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Cai Z, Meng K, Yu T, Xi Y, Yuan Z, Wang X, Wang C, Li L, Fu X. IFN-γ-mediated suppression of ANGPT2-Tie2 in endothelial cells facilitates tumor vascular normalization during immunotherapy. Front Immunol 2025; 16:1551322. [PMID: 40370455 PMCID: PMC12075545 DOI: 10.3389/fimmu.2025.1551322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 04/08/2025] [Indexed: 05/16/2025] Open
Abstract
Introduction Tumor angiogenesis is a critical biological hallmark of cancer, which involves multiple molecularly regulated signaling pathways, including the angiopoietin (ANGPT)-Tie2 and the vascular endothelial growth factor (VEGF) signaling pathways. Despite initial optimism, targeting tumor angiogenesis in the treatment of lung adenocarcinoma (LUAD) has been unsatisfactory. Currently, monotherapy with PD-1/PD-L1 inhibitors, or their combination with bevacizumab, is considered the standard therapeutic approach for LUAD. Recent studies have shown that immunotherapy suppresses tumor angiogenesis and facilitates vascular normalization. However, whether and how anti-PD-L1 therapy influences tumor vasculature remains unclear. Methods To investigate the impact of immunotherapy on the vasculature of LUAD, a mouse model of lung adenocarcinoma was established by subcutaneous implantation of Lewis lung carcinoma cells in vivo. The effects of different treatments on microvessel density and pericyte coverage were explored, and the expression of angiogenesis-related factors was analyzed. Furthermore, to explore the molecular mechanisms through which IFN-γ regulates tumor blood vessels during immunotherapy, we elucidated the specific mechanisms in vitro by means of techniques such as siRNA, ChIP, RT-qPCR, Western blot, and immunofluorescence. Finally, the effects of IFN-γ on the proliferation, migration, and angiogenic function of endothelial cells (ECs) were evaluated through CCK-8, Transwell, and HUVEC tube formation assays. Results Employing a mouse model of LUAD, we demonstrated that PD-L1 blockade therapy inhibits tumor angiogenesis and normalizes vasculature in an IFN-γ-signaling-dependent manner. Notably, anti-PD-L1 therapy reduced Tie2 and ANGPT2 expression, and these effects were reversed by the JAK1/2 inhibitor. Mechanistically, we demonstrated that IFN-γ inhibited Tie2 and ANGPT2 expression in ECs, and suppressed ANGPT2 gene transcription through the AKT-FOXO1 signaling pathway. Interestingly, IFN-γ-mediated activation of STAT1 exerts negative regulation by directly binding to the promoter regions of the ANGPT2 and TEK genes. Functionally, IFN-γ limits the migration, proliferation, and tube formation of ECs. Discussion In conclusion, our results revealed a novel mechanism wherein IFN-γ-mediated inhibition of ANGPT2-Tie2 facilitates vascular normalization during immunotherapy in LUAD, which performs an essential function in the antitumor efficacy of immunotherapy.
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Affiliation(s)
| | | | | | | | | | | | | | - Lequn Li
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, China
| | - Xiangning Fu
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, China
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Thiruvalluvan M, Billet S, Liu Z, Lownik J, Waissengrin B, Kim H, Villamejor AL, Milshteyn L, Li X, Gayhart M, Araña M, Sankar K, Posadas EM, Lopategui J, You S, Reckamp KL, Bhowmick NA. CD105 blockade restores osimertinib sensitivity in drug-resistant EGFR-mutant non-small cell lung cancer. Drug Resist Updat 2025; 81:101237. [PMID: 40090182 DOI: 10.1016/j.drup.2025.101237] [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: 11/06/2024] [Revised: 02/27/2025] [Accepted: 03/08/2025] [Indexed: 03/18/2025]
Abstract
AIM To investigate the role of CD105 in mediating drug resistance to EGFR-targeted therapy in non-small cell lung cancer (NSCLC). METHODS Imaging mass cytometry was conducted on 66 NSCLC tumors, 44 of which had EGFR mutations. We correlated clinical variables, including overall survival, with CD105 (endoglin) expression, a co-receptor for bone morphogenetic protein (BMP) signaling. Two osimertinib-resistant EGFR-mutant cell lines were developed to study the effects of EGFR and CD105 disruption. Single cell RNA sequencing of the isogenic parental and osimertinib resistant lines was performed. Additionally, ATAC sequencing and Single Cell ENergetIc metabolism by profiling Translation inHibition analysis (SCENITH) was used to assess promoter chromatin status and glycolytic state. RESULTS We found a negative correlation between CD105 expression and overall survival in patients. Treatment with osimertinib or EGFR knockdown significantly elevated CD105 expression in EGFR-mutant cell lines. Single-cell RNA sequencing identified a subset of cells with heightened endothelial characteristics and altered pyrimidine metabolism, associated with osimertinib resistance. These cells exhibited a slow-cycling behavior, characterized by elevated chromatin condensation and reduced glycolysis. Combining osimertinib with carotuximab, a CD105 neutralizing antibody, significantly reduced the slow-cycling transcriptomic signature, increased chromatin accessibility, and restored glycolysis compared to osimertinib treatment alone. Mass spectrometry confirmed that carotuximab re-engaged EGFR signaling by coupling it with CD105. Consequently, carotuximab re-sensitized resistant tumors to osimertinib by increasing their mitotic index and ERK signaling in mouse models. CONCLUSION Carotuximab effectively reduced the slow-cycling cell population and restored osimertinib sensitivity, offering a promising strategy for managing refractory NSCLC.
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Affiliation(s)
- Manish Thiruvalluvan
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Cedars-Sinai Cancer Center, Los Angeles, CA, USA
| | - Sandrine Billet
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Cedars-Sinai Cancer Center, Los Angeles, CA, USA
| | - Zhenqiu Liu
- Department of Statistics, Radiation Effects Research Foundation, Hiroshima, Japan
| | - Joseph Lownik
- Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Barliz Waissengrin
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Cedars-Sinai Cancer Center, Los Angeles, CA, USA
| | - Hyoyoung Kim
- Cedars-Sinai Cancer Center, Los Angeles, CA, USA; Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Anton L Villamejor
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | - Xiamo Li
- Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Matthew Gayhart
- Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Manuel Araña
- Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Kamya Sankar
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Cedars-Sinai Cancer Center, Los Angeles, CA, USA
| | - Edwin M Posadas
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Cedars-Sinai Cancer Center, Los Angeles, CA, USA
| | - Jean Lopategui
- Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Sungyong You
- Cedars-Sinai Cancer Center, Los Angeles, CA, USA; Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Karen L Reckamp
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Cedars-Sinai Cancer Center, Los Angeles, CA, USA
| | - Neil A Bhowmick
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Cedars-Sinai Cancer Center, Los Angeles, CA, USA.
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Oliveira FD, Cavaco M, Figueira TN, Napoleão P, Valle J, Neves V, Andreu D, Castanho MA. vCPP2319 interacts with metastatic breast cancer extracellular vesicles (EVs) and transposes a human blood-brain barrier model. Heliyon 2024; 10:e40907. [PMID: 39717586 PMCID: PMC11664409 DOI: 10.1016/j.heliyon.2024.e40907] [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: 04/06/2024] [Revised: 12/02/2024] [Accepted: 12/03/2024] [Indexed: 12/25/2024] Open
Abstract
Brain metastases (BM) are frequently found in cancer patients and, though their precise incidence is difficult to estimate, there is evidence for a correlation between BM and specific primary cancers, such as lung, breast, and skin (melanoma). Among all these, breast cancer is the most frequently diagnosed among women and, in this case, BM cause a critical reduction of the overall survival (OS), especially in triple negative breast cancer (TNBC) patients. The main challenge of BM treatment is the impermeable nature of the blood-brain barrier (BBB), which shields the central nervous systems (CNS) from chemotherapeutic drugs. Extracellular vesicles (EVs) have been proposed as ideal natural drug carriers and these may exhibit some advantages over synthetic nanoparticles (NPs). In this work, we isolate breast cancer-derived EVs and study their ability to carry vCPP2319, a peptide with dual cell-penetration and anticancer activities. The selective cytotoxicity of anticancer peptide-loaded EVs towards breast cancer cells and their ability to translocate an in vitro BBB model are also addressed. Overall, it was possible to conclude that vCPP2319 naturally interacts with breast cancer-derived EVs, being retained at the surface of these vesicles. Moreover, the results revealed a cytotoxic activity for peptide-loaded EVs similar to that obtained with the peptide alone and the ability of peptide-loaded EVs to translocate an in vitro BBB model, which contrasts with the results obtained with the peptide alone. In conclusion, this work supports the use of EVs in the development of biological drug-delivery systems (DDS) capable of translocating the BBB.
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Affiliation(s)
- Filipa D. Oliveira
- Gulbenkian Institute for Molecular Medicine, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisbon, 1649-028, Portugal
| | - Marco Cavaco
- Gulbenkian Institute for Molecular Medicine, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisbon, 1649-028, Portugal
| | - Tiago N. Figueira
- Gulbenkian Institute for Molecular Medicine, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisbon, 1649-028, Portugal
| | - Patrícia Napoleão
- Gulbenkian Institute for Molecular Medicine, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisbon, 1649-028, Portugal
| | - Javier Valle
- Department of Medicine and Life Sciences, Pompeu Fabra University, Barcelona Biomedical Research Park, 08003, Barcelona, Spain
| | - Vera Neves
- Gulbenkian Institute for Molecular Medicine, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisbon, 1649-028, Portugal
| | - David Andreu
- Department of Medicine and Life Sciences, Pompeu Fabra University, Barcelona Biomedical Research Park, 08003, Barcelona, Spain
| | - Miguel A.R.B. Castanho
- Gulbenkian Institute for Molecular Medicine, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisbon, 1649-028, Portugal
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Shetty S, Pereira T, Tamgadge S, Kale S, Kamat P, Kumar S. ENDOGLIN (CD105): A marker of tumour vasculature for assessment of malignant potential of oral submucous fibrosis. J Oral Maxillofac Pathol 2024; 28:589-595. [PMID: 39949694 PMCID: PMC11819617 DOI: 10.4103/jomfp.jomfp_67_24] [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: 03/06/2024] [Revised: 11/09/2024] [Accepted: 11/11/2024] [Indexed: 02/16/2025] Open
Abstract
Background Oral submucous fibrosis (OSMF) is a precancerous condition associated with the use of betel/areca nut in various forms. It is characterized by restricted mouth opening, tongue protrusion and cheek rigidity. Oral submucous fibrosis, is primarily prevalent among the people of the Indian subcontinent and it has been reported that about one third of the OSMF patients develop squamous cell carcinoma.Endoglin (CD-105) is a hypoxia induced protein and a potential marker for activated endothelial cells which signify tumorigenic neoangiogenesis. Aim To determine expression of CD105 and study relation of neoangiogenesis with the clinical staging and histopathological grading of oral submucous fibrosis. Material and Method Immunohistochemical expression of CD105 was evaluated on forty nine (49) paraffin-embedded tissue sections of diagnosed cases of OSF and seven (7) control samples of healthy volunteers. Results There were 13 cases in Stage A, 11 cases in Stage B, 13 cases in Stage C, and 12 cases in Stage D. There were 4 cases in Grade 1 (Very early), 19 cases in Grade 2 (Early), 19 cases in Grade 3 (Moderately advance) and 7 cases in Grade 4 (Advance). Conclusion The present study was first immunohistochemical study to demonstrate MVD, MVP and MVAP with CD105 expression in OSMF cases. However, well-designed studies with larger sample size is required to validate CD105 as a reliable biomarker for malignant transformation in future research.
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Affiliation(s)
- Subraj Shetty
- Department of Oral and Maxillofacial Pathology and Microbiology, D. Y. PATIL University, School of Dentistry, Navi Mumbai, Maharashtra, India
| | - Treville Pereira
- Department of Oral and Maxillofacial Pathology and Microbiology, D. Y. PATIL University, School of Dentistry, Navi Mumbai, Maharashtra, India
| | - Sandhya Tamgadge
- Department of Oral and Maxillofacial Pathology and Microbiology, D. Y. PATIL University, School of Dentistry, Navi Mumbai, Maharashtra, India
| | - Sandeep Kale
- Department of Oral and Maxillofacial Pathology and Microbiology, D. Y. PATIL University, School of Dentistry, Navi Mumbai, Maharashtra, India
| | - Pooja Kamat
- Department of Oral and Maxillofacial Pathology and Microbiology, D. Y. PATIL University, School of Dentistry, Navi Mumbai, Maharashtra, India
| | - Sourab Kumar
- Department of Oral and Maxillofacial Pathology and Microbiology, D. Y. PATIL University, School of Dentistry, Navi Mumbai, Maharashtra, India
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Poddar MS, Chu YD, Yeh CT, Liu CH. Deciphering hepatoma cell resistance to tyrosine kinase inhibitors: insights from a Liver-on-a-Chip model unveiling tumor endothelial cell mechanisms. LAB ON A CHIP 2024; 24:3668-3678. [PMID: 38938178 DOI: 10.1039/d4lc00238e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/29/2024]
Abstract
Liver cancer represents a significant global burden in terms of cancer-related mortality, with resistance to anti-angiogenic drugs such as Sorafenib and Lenvatinib presenting a formidable challenge. Tumor angiogenesis, characterized by the formation of new blood vessels within tumors, plays a pivotal role in cancer progression and metastasis. Tumor endothelial cells, specialized endothelial cells lining tumor blood vessels, exhibit unique phenotypic and functional traits that drive aberrant vessel formation and contribute to therapy resistance. CD105, a cell-surface glycoprotein that is highly expressed on endothelial cells during angiogenesis, including tumor endothelial cells, regulates endothelial cell proliferation, migration, and vessel formation by modulating transforming growth factor-beta (TGF-β) signaling pathways. Elevated CD105 expression on tumor endothelial cells correlates with increased angiogenic activity and poor prognosis in cancer patients. Targeting CD105 with antibodies presents a promising strategy to inhibit tumor angiogenesis and disrupt tumor vasculature, offering potential therapeutic benefits by interfering with the tumor microenvironment and inhibiting its progression. This study investigates tumor angiogenesis through a three-dimensional (3D) microfluidic co-culture system incorporating endothelial cells and hepatocellular carcinoma (HCC) cells. The primary focus is on the role of CD105 expression within the liver tumor microenvironment and its contribution to increased chemoresistance. Additionally, this research examines the influence of CD105 expression on the efficacy of tyrosine kinase inhibitors (TKIs) and its pivotal function in facilitating angiogenesis in liver tumors. The proposed microfluidic chip model investigates liver cancer cell interactions within a microfluidic chip model designed to simulate aspects of liver tumor angiogenesis.
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Affiliation(s)
- Madhu Shree Poddar
- Institute of Nanoengineering and Microsystems, National Tsing Hua University, Hsinchu, 30044, Taiwan, Republic of China.
| | - Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, Republic of China
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 333, Taiwan, Republic of China
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, Republic of China
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, Republic of China
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 333, Taiwan, Republic of China
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan, Republic of China
| | - Cheng-Hsien Liu
- Institute of Nanoengineering and Microsystems, National Tsing Hua University, Hsinchu, 30044, Taiwan, Republic of China.
- Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu 30044, Taiwan, Republic of China
- College of Semiconductor Research, National Tsing Hua University, Hsinchu 30044, Taiwan, Republic of China
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Sandau US, Magaña SM, Costa J, Nolan JP, Ikezu T, Vella LJ, Jackson HK, Moreira LR, Palacio PL, Hill AF, Quinn JF, Van Keuren‐Jensen KR, McFarland TJ, Palade J, Sribnick EA, Su H, Vekrellis K, Coyle B, Yang Y, Falcón‐Perez JM, Nieuwland R, Saugstad JA. Recommendations for reproducibility of cerebrospinal fluid extracellular vesicle studies. J Extracell Vesicles 2024; 13:e12397. [PMID: 38158550 PMCID: PMC10756860 DOI: 10.1002/jev2.12397] [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: 06/30/2023] [Revised: 11/09/2023] [Accepted: 11/21/2023] [Indexed: 01/03/2024] Open
Abstract
Cerebrospinal fluid (CSF) is a clear, transparent fluid derived from blood plasma that protects the brain and spinal cord against mechanical shock, provides buoyancy, clears metabolic waste and transports extracellular components to remote sites in the brain. Given its contact with the brain and the spinal cord, CSF is the most informative biofluid for studies of the central nervous system (CNS). In addition to other components, CSF contains extracellular vesicles (EVs) that carry bioactive cargoes (e.g., lipids, nucleic acids, proteins), and that can have biological functions within and beyond the CNS. Thus, CSF EVs likely serve as both mediators of and contributors to communication in the CNS. Accordingly, their potential as biomarkers for CNS diseases has stimulated much excitement for and attention to CSF EV research. However, studies on CSF EVs present unique challenges relative to EV studies in other biofluids, including the invasive nature of CSF collection, limited CSF volumes and the low numbers of EVs in CSF as compared to plasma. Here, the objectives of the International Society for Extracellular Vesicles CSF Task Force are to promote the reproducibility of CSF EV studies by providing current reporting and best practices, and recommendations and reporting guidelines, for CSF EV studies. To accomplish this, we created and distributed a world-wide survey to ISEV members to assess methods considered 'best practices' for CSF EVs, then performed a detailed literature review for CSF EV publications that was used to curate methods and resources. Based on responses to the survey and curated information from publications, the CSF Task Force herein provides recommendations and reporting guidelines to promote the reproducibility of CSF EV studies in seven domains: (i) CSF Collection, Processing, and Storage; (ii) CSF EV Separation/Concentration; (iii) CSF EV Size and Number Measurements; (iv) CSF EV Protein Studies; (v) CSF EV RNA Studies; (vi) CSF EV Omics Studies and (vii) CSF EV Functional Studies.
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Affiliation(s)
- Ursula S. Sandau
- Department of Anesthesiology & Perioperative MedicineOregon Health & Science UniversityPortlandOregonUSA
| | - Setty M. Magaña
- Center for Clinical and Translational Research, Abigail Wexner Research InstituteNationwide Children's HospitalColumbusOhioUSA
| | - Júlia Costa
- Instituto de Tecnologia Química e Biológica António XavierUniversidade Nova de Lisboa, Avenida da RepúblicaOeirasPortugal
| | - John P. Nolan
- Scintillon Institute for Biomedical and Bioenergy ResearchSan DiegoCaliforniaUSA
| | - Tsuneya Ikezu
- Department of NeuroscienceMayo Clinic FloridaJacksonvilleFloridaUSA
| | - Laura J. Vella
- Department of Surgery, The Royal Melbourne HospitalThe University of MelbourneParkvilleVictoriaAustralia
- The Florey Institute of Neuroscience and Mental HealthUniversity of MelbourneParkville, MelbourneVictoriaAustralia
| | - Hannah K. Jackson
- Department of PathologyUniversity of CambridgeCambridgeUK
- Exosis, Inc.Palm BeachFloridaUSA
| | - Lissette Retana Moreira
- Department of Parasitology, Faculty of MicrobiologyUniversity of Costa RicaSan JoséCosta Rica, Central America
- Centro de Investigación en Enfermedades TropicalesUniversity of Costa RicaSan JoséCosta Rica, Central America
| | - Paola Loreto Palacio
- Center for Clinical and Translational Research, Abigail Wexner Research InstituteNationwide Children's HospitalColumbusOhioUSA
| | - Andrew F. Hill
- Institute for Health and SportVictoria UniversityMelbourneVictoriaAustralia
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular ScienceLa Trobe UniversityBundooraVictoriaAustralia
| | - Joseph F. Quinn
- Department of NeurologyOregon Health & Science UniversityPortlandOregonUSA
- Portland VA Medical CenterPortlandOregonUSA
| | | | - Trevor J. McFarland
- Department of Anesthesiology & Perioperative MedicineOregon Health & Science UniversityPortlandOregonUSA
| | - Joanna Palade
- Neurogenomics DivisionTranslational Genomics Research InstitutePhoenixArizonaUSA
| | - Eric A. Sribnick
- Department of NeurosurgeryNationwide Children's Hospital, The Ohio State UniversityColumbusOhioUSA
| | - Huaqi Su
- The Florey Institute of Neuroscience and Mental HealthUniversity of MelbourneParkville, MelbourneVictoriaAustralia
| | | | - Beth Coyle
- Children's Brain Tumour Research Centre, School of MedicineUniversity of Nottingham Biodiscovery Institute, University of NottinghamNottinghamNottinghamshireUK
| | - You Yang
- Scintillon Institute for Biomedical and Bioenergy ResearchSan DiegoCaliforniaUSA
| | - Juan M. Falcón‐Perez
- Exosomes Laboratory, Center for Cooperative Research in BiosciencesBasque Research and Technology AllianceDerioSpain
- Metabolomics Platform, Center for Cooperative Research in BiosciencesBasque Research and Technology AllianceDerioSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasMadridSpain
- Ikerbasque, Basque Foundation for ScienceBilbaoSpain
| | - Rienk Nieuwland
- Laboratory of Experimental Clinical Chemistry, Amsterdam University Medical Centers, Location AMCUniversity of AmsterdamAmsterdamThe Netherlands
- Amsterdam Vesicle Center, Amsterdam University Medical Centers, Location AMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Julie A. Saugstad
- Department of Anesthesiology & Perioperative MedicineOregon Health & Science UniversityPortlandOregonUSA
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Shah AA, Sheikh AA, Hasin D, Shah F, Aarif O, Shah RA, Ahmad SB, Maqbool S, Pampori ZA. Isolation, in vitro expansion and characterization of ovine fetal adnexa-derived mesenchymal stem cells reveals a source dependent trilineage differentiation and growth kinetics. Anim Biotechnol 2023; 34:3908-3919. [PMID: 37493347 DOI: 10.1080/10495398.2023.2238015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/27/2023]
Abstract
This study was designed to isolate, cultivate, characterize and evaluate the growth kinetics of mesenchymal stem cells (MSCs) derived from fetal adnexa of sheep. The gravid uteri of ewes were collected from a local abattoir. The MSCs isolated from different fetal regions (Wharton's Jelly [oWJ], cord blood [oCB], amniotic fluid [oAF] and amniotic Sac [oAS]) were expanded in vitro and characterized for surface and pluripotency markers. The growth kinetics of MSCs was compared at 3rd and 5th passages. Similarly, the colony-forming efficiency (CFE) assay was performed at 3rd passage. The fetal adnexa-derived ovine MSCs showed the expression of CD73, CD90 and CD105. Similarly, the MSCs also expressed pluripotency markers, OCT4 and SOX2. Besides, cells also differentiated into osteogenic, chondrogenic and adipogenic lineages. The MSCs in culture showed a typical growth curve with initial lag phase, an exponential phase, a plateau phase and a decline phase. The growth rate was highest in oAF-MSCs at P5. The population doubling time (PDT) was highest in oAS-MSCs (87.28 ± 3.24 h), whereas the colony number was highest in oAF-MSCs (53.67 ± 4.06). The study reveals that oAF-MSCs were superior which outperformed other MSCs indicating that oAF-derived MSCs could be utilized for regenerative medicine.
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Affiliation(s)
- Aamir Amin Shah
- Division of Veterinary Physiology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-Kashmir, Shuhama, J & K, India
| | - Aasif Ahmad Sheikh
- Division of Veterinary Physiology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-Kashmir, Shuhama, J & K, India
| | - Dilruba Hasin
- Division of Veterinary Physiology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-Kashmir, Shuhama, J & K, India
| | - Fozia Shah
- Division of Veterinary Physiology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-Kashmir, Shuhama, J & K, India
| | - Ovais Aarif
- Division of Veterinary Physiology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-Kashmir, Shuhama, J & K, India
| | - Riaz Ahmad Shah
- Division of Animal Biotechnology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-Kashmir, Shuhama, J & K, India
| | - Sheikh Bilal Ahmad
- Division of Veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-Kashmir, Shuhama, J & K, India
| | - Showkat Maqbool
- Division of Animal Genetics and Breeding, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-Kashmir, Shuhama, J & K, India
| | - Z A Pampori
- Division of Veterinary Physiology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-Kashmir, Shuhama, J & K, India
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Pohl L, Schiessl IM. Endothelial cell plasticity in kidney fibrosis and disease. Acta Physiol (Oxf) 2023; 239:e14038. [PMID: 37661749 DOI: 10.1111/apha.14038] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/29/2023] [Accepted: 08/11/2023] [Indexed: 09/05/2023]
Abstract
Renal endothelial cells demonstrate an impressive remodeling potential during angiogenic sprouting, vessel repair or while transitioning into mesenchymal cells. These different processes may play important roles in both renal disease progression or regeneration while underlying signaling pathways of different endothelial cell plasticity routes partly overlap. Angiogenesis contributes to wound healing after kidney injury and pharmaceutical modulation of angiogenesis may home a great therapeutic potential. Yet, it is not clear whether any differentiated endothelial cell can proliferate or whether regenerative processes are largely controlled by resident or circulating endothelial progenitor cells. In the glomerular compartment for example, a distinct endothelial progenitor cell population may remodel the glomerular endothelium after injury. Endothelial-to-mesenchymal transition (EndoMT) in the kidney is vastly documented and often associated with endothelial dysfunction, fibrosis, and kidney disease progression. Especially the role of EndoMT in renal fibrosis is controversial. Studies on EndoMT in vivo determined possible conclusions on the pathophysiological role of EndoMT in the kidney, but whether endothelial cells really contribute to kidney fibrosis and if not what other cellular and functional outcomes derive from EndoMT in kidney disease is unclear. Sequencing data, however, suggest no participation of endothelial cells in extracellular matrix deposition. Thus, more in-depth classification of cellular markers and the fate of EndoMT cells in the kidney is needed. In this review, we describe different signaling pathways of endothelial plasticity, outline methodological approaches and evidence for functional and structural implications of angiogenesis and EndoMT in the kidney, and eventually discuss controversial aspects in the literature.
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Affiliation(s)
- Layla Pohl
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
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Yang H, Xun Y, Ke C, Tateishi K, You H. Extranodal lymphoma: pathogenesis, diagnosis and treatment. MOLECULAR BIOMEDICINE 2023; 4:29. [PMID: 37718386 PMCID: PMC10505605 DOI: 10.1186/s43556-023-00141-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 08/18/2023] [Indexed: 09/19/2023] Open
Abstract
Approximately 30% of lymphomas occur outside the lymph nodes, spleen, or bone marrow, and the incidence of extranodal lymphoma has been rising in the past decade. While traditional chemotherapy and radiation therapy can improve survival outcomes for certain patients, the prognosis for extranodal lymphoma patients remains unsatisfactory. Extranodal lymphomas in different anatomical sites often have distinct cellular origins, pathogenic mechanisms, and clinical manifestations, significantly influencing their diagnosis and treatment. Therefore, it is necessary to provide a comprehensive summary of the pathogenesis, diagnosis, and treatment progress of extranodal lymphoma overall and specifically for different anatomical sites. This review summarizes the current progress in the common key signaling pathways in the development of extranodal lymphomas and intervention therapy. Furthermore, it provides insights into the pathogenesis, diagnosis, and treatment strategies of common extranodal lymphomas, including gastric mucosa-associated lymphoid tissue (MALT) lymphoma, mycosis fungoides (MF), natural killer/T-cell lymphoma (nasal type, NKTCL-NT), and primary central nervous system lymphoma (PCNSL). Additionally, as PCNSL is one of the extranodal lymphomas with the worst prognosis, this review specifically summarizes prognostic indicators and discusses the challenges and opportunities related to its clinical applications. The aim of this review is to assist clinical physicians and researchers in understanding the current status of extranodal lymphomas, enabling them to make informed clinical decisions that contribute to improving patient prognosis.
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Affiliation(s)
- Hua Yang
- Department of Basic Medicine and Biomedical Engineering, School of Medicine, Foshan University, Foshan, 528000, China
| | - Yang Xun
- Department of Basic Medicine and Biomedical Engineering, School of Medicine, Foshan University, Foshan, 528000, China
| | - Chao Ke
- Department of Neurosurgery and Neuro-Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Kensuke Tateishi
- Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, 2360004, Japan
| | - Hua You
- Laboratory for Excellence in Systems Biomedicine of Pediatric Oncology, Department of Pediatric Hematology and Oncology, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 401122, China.
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10
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Couto PS, Stibbs DJ, Rotondi MC, Takeuchi Y, Rafiq QA. Scalable manufacturing of gene-modified human mesenchymal stromal cells with microcarriers in spinner flasks. Appl Microbiol Biotechnol 2023; 107:5669-5685. [PMID: 37470820 PMCID: PMC10439856 DOI: 10.1007/s00253-023-12634-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 06/06/2023] [Accepted: 06/11/2023] [Indexed: 07/21/2023]
Abstract
Due to their immunomodulatory properties and in vitro differentiation ability, human mesenchymal stromal cells (hMSCs) have been investigated in more than 1000 clinical trials over the last decade. Multiple studies that have explored the development of gene-modified hMSC-based products are now reaching early stages of clinical trial programmes. From an engineering perspective, the challenge lies in developing manufacturing methods capable of producing sufficient doses of ex vivo gene-modified hMSCs for clinical applications. This work demonstrates, for the first time, a scalable manufacturing process using a microcarrier-bioreactor system for the expansion of gene-modified hMSCs. Upon isolation, umbilical cord tissue mesenchymal stromal cells (UCT-hMSCs) were transduced using a lentiviral vector (LV) with green fluorescent protein (GFP) or vascular endothelial growth factor (VEGF) transgenes. The cells were then seeded in 100 mL spinner flasks using Spherecol microcarriers and expanded for seven days. After six days in culture, both non-transduced and transduced cell populations attained comparable maximum cell concentrations (≈1.8 × 105 cell/mL). Analysis of the culture supernatant identified that glucose was fully depleted after day five across the cell populations. Lactate concentrations observed throughout the culture reached a maximum of 7.5 mM on day seven. Immunophenotype analysis revealed that the transduction followed by an expansion step was not responsible for the downregulation of the cell surface receptors used to identify hMSCs. The levels of CD73, CD90, and CD105 expressing cells were above 90% for the non-transduced and transduced cells. In addition, the expression of negative markers (CD11b, CD19, CD34, CD45, and HLA-DR) was also shown to be below 5%, which is aligned with the criteria established for hMSCs by the International Society for Cell and Gene Therapy (ISCT). This work provides a foundation for the scalable manufacturing of gene-modified hMSCs which will overcome a significant translational and commercial bottleneck. KEY POINTS: • hMSCs were successfully transduced by lentiviral vectors carrying two different transgenes: GFP and VEGF • Transduced hMSCs were successfully expanded on microcarriers using spinner flasks during a period of 7 days • The genetic modification step did not cause any detrimental impact on the hMSC immunophenotype characteristics.
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Affiliation(s)
- Pedro Silva Couto
- Department of Biochemical Engineering, Advanced Centre for Biochemical Engineering, University College London, Gower Street, London, WC1E 6BT UK
| | - Dale J. Stibbs
- Department of Biochemical Engineering, Advanced Centre for Biochemical Engineering, University College London, Gower Street, London, WC1E 6BT UK
| | - Marco C. Rotondi
- Department of Biochemical Engineering, Advanced Centre for Biochemical Engineering, University College London, Gower Street, London, WC1E 6BT UK
| | - Yasuhiro Takeuchi
- Division of Infection and Immunity, University College London, Gower Street, London, WC1E 6BT UK
- Biotherapeutics and Advanced Therapies, Scientific Research and Innovation, Medicines, and Healthcare Products Regulatory Agency, South Mimms, EN6 3QG UK
| | - Qasim A. Rafiq
- Department of Biochemical Engineering, Advanced Centre for Biochemical Engineering, University College London, Gower Street, London, WC1E 6BT UK
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11
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Oladejo M, Nguyen HM, Wood L. CD105 in the progression and therapy of renal cell carcinoma. Cancer Lett 2023; 570:216327. [PMID: 37499740 DOI: 10.1016/j.canlet.2023.216327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 07/20/2023] [Accepted: 07/21/2023] [Indexed: 07/29/2023]
Abstract
Molecular biomarkers that interact with the vascular and immune compartments play an important role in the progression of solid malignancies. CD105, which is a component of the transforming growth factor beta (TGF β) signaling cascade, has long been studied for its role in potentiating angiogenesis in numerous cancers. In renal cell carcinoma (RCC), the role of CD105 is more complicated due to its diverse expression profile on the tumor cells, tumor vasculature, and the components of the immune system. Since its discovery, its angiogenic role has overshadowed other potential functions, especially in cancers. In this review, we aim to summarize the recent evidence and findings of the multifunctional roles of CD105 in angiogenesis and immunomodulation in the context of the various subtypes of RCC, with a specific emphasis on the clear cell RCC subtype. Since CD105 is an established biomarker and tumor antigen, we also provide an update on the preclinical and clinical applications of CD105 as a therapeutic platform in RCC.
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Affiliation(s)
- Mariam Oladejo
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, 79601, USA
| | - Hong-My Nguyen
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, 79601, USA
| | - Laurence Wood
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, 79601, USA.
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12
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Yao H, Xu H, Wu M, Lei W, Li L, Liu D, Wang Z, Ran H, Ma H, Zhou X. Targeted long-term noninvasive treatment of choroidal neovascularization by biodegradable nanoparticles. Acta Biomater 2023; 166:536-551. [PMID: 37196903 DOI: 10.1016/j.actbio.2023.05.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 04/24/2023] [Accepted: 05/10/2023] [Indexed: 05/19/2023]
Abstract
Choroidal neovascularization (CNV) is the main cause of vision loss in patients with wet age-related macular degeneration (AMD). Currently, treatment of these conditions requires repeated intravitreal injections, which may lead to complications such as infection and hemorrhage. So, we have developed a noninvasive method for treating CNV with nanoparticles, namely, Angiopoietin1-anti CD105-PLGA nanoparticles (AAP NPs), which targets the CNV to enhance drug accumulation at the site. These nanoparticles, with PLGA as a carrier, can slowly release encapsulated Angiopoietin 1 (Ang 1) and target the choroidal neovascularization marker CD105 to enhance drug accumulation, increases vascular endothelial cadherin (VE-cadherin) expression between vascular endothelial cells, effectively reduce neovascularization leakage and inhibit Angiopoietin 2(Ang 2) secretion by endothelial cells. In a rat model of laser-induced CNV, intravenous injection of AAP NPs exerted a good therapeutic effect in reducing CNV leakage and area. In short, these synthetic AAP NPs provide an effective alternative treatment for AMD and meet the urgent need for noninvasive treatment in neovascular ophthalmopathy. STATEMENT OF SIGNIFICANCE: This work describes the synthesis, injection-mediated delivery, in vitro and in vivo efficacy of targeted nanoparticles with encapsulated Ang1; via these nanoparticles, the drug can be targeted to choroidal neovascularization lesions for continuous treatment. The release of Ang1 can effectively reduce neovascularization leakage, maintain vascular stability, and inhibit Ang2 secretion and inflammation. This study provides a new approach for the treatment of wet age-related macular degeneration.
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Affiliation(s)
- Hao Yao
- Department of Ophthalmology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400012, China; Chongqing Key Laboratory of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Huan Xu
- Chongqing Key Laboratory of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Mingxing Wu
- Department of Ophthalmology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400012, China
| | - Wulong Lei
- Chongqing Key Laboratory of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Lanjiao Li
- Department of Ophthalmology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400012, China; Chongqing Key Laboratory of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Danning Liu
- Department of Ophthalmology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400012, China
| | - Zhigang Wang
- Chongqing Key Laboratory of Ultrasound Molecular Imaging, Institute of Ultrasound Imaging, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Haitao Ran
- Chongqing Key Laboratory of Ultrasound Molecular Imaging, Institute of Ultrasound Imaging, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Huafeng Ma
- Department of Ophthalmology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400012, China.
| | - Xiyuan Zhou
- Department of Ophthalmology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400012, China; Chongqing Key Laboratory of Ophthalmology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China.
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13
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Li C, Sun C, Lohcharoenkal W, Ali MM, Xing P, Zheng W, Görgens A, Gustafsson MO, El Andaloussi S, Sonkoly E, Pivarcsi A. Cutaneous squamous cell carcinoma-derived extracellular vesicles exert an oncogenic role by activating cancer-associated fibroblasts. Cell Death Discov 2023; 9:260. [PMID: 37495566 PMCID: PMC10372068 DOI: 10.1038/s41420-023-01555-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/04/2023] [Accepted: 07/12/2023] [Indexed: 07/28/2023] Open
Abstract
Cutaneous squamous cell carcinoma (cSCC) is a fast-increasing cancer with metastatic potential. Extracellular vesicles (EVs) are small membrane-bound vesicles that play important roles in intercellular communication, particularly in the tumor microenvironment (TME). Here we report that cSCC cells secrete an increased number of EVs relative to normal human epidermal keratinocytes (NHEKs) and that interfering with the capacity of cSCC to secrete EVs inhibits tumor growth in vivo in a xenograft model of human cSCC. Transcriptome analysis of tumor xenografts by RNA-sequencing enabling the simultaneous quantification of both the human and the mouse transcripts revealed that impaired EV-production of cSCC cells prominently altered the phenotype of stromal cells, in particular genes related to extracellular matrix (ECM)-formation and epithelial-mesenchymal transition (EMT). In line with these results, co-culturing of human dermal fibroblasts (HDFs) with cSCC cells, but not with normal keratinocytes in vitro resulted in acquisition of cancer-associated fibroblast (CAF) phenotype. Interestingly, EVs derived from metastatic cSCC cells, but not primary cSCCs or NHEKs, were efficient in converting HDFs to CAFs. Multiplex bead-based flow cytometry assay and mass-spectrometry (MS)-based proteomic analyses revealed the heterogenous cargo of cSCC-derived EVs and that especially EVs derived from metastatic cSCCs carry proteins associated with EV-biogenesis, EMT, and cell migration. Mechanistically, EVs from metastatic cSCC cells result in the activation of TGFβ signaling in HDFs. Altogether, our study suggests that cSCC-derived EVs mediate cancer-stroma communication, in particular the conversion of fibroblasts to CAFs, which eventually contribute to cSCC progression.
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Affiliation(s)
- Chen Li
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
- Dermatology and Venereology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Chengxi Sun
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
- Department of Clinical Laboratory, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China
| | - Warangkana Lohcharoenkal
- Unit of Dermatology and Venerology, Department of Medicine, Karolinska Institutet, Stockholm, SE, 17176, Sweden
| | - Mohamad Moustafa Ali
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Pengwei Xing
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Wenyi Zheng
- Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden
| | - André Görgens
- Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Manuela O Gustafsson
- Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden
| | - Samir El Andaloussi
- Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden
| | - Enikö Sonkoly
- Dermatology and Venereology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- Unit of Dermatology and Venerology, Department of Medicine, Karolinska Institutet, Stockholm, SE, 17176, Sweden
| | - Andor Pivarcsi
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
- Dermatology and Venereology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
- Unit of Dermatology and Venerology, Department of Medicine, Karolinska Institutet, Stockholm, SE, 17176, Sweden.
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14
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Hakuno SK, Janson SGT, Trietsch MD, de Graaf M, de Jonge-Muller E, Crobach S, Harryvan TJ, Boonstra JJ, Dinjens WNM, Slingerland M, Hawinkels LJAC. Endoglin and squamous cell carcinomas. Front Med (Lausanne) 2023; 10:1112573. [PMID: 37396898 PMCID: PMC10313935 DOI: 10.3389/fmed.2023.1112573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 05/30/2023] [Indexed: 07/04/2023] Open
Abstract
Despite the fact that the role of endoglin on endothelial cells has been extensively described, its expression and biological role on (epithelial) cancer cells is still debatable. Especially its function on squamous cell carcinoma (SCC) cells is largely unknown. Therefore, we investigated SCC endoglin expression and function in three types of SCCs; head and neck (HNSCC), esophageal (ESCC) and vulvar (VSCC) cancers. Endoglin expression was evaluated in tumor specimens and 14 patient-derived cell lines. Next to being expressed on angiogenic endothelial cells, endoglin is selectively expressed by individual SCC cells in tumor nests. Patient derived HNSCC, ESCC and VSCC cell lines express varying levels of endoglin with high interpatient variation. To assess the function of endoglin in signaling of TGF-β ligands, endoglin was overexpressed or knocked out or the signaling was blocked using TRC105, an endoglin neutralizing antibody. The endoglin ligand BMP-9 induced strong phosphorylation of SMAD1 independent of expression of the type-I receptor ALK1. Interestingly, we observed that endoglin overexpression leads to strongly increased soluble endoglin levels, which in turn decreases BMP-9 signaling. On the functional level, endoglin, both in a ligand dependent and independent manner, did not influence proliferation or migration of the SCC cells. In conclusion, these data show endoglin expression on individual cells in the tumor nests in SCCs and a role for (soluble) endoglin in paracrine signaling, without directly affecting proliferation or migration in an autocrine manner.
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Affiliation(s)
- Sarah K. Hakuno
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Stefanus G. T. Janson
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Marjolijn D. Trietsch
- Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
- Department of Gynecology, Leiden University Medical Center, Leiden, Netherlands
| | - Manon de Graaf
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, Netherlands
- Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
| | - Eveline de Jonge-Muller
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Stijn Crobach
- Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
| | - Tom J. Harryvan
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Jurjen J. Boonstra
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Winand N. M. Dinjens
- Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, Netherlands
| | - Marije Slingerland
- Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
| | - Lukas J. A. C. Hawinkels
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, Netherlands
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15
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Galadima M, Kotova I, Schmidt R, Pastor J, Schröder C, Rodríguez-Gil JE, Del Alamo MMR. Canine Mammary Neoplasia Induces Variations in the Peripheral Blood Levels of CD20, CD45RA, and CD99. Int J Mol Sci 2023; 24:ijms24119222. [PMID: 37298173 DOI: 10.3390/ijms24119222] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/17/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
The idea of using tumour biomarkers as diagnostic tools is progressively increasing. Of these, serum biomarkers are of particular interest, as they can provide rapid results. In the present study, serum samples from 26 bitches diagnosed with mammary tumours, plus 4 healthy bitches, were obtained. The samples were analysed using CD antibody microarrays targeting 90 CD surface markers and 56 cytokines/chemokines. A total of five CD proteins, namely CD20, CD45RA, CD53, CD59, and CD99, were selected and further analysed, utilizing immunoblotting techniques to validate the microarray results. CD45RA showed a significantly lower abundance in the serum samples from the bitches carrying mammary neoplasia in comparison to the healthy animals. Regarding CD99, the serum samples from the neoplastic bitches showed it in a significantly higher abundance than those from the healthy patients. Finally, CD20 showed a significantly higher abundance in bitches carrying a malignant mammary tumour in comparison to healthy patients, but no differential expression between malignant and benign tumours was observed. According to these results, both CD99 and CD45RA are indicators of mammary tumour presence, but without distinguishing between malignant and benign.
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Affiliation(s)
- Makchit Galadima
- Department of Animal Medicine and Surgery, Faculty of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Iuliia Kotova
- Sciomics GmbH, Karl-Landsteines-Straβe 6, 69151 Neckargemünd, Germany
| | - Ronny Schmidt
- Sciomics GmbH, Karl-Landsteines-Straβe 6, 69151 Neckargemünd, Germany
| | - Josep Pastor
- Department of Animal Medicine and Surgery, Faculty of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | | | - Joan Enric Rodríguez-Gil
- Department of Animal Medicine and Surgery, Faculty of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Maria Montserrat Rivera Del Alamo
- Department of Animal Medicine and Surgery, Faculty of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
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16
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Prakash N, Kim J, Jeon J, Kim S, Arai Y, Bello AB, Park H, Lee SH. Progress and emerging techniques for biomaterial-based derivation of mesenchymal stem cells (MSCs) from pluripotent stem cells (PSCs). Biomater Res 2023; 27:31. [PMID: 37072836 PMCID: PMC10114339 DOI: 10.1186/s40824-023-00371-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 03/26/2023] [Indexed: 04/20/2023] Open
Abstract
The use of mesenchymal stem cells (MSCs) for clinical purposes has skyrocketed in the past decade. Their multilineage differentiation potentials and immunomodulatory properties have facilitated the discovery of therapies for various illnesses. MSCs can be isolated from infant and adult tissue sources, which means they are easily available. However, this raises concerns because of the heterogeneity among the various MSC sources, which limits their effective use. Variabilities arise from donor- and tissue-specific differences, such as age, sex, and tissue source. Moreover, adult-sourced MSCs have limited proliferation potentials, which hinders their long-term therapeutic efficacy. These limitations of adult MSCs have prompted researchers to develop a new method for generating MSCs. Pluripotent stem cells (PSCs), such as embryonic stem cells and induced PSCs (iPSCs), can differentiate into various types of cells. Herein, a thorough review of the characteristics, functions, and clinical importance of MSCs is presented. The existing sources of MSCs, including adult- and infant-based sources, are compared. The most recent techniques for deriving MSCs from iPSCs, with a focus on biomaterial-assisted methods in both two- and three-dimensional culture systems, are listed and elaborated. Finally, several opportunities to develop improved methods for efficiently producing MSCs with the aim of advancing their various clinical applications are described.
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Affiliation(s)
- Nityanand Prakash
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Jiseong Kim
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Jieun Jeon
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Siyeon Kim
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Yoshie Arai
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Alvin Bacero Bello
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea.
| | - Hansoo Park
- School of Integrative Engineering, Chung-Ang University, Seoul, 06911, Korea.
| | - Soo-Hong Lee
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea.
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17
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Ruiz-Magaña MJ, Puerta JM, Llorca T, Méndez-Malagón C, Martínez-Aguilar R, Abadía-Molina AC, Olivares EG, Ruiz-Ruiz C. Influence of the ectopic location on the antigen expression and functional characteristics of endometrioma stromal cells. Reprod Biomed Online 2023; 46:460-469. [PMID: 36586747 DOI: 10.1016/j.rbmo.2022.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/28/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022]
Abstract
RESEARCH QUESTION Are the alterations observed in the endometriotic cells, such as progesterone resistance, already present in the eutopic endometrium or acquired in the ectopic location? DESIGN The response to decidualization with progesterone and cyclic AMP for up to 28 days was compared in different endometrial stromal cell (EnSC) lines established from samples of endometriomas (eEnSC), eutopic endometrium from women with endometriosis (eBEnSC), endometrial tissue from healthy women (BEnSC) and menstrual blood from healthy donors (mEnSC). RESULTS Usual features of decidualized cells, such as changes in cell morphology and expression of prolactin, were similarly observed in the three types of eutopic EnSC studied, but not in the ectopic cells upon decidualization. Among the phenotypic markers analysed, CD105 was down-regulated under decidualization in all cell types (mEnSC, P = 0.005; BEnSC, P = 0.029; eBEnSC, P = 0.022) except eEnSC. mEnSC and BEnSC underwent apoptosis during decidualization, whereas eBEnSC and eEnSC were resistant to the induction of cell death. Lastly, migration studies revealed that mEnSC secreted undetermined factors during decidualization that inhibited cell motility, whereas eEnSC showed a significantly lower ability to produce those migration-regulating factors (P < 0.0001, P < 0.001 and P = 0.0013 for the migration of mEnSC at 24, 48 and 72 h, respectively; P < 0.0001 for the migration of eEnSC at all times studied). CONCLUSIONS This study provides novel insights into the differences between endometriotic and eutopic endometrial cells and reinforces the idea that the microenvironment in the ectopic location plays additional roles in the acquisition of the alterations that characterize the cells of the endometriotic foci.
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Affiliation(s)
- María José Ruiz-Magaña
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain
| | - José M Puerta
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain; Hospital Quirón Ruber Juan Bravo, Madrid, Spain
| | - Tatiana Llorca
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain; Departamento de Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain
| | - Cristina Méndez-Malagón
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain; Departamento de Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain
| | - Rocío Martínez-Aguilar
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain; Departamento de Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain; Medical Research Council Centre for Reproductive Health, University of Edinburgh, Scotland, UK
| | - Ana Clara Abadía-Molina
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain; Departamento de Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain
| | - Enrique G Olivares
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain; Departamento de Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain; Unidad de Gestión Clínica Laboratorios, Complejo Hospitalario Universitario de Granada, Granada, Spain.
| | - Carmen Ruiz-Ruiz
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Armilla, Granada, Spain; Departamento de Bioquímica y Biología Molecular III e Inmunología, Universidad de Granada, Granada, Spain.
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Initial and ongoing tobacco smoking elicits vascular damage and distinct inflammatory response linked to neurodegeneration. Brain Behav Immun Health 2023; 28:100597. [PMID: 36817509 PMCID: PMC9931921 DOI: 10.1016/j.bbih.2023.100597] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 12/07/2022] [Accepted: 01/21/2023] [Indexed: 01/30/2023] Open
Abstract
Tobacco smoking is strongly linked to vascular damage contributing to the development of hypertension, atherosclerosis, as well as increasing the risk for neurodegeneration. Still, the involvement of the innate immune system in the development of vascular damage upon chronic tobacco use before the onset of clinical symptoms is not fully characterized. Our data provide evidence that a single acute exposure to tobacco elicits the secretion of extracellular vesicles expressing CD105 and CD49e from endothelial cells, granting further recognition of early preclinical biomarkers of vascular damage. Furthermore, we investigated the effects of smoking on the immune system of healthy asymptomatic chronic smokers compared to never-smokers, focusing on the innate immune system. Our data reveal a distinct immune landscape representative for early stages of vascular damage in clinically asymptomatic chronic smokers, before tobacco smoking related diseases develop. These results indicate a dysregulated immuno-vascular axis in chronic tobacco smokers that are otherwise considered as healthy individuals. The distinct alterations are characterized by increased CD36 expression by the blood monocyte subsets, neutrophilia and increased plasma IL-18 and reduced levels of IL-33, IL-10 and IL-8. Additionally, reduced levels of circulating BDNF and elevated sTREM2, which are associated with neurodegeneration, suggest a considerable impact of tobacco smoking on CNS function in clinically healthy individuals. These findings provide profound insight into the initial and ongoing effects of tobacco smoking and the potential vascular damage contributing to neurodegenerative disorders, specifically cerebrovascular dysfunction and dementia.
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Oladejo M, Nguyen HM, Seah H, Datta A, Wood LM. Tumoral CD105 promotes immunosuppression, metastasis, and angiogenesis in renal cell carcinoma. Cancer Immunol Immunother 2022; 72:1633-1646. [PMID: 36586013 DOI: 10.1007/s00262-022-03356-5] [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: 08/11/2022] [Accepted: 12/23/2022] [Indexed: 01/01/2023]
Abstract
CD105 (endoglin) is a transmembrane protein that functions as a TGF-beta coreceptor and is highly expressed on endothelial cells. Unsurprisingly, preclinical and clinical evidence strongly suggests that CD105 is an important contributor to tumor angiogenesis and tumor progression. Emerging evidence suggests that CD105 is also expressed by tumor cells themselves in certain cancers such as renal cell carcinoma (RCC). In human RCC tumor cells, CD105 expression is associated with stem cell-like properties and contributes to the malignant phenotype in vitro and in xenograft models. However, as a regulator of TGF-beta signaling, there is a striking lack of evidence for the role of tumor-expressed CD105 in the anti-tumor immune response and the tumor microenvironment. In this study, we report that tumor cell-expressed CD105 potentiates both the in vitro and in vivo tumorigenic potential of RCC in a syngeneic murine RCC tumor model. Importantly, we find that tumor cell-expressed CD105 sculpts the tumor microenvironment by enhancing the recruitment of immunosuppressive cell types and inhibiting the polyfunctionality of tumor-infiltrating CD4+ and CD8+ T cells. Finally, while CD105 expression by endothelial cells is a well-established contributor to tumor angiogenesis, we also find that tumor cell-expressed CD105 significantly contributes to tumor angiogenesis in RCC.
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Affiliation(s)
- Mariam Oladejo
- Department of Immunotherapeutics and Biotechnology, Jerry H Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, USA
| | - Hong-My Nguyen
- Department of Immunotherapeutics and Biotechnology, Jerry H Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, USA
| | - Hannah Seah
- Department of Immunotherapeutics and Biotechnology, Jerry H Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, USA
| | - Arani Datta
- Department of Immunotherapeutics and Biotechnology, Jerry H Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, USA
| | - Laurence M Wood
- Department of Immunotherapeutics and Biotechnology, Jerry H Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, USA.
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Effect of CD44 signal axis in the gain of mesenchymal stem cell surface antigens from synovial fibroblasts in vitro. Heliyon 2022; 8:e10739. [PMID: 36247177 PMCID: PMC9557910 DOI: 10.1016/j.heliyon.2022.e10739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 05/24/2022] [Accepted: 09/16/2022] [Indexed: 11/24/2022] Open
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Azzarito G, Visentin M, Leeners B, Dubey RK. Transcriptomic and Functional Evidence for Differential Effects of MCF-7 Breast Cancer Cell-Secretome on Vascular and Lymphatic Endothelial Cell Growth. Int J Mol Sci 2022; 23:ijms23137192. [PMID: 35806196 PMCID: PMC9266834 DOI: 10.3390/ijms23137192] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/16/2022] [Accepted: 06/24/2022] [Indexed: 01/14/2023] Open
Abstract
Vascular and lymphatic vessels drive breast cancer (BC) growth and metastasis. We assessed the cell growth (proliferation, migration, and capillary formation), gene-, and protein-expression profiles of Vascular Endothelial Cells (VECs) and Lymphatic Endothelial Cells (LECs) exposed to a conditioned medium (CM) from estrogen receptor-positive BC cells (MCF-7) in the presence or absence of Estradiol. We demonstrated that MCF-7-CM stimulated growth and capillary formation in VECs but inhibited LEC growth. Consistently, MCF-7-CM induced ERK1/2 and Akt phosphorylation in VECs and inhibited them in LECs. Gene expression analysis revealed that the LECs were overall (≈10-fold) more sensitive to MCF-7-CM exposure than VECs. Growth/angiogenesis and cell cycle pathways were upregulated in VECs but downregulated in LECs. An angiogenesis proteome array confirmed the upregulation of 23 pro-angiogenesis proteins in VECs. In LECs, the expression of genes related to ATP synthesis and the ATP content were reduced by MCF-7-CM, whereas MTHFD2 gene, involved in folate metabolism and immune evasion, was upregulated. The contrasting effect of MCF-7-CM on the growth of VECs and LECs was reversed by inhibiting the TGF-β signaling pathway. The effect of MCF-7-CM on VEC growth was also reversed by inhibiting the VEGF signaling pathway. In conclusion, BC secretome may facilitate cancer cell survival and tumor growth by simultaneously promoting vascular angiogenesis and inhibiting lymphatic growth. The differential effects of BC secretome on LECs and VECs may be of pathophysiological relevance in BC.
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Affiliation(s)
- Giovanna Azzarito
- Department of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, Switzerland; (G.A.); (B.L.)
| | - Michele Visentin
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland;
| | - Brigitte Leeners
- Department of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, Switzerland; (G.A.); (B.L.)
| | - Raghvendra K. Dubey
- Department of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, Switzerland; (G.A.); (B.L.)
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15219, USA
- Correspondence:
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Kamel R, El Morsy EM, Elsherbiny ME, Nour-Eldin M. Chrysin promotes angiogenesis in rat hindlimb ischemia: Impact on PI3K/Akt/mTOR signaling pathway and autophagy. Drug Dev Res 2022; 83:1226-1237. [PMID: 35662099 DOI: 10.1002/ddr.21954] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 05/01/2022] [Accepted: 05/17/2022] [Indexed: 11/09/2022]
Abstract
Limb ischemia occurs due to obstruction of blood perfusion to lower limbs, a manifestation that is associated with peripheral artery disease (PAD). Angiogenesis is important for adequate oxygen delivery. The present study investigated a potential role for chrysin, a naturally occurring flavonoid, in promoting angiogenesis in hindlimb ischemia (HLI) rat model. Rats were allocated into four groups: (1) sham-operated control, (2) HLI: subjected to unilateral femoral artery ligation, (3) HLI + chrysin: received 100 mg/kg, i.p. chrysin immediately after HLI, and (4) HLI + chrysin + rapamycin: received 6 mg/kg/day rapamycin i.p. for 5 days then subjected to HLI and dosed with 100 mg/kg chrysin, i.p. Rats were killed 18 h later and gastrocnemius muscles were collected and divided into parts for (1) immunohistochemistry detection of CD31 and CD105, (2) qRT-PCR analysis of eNOS and VEGFR2, (3) colorimetric analysis of NO, (4) ELISA estimation of TGF-β, VEGF, ATG5 and Beclin-1, and (5) Western blot analysis of p-PI3K, PI3K, p-Akt, Akt, p-mTOR, mTOR, and HIF-1α. Chrysin significantly enhanced microvessels growth in HLI muscles as indicated by increased CD31 and CD105 levels and decreased TGF-β. Chrysin's proangiogenic effect is potentially mediated by increased VEGF, VEGFR2 and activation of PI3K/AKT/mTOR pathway, which promoted eNOS and NO levels as it was reversed by the mTOR inhibitor, rapamycin. Chrysin also inhibited autophagy as it decreased ATG5 and Beclin-1. The current study shows that chrysin possesses a proangiogenic effect in HLI rats and might be useful in patients with PAD.
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Affiliation(s)
- Rehab Kamel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt
| | - Engy M El Morsy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Marwa E Elsherbiny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt
| | - Mahmoud Nour-Eldin
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Sadat City (USC), Menoufia, Egypt
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Kutikhin AG, Shishkova DK, Velikanova EA, Sinitsky MY, Sinitskaya AV, Markova VE. Endothelial Dysfunction in the Context of Blood–Brain Barrier Modeling. J EVOL BIOCHEM PHYS+ 2022; 58:781-806. [PMID: 35789679 PMCID: PMC9243926 DOI: 10.1134/s0022093022030139] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 04/04/2022] [Accepted: 04/05/2022] [Indexed: 01/04/2023]
Abstract
Here, we discuss pathophysiological approaches to the defining
of endothelial dysfunction criteria (i.e., endothelial activation,
impaired endothelial mechanotransduction, endothelial-to-mesenchymal
transition, reduced nitric oxide release, compromised endothelial
integrity, and loss of anti-thrombogenic properties) in different
in vitro and in vivo models. The canonical definition of endothelial
dysfunction includes insufficient production of vasodilators, pro-thrombotic
and pro-inflammatory activation of endothelial cells, and pathologically
increased endothelial permeability. Among the clinical consequences
of endothelial dysfunction are arterial hypertension, macro- and
microangiopathy, and microalbuminuria. We propose to extend the definition
of endothelial dysfunction by adding altered endothelial mechanotransduction
and endothelial-to-mesenchymal transition to its criteria. Albeit
interleukin-6, interleukin-8, and MCP-1/CCL2 dictate the pathogenic
paracrine effects of dysfunctional endothelial cells and are therefore
reliable endothelial dysfunction biomarkers in vitro, they are non-specific
for endothelial cells and cannot be used for the diagnostics of
endothelial dysfunction in vivo. Conceptual improvements in the
existing methods to model endothelial dysfunction, specifically,
in relation to the blood–brain barrier, include endothelial cell
culturing under pulsatile flow, collagen IV coating of flow chambers,
and endothelial lysate collection from the blood vessels of laboratory
animals in situ for the subsequent gene and protein expression profiling.
Combined with the simulation of paracrine effects by using conditioned
medium from dysfunctional endothelial cells, these flow-sensitive
models have a high physiological relevance, bringing the experimental
conditions to the physiological scenario.
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Affiliation(s)
- A. G. Kutikhin
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
| | - D. K. Shishkova
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
| | - E. A. Velikanova
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
| | - M. Yu. Sinitsky
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
| | - A. V. Sinitskaya
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
| | - V. E. Markova
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
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Koh B, Ab Rahman FH, Matlan NA, Rajan M, Musta'ain AY, Mohd Jeffry Lee MR, Ramli R, Mohd Yunus SS, Binti Hj Idrus R, Yazid MD. Potential role of dental pulp stem cells conditioned medium for odontoblastic differentiation. Biol Res 2022; 55:11. [PMID: 35246266 PMCID: PMC8895822 DOI: 10.1186/s40659-022-00380-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 02/17/2022] [Indexed: 12/03/2022] Open
Abstract
Background Functional bioengineered tooth regeneration using autologous or allogeneic alternative differentiated cells sources are thought to have a great potential in replacing conventional dentures. This study investigated the potential of dental pulp stem cells (DPSCs) conditioned medium for odontoblastic differentiation of Wharton’s jelly mesenchymal stem cells (WJMSCs). The DPSCs derived from healthy adult permanent first molars were cultured at high confluence prior to conditioned medium collection. The WJMSCs were cultured in six different treatments, with varying ratios of culture media to DPSCs-conditioned medium. MTT assay was used to measure the rate of proliferation of WJMSCs, while immunocytochemistry staining was utilised to detect the expression of dental matrix protein 1 (DMP-1). The deposited calcium was detected and analysed via Alizarin-Red Staining (ARS). Results It was found that the proliferation of WJMSCs cultured under the mixture of complete medium and DPSCs conditioned medium showed significantly lower than the control; presumably the cells started to exit proliferative state prior differentiation. In 14 days of induction, the cells in all treatments showed osteoblastic-like morphology, calcium compound deposits were observed at day 7, 10 and 14 of differentiation suggested that DPSCs conditioned medium could lead to osteoblastic/odontoblastic differentiation. However, the DMP-1 protein can be seen only expressed minimally at day 14 of conditioned medium induction. Conclusions In conclusion, DPSCs conditioned medium appeared as a potential odontoblastic induction approach for WJMSCs. To further investigate the stimulatory effects by DPSCs conditioned medium, specific signalling pathway need to be elucidated to enhance the differentiation efficiency.
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Affiliation(s)
- Benson Koh
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Farynna Hana Ab Rahman
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Najwa Amira Matlan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Manissha Rajan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Aimi Yasmin Musta'ain
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Mohamad Ridhwan Mohd Jeffry Lee
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Roszalina Ramli
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300, Kuala Lumpur, Malaysia
| | - Siti Salmiah Mohd Yunus
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300, Kuala Lumpur, Malaysia
| | - Ruszymah Binti Hj Idrus
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Muhammad Dain Yazid
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia.
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Li L, Zhong L, Tang C, Gan L, Mo T, Na J, He J, Huang Y. CD105: tumor diagnosis, prognostic marker and future tumor therapeutic target. Clin Transl Oncol 2022; 24:1447-1458. [PMID: 35165838 DOI: 10.1007/s12094-022-02792-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/21/2022] [Indexed: 02/06/2023]
Abstract
Cancer is one of the diseases with the highest morbidity and mortality rates worldwide, and its therapeutic options are inadequate. The endothelial glycoprotein, also known as CD105, is a type I transmembrane glycoprotein located on the surface of the cell membranes and it is one of the transforming growth factor-β (TGF-β) receptor complexes. It regulates the responses associated with binding to transforming growth factor β1 egg (Activin-A), bone morphogenetic protein 2 (BMP-2), and bone morphogenetic protein 7 (BMP-7). Additionally, it is involved in the regulation of angiogenesis. This glycoprotein is indispensable in the treatment of tumor angiogenesis, and it also plays a leading role in tumor angiogenesis therapy. Therefore, CD105 is considered to be a novel therapeutic target. In this study, we explored the significance of CD105 in the diagnosis, treatment and prognosis of various tumors, and provided evidence for the effect and mechanism of CD105 on tumors.
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Affiliation(s)
- Lan Li
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Liping Zhong
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Chao Tang
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Lu Gan
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Tong Mo
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Jintong Na
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Jian He
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Yong Huang
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China.
- Guangxi Medical University, Nanning, 530021, Guangxi, China.
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Chen T, Xu T, Cheng M, Fang H, Shen X, Tang Z, Zhao J. Human umbilical cord mesenchymal stem cells regulate CD54 and CD105 in vascular endothelial cells and suppress inflammation in Kawasaki disease. Exp Cell Res 2021; 409:112941. [PMID: 34822812 DOI: 10.1016/j.yexcr.2021.112941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 11/15/2021] [Accepted: 11/18/2021] [Indexed: 11/18/2022]
Abstract
OBJECTIVE The objective was to evaluate the expression levels of CD31+CD54+ and CD31+CD105+ endothelial microparticles (EMPs) before and after intravenous immunoglobulin (IVIG) treatment of Kawasaki disease (KD). To explore the role of human umbilical cord mesenchymal stem cells (hucMSCs) in inhibiting endothelial inflammation in KD, the effects of hucMSCs on the expression of CD54 and CD105 in endothelial cells in KD were analyzed in vivo and in vitro. METHODS The concentrations of IL-1β and VEGF in the peripheral blood of KD or healthy children were detected, and the distributions of CD31+CD54+ and CD31+CD105+ EMPs in platelet-poor plasma (PPP) were analyzed by flow cytometry. Human umbilical vein endothelial cells (HUVECs) were first cocultured with the patients' peripheral blood mononuclear cells (PBMCs). Next, HUVECs were cocultured with hucMSCs after stimulation with inactivated serum from patients. Cell proliferation and migration activities were assessed, and the expression of CD54, CD105 and IL-1β was analyzed. In an in vivo study, hucMSCs were transplanted into KD mice. The locations and expression levels of CD54, CD105 and IL-1β in the heart tissues of mice were analyzed. RESULTS The levels of IL-1β and CD31+CD54+ EMPs were significantly higher before IVIG treatment and 2 weeks after treatment in KD patients (P < 0.01). However, the levels of VEGF and CD31+CD105+ EMPs increased significantly in KD only after IVIG treatment (P < 0.01). KD-inactivated serum stimulation combined with cocultivation of PBMCs can activate inflammation in HUVECs, leading to reduced cell proliferation and migration activities. Cocultivation also increased the expression of CD54 and decreased the expression of CD105 (P < 0.001). Cocultivation with hucMSCs can reverse these changes. Additionally, hucMSC transplantation downregulated the expression of IL-1β and CD54 and significantly upregulated the expression of CD105 in KD mice. CONCLUSION The expression levels of CD31+CD54+ and CD31+CD105+ EMPs showed inconsistent changes at different KD statuses, providing potential markers for clinical application. HucMSCs suppress inflammation and regulate the expression levels of CD54 and CD105 in vascular endothelial cells in KD, possibly providing a new basis for stem cell therapy for KD.
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Affiliation(s)
- Tao Chen
- Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China; Research Institute of Comparative Medicine, Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Ting Xu
- Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China; Research Institute of Comparative Medicine, Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Mingye Cheng
- Department of Pediatrics, Zhongda Hospital Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Hao Fang
- Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Xianjuan Shen
- Department of Clinical Laboratory, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Zhiyuan Tang
- Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
| | - Jianmei Zhao
- Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China.
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Sharma D, Hamlet S, Vaquette C, Petcu EB, Ramamurthy P, Ivanovski S. Local delivery of hydrogel encapsulated vascular endothelial growth factor for the prevention of medication-related osteonecrosis of the jaw. Sci Rep 2021; 11:23371. [PMID: 34862395 PMCID: PMC8642483 DOI: 10.1038/s41598-021-02637-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 11/17/2021] [Indexed: 11/16/2022] Open
Abstract
The anti-angiogenic effects of bisphosphonates have been hypothesized as one of the major etiologic factors in the development of medication-related osteonecrosis of the jaw (MRONJ), a severe debilitating condition with limited treatment options. This study evaluated the potential of a gelatine-hyaluronic acid hydrogel loaded with the angiogenic growth factor, vascular endothelial growth factor (VEGF), as a local delivery system to aid in maintaining vascularization in a bisphosphonate-treated (Zoledronic Acid) rodent maxillary extraction defect. Healing was assessed four weeks after implantation of the VEGF-hydrogel into extraction sockets. Gross examination and histological assessment showed that total osteonecrosis and inflammatory infiltrate was significantly reduced in the presence of VEGF. Also, total vascularity and specifically neovascularization, was significantly improved in animals that received VEGF hydrogel. Gene expression of vascular, inflammatory and bone specific markers within the defect area were also significantly altered in the presence of VEGF. Furthermore, plasma cytokine levels were assessed to determine the systemic effect of locally delivered VEGF and showed similar outcomes. In conclusion, the use of locally delivered VEGF within healing extraction sockets assists bone healing and prevents MRONJ via a pro-angiogenic and immunomodulatory mechanism.
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Affiliation(s)
- Dileep Sharma
- College of Medicine and Dentistry, James Cook University, Cairns Campus, PO Box 6811, Cairns, 4870, Australia. .,Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.
| | - Stephen Hamlet
- Menzies Health Institute Queensland, School of Medicine and Dentistry, Griffith University, Gold Coast Campus, Gold Coast, 4222, Australia
| | - Cedryck Vaquette
- School of Dentistry, Faculty of Health and Behavioral Sciences, The University of Queensland, Herston Campus, Brisbane, 4006, Australia
| | - Eugen Bogdan Petcu
- New York Institute of Technology College of Osteopathic Medicine (NYIT), Old Westbury, NY, 11545, USA.,School of Dentistry and Oral Health, Griffith University, Gold Coast, Australia
| | - Poornima Ramamurthy
- College of Medicine and Dentistry, James Cook University, Cairns Campus, PO Box 6811, Cairns, 4870, Australia
| | - Saso Ivanovski
- School of Dentistry, Faculty of Health and Behavioral Sciences, The University of Queensland, Herston Campus, Brisbane, 4006, Australia.
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van Dam MA, Vuijk FA, Stibbe JA, Houvast RD, Luelmo SAC, Crobach S, Shahbazi Feshtali S, de Geus-Oei LF, Bonsing BA, Sier CFM, Kuppen PJK, Swijnenburg RJ, Windhorst AD, Burggraaf J, Vahrmeijer AL, Mieog JSD. Overview and Future Perspectives on Tumor-Targeted Positron Emission Tomography and Fluorescence Imaging of Pancreatic Cancer in the Era of Neoadjuvant Therapy. Cancers (Basel) 2021; 13:6088. [PMID: 34885196 PMCID: PMC8656821 DOI: 10.3390/cancers13236088] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/25/2021] [Accepted: 11/28/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Despite recent advances in the multimodal treatment of pancreatic ductal adenocarcinoma (PDAC), overall survival remains poor with a 5-year cumulative survival of approximately 10%. Neoadjuvant (chemo- and/or radio-) therapy is increasingly incorporated in treatment strategies for patients with (borderline) resectable and locally advanced disease. Neoadjuvant therapy aims to improve radical resection rates by reducing tumor mass and (partial) encasement of important vascular structures, as well as eradicating occult micrometastases. Results from recent multicenter clinical trials evaluating this approach demonstrate prolonged survival and increased complete surgical resection rates (R0). Currently, tumor response to neoadjuvant therapy is monitored using computed tomography (CT) following the RECIST 1.1 criteria. Accurate assessment of neoadjuvant treatment response and tumor resectability is considered a major challenge, as current conventional imaging modalities provide limited accuracy and specificity for discrimination between necrosis, fibrosis, and remaining vital tumor tissue. As a consequence, resections with tumor-positive margins and subsequent early locoregional tumor recurrences are observed in a substantial number of patients following surgical resection with curative intent. Of these patients, up to 80% are diagnosed with recurrent disease after a median disease-free interval of merely 8 months. These numbers underline the urgent need to improve imaging modalities for more accurate assessment of therapy response and subsequent re-staging of disease, thereby aiming to optimize individual patient's treatment strategy. In cases of curative intent resection, additional intra-operative real-time guidance could aid surgeons during complex procedures and potentially reduce the rate of incomplete resections and early (locoregional) tumor recurrences. In recent years intraoperative imaging in cancer has made a shift towards tumor-specific molecular targeting. Several important molecular targets have been identified that show overexpression in PDAC, for example: CA19.9, CEA, EGFR, VEGFR/VEGF-A, uPA/uPAR, and various integrins. Tumor-targeted PET/CT combined with intraoperative fluorescence imaging, could provide valuable information for tumor detection and staging, therapy response evaluation with re-staging of disease and intraoperative guidance during surgical resection of PDAC. METHODS A literature search in the PubMed database and (inter)national trial registers was conducted, focusing on studies published over the last 15 years. Data and information of eligible articles regarding PET/CT as well as fluorescence imaging in PDAC were reviewed. Areas covered: This review covers the current strategies, obstacles, challenges, and developments in targeted tumor imaging, focusing on the feasibility and value of PET/CT and fluorescence imaging for integration in the work-up and treatment of PDAC. An overview is given of identified targets and their characteristics, as well as the available literature of conducted and ongoing clinical and preclinical trials evaluating PDAC-targeted nuclear and fluorescent tracers.
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Affiliation(s)
- Martijn A. van Dam
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (F.A.V.); (J.A.S.); (R.D.H.); (B.A.B.); (C.F.M.S.); (P.J.K.K.); (J.B.); (A.L.V.); (J.S.D.M.)
| | - Floris A. Vuijk
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (F.A.V.); (J.A.S.); (R.D.H.); (B.A.B.); (C.F.M.S.); (P.J.K.K.); (J.B.); (A.L.V.); (J.S.D.M.)
| | - Judith A. Stibbe
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (F.A.V.); (J.A.S.); (R.D.H.); (B.A.B.); (C.F.M.S.); (P.J.K.K.); (J.B.); (A.L.V.); (J.S.D.M.)
| | - Ruben D. Houvast
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (F.A.V.); (J.A.S.); (R.D.H.); (B.A.B.); (C.F.M.S.); (P.J.K.K.); (J.B.); (A.L.V.); (J.S.D.M.)
| | - Saskia A. C. Luelmo
- Department of Medical Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
| | - Stijn Crobach
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
| | | | - Lioe-Fee de Geus-Oei
- Department of Radiology, Section of Nuclear Medicine, University Medical Center Leiden, 2333 ZA Leiden, The Netherlands;
- Biomedical Photonic Imaging Group, University of Twente, 7522 NB Enschede, The Netherlands
| | - Bert A. Bonsing
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (F.A.V.); (J.A.S.); (R.D.H.); (B.A.B.); (C.F.M.S.); (P.J.K.K.); (J.B.); (A.L.V.); (J.S.D.M.)
| | - Cornelis F. M. Sier
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (F.A.V.); (J.A.S.); (R.D.H.); (B.A.B.); (C.F.M.S.); (P.J.K.K.); (J.B.); (A.L.V.); (J.S.D.M.)
- Percuros B.V., 2333 CL Leiden, The Netherlands
| | - Peter J. K. Kuppen
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (F.A.V.); (J.A.S.); (R.D.H.); (B.A.B.); (C.F.M.S.); (P.J.K.K.); (J.B.); (A.L.V.); (J.S.D.M.)
| | | | - Albert D. Windhorst
- Department of Radiology, Section of Nuclear Medicine, Amsterdam UMC, Location VUmc, 1081 HV Amsterdam, The Netherlands;
| | - Jacobus Burggraaf
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (F.A.V.); (J.A.S.); (R.D.H.); (B.A.B.); (C.F.M.S.); (P.J.K.K.); (J.B.); (A.L.V.); (J.S.D.M.)
- Centre for Human Drug Research, 2333 CL Leiden, The Netherlands
| | - Alexander L. Vahrmeijer
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (F.A.V.); (J.A.S.); (R.D.H.); (B.A.B.); (C.F.M.S.); (P.J.K.K.); (J.B.); (A.L.V.); (J.S.D.M.)
| | - J. Sven D. Mieog
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (F.A.V.); (J.A.S.); (R.D.H.); (B.A.B.); (C.F.M.S.); (P.J.K.K.); (J.B.); (A.L.V.); (J.S.D.M.)
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Study of angiogenesis in invasive breast carcinoma by morphometry and immunohistochemistry. Med J Armed Forces India 2021; 78:345-354. [DOI: 10.1016/j.mjafi.2021.10.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 10/11/2021] [Indexed: 11/20/2022] Open
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Pereira DR, Silva-Correia J, Oliveira JM, Reis RL, Pandit A. Macromolecular modulation of a 3D hydrogel construct differentially regulates human stem cell tissue-to-tissue interface. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 133:112611. [DOI: 10.1016/j.msec.2021.112611] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/25/2021] [Accepted: 12/11/2021] [Indexed: 01/21/2023]
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Guo K, Xiao N, Liu Y, Wang Z, Tóth J, Gyenis J, Thakur VK, Oyane A, Shubhra QT. Engineering polymer nanoparticles using cell membrane coating technology and their application in cancer treatments: Opportunities and challenges. NANO MATERIALS SCIENCE 2021. [DOI: 10.1016/j.nanoms.2021.12.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Khanam R, Fleischer TC, Boghossian NS, Nisar I, Dhingra U, Rahman S, Fox AC, Ilyas M, Dutta A, Naher N, Polpitiya AD, Mehmood U, Deb S, Choudhury AA, Badsha MB, Muhammad K, Ali SM, Ahmed S, Hickok DE, Iqbal N, Juma MH, Quaiyum MA, Boniface JJ, Yoshida S, Manu A, Bahl R, Jehan F, Sazawal S, Burchard J, Baqui AH. Performance of a validated spontaneous preterm delivery predictor in South Asian and Sub-Saharan African women: a nested case control study. J Matern Fetal Neonatal Med 2021; 35:8878-8886. [PMID: 34847802 DOI: 10.1080/14767058.2021.2005573] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
OBJECTIVES To address the disproportionate burden of preterm birth (PTB) in low- and middle-income countries, this study aimed to (1) verify the performance of the United States-validated spontaneous PTB (sPTB) predictor, comprised of the IBP4/SHBG protein ratio, in subjects from Bangladesh, Pakistan and Tanzania enrolled in the Alliance for Maternal and Newborn Health Improvement (AMANHI) biorepository study, and (2) discover biomarkers that improve performance of IBP4/SHBG in the AMANHI cohort. STUDY DESIGN The performance of the IBP4/SHBG biomarker was first evaluated in a nested case control validation study, then utilized in a follow-on discovery study performed on the same samples. Levels of serum proteins were measured by targeted mass spectrometry. Differences between the AMANHI and U.S. cohorts were adjusted using body mass index (BMI) and gestational age (GA) at blood draw as covariates. Prediction of sPTB < 37 weeks and < 34 weeks was assessed by area under the receiver operator curve (AUC). In the discovery phase, an artificial intelligence method selected additional protein biomarkers complementary to IBP4/SHBG in the AMANHI cohort. RESULTS The IBP4/SHBG biomarker significantly predicted sPTB < 37 weeks (n = 88 vs. 171 terms ≥ 37 weeks) after adjusting for BMI and GA at blood draw (AUC= 0.64, 95% CI: 0.57-0.71, p < .001). Performance was similar for sPTB < 34 weeks (n = 17 vs. 184 ≥ 34 weeks): AUC = 0.66, 95% CI: 0.51-0.82, p = .012. The discovery phase of the study showed that the addition of endoglin, prolactin, and tetranectin to the above model resulted in the prediction of sPTB < 37 with an AUC= 0.72 (95% CI: 0.66-0.79, p-value < .001) and prediction of sPTB < 34 with an AUC of 0.78 (95% CI: 0.67-0.90, p < .001). CONCLUSION A protein biomarker pair developed in the U.S. may have broader application in diverse non-U.S. populations.
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Affiliation(s)
- Rasheda Khanam
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, United States
| | | | - Nansi S Boghossian
- Department of Epidemiology and Biostatistics, University of South Carolina, Arnold School of Public Health, Columbia, United States
| | - Imran Nisar
- Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | - Usha Dhingra
- Global Division, Center for Public Health Kinetics, New Delhi, India
| | | | - Angela C Fox
- Sera Prognostics, Inc., Salt Lake City, United States
| | - Muhammad Ilyas
- Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | - Arup Dutta
- Global Division, Center for Public Health Kinetics, New Delhi, India
| | - Nurun Naher
- Projahnmo Research Foundation, Dhaka, Bangladesh
| | | | - Usma Mehmood
- Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | - Saikat Deb
- Global Division, Center for Public Health Kinetics, New Delhi, India.,Public Health Laboratory-IDC, Pemba, Tanzania
| | | | | | - Karim Muhammad
- Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | | | | | | | - Najeeha Iqbal
- Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | | | - Md Abdul Quaiyum
- International Centre for Diarrheal Disease Research, Dhaka, Bangladesh
| | | | | | - Alexandar Manu
- World Health Organization (MCA/MRD), Geneva, Switzerland
| | - Rajiv Bahl
- World Health Organization (MCA/MRD), Geneva, Switzerland
| | - Fyezah Jehan
- Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan
| | - Sunil Sazawal
- Global Division, Center for Public Health Kinetics, New Delhi, India.,Public Health Laboratory-IDC, Pemba, Tanzania
| | | | - Abdullah H Baqui
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, United States
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The Cardiac Glycoside Deslanoside Exerts Anticancer Activity in Prostate Cancer Cells by Modulating Multiple Signaling Pathways. Cancers (Basel) 2021; 13:cancers13225809. [PMID: 34830961 PMCID: PMC8616045 DOI: 10.3390/cancers13225809] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/03/2021] [Accepted: 11/10/2021] [Indexed: 12/23/2022] Open
Abstract
Simple Summary Prostate cancer is a leading cause of cancer-related deaths among men, and novel therapies for advanced PCa are urgently needed. Cardiac glycosides are a group of attractive candidates for anticancer repurposing, but deslanoside has not been tested for a potential anticancer effect so far. This study aims to test the anticancer effect of deslanoside in PCa and investigate the underlying mechanisms. Deslanoside effectively inhibited colony formation and tumor growth in multiple prostate cancer cell lines. Such an inhibitory effect involved both the cell cycle arrest at G2/M and the induction of apoptosis. Deslanoside altered the expression of many genes, which belonged to various cancer-associated cellular processes and signaling pathways. Altered expression levels for 15 deslanoside-modulated genes correlate with recurrence-free survival or overall survival in PCa patients, some of which have not been implicated in cancer before. Therefore, deslanoside exerts anticancer activity in PCa cells by modulating gene expression. Abstract Prostate cancer (PCa) is a leading cause of cancer-related deaths among men worldwide, and novel therapies for advanced PCa are urgently needed. Cardiac glycosides represent an attractive group of candidates for anticancer repurposing, but the cardiac glycoside deslanoside has not been tested for potential anticancer activity so far. We found that deslanoside effectively inhibited colony formation in vitro and tumor growth in nude mice of PCa cell lines 22Rv1, PC-3, and DU 145. Such an anticancer activity was mediated by both the cell cycle arrest at G2/M and the induction of apoptosis, as demonstrated by different functional assays and the expression status of regulatory proteins of cell cycle and apoptosis in cultured cells. Moreover, deslanoside suppressed the invasion and migration of PCa cell lines. Genome-wide expression profiling and bioinformatic analyses revealed that 130 genes were either upregulated or downregulated by deslanoside in both 22Rv1 and PC-3 cell lines. These genes enriched multiple cellular processes, such as response to steroid hormones, regulation of lipid metabolism, epithelial cell proliferation and its regulation, and negative regulation of cell migration. They also enriched multiple signaling pathways, such as necroptosis, MAPK, NOD-like receptor, and focal adhesion. Survival analyses of the 130 genes in the TCGA PCa database revealed that 10 of the deslanoside-downregulated genes (ITG2B, CNIH2, FBF1, PABPC1L, MMP11, DUSP9, TMEM121, SOX18, CMPK2, and MAMDC4) inversely correlated, while one deslanoside-upregulated gene (RASD1) positively correlated, with disease-free survival in PCa patients. In addition, one deslanoside-downregulated gene (ENG) inversely correlated, while three upregulated genes (JUN, MXD1, and AQP3) positively correlated with overall survival in PCa patients. Some of the 15 genes have not been implicated in cancer before. These findings provide another candidate for repurposing cardiac glycosides for anticancer drugs. They also suggest that a diverse range of molecular events underlie deslanoside’s anticancer activity in PCa cells.
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Douglas SR, Yeung KT, Yang J, Blair SL, Cohen O, Eliceiri BP. Identification of CD105+ Extracellular Vesicles as a Candidate Biomarker for Metastatic Breast Cancer. J Surg Res 2021; 268:168-173. [PMID: 34314883 DOI: 10.1016/j.jss.2021.06.050] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 05/17/2021] [Accepted: 06/14/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND Extracellular vehicles (EVs) released by malignant tumor cells can mediate the immune response and promote metastasis through intercellular communication. EV analysis is an emerging cancer surveillance tool with advantages over traditional liquid biopsy methods. The aim of this pilot study is to identify actionable EV signatures in metastatic breast cancer. MATERIALS AND METHODS Under an IRB-approved protocol for the analysis of patient plasma, samples were collected from women with newly diagnosed or progressive metastatic breast cancer and from women without cancer. Enriched EVs were analyzed via a bead-based multiplex assay designed to detect 37 distinct tumor-relevant epitopes. The mean fluorescent intensity of EV epitopes meeting a minimum threshold of detectability was compared between groups via independent samples t-test. Subgroup analysis was conducted for metastatic breast cancer patients who were positive for estrogen and/or progesterone receptors and negative for HER2. Other variables potentially affecting CD105 levels were also analyzed. RESULTS CD105 was found to have a significantly higher mean fluorescent intensity in participants with metastatic breast cancer compared to control participants (P = 0.04). ER/PR+ subgroup analysis revealed a similar pattern compared to control participants (P = 0.01). Other analyzed variables were not found to have a significant correlation with CD105 levels. CONCLUSIONS CD105 EV levels were significantly higher in samples from participants with breast cancer compared to controls. Given that CD105 is known to mediate angiogenesis and promote metastasis, EV-associated CD105 in plasma represents a potential biomarker for diagnosis, surveillance and therapeutic targeting in patients with metastatic breast cancer.
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Affiliation(s)
- Sasha R Douglas
- Department of Surgery, University of California San Diego, La Jolla, California
| | - Kay T Yeung
- Department of Medicine, Division of Hematology and Oncology, University of California San Diego, La Jolla, California
| | - Jing Yang
- Department of Pharmacology, Moores Cancer Center, University of California San Diego, California
| | - Sarah L Blair
- Division of Breast Surgery and The Comprehensive Breast Health Center, University of California San Diego, La Jolla, California
| | - Olga Cohen
- Department of Surgery, University of California San Diego, La Jolla, California
| | - Brian P Eliceiri
- Department of Surgery, University of California San Diego, La Jolla, California.
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Anti-Angiogenic Treatment in Pseudomyxoma Peritonei-Still a Strong Preclinical Rationale. Cancers (Basel) 2021; 13:cancers13112819. [PMID: 34198773 PMCID: PMC8201024 DOI: 10.3390/cancers13112819] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/02/2021] [Accepted: 06/02/2021] [Indexed: 12/30/2022] Open
Abstract
Simple Summary Patients with pseudomyxoma peritonei that are not cured by the standard treatment (cytoreductive surgery and hyperthermic intraperitoneal chemotherapy) have no efficacious treatment options. Drugs that inhibit formation of new vessels (anti-angiogenic drugs) could be a therapeutic option for these patients. Using patient samples and animal models we show that angiogenesis is important in pseudomyxoma peritonei and that anti-angiogenic drugs may indeed have an effect. Our results support continued efforts to determine the role of anti-angiogenic treatment in pseudomyxoma peritonei. Abstract Pseudomyxoma peritonei (PMP) is a rare, slow-growing cancer characterized by progressive accumulation of intraperitoneal mucinous tumor deposits. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) cures approximately 50% of patients, but in unresectable and recurrent cases, treatment options are limited. Anti-angiogenic treatment is being explored as a potential therapeutic option. Using PMP patient samples, microvessel densities (immunostaining for CD31 and CD105) and pro-angiogenic factors were analyzed, and the proliferative response upon incubation with human umbilical cord vascular endothelial cells (HUVEC) was determined. Growth inhibition by anti-angiogenic drugs was analyzed in patient-derived xenograft models of PMP. PMP tumor tissues were found to be highly vascularized and contained key pro-angiogenic factors, in particular related to vascular endothelial growth factor (VEGF) signaling, but interestingly, high levels of fibroblast growth factor 2 were also detected. HUVEC proliferation was stimulated upon incubation with fresh tumor samples and the observed proliferation could be inhibited by VEGF pathway inhibitor bevacizumab. In xenograft models the two VEGF pathway inhibitors, bevacizumab and aflibercept, inhibited tumor growth. This work reemphasizes the importance of angiogenesis as a major driver in PMP and strengthens the preclinical rationale for continued exploration of angiogenesis inhibition in the hope of providing novel treatment to a group of patients that have few other treatment options.
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Costa Neto H, Andrade ALDLD, Carmo AFD, Freitas RDA, Galvão HC. Involvement of tryptase-positive mast cells and angiogenesis in the growth of inflammatory odontogenic cysts. Braz Oral Res 2021; 35:e061. [PMID: 34076187 DOI: 10.1590/1807-3107bor-2021.vol35.0061] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 02/01/2021] [Indexed: 11/22/2022] Open
Abstract
Inflammatory periapical lesions are characterized by infiltration of different immune cell types, the functions of which depend on an effective vascular network. This study aimed to evaluate the mast cells density (MCD) in inflamatory odontogenic cysts capsules concerning microvascular density (MVD), microvascular area (MVA), and microvascular perimeter (MVP), and correlate such findings with the type of lesion, intensity of the inflammatory infiltrate, and thickness of the epithelial lining. Twenty inflamatory dentigerous cysts (IDCs), twenty radicular cysts (RCs), and twenty residual radicular cysts (RRCs) were submitted to immunohistochemical analysis using anti-tryptase and anti-CD34 antibodies. RCs exhibited the highest MCD, MVD, MVA, and MVP indexes (p = < 0.001, p = 0.008, p = 0.003 and p = < 0.001, respectively), and lesions with inflammatory infiltrate grade III showed the highest MVD (p = 0.044). Considering epithelial thickness, a higher MVP index was identified in lesions with hyperplastic epithelium (p = 0.018). In IDCs, RCs, and RRCs, a strong positive correlation was observed between MVA and MVP (r = 0.950 and p = < 0.001; r = 0.914 and p = < 0.001; r = 0.713 and p = < 0.001, respectively). In IDCs, a moderate correlation was observed between MCD and both MVA and MVP (r = 0.660 and p = 0.002; r = 0.634 and p = 0.003, respectively). These results suggest that tryptase-positive mast cells might play an important role in the angiogenic activity of IDCs, while RCs had the highest indexes. Our findings also confirmed that the intensity of the inflammatory infiltrate and epithelial thickness influence angiogenesis.
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Affiliation(s)
- Hugo Costa Neto
- Universidade Federal do Rio Grande do Norte - UFRN, Department of Dentistry, Natal, RN, Brazil
| | | | | | | | - Hébel Cavalcanti Galvão
- Universidade Federal do Rio Grande do Norte - UFRN, Department of Dentistry, Natal, RN, Brazil
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Choueiri TK, Zakharia Y, Pal S, Kocsis J, Pachynski R, Poprach A, Nixon AB, Liu Y, Starr M, Lyu J, Owzar K, deShazo M, Lara P, Geczi L, Ho TH, Walsh M, Adams B, Robertson L, Darif M, Theuer C, Agarwal N. Clinical Results and Biomarker Analyses of Axitinib and TRC105 versus Axitinib Alone in Patients with Advanced or Metastatic Renal Cell Carcinoma (TRAXAR). Oncologist 2021; 26:560-e1103. [PMID: 33829609 DOI: 10.1002/onco.13777] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/05/2021] [Indexed: 12/17/2022] Open
Abstract
LESSONS LEARNED The combination of carotuximab with axitinib did not provide a benefit over axitinib monotherapy in patients with metastatic clear cell renal cell carcinoma who had previously progressed on one or more vascular endothelial growth factor (VEGF)-targeted therapies. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels. BACKGROUND Endoglin is an angiogenic receptor expressed on proliferating tumor vessels and renal cell carcinoma (RCC) stem cells that is implicated as a mechanism of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors. This study evaluated an antiendoglin monoclonal antibody (carotuximab, TRC105) combined with axitinib in patients with advanced or metastatic clear cell renal cell carcinoma (mccRCC) who had progressed following one or more prior VEGF inhibitors. METHODS TRAXAR was a multicenter, international randomized 1:1 (stratified by ECOG, 0 vs. 1), phase II study of carotuximab combined with axitinib versus axitinib alone in mccRCC patients who had progressed following one or more prior VEGF inhibitors. The primary endpoint was progression-free survival (PFS) assessed by independent central review (ICR) per RECIST 1.1 RESULTS: A total of 150 patients were randomized. The combination therapy resulted in shorter median PFS by RECIST 1.1 than axitinib monotherapy (6.7 vs. 11.4 months). The combination was tolerated similarly to axitinib monotherapy, and there were no treatment related deaths. Exploratory evaluation of pretreatment circulating biomarkers suggested the combination might benefit patients who have low baseline VEGF levels. CONCLUSION The combination of carotuximab with axitinib did not demonstrate additional efficacy over single agent axitinib in patients with mccRCC who progressed following one or more prior VEGF inhibitor treatment.
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Affiliation(s)
| | - Yousef Zakharia
- University of Iowa, Holden Comprehensive Cancer Center, Iowa City, Iowa, USA
| | - Sumanta Pal
- City of Hope National Medical Center, Duarte, California, USA
| | - Judit Kocsis
- Bács-Kiskun County Hospital, Oncoradiology Center, Kecskemét, Hungary
| | - Russell Pachynski
- Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Alexandr Poprach
- Department of Comprehensive Cancer Care and Faculty of Medicine, Masaryk Memorial Cancer Institute and Masaryk University, Brno, Czech Republic
| | - Andrew B Nixon
- Department of Medicine, Duke University Medical Center, Durham, North, Carolina, USA
| | - Yingmiao Liu
- Department of Medicine, Duke University Medical Center, Durham, North, Carolina, USA
| | - Mark Starr
- Department of Medicine, Duke University Medical Center, Durham, North, Carolina, USA
| | - Jing Lyu
- Graduate Group in Biostatistics, University of California Davis, Davis, California, USA
| | - Kouros Owzar
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, USA
| | - Mollie deShazo
- Division of Hematology/Oncology, Department of Internal Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Primo Lara
- University of California, Davis Medical Center, Sacramento, California, USA
| | - Lajos Geczi
- Országos Onkológiai Intézet, Budapest, Hungary
| | - Thai H Ho
- Division of Hematology/Oncology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Meghara Walsh
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Bonne Adams
- TRACON Pharmaceuticals, Inc., San Diego, California, USA
| | - Liz Robertson
- TRACON Pharmaceuticals, Inc., San Diego, California, USA
| | - Mohamed Darif
- TRACON Pharmaceuticals, Inc., San Diego, California, USA
| | - Charles Theuer
- TRACON Pharmaceuticals, Inc., San Diego, California, USA
| | - Neeraj Agarwal
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
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Surov A, Wienke A. Associations Between FDG PET and Expression of VEGF and Microvessel Density in Different Solid Tumors: A Meta-analysis. Acad Radiol 2021; 28:e110-e117. [PMID: 32327296 DOI: 10.1016/j.acra.2020.02.030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 02/29/2020] [Accepted: 02/29/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND To date, there are inconsistent data about relationships between 2-deoxy-2 [18F] fluoro-D-glucose positron emission tomography (FDG-PET) and expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD). The aim of the present meta-analysis was to systematize the reported data about associations between maximal standardized uptake value (SUVmax) derived from FDG PET and expression of VEGF and as well as MVD. METHODS MEDLINE library, SCOPUS and EMBASE data bases were screened for relationships between SUVmax and VEGF/MVD up to October 2019. Overall, in 18 studies correlations between SUVmax and VEGF and in 13 studies correlations between SUVmax and MVD were reported. The following data were extracted from the literature: authors, year of publication, number of patients, and correlation coefficients. RESULTS Associations between 18F-FDG PET and VEGF were reported in 18 studies (935 patients). The calculated correlation coefficients between SUVmax and VEGF expression ranged from -0.16 to 0.88. The pooled correlation coefficient was 0.32, (95% confidence interval [CI] = [0.15; 0.48]). Associations between 18F-FDG PET and MVD were investigated in 13 studies (593 patients). The reported correlation coefficients ranged from -0.23 to 0.91. The pooled correlation coefficient was 0.27, (95% CI = [0.00; 0.53]). Analysis of MVD based on CD105 immunohistochemical staining was performed in four studies (117 patients). The pooled correlation coefficient was 0.41 (95% CI = [0.22; 0.59]). In three reports with 233 patients, MVD was estimated by staining with CD31 antibody. The pooled correlation coefficient was 0.01, (95% CI = [-0.44; 0.47]). Finally, in 9 studies (280 patients) MVD was performed on CD34 stained specimens. The pooled correlation coefficient was 0.36, (95% CI = [0.09; 0.63]). CONCLUSION SUVmax of FDG PET correlated weakly with expression of VEGF and with MVD. Therefore, FDG PET cannot predict neoangiogenesis in malignant tumors.
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Affiliation(s)
- Alexey Surov
- Department of Radiology and Nuclear Medicine, Otto-von-Guericke University Magdeburg, Germany.
| | - Andreas Wienke
- Institute of Medical Epidemiology, Biostatistics, and Informatics, Martin-Luther-University Halle-Wittenberg, Germany
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Jeng KS, Sheen IS, Lin SS, Leu CM, Chang CF. The Role of Endoglin in Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms22063208. [PMID: 33809908 PMCID: PMC8004096 DOI: 10.3390/ijms22063208] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 03/19/2021] [Accepted: 03/19/2021] [Indexed: 12/31/2022] Open
Abstract
Endoglin (CD105) is a type-1 integral transmembrane glycoprotein and coreceptor for transforming growth factor-β (TGF-β) ligands. The endoglin/TGF-β signaling pathway regulates hemostasis, cell proliferation/migration, extracellular matrix (ECM) synthesis and angiogenesis. Angiogenesis contributes to early progression, invasion, postoperative recurrence, and metastasis in hepatocellular carcinoma (HCC), one of the most widespread malignancies globally. Endoglin is overexpressed in newly formed HCC microvessels. It increases microvessel density in cirrhotic and regenerative HCC nodules. In addition, circulating endoglin is present in HCC patients, suggesting potential for use as a diagnostic or prognostic factor. HCC angiogenesis is dynamic and endoglin expression varies by stage. TRC105 (carotuximab) is an antibody against endoglin, and three of its clinical trials were related to liver diseases. A partial response was achieved when combining TRC105 with sorafenib. Although antiangiogenic therapy still carries some risks, combination therapy with endoglin inhibitors or other targeted therapies holds promise.
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Affiliation(s)
- Kuo-Shyang Jeng
- Division of General Surgery, Far Eastern Memorial Hospital, New Taipei 22060, Taiwan; (K.-S.J.); (S.-S.L.)
| | - I-Shyan Sheen
- Department of Hepatogastroenterology, Chang-Gung Memorial Hospital, Linkou Medical Center, Chang-Gung University, Taoyuan city 33305, Taiwan;
| | - Shu-Sheng Lin
- Division of General Surgery, Far Eastern Memorial Hospital, New Taipei 22060, Taiwan; (K.-S.J.); (S.-S.L.)
| | - Chuen-Miin Leu
- Institute of Microbiology and Immunology, National Yang-Ming Chiao-Tung University, Taipei city 11221, Taiwan;
| | - Chiung-Fang Chang
- Division of General Surgery, Far Eastern Memorial Hospital, New Taipei 22060, Taiwan; (K.-S.J.); (S.-S.L.)
- Correspondence: ; Tel.: +886-2-7728-4564
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Low Molecular Weight Hyaluronic Acid Effect on Dental Pulp Stem Cells In Vitro. Biomolecules 2020; 11:biom11010022. [PMID: 33379324 PMCID: PMC7823925 DOI: 10.3390/biom11010022] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 12/22/2020] [Accepted: 12/24/2020] [Indexed: 02/06/2023] Open
Abstract
Hyaluronic acid (HA) and dental pulp stem cells (DPSCs) are attractive research topics, and their combined use in the field of tissue engineering seems to be very promising. HA is a natural extracellular biopolymer found in various tissues, including dental pulp, and due to its biocompatibility and biodegradability, it is also a suitable scaffold material. However, low molecular weight (LMW) fragments, produced by enzymatic cleavage of HA, have different bioactive properties to high molecular weight (HMW) HA. Thus, the impact of HA must be assessed separately for each molecular weight fraction. In this study, we present the effect of three LMW-HA fragments (800, 1600, and 15,000 Da) on DPSCs in vitro. Discrete biological parameters such as DPSC viability, morphology, and cell surface marker expression were determined. Following treatment with LMW-HA, DPSCs initially presented with an acute reduction in proliferation (p < 0.0016) and soon recovered in subsequent passages. They displayed significant size reduction (p = 0.0078, p = 0.0019, p = 0.0098) while maintaining high expression of DPSC markers (CD29, CD44, CD73, CD90). However, in contrast to controls, a significant phenotypic shift (p < 0.05; CD29, CD34, CD90, CD106, CD117, CD146, CD166) of surface markers was observed. These findings provide a basis for further detailed investigations and present a strong argument for the importance of HA scaffold degradation kinetics analysis.
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Liu Y, Paauwe M, Nixon AB, Hawinkels LJ. Endoglin Targeting: Lessons Learned and Questions That Remain. Int J Mol Sci 2020; 22:ijms22010147. [PMID: 33375670 PMCID: PMC7795616 DOI: 10.3390/ijms22010147] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 12/21/2020] [Accepted: 12/22/2020] [Indexed: 12/13/2022] Open
Abstract
Approximately 30 years ago, endoglin was identified as a transforming growth factor (TGF)-β coreceptor with a crucial role in developmental biology and tumor angiogenesis. Its selectively high expression on tumor vessels and its correlation with poor survival in cancer patients led to the exploration of endoglin as a therapeutic target for cancer. The endoglin neutralizing antibody TRC105 (Carotuximab®, Tracon Pharmaceuticals (San Diego, CA, USA) was subsequently tested in a wide variety of preclinical cancer models before being tested in phase I-III clinical studies in cancer patients as both a monotherapy and in combination with other chemotherapeutic and anti-angiogenic therapies. The combined data of these studies have revealed new insights into the role of endoglin in angiogenesis and its expression and functional role on other cells in the tumor microenvironment. In this review, we will summarize the preclinical work, clinical trials and biomarker studies of TRC105 and explore what these studies have enabled us to learn and what questions remain unanswered.
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Affiliation(s)
- Yingmiao Liu
- Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; (Y.L.); (A.B.N.)
| | - Madelon Paauwe
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
| | - Andrew B. Nixon
- Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; (Y.L.); (A.B.N.)
| | - Lukas J.A.C. Hawinkels
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
- Correspondence: ; Tel.: +31-71-526-6736
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Petinati N, Kapranov N, Davydova Y, Bigildeev A, Pshenichnikova O, Karpenko D, Drize N, Kuzmina L, Parovichnikova E, Savchenko V. Immunophenotypic characteristics of multipotent mesenchymal stromal cells that affect the efficacy of their use in the prevention of acute graft vs host disease. World J Stem Cells 2020; 12:1377-1395. [PMID: 33312405 PMCID: PMC7705461 DOI: 10.4252/wjsc.v12.i11.1377] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/31/2020] [Accepted: 09/01/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Multipotent mesenchymal stromal cells (MSCs) are widely used in the clinic due to their unique properties, namely, their ability to differentiate in all mesenchymal directions and their immunomodulatory activity. Healthy donor MSCs were used to prevent the development of acute graft vs host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT). The administration of MSCs to patients was not always effective. The MSCs obtained from different donors have individual characteristics. The differences between MSC samples may affect their clinical efficacy.
AIM To study the differences between effective and ineffective MSCs.
METHODS MSCs derived from the bone marrow of a hematopoietic stem cells donor were injected intravenously into allo-BMT recipients for GVHD prophylaxis at the moment of blood cell reconstitution. Aliquots of 52 MSC samples that were administered to patients were examined, and the same cells were cultured in the presence of peripheral blood mononuclear cells (PBMCs) from a third-party donor or treated with the pro-inflammatory cytokines IL-1β, IFN and TNF. Flow cytometry revealed the immunophenotype of the nontreated MSCs, the MSCs cocultured with PBMCs for 4 d and the MSCs exposed to cytokines. The proportions of CD25-, CD146-, CD69-, HLA-DR- and PD-1-positive CD4+ and CD8+ cells and the distribution of various effector and memory cell subpopulations in the PBMCs cocultured with the MSCs were also determined.
RESULTS Differences in the immunophenotypes of effective and ineffective MSCs were observed. In the effective samples, the mean fluorescence intensity (MFI) of HLA-ABC, HLA-DR, CD105, and CD146 was significantly higher. After MSCs were treated with IFN or cocultured with PBMCs, the HLA-ABC, HLA-DR, CD90 and CD54 MFI showed a stronger increase in the effective MSCs, which indicated an increase in the immunomodulatory activity of these cells. When PBMCs were cocultured with effective MSCs, the proportions of CD4+ and CD8+central memory cells significantly decreased, and the proportion of CD8+CD146+ lymphocytes increased more than in the subpopulations of lymphocytes cocultured with MSC samples that were ineffective in the prevention of GVHD; in addition, the proportion of CD8+effector memory lymphocytes decreased in the PBMCs cocultured with the effective MSC samples but increased in the PBMCs cocultured with the ineffective MSC samples. The proportion of CD4+CD146+ lymphocytes increased only when cocultured with the inefficient samples.
CONCLUSION For the first time, differences were observed between MSC samples that were effective for GVHD prophylaxis and those that were ineffective. Thus, it was shown that the immunomodulatory activity of MSCs depends on the individual characteristics of the MSC population.
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Affiliation(s)
- Nataliya Petinati
- Laboratory for Physiology of Hematopoiesis, National Research Center for Hematology, Moscow 125167, Russia
| | - Nikolay Kapranov
- Laboratory for Immunophenotyping of Blood and Bone Marrow Cells, National Research Center for Hematology, Moscow 125167, Russia
| | - Yulia Davydova
- Laboratory for Immunophenotyping of Blood and Bone Marrow Cells, National Research Center for Hematology, Moscow 125167, Russia
| | - Alexey Bigildeev
- Laboratory for Physiology of Hematopoiesis, National Research Center for Hematology, Moscow 125167, Russia
| | - Olesya Pshenichnikova
- Laboratory for Genetic Engineering, National Research Center for Hematology, Moscow 125167, Russia
| | - Dmitriy Karpenko
- Laboratory for Physiology of Hematopoiesis, National Research Center for Hematology, Moscow 125167, Russia
| | - Nina Drize
- Laboratory for Physiology of Hematopoiesis, National Research Center for Hematology, Moscow 125167, Russia
| | - Larisa Kuzmina
- Hematopoiesis Depression and Bone Marrow Transplantation Department, National Research Center for Hematology, Moscow 125167, Russia
| | - Elena Parovichnikova
- Hematopoiesis Depression and Bone Marrow Transplantation Department, National Research Center for Hematology, Moscow 125167, Russia
| | - Valeriy Savchenko
- Hematopoiesis Depression and Bone Marrow Transplantation Department, National Research Center for Hematology, Moscow 125167, Russia
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Co-Culture of Primary Human Coronary Artery and Internal Thoracic Artery Endothelial Cells Results in Mutually Beneficial Paracrine Interactions. Int J Mol Sci 2020; 21:ijms21218032. [PMID: 33126651 PMCID: PMC7663246 DOI: 10.3390/ijms21218032] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/21/2020] [Accepted: 10/27/2020] [Indexed: 12/12/2022] Open
Abstract
Although saphenous veins (SVs) are commonly used as conduits for coronary artery bypass grafting (CABG), internal thoracic artery (ITA) grafts have significantly higher long-term patency. As SVs and ITA endothelial cells (ECs) have a considerable level of heterogeneity, we suggested that synergistic paracrine interactions between CA and ITA ECs (HCAECs and HITAECs, respectively) may explain the increased resistance of ITA grafts and adjacent CAs to atherosclerosis and restenosis. In this study, we measured the gene and protein expression of the molecules responsible for endothelial homeostasis, pro-inflammatory response, and endothelial-to-mesenchymal transition in HCAECs co-cultured with either HITAECs or SV ECs (HSaVECs) for an ascending duration. Upon the co-culture, HCAECs and HITAECs showed augmented expression of endothelial nitric oxide synthase (eNOS) and reduced expression of endothelial-to-mesenchymal transition transcription factors Snail and Slug when compared to the HCAEC–HSaVEC model. HCAECs co-cultured with HITAECs demonstrated an upregulation of HES1, a master regulator of arterial specification, of which the expression was also exclusively induced in HSaVECs co-cultured with HCAECs, suggestive of their arterialisation. In addition, co-culture of HCAECs and HITAECs promoted the release of pro-angiogenic molecules. To conclude, co-culture of HCAECs and HITAECs results in reciprocal and beneficial paracrine interactions that might contribute to the better performance of ITA grafts upon CABG.
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Leal V, Ribeiro CF, Oliveiros B, António N, Silva S. Intrinsic Vascular Repair by Endothelial Progenitor Cells in Acute Coronary Syndromes: an Update Overview. Stem Cell Rev Rep 2020; 15:35-47. [PMID: 30345477 DOI: 10.1007/s12015-018-9857-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Bone marrow-derived endothelial progenitor cells (EPCs) play a key role in the maintenance of endothelial homeostasis and endothelial repair at areas of vascular damage. The quantification of EPCs in peripheral blood by flow cytometry is a strategy to assess this reparative capacity. The number of circulating EPCs is inversely correlated with the number of cardiovascular risk factors and to the occurrence of cardiovascular events. Therefore, monitoring EPCs levels may provide an accurate assessment of susceptibility to cardiovascular injury, greatly improving risk stratification of patients with high cardiovascular risk, such as those with an acute myocardial infarction. However, there are many issues in the field of EPC identification and quantification that remain unsolved. In fact, there have been conflicting protocols used to the phenotypic identification of EPCs and there is still no consensual immunophenotypical profile that corresponds exactly to EPCs. In this paper we aim to give an overview on EPCs-mediated vascular repair with special focus on acute coronary syndromes and to discuss the different phenotypic profiles that have been used to identify and quantify circulating EPCs in several clinical studies. Finally, we will synthesize evidence on the prognostic role of EPCs in patients with high cardiovascular risk.
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Affiliation(s)
- Vânia Leal
- Group of Pharmacology and Pharmaceutical Care, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.
| | - Carlos Fontes Ribeiro
- Institute of Pharmacology and Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Bárbara Oliveiros
- Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal.,Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Natália António
- Institute of Pharmacology and Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Cardiology Department, Coimbra Hospital and Universitary Centre, Coimbra, Portugal
| | - Sónia Silva
- Group of Pharmacology and Pharmaceutical Care, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.,Institute of Pharmacology and Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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Evaluation of microvessel density with CD31 and CD105 in patients with psoriasis under methotrexate and acitretin therapy. Postepy Dermatol Alergol 2020; 37:422-427. [PMID: 32792887 PMCID: PMC7394166 DOI: 10.5114/ada.2019.87279] [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: 11/02/2018] [Accepted: 11/19/2018] [Indexed: 11/18/2022] Open
Abstract
Introduction Methotrexate and acitretin are known to be effective in the treatment of psoriasis, but the mechanisms of the effects of these drugs are not fully known. Aim To investigate the effect of methotrexate and acitretin on microvessel density (MVD) in psoriasis. Material and methods Eighteen patients with psoriasis treated with methotrexate and 9 patients with psoriasis treated with acitretin (AT) were included in this study. MVD was evaluated immunohistochemically by using CD31 and CD105 (endoglin) antibodies. Results In the methotrexate group, the decrease in CD31 levels after treatment was found to be statistically significant, while in the AT group it was found to be highly significant. In both methotrexate and AT group, there was a statistically highly significant decrease in CD105 levels after treatment. There was no statistically significant difference between CD31 measurements of methotrexate and AT groups. When CD105 levels were measured before and after treatment, no statistically significant difference was found between methotrexate and AT. According to the results of CD31 changes before and after treatment, the CD31 difference was not statistically significant in both groups while the difference was higher in the AT group. CD105 differences were not statistically significant in both treatment groups before and after treatment. Conclusions CD31 and CD105 dyes indicate the effects of therapies on vascular proliferation and may be indicators that can be used in daily routine and follow-up studies for psoriasis.
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Komaki S, Sugita Y, Furuta T, Yamada K, Moritsubo M, Abe H, Akiba J, Miyagi N, Nakamura H, Miyoshi H, Ohshima K, Morioka M. Expression of GLUT1 in Pseudopalisaded and Perivascular Tumor Cells Is an Independent Prognostic Factor for Patients With Glioblastomas. J Neuropathol Exp Neurol 2020; 78:389-397. [PMID: 30990881 PMCID: PMC6467190 DOI: 10.1093/jnen/nly124] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Glioblastomas are highly aggressive brain tumors with a particularly poor prognosis. Glucose transporter-1 (GLUT1/SLC2A1), a uniporter that is expressed by various carcinomas and may be involved in malignant neoplasm glycometabolism, may also be related to prognosis in glioblastomas. GLUT1 is essential to central nervous system glycometabolism. To clarify the exact role of GLUT1 in glioblastoma, we assessed the expression and localization of GLUT1 in patient samples by immunohistochemistry and in situ RNA hybridization. This revealed that GLUT1 was mainly expressed on perivascular and pseudopalisaded tumor cell membranes. All samples expressed GLUT1 to some degree, with 30.8% showing stronger staining. On the basis of these data, samples were divided into high and low expression groups, although SLC2A1 mRNA expression was also higher in the high GLUT1 expression group. Kaplan-Meier survival curves revealed that high GLUT1 expression associated with lower overall survival (log-rank test, p = 0.001) and worse patient prognoses (p = 0.001). Finally, MIB-1 staining was stronger in high GLUT1 expression samples (p = 0.0004), suggesting a link with proliferation. We therefore hypothesize that GLUT1 expression in glioblastomas may enhance glycolysis, affecting patient prognosis. Examination of GLUT1 in patients with glioblastomas may provide a new prognostic tool to improve outcome.
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Affiliation(s)
- Satoru Komaki
- Departments of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.,Neurosurgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Yasuo Sugita
- Departments of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Takuya Furuta
- Departments of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Kyohei Yamada
- Departments of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Mayuko Moritsubo
- Departments of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Hideyuki Abe
- Diagnostic Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Jun Akiba
- Diagnostic Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Naohisa Miyagi
- Neurosurgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Hideo Nakamura
- Neurosurgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Hiroaki Miyoshi
- Departments of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Koichi Ohshima
- Departments of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Motohiro Morioka
- Neurosurgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan
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Nair A, Ingram N, Verghese ET, Wijetunga I, Markham AF, Wyatt J, Prasad KR, Coletta PL. CD105 is a prognostic marker and valid endothelial target for microbubble platforms in cholangiocarcinoma. Cell Oncol (Dordr) 2020; 43:835-845. [PMID: 32468445 PMCID: PMC7581571 DOI: 10.1007/s13402-020-00530-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/30/2020] [Indexed: 12/22/2022] Open
Abstract
Purpose The current treatment outcomes in cholangiocarcinoma are poor with cure afforded only by surgical extirpation. The efficacy of targeting the tumoural endothelial marker CD105 in cholangiocarcinoma, as a basis for potential microbubble-based treatment, is unknown and was explored here. Methods Tissue expression of CD105 was quantified using immunohistochemistry in 54 perihilar cholangiocarcinoma samples from patients who underwent resection in a single centre over a ten-year period, and analysed against clinicopathological data. In vitro flow assays using microbubbles functionalised with CD105 antibody were conducted to ascertain specificity of binding to murine SVR endothelial cells. Finally, CD105-microbubbles were intravenously administered to 10 Balb/c nude mice bearing heterotopic subcutaneous human extrahepatic cholangiocarcinoma (TFK-1 and EGI-1) xenografts after which in vivo binding was assessed following contrast-enhanced destruction replenishment ultrasound application. Results Though not significantly associated with any examined clinicopathological variable, we found that higher CD105 expression was independently associated with poorer patient survival (median 12 vs 31 months; p = 0.002). In vitro studies revealed significant binding of CD105-microbubbles to SVR endothelial cells in comparison to isotype control (p = 0.01), as well as in vivo to TFK-1 (p = 0.02) and EGI-1 (p = 0.04) mouse xenograft vasculature. Conclusion Our results indicate that CD105 is a biomarker eminently suitable for cholangiocarcinoma targeting using functionalised microbubbles.
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Affiliation(s)
- Amit Nair
- Leeds Institute of Medical Research, St James's University Hospital, Leeds, LS9 7TF, UK.
| | - Nicola Ingram
- Leeds Institute of Medical Research, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Eldo T Verghese
- Leeds Institute of Medical Research, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Imeshi Wijetunga
- Leeds Institute of Medical Research, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Alexander F Markham
- Leeds Institute of Medical Research, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Judy Wyatt
- Department of Histopathology, St James's University Hospital, Leeds, LS9 7TF, UK
| | - K Rajendra Prasad
- Department of Hepatobiliary and Transplant Surgery, St James's University Hospital, Leeds, LS9 7TF, UK
| | - P Louise Coletta
- Leeds Institute of Medical Research, St James's University Hospital, Leeds, LS9 7TF, UK
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Andreuzzi E, Capuano A, Poletto E, Pivetta E, Fejza A, Favero A, Doliana R, Cannizzaro R, Spessotto P, Mongiat M. Role of Extracellular Matrix in Gastrointestinal Cancer-Associated Angiogenesis. Int J Mol Sci 2020; 21:E3686. [PMID: 32456248 PMCID: PMC7279269 DOI: 10.3390/ijms21103686] [Citation(s) in RCA: 19] [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: 05/04/2020] [Revised: 05/20/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023] Open
Abstract
Gastrointestinal tumors are responsible for more cancer-related fatalities than any other type of tumors, and colorectal and gastric malignancies account for a large part of these diseases. Thus, there is an urgent need to develop new therapeutic approaches to improve the patients' outcome and the tumor microenvironment is a promising arena for the development of such treatments. In fact, the nature of the microenvironment in the different gastrointestinal tracts may significantly influence not only tumor development but also the therapy response. In particular, an important microenvironmental component and a potential therapeutic target is the vasculature. In this context, the extracellular matrix is a key component exerting an active effect in all the hallmarks of cancer, including angiogenesis. Here, we summarized the current knowledge on the role of extracellular matrix in affecting endothelial cell function and intratumoral vascularization in the context of colorectal and gastric cancer. The extracellular matrix acts both directly on endothelial cells and indirectly through its remodeling and the consequent release of growth factors. We envision that a deeper understanding of the role of extracellular matrix and of its remodeling during cancer progression is of chief importance for the development of new, more efficacious, targeted therapies.
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Affiliation(s)
- Eva Andreuzzi
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Alessandra Capuano
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Evelina Poletto
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Eliana Pivetta
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Albina Fejza
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Andrea Favero
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Roberto Doliana
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Renato Cannizzaro
- Department of Clinical Oncology, Experimental Gastrointestinal Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy;
| | - Paola Spessotto
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Maurizio Mongiat
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
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Xu B, Ye J, Yuan FZ, Zhang JY, Chen YR, Fan BS, Jiang D, Jiang WB, Wang X, Yu JK. Advances of Stem Cell-Laden Hydrogels With Biomimetic Microenvironment for Osteochondral Repair. Front Bioeng Biotechnol 2020; 8:247. [PMID: 32296692 PMCID: PMC7136426 DOI: 10.3389/fbioe.2020.00247] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 03/10/2020] [Indexed: 12/12/2022] Open
Abstract
Osteochondral damage from trauma or osteoarthritis is a general joint disease that can lead to an increased social and economic burden in the modern society. The inefficiency of osteochondral defects is mainly due to the absence of suitable tissue-engineered substrates promoting tissue regeneration and replacing damaged areas. The hydrogels are becoming a promising kind of biomaterials for tissue regeneration. The biomimetic hydrogel microenvironment can be tightly controlled by modulating a number of biophysical and biochemical properties, including matrix mechanics, degradation, microstructure, cell adhesion, and intercellular interactions. In particular, advances in stem cell-laden hydrogels have offered new ideas for the cell therapy and osteochondral repair. Herein, the aim of this review is to underpin the importance of stem cell-laden hydrogels on promoting the development of osteochondral regeneration, especially in the field of manipulation of biomimetic microenvironment and utilization growth factors with various delivery methods.
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Affiliation(s)
- Bingbing Xu
- Knee Surgery Department of the Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
| | - Jing Ye
- Knee Surgery Department of the Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
| | - Fu-Zhen Yuan
- Knee Surgery Department of the Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
| | - Ji-Ying Zhang
- Knee Surgery Department of the Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
| | - You-Rong Chen
- Knee Surgery Department of the Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
| | - Bao-Shi Fan
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Dong Jiang
- Knee Surgery Department of the Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
| | - Wen-Bo Jiang
- Clinical Translational R&D Center of 3D Printing Technology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xing Wang
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics & Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jia-Kuo Yu
- Knee Surgery Department of the Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
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Haybar H, Maleki Behzad M, Shahrabi S, Ansari N, Saki N. Expression of Blood Cells Associated CD Markers and Cardiovascular Diseases: Clinical Applications in Prognosis. Lab Med 2020; 51:122-142. [PMID: 31340048 DOI: 10.1093/labmed/lmz049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Cardiovascular diseases (CVDs) are a major cause of mortality worldwide. The results of various studies have shown that abnormality in the frequency and function of blood cells can be involved in CVD complications. In this review, we have focused on abnormalities in the expression of the CD (cluster of differentiation) markers of blood cells to assess the association of these abnormalities with CVD prognosis. METHODS We identified the relevant literature through a PubMed search (1990-2018) of English-language articles using the terms "Cardiovascular diseases", "CD markers", "leukocytes", "platelets", and "endothelial cells". RESULTS There is a variety of mechanisms for the effect of CD-marker expressions on CVDs prognosis, ranging from proinflammatory processes to dysfunctional effects in blood cells. CONCLUSION Considering the possible effects of CD-marker expression on CVDs prognosis, particularly prognosis of acute myocardial infarction and atherosclerosis, long-term studies in large cohorts are required to identify the prognostic value of CD markers and to target them with appropriate therapeutic agents.
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Affiliation(s)
- Habib Haybar
- Atherosclerosis Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Masumeh Maleki Behzad
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeid Shahrabi
- Department of Biochemistry and Hematology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Narges Ansari
- Isfahan Bone Metabolic Disorders Research Center, Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Najmaldin Saki
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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