM. EVL regulates VEGF receptor-2 internalization and signaling in developmental angiogenesis. EMBO Rep 2021; 22:e48961. [PMID: 33512764 PMCID: PMC7857432 DOI: 10.15252/embr.201948961] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 12/03/2020] [Accepted: 12/09/2020] [Indexed: 12/11/2022] Open
Abstract
Endothelial tip cells are essential for VEGF‐induced angiogenesis, but underlying mechanisms are elusive. The Ena/VASP protein family, consisting of EVL, VASP, and Mena, plays a pivotal role in axon guidance. Given that axonal growth cones and endothelial tip cells share many common features, from the morphological to the molecular level, we investigated the role of Ena/VASP proteins in angiogenesis. EVL and VASP, but not Mena, are expressed in endothelial cells of the postnatal mouse retina. Global deletion of EVL (but not VASP) compromises the radial sprouting of the vascular plexus in mice. Similarly, endothelial‐specific EVL deletion compromises the radial sprouting of the vascular plexus and reduces the endothelial tip cell density and filopodia formation. Gene sets involved in blood vessel development and angiogenesis are down‐regulated in EVL‐deficient P5‐retinal endothelial cells. Consistently, EVL deletion impairs VEGF‐induced endothelial cell proliferation and sprouting, and reduces the internalization and phosphorylation of VEGF receptor 2 and its downstream signaling via the MAPK/ERK pathway. Together, we show that endothelial EVL regulates sprouting angiogenesis via VEGF receptor‐2 internalization and signaling.
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Affiliation(s)
- Joana Zink
- Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Frankfurt am Main, Germany.,German Centre of Cardiovascular Research (DZHK), Partner site Rhein-Main, Frankfurt am Main, Germany
| | - Maike Frye
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Timo Frömel
- Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Frankfurt am Main, Germany.,German Centre of Cardiovascular Research (DZHK), Partner site Rhein-Main, Frankfurt am Main, Germany
| | - Claudia Carlantoni
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David John
- German Centre of Cardiovascular Research (DZHK), Partner site Rhein-Main, Frankfurt am Main, Germany.,Insitute for Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany
| | - Danny Schreier
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas Weigert
- Institute of Biochemistry I-Pathobiochemistry, Faculty of Medicine, Goethe-University, Frankfurt am Main, Germany
| | - Hebatullah Laban
- Department of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
| | - Gabriela Salinas
- NGS-Integrative Genomics Core Unit (NIG), Institute of Human Genetics, University Medical Center Göttingen (UMG), Göttingen, Germany
| | - Heike Stingl
- Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Frankfurt am Main, Germany.,German Centre of Cardiovascular Research (DZHK), Partner site Rhein-Main, Frankfurt am Main, Germany
| | - Lea Günther
- Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Frankfurt am Main, Germany.,German Centre of Cardiovascular Research (DZHK), Partner site Rhein-Main, Frankfurt am Main, Germany
| | - Rüdiger Popp
- Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Frankfurt am Main, Germany.,German Centre of Cardiovascular Research (DZHK), Partner site Rhein-Main, Frankfurt am Main, Germany
| | - Jiong Hu
- Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Frankfurt am Main, Germany.,German Centre of Cardiovascular Research (DZHK), Partner site Rhein-Main, Frankfurt am Main, Germany
| | - Benoit Vanhollebeke
- Laboratory of Neurovascular Signaling, ULB Neuroscience Institute Department of Molecular Biology, University of Brussels, Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Brussels, Belgium
| | - Hannes Schmidt
- Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
| | - Amparo Acker-Palmer
- Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt am Main, Germany
| | - Thomas Renné
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ingrid Fleming
- Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Frankfurt am Main, Germany.,German Centre of Cardiovascular Research (DZHK), Partner site Rhein-Main, Frankfurt am Main, Germany
| | - Peter M Benz
- Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Frankfurt am Main, Germany.,German Centre of Cardiovascular Research (DZHK), Partner site Rhein-Main, Frankfurt am Main, Germany
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Abstract
Cardiac neural crest (CNC) cells are pluripotent cells derived from the dorsal neural tube that migrate and contribute to the remodeling of pharyngeal arch arteries and septation of the cardiac outflow tract (OFT). Numerous molecular cascades regulate the induction, specification, delamination, and migration of the CNC. Extensive analyses of the CNC ranging from chick ablation models to molecular biology studies have explored the mechanisms of heart development and disease, particularly involving the OFT and aortic arch (AA) system. Recent studies focus more on reciprocal signaling between the CNC and cells originated from the second heart field (SHF), which are essential for the development of the OFT myocardium, providing new insights into the molecular mechanisms underlying congenital heart diseases (CHDs) and some human syndromes.
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Affiliation(s)
- Hiroyuki Yamagishi
- Division of Pediatric Cardiology, Department of Pediatrics, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
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40
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Higgins DMO, Caliva M, Schroeder M, Carlson B, Upadhyayula PS, Milligan BD, Cheshier SH, Weissman IL, Sarkaria JN, Meyer FB, Henley JR. Semaphorin 3A mediated brain tumor stem cell proliferation and invasion in EGFRviii mutant gliomas. BMC Cancer 2020; 20:1213. [PMID: 33302912 PMCID: PMC7727139 DOI: 10.1186/s12885-020-07694-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 11/26/2020] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, with a median survival of approximately 15 months. Semaphorin 3A (Sema3A), known for its axon guidance and antiangiogenic properties, has been implicated in GBM growth. We hypothesized that Sema3A directly inhibits brain tumor stem cell (BTSC) proliferation and drives invasion via Neuropilin 1 (Nrp1) and Plexin A1 (PlxnA1) receptors. METHODS GBM BTSC cell lines were assayed by immunostaining and PCR for levels of Semaphorin 3A (Sema3A) and its receptors Nrp1 and PlxnA1. Quantitative BrdU, cell cycle and propidium iodide labeling assays were performed following exogenous Sema3A treatment. Quantitative functional 2-D and 3-D invasion assays along with shRNA lentiviral knockdown of Nrp1 and PlxnA1 are also shown. In vivo flank studies comparing tumor growth of knockdown versus control BTSCs were performed. Statistics were performed using GraphPad Prism v7. RESULTS Immunostaining and PCR analysis revealed that BTSCs highly express Sema3A and its receptors Nrp1 and PlxnA1, with expression of Nrp1 in the CD133 positive BTSCs, and absence in differentiated tumor cells. Treatment with exogenous Sema3A in quantitative BrdU, cell cycle, and propidium iodide labeling assays demonstrated that Sema3A significantly inhibited BTSC proliferation without inducing cell death. Quantitative functional 2-D and 3-D invasion assays showed that treatment with Sema3A resulted in increased invasion. Using shRNA lentiviruses, knockdown of either NRP1 or PlxnA1 receptors abrogated Sema3A antiproliferative and pro-invasive effects. Interestingly, loss of the receptors mimicked Sema3A effects, inhibiting BTSC proliferation and driving invasion. Furthermore, in vivo studies comparing tumor growth of knockdown and control infected BTSCs implanted into the flanks of nude mice confirmed the decrease in proliferation with receptor KD. CONCLUSIONS These findings demonstrate the importance of Sema3A signaling in GBM BTSC proliferation and invasion, and its potential as a therapeutic target.
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Affiliation(s)
- Dominique M O Higgins
- Mayo Clinic: College of Medicine, Rochester, MN, 55905, USA.
- Department of Neurosurgery, Columbia University Medical Center, 710 W. 168th Street, New York, NY, 10032, USA.
| | - Maisel Caliva
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, 55905, USA
- Currently: Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, HI, 96813, USA
| | - Mark Schroeder
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Brett Carlson
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Pavan S Upadhyayula
- Department of Neurosurgery, Columbia University Medical Center, 710 W. 168th Street, New York, NY, 10032, USA
| | - Brian D Milligan
- Mayo Clinic: College of Medicine, Rochester, MN, 55905, USA
- Currently: Department of Neurosurgery, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Samuel H Cheshier
- Division of Pediatric Neurosurgery, Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84113, USA
| | - Irving L Weissman
- Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center, Stanford University Medical Center, Stanford, CA, 94305, USA
| | - Jann N Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Fredric B Meyer
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, 55905, USA
| | - John R Henley
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, 55905, USA
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Villari G, Enrico Bena C, Del Giudice M, Gioelli N, Sandri C, Camillo C, Fiorio Pla A, Bosia C, Serini G. Distinct retrograde microtubule motor sets drive early and late endosome transport. EMBO J 2020; 39:e103661. [PMID: 33215754 PMCID: PMC7737607 DOI: 10.15252/embj.2019103661] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 10/01/2020] [Accepted: 10/14/2020] [Indexed: 11/23/2022] Open
Abstract
Although subcellular positioning of endosomes significantly impacts on their functions, the molecular mechanisms governing the different steady‐state distribution of early endosomes (EEs) and late endosomes (LEs)/lysosomes (LYs) in peripheral and perinuclear eukaryotic cell areas, respectively, are still unsolved. We unveil that such differences arise because, while LE retrograde transport depends on the dynein microtubule (MT) motor only, the one of EEs requires the cooperative antagonism of dynein and kinesin‐14 KIFC1, a MT minus end‐directed motor involved in cancer progression. Mechanistically, the Ser‐x‐Ile‐Pro (SxIP) motif‐mediated interaction of the endoplasmic reticulum transmembrane protein stromal interaction molecule 1 (STIM1) with the MT plus end‐binding protein 1 (EB1) promotes its association with the p150Glued subunit of the dynein activator complex dynactin and the distinct location of EEs and LEs/LYs. The peripheral distribution of EEs requires their p150Glued‐mediated simultaneous engagement with dynein and SxIP motif‐containing KIFC1, via HOOK1 and HOOK3 adaptors, respectively. In sum, we provide evidence that distinct minus end‐directed MT motor systems drive the differential transport and subcellular distribution of EEs and LEs in mammalian cells.
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Affiliation(s)
- Giulia Villari
- Department of Oncology, University of Torino School of Medicine, Candiolo, Italy.,Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Torino, Italy
| | - Chiara Enrico Bena
- Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Torino, Italy.,IIGM - Italian Institute for Genomic Medicine, Candiolo, Italy
| | - Marco Del Giudice
- Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Torino, Italy.,IIGM - Italian Institute for Genomic Medicine, Candiolo, Italy
| | - Noemi Gioelli
- Department of Oncology, University of Torino School of Medicine, Candiolo, Italy.,Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Torino, Italy
| | - Chiara Sandri
- Department of Oncology, University of Torino School of Medicine, Candiolo, Italy.,Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Torino, Italy
| | - Chiara Camillo
- Department of Oncology, University of Torino School of Medicine, Candiolo, Italy.,Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Torino, Italy
| | - Alessandra Fiorio Pla
- Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy
| | - Carla Bosia
- IIGM - Italian Institute for Genomic Medicine, Candiolo, Italy.,Department of Applied Science and Technology, Polytechnic of Torino, Torino, Italy
| | - Guido Serini
- Department of Oncology, University of Torino School of Medicine, Candiolo, Italy.,Candiolo Cancer Institute - Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Torino, Italy
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Chen J, Hendriks M, Chatzis A, Ramasamy SK, Kusumbe AP. Bone Vasculature and Bone Marrow Vascular Niches in Health and Disease. J Bone Miner Res 2020; 35:2103-2120. [PMID: 32845550 DOI: 10.1002/jbmr.4171] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/21/2020] [Accepted: 08/05/2020] [Indexed: 12/20/2022]
Abstract
Bone vasculature and bone marrow vascular niches supply oxygen, nutrients, and secrete angiocrine factors required for the survival, maintenance, and self-renewal of stem and progenitor cells. In the skeletal system, vasculature creates nurturing niches for bone and blood-forming stem cells. Blood vessels regulate hematopoiesis and drive bone formation during development, repair, and regeneration. Dysfunctional vascular niches induce skeletal aging, bone diseases, and hematological disorders. Recent cellular and molecular characterization of the bone marrow microenvironment has provided unprecedented insights into the complexity, heterogeneity, and functions of the bone vasculature and vascular niches. The bone vasculature is composed of distinct vessel subtypes that differentially regulate osteogenesis, hematopoiesis, and disease conditions in bones. Further, bone marrow vascular niches supporting stem cells are often complex microenvironments involving multiple different cell populations and vessel subtypes. This review provides an overview of the emerging vascular cell heterogeneity in bone and the new roles of the bone vasculature and associated vascular niches in health and disease. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Junyu Chen
- Tissue and Tumor Microenvironments Group, The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Michelle Hendriks
- Institute of Clinical Sciences, Imperial College London, London, UK
- MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Alexandros Chatzis
- Tissue and Tumor Microenvironments Group, The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Saravana K Ramasamy
- Institute of Clinical Sciences, Imperial College London, London, UK
- MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Anjali P Kusumbe
- Tissue and Tumor Microenvironments Group, The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
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Hypoxia-induced downregulation of Sema3a and CXCL12/CXCR4 regulate the formation of the coronary artery stem at the proper site. J Mol Cell Cardiol 2020; 147:62-73. [PMID: 32777295 DOI: 10.1016/j.yjmcc.2020.08.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 07/18/2020] [Accepted: 08/03/2020] [Indexed: 11/23/2022]
Abstract
BACKGROUND During the formation of the coronary artery stem, endothelial strands from the endothelial progenitor pool surrounding the conotruncus penetrate into the aortic wall. Vascular endothelial growth factors (VEGFs) as well as CXCL12/CXCR4 signaling are thought to play a role in the formation of the coronary stem. However, the mechanisms regulating how endothelial strands exclusively invade into the aorta remain unknown. METHODS AND RESULTS Immunohistochemistry showed that before the formation of endothelial strands, Sema3a was highly expressed in endothelial progenitors surrounding the great arteries. At the onset of/during invasion of endothelial strands into the aorta, Sema3a was downregulated and CXCR4 was upregulated in the endothelial strands. In situ hybridization showed that Cxcl12 was highly expressed in the aortic wall compared with in the pulmonary artery. Using avian embryonic hearts, we established two types of endothelial penetration assay, in which coronary endothelial strands preferentially invaded into the aorta in culture. Sema3a blocking peptide induced an excess number of endothelial strands penetrating into the pulmonary artery, whereas recombinant Sema3a inhibited the formation of endothelial strands. In cultured coronary endothelial progenitors, recombinant VEGF protein induced CXCR4-positive endothelial strands, which were capable of being attracted by CXCL12-impregnated beads. Monoazo rhodamine detected that hypoxia was predominant in aortic/subaortic region in ovo and hypoxic condition downregulated the expression of Sema3a in culture. CONCLUSION Results suggested that hypoxia in the aortic region downregulates the expression of Sema3a, thereby enhancing VEGF activity to induce the formation of CXCR4-positive endothelial strands, which are subsequently attracted into the Cxcl12-positive aortic wall to connect the aortic lumen.
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The Role of Semaphorins in Metabolic Disorders. Int J Mol Sci 2020; 21:ijms21165641. [PMID: 32781674 PMCID: PMC7460634 DOI: 10.3390/ijms21165641] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 07/20/2020] [Accepted: 07/28/2020] [Indexed: 12/15/2022] Open
Abstract
Semaphorins are a family originally identified as axonal guidance molecules. They are also involved in tumor growth, angiogenesis, immune regulation, as well as other biological and pathological processes. Recent studies have shown that semaphorins play a role in metabolic diseases including obesity, adipose inflammation, and diabetic complications, including diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic wound healing, and diabetic osteoporosis. Evidence provides mechanistic insights regarding the role of semaphorins in metabolic diseases by regulating adipogenesis, hypothalamic melanocortin circuit, immune responses, and angiogenesis. In this review, we summarize recent progress regarding the role of semaphorins in obesity, adipose inflammation, and diabetic complications.
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45
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Hosein AN, Brekken RA, Maitra A. Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat Rev Gastroenterol Hepatol 2020; 17:487-505. [PMID: 32393771 PMCID: PMC8284850 DOI: 10.1038/s41575-020-0300-1] [Citation(s) in RCA: 585] [Impact Index Per Article: 117.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/24/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the Western world with limited therapeutic options and dismal long-term survival. The neoplastic epithelium exists within a dense stroma, which is recognized as a critical mediator of disease progression through direct effects on cancer cells and indirect effects on the tumour immune microenvironment. The three dominant entities in the PDAC stroma are extracellular matrix (ECM), vasculature and cancer-associated fibroblasts (CAFs). The ECM can function as a barrier to effective drug delivery to PDAC cancer cells, and a multitude of strategies to target the ECM have been attempted in the past decade. The tumour vasculature is a complex system and, although multiple anti-angiogenesis agents have already failed late-stage clinical trials in PDAC, other vasculature-targeting approaches aimed at vessel normalization and tumour immunosensitization have shown promise in preclinical models. Lastly, PDAC CAFs participate in active cross-talk with cancer cells within the tumour microenvironment. The existence of intratumoural CAF heterogeneity represents a paradigm shift in PDAC CAF biology, with myofibroblastic and inflammatory CAF subtypes that likely make distinct contributions to PDAC progression. In this Review, we discuss our current understanding of the three principal constituents of PDAC stroma, their effect on the prevalent immune landscape and promising therapeutic targets within this compartment.
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Affiliation(s)
- Abdel N Hosein
- Department of Internal Medicine, Division of Hematology & Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rolf A Brekken
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Hamon Center for Therapeutic Oncology Research and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Anirban Maitra
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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The role of semaphorins in small vessels of the eye and brain. Pharmacol Res 2020; 160:105044. [PMID: 32590102 DOI: 10.1016/j.phrs.2020.105044] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 06/19/2020] [Accepted: 06/19/2020] [Indexed: 12/20/2022]
Abstract
Small vessel diseases, such as ischemic retinopathy and cerebral small vessel disease (CSVD), are increasingly recognized in patients with diabetes, dementia and cerebrovascular disease. The mechanisms of small vessel diseases are poorly understood, but the latest studies suggest a role for semaphorins. Initially identified as axon guidance cues, semaphorins are mainly studied in neuronal morphogenesis, neural circuit assembly, and synapse assembly and refinement. In recent years, semaphorins have been found to play important roles in regulating vascular growth and development and in many pathophysiological processes, including atherosclerosis, angiogenesis after stroke and retinopathy. Growing evidence indicates that semaphorins affect the occurrence, perfusion and regression of both the macrovasculature and microvasculature by regulating the proliferation, apoptosis, migration, barrier function and inflammatory response of endothelial cells, vascular smooth muscle cells (VSMCs) and pericytes. In this review, we concentrate on the regulatory effects of semaphorins on the cell components of the vessel wall and their potential roles in microvascular diseases, especially in the retina and cerebral small vessel. Finally, we discuss potential molecular approaches in targeting semaphorins as therapies for microvascular disorders in the eye and brain.
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47
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Immune semaphorins: Crucial regulatory signals and novel therapeutic targets in asthma and allergic diseases. Eur J Pharmacol 2020; 881:173209. [PMID: 32454117 DOI: 10.1016/j.ejphar.2020.173209] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 05/14/2020] [Accepted: 05/18/2020] [Indexed: 11/20/2022]
Abstract
Asthma and allergic diseases are a group of chronic inflammatory disorders that arise as a result of excessive responses of the immune system against intrinsically harmless environmental substances. It is well known that substantial joint characteristics exist between the immune and nervous systems. The semaphorins (Semas) were initially characterized as axon-guidance molecules that play a crucial role during the development of the nervous system. However, increasing evidence indicates that a subset of Semas, termed "immune Semas", acting through their cognate receptors, namely, plexins (Plxns), and neuropilins (Nrps), also contributes to both physiological and pathological responses of the immune system. Notably, immune Semas exert critical roles in regulating a broad spectrum of biological processes, including immune cell-cell interactions, activation, differentiation, cell migration and mobility, angiogenesis, tumor progression, as well as inflammatory responses. Accumulating evidence indicates that the modification in the signaling of immune Semas could lead to various immune-mediated inflammatory diseases, ranging from cancer to autoimmunity and allergies. This review summarizes the recent evidence regarding the role of immune Semas in the pathogenesis of asthma and allergic diseases and discusses their therapeutic potential for treating these diseases.
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48
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Emerson SE, Stergas HR, Bupp-Chickering SO, Ebert AM. Shootin-1 is required for nervous system development in zebrafish. Dev Dyn 2020; 249:1285-1295. [PMID: 32406957 DOI: 10.1002/dvdy.194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 04/09/2020] [Accepted: 05/05/2020] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Semaphorin6A (Sema6A) and its PlexinA2 (PlxnA2) receptor canonically function as repulsive axon guidance cues. To understand downstream signaling mechanisms, we performed a microarray screen and identified the "clutch molecule" shootin-1 (shtn-1) as a transcriptionally repressed target. Shtn-1 is a key proponent of cell migration and neuronal polarization and must be regulated during nervous system development. The mechanisms of Shtn-1 regulation and the phenotypic consequences of loss of repression are poorly understood. RESULTS We demonstrate shtn-1 overexpression results in impaired migration of the optic vesicles, lack of retinal pigmented epithelium, and pathfinding errors of retinotectal projections. We also observed patterning defects in the peripheral nervous system. Importantly, these phenotypes were rescued by overexpressing PlxnA2. CONCLUSIONS We demonstrate a functional role for repression of shtn-1 by PlxnA2 in development of the eyes and peripheral nervous system in zebrafish. These results demonstrate that careful regulation of shtn-1 is critical for development of the nervous system.
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Affiliation(s)
- Sarah E Emerson
- Department of Biology, University of Vermont, Burlington, Vermont, USA
| | - Helaina R Stergas
- Department of Biology, University of Vermont, Burlington, Vermont, USA
| | | | - Alicia M Ebert
- Department of Biology, University of Vermont, Burlington, Vermont, USA
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49
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Conformationally active integrin endocytosis and traffic: why, where, when and how? Biochem Soc Trans 2020; 48:83-93. [PMID: 32065228 PMCID: PMC7054750 DOI: 10.1042/bst20190309] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 01/16/2020] [Accepted: 01/28/2020] [Indexed: 12/30/2022]
Abstract
Spatiotemporal control of integrin-mediated cell adhesion to the extracellular matrix (ECM) is critical for physiological and pathological events in multicellular organisms, such as embryonic development, angiogenesis, platelet aggregation, leukocytes extravasation, and cancer cell metastatic dissemination. Regulation of integrin adhesive function and signaling relies on the modulation of both conformation and traffic. Indeed, integrins exist in a dynamic equilibrium between a bent/closed (inactive) and an extended/open (active) conformation, respectively endowed with low and high affinity for ECM ligands. Increasing evidence proves that, differently to what hypothesized in the past, detachment from the ECM and conformational inactivation are not mandatory for integrin to get endocytosed and trafficked. Specific transmembrane and cytosolic proteins involved in the control of ECM proteolytic fragment-bound active integrin internalization and recycling exist. In the complex masterplan that governs cell behavior, active integrin traffic is key to the turnover of ECM polymers and adhesion sites, the polarized secretion of endogenous ECM proteins and modifying enzymes, the propagation of motility and survival endosomal signals, and the control of cell metabolism.
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50
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Dai W, Li JD, Zhao Y, Wu J, Jiang F, Chen DN, Zheng R, Men M. Functional analysis of SEMA3A variants identified in Chinese patients with isolated hypogonadotropic hypogonadism. Clin Genet 2020; 97:696-703. [PMID: 32060892 DOI: 10.1111/cge.13723] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/04/2020] [Accepted: 02/11/2020] [Indexed: 11/28/2022]
Abstract
Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder characterized by impaired sexual development and infertility, caused by the deficiency of hypothalamic gonadotropin-releasing hormone neurons. IHH is named Kallmann's syndrome (KS) or normosmic IHH (nIHH) when associated with a defective or normal sense of smell. Variants in SEMA3A have been recently identified in patients with KS. In this study, we screened SEMA3A variants in a cohort of Chinese patients with IHH by whole exome sequencing. Three novel heterozygous SEMA3A variants (R197Q, R617Q and V458I) were identified in two nIHH and one KS patients, respectively. Functional studies indicated that R197Q and R617Q variants were ineffective in activating the phosphorylation of FAK (focal adhesion kinase) in GN11 cells, despite normal production and secretion in HEK293T cells. The V458I SEMA3A had defect in secretion as it was not detected in the conditioned medium from HEK293T cells. Compared with wild type SEMA3A protein, all three SEMA3A mutant proteins were ineffective in inducing the migration of GN11 cells. Our study further showed the contribution of SEMA3A loss-of-function variants to the pathogenesis of IHH.
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Affiliation(s)
- Wenting Dai
- School of Life Sciences, Central South University, Changsha, China.,Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China.,Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, China
| | - Jia-Da Li
- School of Life Sciences, Central South University, Changsha, China.,Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China.,Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, China
| | - Yaguang Zhao
- School of Life Sciences, Central South University, Changsha, China.,Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China.,Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, China
| | - Jiayu Wu
- School of Life Sciences, Central South University, Changsha, China.,Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China.,Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, China
| | - Fang Jiang
- School of Life Sciences, Central South University, Changsha, China.,Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China.,Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, China
| | - Dan-Na Chen
- Department of Basic Medical Sciences, Changsha Medical University, Changsha, China
| | - Ruizhi Zheng
- Department of Endocrinology, the People's Hospital of Henan Province, Zhengzhou, China
| | - Meichao Men
- Health Management Center of Xiangya Hospital, Central South University, Changsha, China
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