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Eissazadeh S, Fikrova P, Rathouska JU, Nemeckova I, Tripska K, Vasinova M, Havelek R, Mohammadi S, Igreja Sa IC, Theuer C, König M, Micuda S, Nachtigal P. Anti-Endoglin monoclonal antibody prevents the progression of liver sinusoidal endothelial inflammation and fibrosis in MASH. Life Sci 2025; 364:123428. [PMID: 39889923 DOI: 10.1016/j.lfs.2025.123428] [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: 11/11/2024] [Revised: 01/22/2025] [Accepted: 01/27/2025] [Indexed: 02/03/2025]
Abstract
Liver sinusoidal endothelial inflammation/dysfunction and fibrosis are a crucial part of Metabolic Dysfunction Associated Steatohepatitis (MASH) development. TRC105 and M1043 are anti-endoglin (ENG) monoclonal antibodies that bind ENG. In this study, we hypothesized that treatment with anti-ENG antibodies would prevent the progression of LSECs inflammation and fibrosis in vivo and in vitro. MASH was induced in male C57BL/6 mice fed a choline-deficient L-amino acid-defined high-fat diet (CDAA-HFD) for 4 or 8 weeks. In the rescue study, mice were divided into three groups: a control group (chow diet), a MASH group (CDAA-HFD + IgG), and a rescue group (CDAA-HFD + M1043). Later, two groups received rat IgG1 (10 mg/kg) and M1043 (10 mg/kg). In in vitro experiments, inflammation was induced in human LSECs by ox-LDL (50 μg/mL) and treated with TRC105 (300 μg/mL). Liver sinusoidal endothelial inflammation/dysfunction in MASH animals was characterized by endothelial overexpression of ENG, VCAM-1, and ICAM-1 and reduced VE-cadherin and p-eNOS/eNOS expression. M1043 treatment prevented the overexpression of ENG, VCAM-1, and ICAM-1, the progression of liver fibrosis, and the increase of liver-to-body weight ratio. In vitro experiments with TRC105 confirmed the prevention of LSECs inflammation development by reduced ENG and VCAM-1 expression, as well as decreased THP-1 monocytic cell adhesion in ox-LDL activated LSECs. In conclusion, we demonstrate that anti-ENG antibody treatment can prevent LSECs inflammation and fibrosis progression in a MASH animal model and LSECs inflammation in vitro. Thus, we propose directly targeted ENG may represent a promising pharmacological approach for addressing LSECs inflammation and liver fibrosis.
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Affiliation(s)
- Samira Eissazadeh
- Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Petra Fikrova
- Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Jana Urbankova Rathouska
- Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Ivana Nemeckova
- Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Katarina Tripska
- Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Martina Vasinova
- Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Radim Havelek
- Department of Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - SeyedehNiloufar Mohammadi
- Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Ivone Cristina Igreja Sa
- Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic; Department of Clinical Microbiology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Charles Theuer
- Tracon Pharmaceuticals, Inc., San Diego, CA, United States
| | - Matthias König
- Institute for Theoretical Biology, Institute for Biology, Systems Medicine of the Liver, Humboldt University Berlin, Germany
| | - Stanislav Micuda
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Petr Nachtigal
- Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic.
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Pedersen C, Chen VT, Herbst P, Zhang R, Elfert A, Krishan A, Azar DT, Chang JH, Hu WY, Kremsmayer TP, Jalilian E, Djalilian AR, Guaiquil VH, Rosenblatt MI. Target specification and therapeutic potential of extracellular vesicles for regulating corneal angiogenesis, lymphangiogenesis, and nerve repair. Ocul Surf 2024; 34:459-476. [PMID: 39426677 PMCID: PMC11921040 DOI: 10.1016/j.jtos.2024.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/16/2024] [Accepted: 10/15/2024] [Indexed: 10/21/2024]
Abstract
Extracellular vesicles, including exosomes, are small extracellular vesicles that range in size from 30 nm to 10 μm in diameter and have specific membrane markers. They are naturally secreted and are present in various bodily fluids, including blood, urine, and saliva, and through the variety of their internal cargo, they contribute to both normal physiological and pathological processes. These processes include immune modulation, neuronal synapse formation, cell differentiation, cancer metastasis, angiogenesis, lymphangiogenesis, progression of infectious disease, and neurodegenerative disorders like Alzheimer's and Parkinson's disease. In recent years, interest has grown in the use of exosomes as a potential drug delivery system for various diseases and injuries. Importantly, exosomes originating from a patient's own cells exhibit minimal immunogenicity and possess remarkable stability along with inherent and adjustable targeting capabilities. This review explores the roles of exosomes in angiogenesis, lymphangiogenesis, and nerve repair with a specific emphasis on these processes within the cornea. Furthermore, it examines exosomes derived from specific cell types, discusses the advantages of exosome-based therapies in modulating these processes, and presents some of the most established methods for exosome isolation. Exosome-based treatments are emerging as potential minimally invasive and non-immunogenic therapies that modulate corneal angiogenesis and lymphangiogenesis, as well as enhance and accelerate endogenous corneal nerve repair.
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Affiliation(s)
- Cameron Pedersen
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Victoria T Chen
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Paula Herbst
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Runze Zhang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Amr Elfert
- University of Illinois Cancer Center, Chicago, IL, USA
| | - Abhi Krishan
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Dimitri T Azar
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Jin-Hong Chang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
| | - Wen-Yang Hu
- Department of Urology, University of Illinois at Chicago, Chicago, IL, USA
| | - Tobias P Kremsmayer
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Elmira Jalilian
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA; Richard and Loan Hill Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60607, USA
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Victor H Guaiquil
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Mark I Rosenblatt
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
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Braczkowski MJ, Kufel KM, Kulińska J, Czyż DŁ, Dittmann A, Wiertelak M, Młodzik MS, Braczkowski R, Soszyński D. Pleiotropic Action of TGF-Beta in Physiological and Pathological Liver Conditions. Biomedicines 2024; 12:925. [PMID: 38672279 PMCID: PMC11048627 DOI: 10.3390/biomedicines12040925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 04/12/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
The aim of this study is to review and analyze the pleiotropic effects of TGF-β in physiological and pathological conditions of the liver, with particular emphasis on its role in immune suppression, wound healing, regulation of cell growth and differentiation, and liver cell apoptosis. A literature review was conducted, including 52 studies, comprising review articles, in vitro and in vivo studies, and meta-analyses. Only studies published in peer-reviewed scientific journals were included in the analysis. TGF-β is a pleiotropic growth factor that is crucial for the liver, both in physiology and pathophysiology. Although its functions are complex and diverse, TGF-β plays a constant role in immune suppression, wound healing, and the regulation of cell growth and differentiation. In concentrations exceeding the norm, it can induce the apoptosis of liver cells. Increased TGF-β levels are observed in many liver diseases, such as fibrosis, inflammation, and steatosis. TGF-β has been shown to play a key role in many physiological and pathological processes of the liver, and its concentration may be a potential diagnostic and prognostic marker in liver diseases.
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Affiliation(s)
- Michał Jakub Braczkowski
- Department of Physiology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland;
| | - Klaudia Maria Kufel
- Student Scientific Society of Physiology, Department of Physiology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland; (K.M.K.); (J.K.); (A.D.); (M.W.)
| | - Julia Kulińska
- Student Scientific Society of Physiology, Department of Physiology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland; (K.M.K.); (J.K.); (A.D.); (M.W.)
| | - Daniel Łukasz Czyż
- Student Scientific Society of Physiology, Department of Physiology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland; (K.M.K.); (J.K.); (A.D.); (M.W.)
| | - Aleksander Dittmann
- Student Scientific Society of Physiology, Department of Physiology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland; (K.M.K.); (J.K.); (A.D.); (M.W.)
| | - Michał Wiertelak
- Student Scientific Society of Physiology, Department of Physiology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland; (K.M.K.); (J.K.); (A.D.); (M.W.)
| | - Marcin Sławomir Młodzik
- Department of Pathology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland;
| | | | - Dariusz Soszyński
- Department of Physiology, Institute of Medical Sciences, University of Opole, 45040 Opole, Poland;
- Department of Human Physiology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 87100 Torun, Poland
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Abstract
PURPOSE OF THE REVIEW Angiogenesis plays a key role in bladder cancer (BC) pathogenesis. In the last two decades, an increasing number of publications depicting a multitude of novel angiogenic molecules and pathways have emerged. The growing complexity necessitates an evaluation of the breadth of current knowledge to highlight key findings and guide future research. RECENT FINDINGS Angiogenesis is a dynamic biologic process that is inherently difficult to assess. Clinical assessment of angiogenesis in BCs is advancing with the integration of image analysis systems and dynamic contrast-enhanced and magnetic resonance imaging (DCE-MRI). Tumour-associated macrophages (TAMs) significantly influence the angiogenic process, and further research is needed to assess their potential as therapeutic targets. A rapidly growing list of non-coding RNAs affect angiogenesis in BCs, partly through modulation of vascular endothelial growth factor (VEGF) activity. Vascular mimicry (VM) has been repeatedly associated with increased tumour aggressiveness in BCs. Standardised assays are needed for appropriate identification and quantification of VM channels. This article demonstrates the dynamic and complex nature of the angiogenic process and asserts the need for further studies to deepen our understanding.
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Affiliation(s)
- Ghada Elayat
- Department of Natural Science, Middlesex University, London, UK
- Department of Histopathology, Tanta University, Tanta, Egypt
| | - Ivan Punev
- Department of Natural Science, Middlesex University, London, UK
| | - Abdel Selim
- Histopathology Department, King’s Health Partners, King’s College Hospital, London, UK
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Curcuminoids Inhibit Angiogenic Behaviors of Human Umbilical Vein Endothelial Cells via Endoglin/Smad1 Signaling. Int J Mol Sci 2022; 23:ijms23073889. [PMID: 35409247 PMCID: PMC8998963 DOI: 10.3390/ijms23073889] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/26/2022] [Accepted: 03/30/2022] [Indexed: 12/26/2022] Open
Abstract
Background: Angiogenesis is primarily attributed to the excessive proliferation and migration of endothelial cells. Targeting the vascular endothelial growth factor (VEGF) is therefore significant in anti-angiogenic therapy. Although these treatments have not reached clinical expectations, the upregulation of alternative angiogenic pathways (endoglin/Smad1) may play a critical role in drug (VEGF-neutralizing agents) resistance. Enhanced endoglin expression following a VEGF-neutralizing therapy (semaxanib®) was noted in patients. Treatment with an endoglin-targeting antibody augmented VEGF expression in human umbilical vein endothelial cells (HUVECs). Therefore, approaches that inhibit both the androgen and VEGF pathways enhance the HUVECs cytotoxicity and reverse semaxanib resistance. The purpose of this study was to find natural-occurring compounds that inhibited the endoglin-targeting pathway. Methods: Curcuminoids targeting endoglin were recognized from two thousand compounds in the Traditional Chinese Medicine Database@Taiwan (TCM Database@Taiwan) using Discovery Studio 4.5. Results: Our results, obtained using cytotoxicity, migration/invasion, and flow cytometry assays, showed that curcumin (Cur) and demethoxycurcumin (DMC) reduced angiogenesis. In addition, Cur and DMC downregulated endoglin/pSmad1 phosphorylation. Conclusions: The study first showed that Cur and DMC demonstrated antiangiogenic activity via the inhibition of endoglin/Smad1 signaling. Synergistic effects of curcuminoids (i.e., curcumin and DMC) and semaxanib on HUVECs were found. This might be attributed to endoglin/pSmad1 downregulation in HUVECs. Combination treatment with curcuminoids and a semaxanib is therefore expected to reverse semaxanib resistance.
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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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Peng L, Gautrot JE. Long term expansion profile of mesenchymal stromal cells at protein nanosheet-stabilised bioemulsions for next generation cell culture microcarriers. Mater Today Bio 2021; 12:100159. [PMID: 34841241 PMCID: PMC8605361 DOI: 10.1016/j.mtbio.2021.100159] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 11/10/2021] [Accepted: 11/13/2021] [Indexed: 12/27/2022] Open
Abstract
Tremendous progress in the identification, isolation and expansion of stem cells has allowed their application in regenerative medicine and tissue engineering, and their use as advanced in vitro models. As a result, stem cell manufacturing increasingly requires scale up, parallelisation and automation. However, solid substrates currently used for the culture of adherent cells are poorly adapted for such applications, owing to their difficult processing from cell products, relatively high costs and their typical reliance on difficult to recycle plastics and microplastics. In this work, we show that bioemulsions formed of microdroplets stabilised by protein nanosheets displaying strong interfacial mechanics are well-suited for the scale up of adherent stem cells such as mesenchymal stromal cells (MSCs). We demonstrate that, over multiple passages (up to passage 10), MSCs retain comparable phenotypes when cultured on such bioemulsions, solid microcarriers (Synthemax II) and classic 2D tissue culture polystyrene. Phenotyping (cell proliferation, morphometry, flow cytometry and differentiation assays) of MSCs cultured for multiple passages on these systems indicate that, although stemness is lost at late passages when cultured on these different substrates, stem cell phenotypes remained comparable between different culture conditions, at any given passage. Hence our study validates the use of bioemulsions for the long term expansion of adherent stem cells and paves the way to the design of novel 3D bioreactors based on microdroplet microcarriers.
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Affiliation(s)
- Lihui Peng
- Institute of Bioengineering and, UK.,School of Engineering and Materials Science, Queen Mary, University of London, Mile End Road, London, E1 4NS, UK
| | - Julien E Gautrot
- Institute of Bioengineering and, UK.,School of Engineering and Materials Science, Queen Mary, University of London, Mile End Road, London, E1 4NS, UK
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FOXA1 promotes prostate cancer angiogenesis by inducing multiple pro-angiogenic factors expression. J Cancer Res Clin Oncol 2021; 147:3225-3243. [PMID: 34258652 DOI: 10.1007/s00432-021-03730-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 07/05/2021] [Indexed: 01/04/2023]
Abstract
PURPOSE FOXA1, as a pioneering transcription factor, has been shown to drive prostate cancer progression. Previous studies showed that FOXA1 expression in prostate cancer was positively associated with cancer angiolymphatic invasion and metastasis. However, the mechanism underlying the correlation between FOXA1 and prostate cancer angiolymphatic invasion and metastasis remains largely unclear. METHODS Herein, we set out to investigate the role of FOXA1 in the interactions between prostate cancer cells and endothelial cells. Endothelial cells' phenotypes were assessed through CCK-8 assay, Transwell migration assay, and tube formation assay. The angiogenic factors acting on endothelial cells mediated by FOXA1were characterized by RNA-seq, qPCR array, angiogenesis cytokines array, and ELISA assay. The impact of FOXA1 on tumor angiogenesis was examined in a xenograft model in nude mice. The effect of FOXA1 on prostate cancer angiogenesis was validated on a primary prostate cancer tissue microarray. RESULTS FOXA1 expression in prostate cancer cells promoted endothelial cell proliferation, migration, and tube formation in vitro. Mechanistically, FOXA1 increased pro-angiogenic factors production, including EGF, Endothelin-1, and Endoglin. Moreover, in vivo study showed that FOXA1 facilitated tumor angiogenesis. Furthermore, clinical samples investigation indicated that FOXA1 enhanced prostate cancer angiogenesis. CONCLUSION Overall, these findings illustrated a tumor angiogenesis-promoting role of FOXA1 in prostate cancer.
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Ollauri-Ibáñez C, Ayuso-Íñigo B, Pericacho M. Hot and Cold Tumors: Is Endoglin (CD105) a Potential Target for Vessel Normalization? Cancers (Basel) 2021; 13:1552. [PMID: 33800564 PMCID: PMC8038031 DOI: 10.3390/cancers13071552] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/24/2021] [Accepted: 03/26/2021] [Indexed: 12/15/2022] Open
Abstract
Tumors are complex masses formed by malignant but also by normal cells. The interaction between these cells via cytokines, chemokines, growth factors, and enzymes that remodel the extracellular matrix (ECM) constitutes the tumor microenvironment (TME). This TME can be determinant in the prognosis and the response to some treatments such as immunotherapy. Depending on their TME, two types of tumors can be defined: hot tumors, characterized by an immunosupportive TME and a good response to immunotherapy; and cold tumors, which respond poorly to this therapy and are characterized by an immunosuppressive TME. A therapeutic strategy that has been shown to be useful for the conversion of cold tumors into hot tumors is vascular normalization. In this review we propose that endoglin (CD105) may be a useful target of this strategy since it is involved in the three main processes involved in the generation of the TME: angiogenesis, inflammation, and cancer-associated fibroblast (CAF) accumulation. Moreover, the analysis of endoglin expression in tumors, which is already used in the clinic to study the microvascular density and that is associated with worse prognosis, could be used to predict a patient's response to immunotherapy.
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Affiliation(s)
| | | | - Miguel Pericacho
- Renal and Cardiovascular Research Unit, Group of Physiopathology of the Vascular Endothelium (ENDOVAS), Biomedical Research Institute of Salamanca (IBSAL), Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain; (C.O.-I.); (B.A.-Í.)
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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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Elkholy RA, Fouda MH, Elhawary EE, Elkholy RA, Elshora OA. Impact of CD105 Flow-Cytometric Expression on Childhood B-Acute Lymphoblastic Leukemia. J Blood Med 2021; 12:147-156. [PMID: 33758569 PMCID: PMC7981143 DOI: 10.2147/jbm.s300067] [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: 01/01/2021] [Accepted: 03/02/2021] [Indexed: 11/23/2022] Open
Abstract
Background CD105 (Endoglin) is a receptor of the transforming growth factor-Beta (TGF- β) superfamily. It is expressed in angiogenic endothelial cells and is considered a powerful marker of angiogenesis and a potential main player in the pathogenesis of vascular diseases as well as tumor progression. CD105 expression was correlated with poor prognosis in many types of solid malignancies, however, its influence on hematological neoplasms is still an area of interest. Purpose To assess the flow-cytometric expression of CD105 in childhood B-acute lymphoblastic leukemia (B-ALL) and its relation to disease response after the induction chemotherapy. Subjects and Methods Eighty children newly diagnosed with B-ALL were screened for flow-cytometric expression of CD105 at time of diagnosis, then they were followed up to detect their response to induction therapy. Results CD105 was expressed in 41.2% of B-ALL patients. Higher expression of CD105 was observed in high and very high-risk groups. The multivariate analysis considered CD105 positivity as an independent prognostic marker for response to induction therapy. Values higher than 2.5 Specific fluorescence indices (SFIs) and 35% expression were sensitive predictors to induction failure. Conclusion CD105 can be considered as a potential prognostic marker for the detection of response to induction therapy in childhood B-ALL, and it can serve to optimize treatment decisions.
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Affiliation(s)
- Rasha A Elkholy
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohamed H Fouda
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Eslam E Elhawary
- Pediatrics Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Reem A Elkholy
- Pharmacology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Ola A Elshora
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
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12
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Zeaxanthin-Rich Extract from Superfood Lycium barbarum Selectively Modulates the Cellular Adhesion and MAPK Signaling in Melanoma versus Normal Skin Cells In Vitro. Molecules 2021; 26:molecules26020333. [PMID: 33440679 PMCID: PMC7827977 DOI: 10.3390/molecules26020333] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/28/2020] [Accepted: 01/02/2021] [Indexed: 12/12/2022] Open
Abstract
The concern for implementing bioactive nutraceuticals in antioxidant-related therapies is of great importance for skin homeostasis in benign or malignant diseases. In order to elucidate some novel insights of Lycium barbarum (Goji berry) activity on skin cells, the present study focused on its active compound zeaxanthin. By targeting the stemness markers CD44 and CD105, with deep implications in skin oxidative stress mechanisms, we revealed, for the first time, selectivity in zeaxanthin activity. When applied in vitro on BJ human fibroblast cell line versus the A375 malignant melanoma cells, despite the moderate cytotoxicity, the zeaxanthin-rich extracts 1 and 2 were able to downregulate significantly the CD44 and CD105 membrane expression and extracellular secretion in A375, and to upregulate them in BJ cells. At mechanistic level, the present study is the first to demonstrate that the zeaxanthin-rich Goji extracts are able to influence selectively the mitogen-activated protein kinases (MAPK): ERK, JNK and p38 in normal BJ versus tumor-derived A375 skin cells. These results point out towards the applications of zeaxanthin from L. barbarum as a cytoprotective agent in normal skin and raises questions about its use as an antitumor prodrug alone or in combination with standard therapy.
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13
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Pouloudi D, Sotiriadis A, Theodorakidou M, Sarantis P, Pergaris A, Karamouzis MV, Theocharis S. The Impact of Angiogenesis in the Most Common Salivary Gland Malignant Tumors. Int J Mol Sci 2020; 21:ijms21249335. [PMID: 33302367 PMCID: PMC7762607 DOI: 10.3390/ijms21249335] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/26/2020] [Accepted: 12/04/2020] [Indexed: 12/14/2022] Open
Abstract
Salivary gland carcinomas (SGCs) represent a group of rare tumors, with complete surgical resection being the main treatment option. Therapeutic armory for cases of locally aggressive, recurrent, and/or metastatic SGCs, though, remains poor since they exhibit high rates of resistance to systematic therapy. Angiogenesis is considered one of the contemporary hallmarks of cancer and anti-angiogenic factors have already been approved for the treatment of several cancer types. This review aims to summarize, in a histotype-specific manner, the most current available data on the angiogenic factors implicated in SGC angiogenesis, in order to highlight the differences between the most common SGC histotypes and the factors that may have a potential role as therapeutic targets.
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Affiliation(s)
- Despoina Pouloudi
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.P.); (A.S.); (M.T.); (A.P.)
| | - Aristoteles Sotiriadis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.P.); (A.S.); (M.T.); (A.P.)
| | - Margarita Theodorakidou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.P.); (A.S.); (M.T.); (A.P.)
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.)
| | - Alexandros Pergaris
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.P.); (A.S.); (M.T.); (A.P.)
| | - Michalis V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (M.V.K.)
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (D.P.); (A.S.); (M.T.); (A.P.)
- Correspondence: or ; Tel.: +30-210-7462178; Fax: +30-210-7456259
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14
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Jonsdottir-Buch SM, Gunnarsdottir K, Sigurjonsson OE. Human Embryonic-Derived Mesenchymal Progenitor Cells (hES-MP Cells) are Fully Supported in Culture with Human Platelet Lysates. Bioengineering (Basel) 2020; 7:bioengineering7030075. [PMID: 32698321 PMCID: PMC7552691 DOI: 10.3390/bioengineering7030075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/09/2020] [Accepted: 07/19/2020] [Indexed: 12/28/2022] Open
Abstract
Human embryonic stem cell-derived mesenchymal progenitor (hES-MP) cells are mesenchymal-like cells, derived from human embryonic stem cells without the aid of feeder cells. They have been suggested as a potential alternative to mesenchymal stromal cells (MSCs) in regenerative medicine due to their mesenchymal-like proliferation and differentiation characteristics. Cells and cell products intended for regenerative medicine in humans should be derived, expanded and differentiated using conditions free of animal-derived products to minimize risk of animal-transmitted disease and immune reactions to foreign proteins. Human platelets are rich in growth factors needed for cell culture and have been used successfully as an animal serum replacement for MSC expansion and differentiation. In this study, we compared the proliferation of hES-MP cells and MSCs; the hES-MP cell growth was sustained for longer than that of MSCs. Growth factors, gene expression, and surface marker expression in hES-MP cells cultured with either human platelet lysate (hPL) or fetal bovine serum (FBS) supplementation were compared, along with differentiation to osteogenic and chondrogenic lineages. Despite some differences between hES-MP cells grown in hPL- and FBS-supplemented media, hPL was found to be a suitable replacement for FBS. In this paper, we demonstrate for the first time that hES-MP cells can be grown using platelet lysates from expired platelet concentrates (hPL).
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Affiliation(s)
- Sandra M. Jonsdottir-Buch
- The Blood Bank, Landspitali—The National University Hospital of Iceland, Snorrabraut 60, 101 Reykjavik, Iceland; (S.M.J.-B.); (K.G.)
- Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, Iceland
- Platome Biotechnology, Alfaskeid 27, 220 Hafnarfjordur, Iceland
| | - Kristbjorg Gunnarsdottir
- The Blood Bank, Landspitali—The National University Hospital of Iceland, Snorrabraut 60, 101 Reykjavik, Iceland; (S.M.J.-B.); (K.G.)
- Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, Iceland
| | - Olafur E. Sigurjonsson
- The Blood Bank, Landspitali—The National University Hospital of Iceland, Snorrabraut 60, 101 Reykjavik, Iceland; (S.M.J.-B.); (K.G.)
- Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, Iceland
- Platome Biotechnology, Alfaskeid 27, 220 Hafnarfjordur, Iceland
- School of Science and Engineering, University of Reykjavik, Menntavegur 1, 101 Reykjavik, Iceland
- Correspondence: ; Tel.: +354-543-5523 or +354-694-9427
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15
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CD105 (endoglin) as risk marker in AML patients undergoing stem cell transplantation. Int J Hematol 2020; 112:57-64. [PMID: 32266669 DOI: 10.1007/s12185-020-02875-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/27/2020] [Accepted: 03/29/2020] [Indexed: 10/24/2022]
Abstract
Several genetic and molecular markers are general predictors of outcome in acute myeloid leukemia (AML), but only few are predictive of outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). Novel markers are needed to improve treatment decisions regarding HSCT. CD105 (endoglin) is a type I transmembrane protein capable of activating endothelial cells. Moreover, CD105 mediates stem cell properties of hematopoietic stem cells and enables repopulation within the bone marrow. Expression of CD105 on vessels of solid tumors and on AML blasts is correlated with poor prognosis. We recently demonstrated that CD105 expression is an independent predictor of overall survival in AML. However, its role in patients receiving intensive treatment with consecutive allogenic transplantation has not been assessed. Using flow cytometry, we analyzed primary samples of 41 patients who underwent HSCT. Using the previously defined SFI cut-off of 5.2, we identified differences in CD105 expression regarding FAB classification and NCCN risk score. Moreover, we detected differences regarding transplant indication and WHO classification with regards to CD105 surface levels. In patients undergoing HSCT high CD105 expression correlated significantly with poor overall survival. We identify CD105 expression in AML as prognostic marker for outcome after HSCT in AML.
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16
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Sakamoto R, Kajihara I, Miyauchi H, Maeda-Otsuka S, Yamada-Kanazawa S, Sawamura S, Kanemaru H, Makino K, Aoi J, Makino T, Fukushima S, Masuzawa M, Masuzawa M, Amoh Y, Hoshina D, Abe R, Ihn H. Inhibition of Endoglin Exerts Antitumor Effects through the Regulation of Non-Smad TGF-β Signaling in Angiosarcoma. J Invest Dermatol 2020; 140:2060-2072.e6. [PMID: 32142796 DOI: 10.1016/j.jid.2020.01.031] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 01/10/2020] [Accepted: 01/30/2020] [Indexed: 12/21/2022]
Abstract
Angiosarcoma is a rare malignant tumor derived from endothelial cells, and its prognosis is poor because advanced angiosarcoma is often resistant to taxane therapy. Endoglin (CD105) acts as a coreceptor for TGF-β signaling and is overexpressed in tumor-associated endothelial cells and enhances tumor angiogenesis. Numerous clinical trials are testing the effectiveness of anti-endoglin antibodies in various types of malignancies. Here, we investigated the role of endoglin in the pathogenesis of angiosarcoma and whether endoglin inhibition results in antitumor activity. Endoglin was overexpressed in angiosarcoma, and its inhibition was effective in promoting apoptosis and the suppression of migration, invasion, tube formation, and Warburg effect in angiosarcoma cells. Knockdown of endoglin activated caspase 3/7 that is essential for apoptosis, reduced survivin levels, and decreased paxillin and vascular endothelial cadherin phosphorylation and matrix metalloproteinase 2 and matrix metalloproteinase 9 activities in angiosarcoma cells. Although endoglin is a coreceptor that regulates TGF-β signaling, the antitumor effect of endoglin in angiosarcoma was not based on Smad signaling regulation but on non-Smad TGF-β signaling. Taken together, these results indicated that endoglin could be a novel therapeutic target for angiosarcoma.
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Affiliation(s)
- Ryoko Sakamoto
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Ikko Kajihara
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
| | - Hitomi Miyauchi
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Saki Maeda-Otsuka
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Saori Yamada-Kanazawa
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Soichiro Sawamura
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hisashi Kanemaru
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Katsunari Makino
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Jun Aoi
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Takamitsu Makino
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Satoshi Fukushima
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Mamiko Masuzawa
- Department of Dermatology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Mikio Masuzawa
- Department of Molecular Diagnostics, School of Allied Health Sciences, Kitasato University, Kanagawa, Japan
| | - Yasuyuki Amoh
- Department of Dermatology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Daichi Hoshina
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan
| | - Riichiro Abe
- Department of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hironobu Ihn
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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17
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DLC-1 tumor suppressor regulates CD105 expression on human non-small cell lung carcinoma cells through inhibiting TGF-β1 signaling. Exp Cell Res 2020; 386:111732. [DOI: 10.1016/j.yexcr.2019.111732] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 10/31/2019] [Accepted: 11/15/2019] [Indexed: 12/13/2022]
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Abstract
While several genetic and morphological markers are established and serve to guide therapy of acute myeloid leukaemia (AML), there is still profound need to identify additional markers to better stratify patients. CD105 (Endoglin) is a type I transmembrane protein reported to induce activation and proliferation of endothelial cells. In addition, CD105 is expressed in haematological malignancies and the vessels of solid tumours. Here, CD105 associates with unfavourable disease course, but so far no data are available on the prognostic relevance of CD105 in haematological malignancies. We here generated a novel CD105 antibody for analysis of expression and prognostic relevance of CD105 in a cohort of 62 AML patients. Flow cytometric analysis revealed substantial expression in the various AML FAB types, with FAB M3 type displaying significantly lower surface levels. Next we established a cut-off specific fluorescence level of 5.22 using receiver-operating characteristics, which allowed to group patients in cases with CD105lo and CD105hi surface expression and revealed that high CD105 expression correlated significantly with poor overall and progression free survival. In conclusion, we here identify CD105 expression as a novel prognostic marker in AML, which may serve to optimize follow up and treatment decisions for AML patients.
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19
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Kasprzak A, Adamek A. Role of Endoglin (CD105) in the Progression of Hepatocellular Carcinoma and Anti-Angiogenic Therapy. Int J Mol Sci 2018; 19:E3887. [PMID: 30563158 PMCID: PMC6321450 DOI: 10.3390/ijms19123887] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 12/02/2018] [Accepted: 12/03/2018] [Indexed: 02/08/2023] Open
Abstract
The liver is perfused by both arterial and venous blood, with a resulting abnormal microenvironment selecting for more-aggressive malignancies. Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, the sixth most common cancer globally, and the third leading cause of cancer-related mortality worldwide. HCC is characterized by its hypervascularization. Improving the efficiency of anti-angiogenic treatment and mitigation of anti-angiogenic drug resistance are the top priorities in the development of non-surgical HCC therapies. Endoglin (CD105), a transmembrane glycoprotein, is one of the transforming growth factor β (TGF-β) co-receptors. Involvement of that protein in angiogenesis of solid tumours is well documented. Endoglin is a marker of activated endothelial cells (ECs), and is preferentially expressed in the angiogenic endothelium of solid tumours, including HCC. HCC is associated with changes in CD105-positive ECs within and around the tumour. The large spectrum of endoglin effects in the liver is cell-type- and HCC- stage-specific. High expression of endoglin in non-tumour tissue suggests that this microenvironment might play an especially important role in the progression of HCC. Evaluation of tissue expression, as well as serum concentrations of this glycoprotein in HCC, tends to confirm its role as an important biomarker in HCC diagnosis and prognosis. The role of endoglin in liver fibrosis and HCC progression also makes it an attractive therapeutic target. Despite these facts, the exact molecular mechanisms of endoglin functioning in hepatocarcinogenesis are still poorly understood. This review summarizes the current data concerning the role and signalling pathways of endoglin in hepatocellular carcinoma development and progression, and provides an overview of the strategies available for a specific targeting of CD105 in anti-angiogenic therapy in HCC.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Poznań 60-781, Poland.
| | - Agnieszka Adamek
- Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, University of Medical Sciences, Poznań 61-285, Poland.
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20
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Mastio J, Simand C, Cova G, Kastner P, Chan S, Kirstetter P. Ikaros cooperates with Notch activation and antagonizes TGFβ signaling to promote pDC development. PLoS Genet 2018; 14:e1007485. [PMID: 30001316 PMCID: PMC6042690 DOI: 10.1371/journal.pgen.1007485] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 06/13/2018] [Indexed: 12/17/2022] Open
Abstract
Plasmacytoid and conventional dendritic cells (pDCs and cDCs) arise from monocyte and dendritic progenitors (MDPs) and common dendritic progenitors (CDPs) through gene expression changes that remain partially understood. Here we show that the Ikaros transcription factor is required for DC development at multiple stages. Ikaros cooperates with Notch pathway activation to maintain the homeostasis of MDPs and CDPs. Ikaros then antagonizes TGFβ function to promote pDC differentiation from CDPs. Strikingly, Ikaros-deficient CDPs and pDCs express a cDC-like transcriptional signature that is correlated with TGFβ activation, suggesting that Ikaros is an upstream negative regulator of the TGFβ pathway and a repressor of cDC-lineage genes in pDCs. Almost all of these phenotypes can be rescued by short-term in vitro treatment with γ-secretase inhibitors, which affects both TGFβ-dependent and -independent pathways, but is Notch-independent. We conclude that Ikaros is a crucial differentiation factor in early dendritic progenitors that is required for pDC identity. Dendritic cells (DCs) are an important component of the immune system, and exist as two major subtypes: conventional DCs (cDCs) which present antigen via major histocompatibility class II molecules, and plasmacytoid DCs (pDCs) which act mainly as producers of type-I interferon in response to viral infections. Both types of DCs derive from a common dendritic progenitor (CDP), but the genetic pathways that influence their development are not completely understood. A better understanding of these pathways is important, which may lead to protocols for generating specific DCs in culture, depending on the need. In this study, we have discovered important roles for the Ikaros transcription factor in DC development. We found that: (i) Ikaros cooperates with the Notch pathway to promote the development or homeostasis of CDPs; (ii) Ikaros controls pDC differentiation from CDPs through a γ-secretase sensitive pathway; and (iii) Ikaros antagonizes the TGFβ pathway to inhibit cDC differentiation. Our results thus identify Ikaros as a key player in the early steps of DC development.
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Affiliation(s)
- Jérôme Mastio
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS UMR 7104, Université de Strasbourg, Illkirch, France
| | - Célestine Simand
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS UMR 7104, Université de Strasbourg, Illkirch, France
| | - Giovanni Cova
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS UMR 7104, Université de Strasbourg, Illkirch, France
| | - Philippe Kastner
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS UMR 7104, Université de Strasbourg, Illkirch, France.,Faculté de Médecine, Université de Strasbourg, Strasbourg, France
| | - Susan Chan
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS UMR 7104, Université de Strasbourg, Illkirch, France
| | - Peggy Kirstetter
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS UMR 7104, Université de Strasbourg, Illkirch, France
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21
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Hosseinzadeh A, Javad-Moosavi SA, Reiter RJ, Hemati K, Ghaznavi H, Mehrzadi S. Idiopathic pulmonary fibrosis (IPF) signaling pathways and protective roles of melatonin. Life Sci 2018; 201:17-29. [PMID: 29567077 DOI: 10.1016/j.lfs.2018.03.032] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 03/13/2018] [Accepted: 03/15/2018] [Indexed: 12/19/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by the progressive loss of lung function due to tissue scarring. A variety of pro-inflammatory and pro-fibrogenic factors including interleukin‑17A, transforming growth factor β, Wnt/β‑catenin, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factors, endotelin‑1, renin angiotensin system and impaired caveolin‑1 function are involved in the IPF pathogenesis. Current therapies for IPF have some limitations and this highlights the need for effective therapeutic agents to treat this fatal disease. Melatonin and its metabolites are broad-spectrum antioxidants that not only remove reactive oxygen and nitrogen species by radical scavenging but also up-regulate the expression and activity of endogenous antioxidants. Via these actions, melatonin and its metabolites modulate a variety of molecular pathways in different pathophysiological conditions. Herein, we review the signaling pathways involved in the pathophysiology of IPF and the potentially protective effects of melatonin on these pathways.
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Affiliation(s)
- Azam Hosseinzadeh
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health, San Antonio, TX, USA
| | - Karim Hemati
- Department of Anesthesiology, Iran University of Medical Sciences, Tehran, Iran; Department of Anesthesiology, Ilam University of Medical Sciences, Ilam, Iran
| | - Habib Ghaznavi
- Department of Pharmacology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Saeed Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
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22
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Ingram PN, Hind LE, Jiminez-Torres JA, Huttenlocher A, Beebe DJ. An Accessible Organotypic Microvessel Model Using iPSC-Derived Endothelium. Adv Healthc Mater 2018; 7. [PMID: 29364596 DOI: 10.1002/adhm.201700497] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 07/03/2017] [Indexed: 12/30/2022]
Abstract
While organotypic approaches promise increased relevance through the inclusion of increased complexity (e.g., 3D extracellular microenvironment, structure/function relationships, presence of multiple cell types), cell source is often overlooked. Induced pluripotent stem cell (iPSC)-derived cells are potentially more physiologically relevant than cell lines, while also being less variable than primary cells, and recent advances have made them commercially available at costs similar to cell lines. Here, the use of induced pluripotent stem cell-derived endothelium for the generation of a functional microvessel model is demonstrated. High precision structural and microenvironmental control afforded by the design approach synergizes with the advantages of iPSC to produce microvessels for modeling endothelial biology in vitro. iPSC microvessels show endothelial characteristics, exhibit barrier function, secrete angiogenic and inflammatory mediators, and respond to changes in the extracellular microenvironment by altering vessel phenotype. Importantly, when deployed in the investigation of neutrophils during innate immune recruitment, the presence of the iPSC endothelial vessel facilitates neutrophil extravasation and migration toward a chemotactic source. Relevant cell sources, such as iPSC, combine with organotypic models to open the way for improved and increasingly accessible in vitro tissue, disease, and patient-specific models.
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Affiliation(s)
- Patrick N. Ingram
- Department of Biomedical Engineering; Wisconsin Institutes for Medical Research; University of Wisconsin-Madison; WIMR I Room 6028, 1111 Highland Ave Madison WI 53705 USA
| | - Laurel E. Hind
- Departments of Pediatrics and Medical Microbiology and Immunology; University of Wisconsin-Madison; Microbial Sciences Building Room 4205, 1550 Linden Dr Madison WI 53705 USA
| | - Jose A. Jiminez-Torres
- Department of Biomedical Engineering; Wisconsin Institutes for Medical Research; University of Wisconsin-Madison; WIMR I Room 6028, 1111 Highland Ave Madison WI 53705 USA
| | - Anna Huttenlocher
- Departments of Pediatrics and Medical Microbiology and Immunology; University of Wisconsin-Madison; Microbial Sciences Building Room 4205, 1550 Linden Dr Madison WI 53705 USA
| | - David J. Beebe
- Department of Biomedical Engineering; Wisconsin Institutes for Medical Research; University of Wisconsin-Madison; WIMR I Room 6028, 1111 Highland Ave Madison WI 53705 USA
- University of Wisconsin Carbone Cancer Center; University of Wisconsin-Madison; WIMR I Room 6009, 1111 Highland Ave Madison WI 53705 USA
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23
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Peker KD, Ozkanli SS, Akyuz C, Uzun O, Yasar NF, Duman M, Yol S. Preoperative immunonutrition regulates tumor infiltrative lymphocytes and increases tumor angiogenesis in gastric cancer patients. Arch Med Sci 2017; 13:1365-1372. [PMID: 29181067 PMCID: PMC5701679 DOI: 10.5114/aoms.2016.60054] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 08/06/2015] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION An increased number of tumor infiltrative lymphocytes (TILs) is considered a favorable prognostic factor in various cancers because it is a marker of antitumoral activity of the immune system. In this prospective, non-randomized clinical trial, we evaluated the impact of preoperative immunonutrition on tumor infiltrative lymphocytes and neoangiogenesis in cancerous tissue in patients with locoregional and resectable gastric adenocarcinoma. MATERIAL AND METHODS Patients with locoregional and resectable gastric adenocarcinoma were divided non-randomly into two study groups. The first (control) group included patients who had standard nutrition, and the second group included those who had immunonutrition for 7 days before surgery. The biopsy samples taken endoscopically in the preoperative period, as well as the gastrectomy samples, were subjected to immunohistochemical staining for quantitative analysis of CD4, CD8, CD16, CD56, CD31 and CD105 antibodies. Main outcome measures were CD4-to-CD8 ratio and CD105 levels. RESULTS Fifty patients were included in the study between January 2013 and December 2014. Twenty-five patients were assigned to each of the first and second group. The CD4-to-CD8 ratio and CD105 levels determined in endoscopic biopsy samples were similar in both groups. The CD4-to-CD8 ratio in gastrectomy samples was significantly higher in the first group (p = 0.0001). The CD105 levels in gastrectomy samples were significantly lower in the first group (p = 0.01). CONCLUSIONS Seven-day preoperative immunonutrition use regulates TILs in gastric cancer patients, but prolonged use increases tumor angiogenesis.
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Affiliation(s)
- Kivanc Derya Peker
- Department of Gastroenterologic Surgery, Kartal Kosuyolu Training and Research Hospital, Istanbul, Turkey
| | - Sidika Seyma Ozkanli
- Department of Pathology, Medical Faculty, Istanbul Medeniyet University, Istanbul, Turkey
| | - Cebrail Akyuz
- Department of Gastroenterologic Surgery, Kartal Kosuyolu Training and Research Hospital, Istanbul, Turkey
| | - Orhan Uzun
- Department of Gastroenterologic Surgery, Kartal Kosuyolu Training and Research Hospital, Istanbul, Turkey
| | - Necdet Fatih Yasar
- Department of Gastroenterologic Surgery, Kartal Kosuyolu Training and Research Hospital, Istanbul, Turkey
| | - Mustafa Duman
- Department of Gastroenterologic Surgery, Kartal Kosuyolu Training and Research Hospital, Istanbul, Turkey
| | - Sinan Yol
- Department of General Surgery and Subspecialty (Gastrointestinal) Surgery, Faculty of Health Sciences, Istanbul Medeniyet University, Istanbul, Turkey
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Núñez-Gómez E, Pericacho M, Ollauri-Ibáñez C, Bernabéu C, López-Novoa JM. The role of endoglin in post-ischemic revascularization. Angiogenesis 2016; 20:1-24. [PMID: 27943030 DOI: 10.1007/s10456-016-9535-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 11/29/2016] [Indexed: 12/12/2022]
Abstract
Following arterial occlusion, blood vessels respond by forming a new network of functional capillaries (angiogenesis), by reorganizing preexisting capillaries through the recruitment of smooth muscle cells to generate new arteries (arteriogenesis) and by growing and remodeling preexisting collateral arterioles into physiologically relevant arteries (collateral development). All these processes result in the recovery of organ perfusion. The importance of endoglin in post-occlusion reperfusion is sustained by several observations: (1) endoglin expression is increased in vessels showing active angiogenesis/remodeling; (2) genetic endoglin haploinsufficiency in humans causes deficient angiogenesis; and (3) the reduction of endoglin expression by gene disruption or the administration of endoglin-neutralizing antibodies reduces angiogenesis and revascularization. However, the precise role of endoglin in the several processes associated with revascularization has not been completely elucidated and, in some cases, the function ascribed to endoglin by different authors is controversial. The purpose of this review is to organize in a critical way the information available for the role of endoglin in several phenomena (angiogenesis, arteriogenesis and collateral development) associated with post-ischemic revascularization.
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Affiliation(s)
- Elena Núñez-Gómez
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.,Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - Miguel Pericacho
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.,Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - Claudia Ollauri-Ibáñez
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.,Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - Carmelo Bernabéu
- Centro de Investigaciones Biológicas, Spanish National Research Council (CIB, CSIC), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
| | - José M López-Novoa
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain. .,Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.
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Casey SC, Amedei A, Aquilano K, Azmi AS, Benencia F, Bhakta D, Bilsland AE, Boosani CS, Chen S, Ciriolo MR, Crawford S, Fujii H, Georgakilas AG, Guha G, Halicka D, Helferich WG, Heneberg P, Honoki K, Keith WN, Kerkar SP, Mohammed SI, Niccolai E, Nowsheen S, Vasantha Rupasinghe HP, Samadi A, Singh N, Talib WH, Venkateswaran V, Whelan RL, Yang X, Felsher DW. Cancer prevention and therapy through the modulation of the tumor microenvironment. Semin Cancer Biol 2015; 35 Suppl:S199-S223. [PMID: 25865775 PMCID: PMC4930000 DOI: 10.1016/j.semcancer.2015.02.007] [Citation(s) in RCA: 265] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 02/26/2015] [Accepted: 02/27/2015] [Indexed: 02/06/2023]
Abstract
Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer.
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Affiliation(s)
- Stephanie C Casey
- Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, United States
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Katia Aquilano
- Department of Biology, University of Rome "Tor Vergata", Rome, Italy
| | - Asfar S Azmi
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States
| | - Fabian Benencia
- Department of Biomedical Sciences, Ohio University, Athens, OH, United States
| | - Dipita Bhakta
- School of Chemical and Biotechnology, SASTRA University, Thanjavur 613401, Tamil Nadu, India
| | - Alan E Bilsland
- Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Chandra S Boosani
- Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE, United States
| | - Sophie Chen
- Ovarian and Prostate Cancer Research Laboratory, Guildford, Surrey, United Kingdom
| | | | - Sarah Crawford
- Department of Biology, Southern Connecticut State University, New Haven, CT, United States
| | - Hiromasa Fujii
- Department of Orthopedic Surgery, Nara Medical University, Kashihara, Japan
| | - Alexandros G Georgakilas
- Physics Department, School of Applied Mathematics and Physical Sciences, National Technical University of Athens, Athens, Greece
| | - Gunjan Guha
- School of Chemical and Biotechnology, SASTRA University, Thanjavur 613401, Tamil Nadu, India
| | | | - William G Helferich
- University of Illinois at Urbana-Champaign, Champaign-Urbana, IL, United States
| | - Petr Heneberg
- Charles University in Prague, Third Faculty of Medicine, Prague, Czech Republic
| | - Kanya Honoki
- Department of Orthopedic Surgery, Nara Medical University, Kashihara, Japan
| | - W Nicol Keith
- Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Sid P Kerkar
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Sulma I Mohammed
- Department of Comparative Pathobiology, Purdue University Center for Cancer Research, West Lafayette, IN, United States
| | | | - Somaira Nowsheen
- Medical Scientist Training Program, Mayo Graduate School, Mayo Medical School, Mayo Clinic, Rochester, MN, United States
| | - H P Vasantha Rupasinghe
- Department of Environmental Sciences, Faculty of Agriculture, Dalhousie University, Nova Scotia, Canada
| | | | - Neetu Singh
- Advanced Molecular Science Research Centre (Centre for Advanced Research), King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Wamidh H Talib
- Department of Clinical Pharmacy and Therapeutics, Applied Science University, Amman, Jordan
| | | | - Richard L Whelan
- Mount Sinai Roosevelt Hospital, Icahn Mount Sinai School of Medicine, New York City, NY, United States
| | - Xujuan Yang
- University of Illinois at Urbana-Champaign, Champaign-Urbana, IL, United States
| | - Dean W Felsher
- Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, United States.
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Huang YK, Liu H, Wang XZ, Zhu S. Annexin A2 and CD105 expression in pancreatic ductal adenocarcinoma is associated with tumor recurrence and prognosis. Asian Pac J Cancer Prev 2015; 15:9921-6. [PMID: 25520129 DOI: 10.7314/apjcp.2014.15.22.9921] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
To investigate the value of expression of annexin A2, microvessel density (MVD) and CD105 in pancreatic ductal adenocarcinoma (PDAC) tissues and adjacent normal tissues, immunohistochemical staining was used. The positive expression rate of Annexin A2 and the MVD in pancreatic ductal adenocarcinoma tissues was higher than that in in adjacent normal tissues (p<0.005). Expression of Annexin A2 and MVD correlated with histological grade (p<0.05). MVD of cancers in TNM stage IIb was higher than that in TNM stageI~IIa (p<0.026). Cancerous tissues with Annexin A2 staining grade 3+ had lower MVD than the tissues with the other Annexin A2 staining grade (p<0.05). Patients with high MVD had worse prognosis. However , our study did not confirm Annexin A2 was an independent risk factor for patients with PDAC. We confirmed MVD labeled by CD105 was an independent risk factor for patients with PDAC and had moderate predictive value of prognosis.
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Affiliation(s)
- Ya-Kai Huang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China E-mail :
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Lee JG, Bak SY, Nahm JH, Lee SW, Min SO, Kim KS. Toward angiogenesis of implanted bio-artificial liver using scaffolds with type I collagen and adipose tissue-derived stem cells. KOREAN JOURNAL OF HEPATO-BILIARY-PANCREATIC SURGERY 2015; 19:47-58. [PMID: 26155277 PMCID: PMC4494077 DOI: 10.14701/kjhbps.2015.19.2.47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Revised: 05/25/2015] [Accepted: 05/28/2015] [Indexed: 12/01/2022]
Abstract
Backgrounds/Aims Stem cell therapies for liver disease are being studied by many researchers worldwide, but scientific evidence to demonstrate the endocrinologic effects of implanted cells is insufficient, and it is unknown whether implanted cells can function as liver cells. Achieving angiogenesis, arguably the most important characteristic of the liver, is known to be quite difficult, and no practical attempts have been made to achieve this outcome. We carried out this study to observe the possibility of angiogenesis of implanted bio-artificial liver using scaffolds. Methods This study used adipose tissue-derived stem cells that were collected from adult patients with liver diseases with conditions similar to the liver parenchyma. Specifically, microfilaments were used to create an artificial membrane and maintain the structure of an artificial organ. After scratching the stomach surface of severe combined immunocompromised (SCID) mice (n=4), artificial scaffolds with adipose tissue-derived stem cells and type I collagen were implanted. Expression levels of angiogenesis markers including vascular endothelial growth factor (VEGF), CD34, and CD105 were immunohistochemically assessed after 30 days. Results Grossly, the artificial scaffolds showed adhesion to the stomach and surrounding organs; however, there was no evidence of angiogenesis within the scaffolds; and VEGF, CD34, and CD105 expressions were not detected after 30 days. Conclusions Although implantation of cells into artificial scaffolds did not facilitate angiogenesis, the artificial scaffolds made with type I collagen helped maintain implanted cells, and surrounding tissue reactions were rare. Our findings indicate that type I collagen artificial scaffolds can be considered as a possible implantable biomaterial.
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Affiliation(s)
- Jae Geun Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Seon Young Bak
- Graduate Program of Nano Science and Technology, Graduate School of Yonsei University, Seoul, Korea
| | - Ji Hae Nahm
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Woo Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea. ; Graduate Program of Nano Science and Technology, Graduate School of Yonsei University, Seoul, Korea
| | - Seon Ok Min
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea. ; Graduate Program of Nano Science and Technology, Graduate School of Yonsei University, Seoul, Korea
| | - Kyung Sik Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea. ; Graduate Program of Nano Science and Technology, Graduate School of Yonsei University, Seoul, Korea. ; Cell Therapy Center, Severance Hospital, Seoul, Korea
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Microvessel Landscape Assessment in Pancreatic Ductal Adenocarcinoma: Unclear Value of Targeting Endoglin (CD105) as Prognostic Factor of Clinical Outcome. Pancreas 2015; 44:87-92. [PMID: 25058886 DOI: 10.1097/mpa.0000000000000197] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVES Tumor angiogenesis based on microvessel density assessment has been associated with poor prognosis in several studies of patients with pancreatic ductal adenocarcinoma (PDAC). Expression of endoglin (CD105), a tumor-induced vascularization marker, has been found to represent a negative prognostic factor in many malignant tumors. The aim of our study was to assess the value of tumoral microvascularity both with pan-endothelial markers and endoglin as well, in correlation with the clinical outcome of patients with PDAC. METHODS Fifty-eight patients with PDAC, 36 males and 22 females, with a mean (SD) age of 65.4 (10.0) years were included in the study. Deparaffinized sections from formalin-fixed areas both from the center and periphery (invasion front) of the tumors were immunostained for CD105 as well as for the endothelial markers CD31 and CD34. Tumoral angiogenesis was assessed on the basis of microvessel density (number of vessels per square millimeter) and on microvascular area (square micrometers) as well. RESULTS High intratumoral microvascular area, in endoglin-stained sections, was found to be of marginal prognostic significance for recurrence (log rank, P 0.05). Survival was also marginally associated with CD31 intratumoral microvascular area (log rank, P 0.05). CONCLUSIONS Further studies are needed before endoglin replaces the conventional angiogenesis markers in PDCA.
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29
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Hansen TF, Kjær-Frifeldt S, Morgenthaler S, Blondal T, Lindebjerg J, Jakobsen A, Sørensen FB. The prognostic value of microRNA-126 and microvessel density in patients with stage II colon cancer: results from a population cohort. J Transl Med 2014; 12:254. [PMID: 25199818 PMCID: PMC4174250 DOI: 10.1186/s12967-014-0254-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 09/03/2014] [Indexed: 12/21/2022] Open
Abstract
Background Angiogenesis plays a pivotal role in malignant tumour growth and the metastatic process. We analysed the prognostic value of two angiogenesis parameters, microRNA-126 (miRNA-126) and microvessel density (MVD), in a population based cohort of patients operated for stage II colon cancer. Methods A total of 560 patients were included. Analyses were performed on formalin fixed paraffin embedded tissue from the primary tumours. The analysis of miRNA-126 expression was performed by qPCR. Microvessels were visualised by CD105 and quantified in hot spots using a light microscope. The analyses were correlated with recurrence-free cancer specific survival (RF-CSS) and overall survival (OS). Results Low miRNA-126 expression was significantly correlated to T4, high malignancy grade, tumour perforation, fixation, and the presence of microsatellite instability. A prognostic impact on OS was detected in the simple analysis favouring patients with high miRNA-126 expression p = 0.03, and borderline significance as to RF-CSS, p = 0.08. The impact on OS demonstrated borderline significance in a following multiple Cox regression analysis, hazard ratio 0.76 (95% confidence interval, 0.58-1.00), p = 0.051. The MVD estimate was not associated with either RF-CSS, p = 0.49, or OS, p = 0.94. Conclusion The current population based study of patients operated for stage II colon cancer demonstrated correlations between several prognostic unfavourable characteristics and miRNA-126 and argues for a possible prognostic impact on overall survival. An influence on survival by the MVD estimate was not detected.
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Angiogenesis and tumor microenvironment: bevacizumab in the breast cancer model. Target Oncol 2014; 10:189-98. [PMID: 25185646 DOI: 10.1007/s11523-014-0334-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Accepted: 08/29/2014] [Indexed: 01/05/2023]
Abstract
Solid tumors require blood vessels for growth, and many new cancer therapies are directed against the tumor vasculature. Antiangiogenic therapies should destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. According to Jain et al., an alternative hypothesis could be that certain antiangiogenic agents can also transiently "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery. With emphasize on the research works of Jain et al., the aim of this review is to describe the impact of antivascular endothelial growth factor (VEGF) therapy on "pseudo-normalization" of tumor vasculature and tumor microenvironment, its role in early and metastatic breast cancer, and the clinical evidence supporting this original concept. The phase III clinical trials showed that extended tumors, metastatic or locally advanced, are likely to benefit from bevacizumab therapy in combination with chemotherapy, assuming that a high level of tumor neoangiogenesis as in triple-negative tumors is the best target. In adjuvant setting, the lower level of tumor vasculature could mask a potential benefit of anti-VEGF therapy. All these findings highlight the need to identify biomarkers to help in the selection of patients most likely to respond to anti-VEGF therapy, to better understand the mechanism of angiogenesis and of resistance to anti-VEGF therapy according to molecular subtypes.
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Duan CL, Hou GH, Liu YP, Liang T, Song J, Han JK, Zhang C. Tumor vascular homing endgolin-targeted radioimmunotherapy in hepatocellular carcinoma. Tumour Biol 2014; 35:12205-15. [PMID: 25164610 DOI: 10.1007/s13277-014-2529-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2014] [Accepted: 08/20/2014] [Indexed: 12/29/2022] Open
Abstract
Endoglin is a proliferation-associated cell membrane antigen and overexpressed in the angiogenic vasculature of solid tumors. However, the applications of endoglin (ENG)-targeted radioimmunotheray in hepatocellular carcinoma have not been reported yet. Therefore, the aim of this study was the visualization of both the development of hepatocellular carcinoma (HCC) tumor burden and therapeutic effect with ENG-targeted (131)I-anti-ENG mAb (A8), via in vivo noninvasive fluorescence imaging (NIFLI) of SMMC7721-green fluorescent protein (GFP) cells. A8 showed a dose-dependent, time-dependent suppression on the proliferation of SMMC7721-GFP cells and human umbilical vein endothelial cells (HUVECs) in vitro. Tube formation assay showed that (131)I-A8 markedly inhibits HUVECs to form extensive and enclosed tube networks. The results showed that the radiochemical purity of (131)I-A8 was 92.8 % and (131)I-A8 maintained more stable in serum than in saline and had high affinity against SMMC7721-GFP cells. The pharmacokinetics of (131)I-A8 was in accordance with the two-compartment model, with a rapid distribution phase and a slow decline phase. NIFLI exhibited a good relation between the fluorescent signal and tumor volume in vivo. Furthermore, treatment with (131)I-A8 resulted in significant tumor-growth suppression on the basis of the reducing fluorescent signal and a remarkably decreased tumor weight in treated animals. These results were further verified by RT-PCR and immunohistochemistry staining. Our findings indicate that (131)I-A8 can be used as ENG-targeted therapy for hepatocellular carcinoma, and noninvasive fluorescence imaging provides valuable information on tumor burden and effectiveness of therapy.
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Affiliation(s)
- Chong-Ling Duan
- Key Laboratory for Experimental Teratology of the Ministry of Education and Institute of Experimental Nuclear Medicine, School of Medicine, Shandong University, Jinan, China
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Ishibashi O, Inui T. Identification of endoglin-dependent BMP-2-induced genes in the murine periodontal ligament cell line PDL-L2. J Mol Signal 2014; 9:5. [PMID: 24949082 PMCID: PMC4062770 DOI: 10.1186/1750-2187-9-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 06/10/2014] [Indexed: 11/30/2022] Open
Abstract
Background The periodontal ligament (PDL), connective tissue located between the cementum of teeth and alveolar bone of the mandibula, plays an important role in the maintenance and regeneration of periodontal tissues. We reported previously that endoglin was involved in the BMP-2-induced osteogenic differentiation of mouse PDL cells, which is associated with Smad-2 phosphorylation but not Smad-1/5/8 phosphorylation. In this study, to elucidate the detailed mechanism underlying the BMP-2 signalling pathway unique to PDL cells, we performed a microarray analysis to identify BMP-2-inducible genes in PDL-L2 cells, a mouse PDL-derived cell line, with or without endoglin knockdown. Findings Sixty-four genes were upregulated more than twofold by BMP-2 in PDL-L2 cells. Of these genes, 11 were endoglin-dependent, including Id4, which encodes ID4, a helix-loop-helix transcription factor closely associated with TGF-β signaling and osteoblast differentiation. The endoglin-dependent induction of ID4 by BMP-2 was also verified at a protein level. Conclusion Our findings indicate that ID4 could be a signal mediator involved in the BMP-2-induced endoglin-dependent osteogenic differentiation of PDL cells.
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Affiliation(s)
- Osamu Ishibashi
- Laboratory of Biological Macromolecules, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai 599-8531, Japan
| | - Takashi Inui
- Laboratory of Biological Macromolecules, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai 599-8531, Japan
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Angiogenesis in myeloproliferative neoplasms, new markers and future directions. MEMO-MAGAZINE OF EUROPEAN MEDICAL ONCOLOGY 2014; 7:206-210. [PMID: 25544863 PMCID: PMC4274371 DOI: 10.1007/s12254-014-0142-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 04/22/2014] [Indexed: 12/11/2022]
Abstract
Tumor angiogenesis has been identified to play a critical role in tumor growth and tumor progression, and is regulated by a balance of angiogenic and antiangiogenic cytokines. This has been documented for solid tumors, and there is emerging evidence suggesting that tumor progression of hematological malignancies also depends on the induction of new blood vessel formation. Data on angiogenesis in the bone marrow of BCR-ABL1-negative myeloproliferative neoplasm patients suggest an increase of the microvessel density and vascular endothelial growth factor (VEGF) expression, and there is a relation to the JAK2-V617F status. The most important proangiogenic agent is VEGF, activating VEGF receptors 1 and 2. Inhibition of VEGF signaling by monoclonal antibodies or small molecules (kinase inhibitors) has already been successfully established for the treatment of different cancer entities, and multiple new drugs are being tested in clinical trials. Most patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF) that was not associated with a JAK2 or MPL alteration carried a somatic mutation in calreticulin (CALR). Thus, CALR mutations should be included in the next classification system for ET/PMF. This review summarizes recent advances in the basic understanding of the role of angiogenesis in myeloproliferative neoplasms and the translation of such basic findings into clinical studies.
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Sato M, Toriumi T, Watanabe N, Watanabe E, Akita D, Mashimo T, Akiyama Y, Isokawa K, Shirakawa T, Honda MJ. Characterization of mesenchymal progenitor cells in crown and root pulp from human mesiodentes. Oral Dis 2014; 21:e86-97. [PMID: 24605962 DOI: 10.1111/odi.12234] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Revised: 01/08/2014] [Accepted: 02/02/2014] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Mesiodentes are usually found in the central position of the upper or lower jaw as supernumerary teeth. Here, we obtained 10 mesiodentes and three permanent teeth (PT) and separated the dental pulp (DP) from these into crown and root portions. We then characterized and compared the isolated crown portion-derived cells (crown cells) with root portion-derived cells (root cells) using a range of in vitro assays. MATERIALS AND METHODS Crown cells and root cells were examined for cell surface marker expression, colony-forming unit-fibroblast (CFU-F), cell proliferation, cell cycle characteristics and markers, and osteogenic and adipogenic differentiation. RESULTS The proportion of CD105-positive cells (CD105(+) cells) in the crown cells vs the root cells varied among the mesiodentes, but not among the PT. When there were more CD105(+) cells in the root cells than in the crown cells, the root cells showed higher CFU-F, proliferation capacity, and osteogenic differentiation capacity. In contrast, when the crown cells contained more CD105(+) cells than the root cells, the crown cells showed the higher CFU-F, proliferation capacity, and osteogenic differentiation capacity. In addition, the sorted CD105(+) cells showed higher CFU-F and proliferation capacity than the sorted CD105(-) cells. CONCLUSION These results indicated that proportion of CD105(+) cells is an effective means of characterizing DP-derived cells in mesiodentes.
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Affiliation(s)
- M Sato
- Nihon University Graduate School of Dentistry, Tokyo, Japan
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Karmani L, Bouchat V, Bouzin C, Levêque P, Labar D, Bol A, Deumer G, Marega R, Bonifazi D, Haufroid V, Michiels C, Grégoire V, Feron O, Lucas S, Vander Borght T, Gallez B. (89)Zr-labeled anti-endoglin antibody-targeted gold nanoparticles for imaging cancer: implications for future cancer therapy. Nanomedicine (Lond) 2014; 9:1923-37. [PMID: 24547782 DOI: 10.2217/nnm.13.185] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIMS Antibody-labeled gold nanoparticles represent an attractive tool for cancer imaging and therapy. In this study, the anti-CD105 antibody was conjugated with gold nanoparticles (AuNPs) for the first time. The antibody biodistribution in mice before and after conjugation to AuNPs was studied, with a focus on tumor targeting. MATERIALS & METHODS Antibodies were radiolabeled with 89Zr before conjugation to AuNPs (5 nm). Immunonanoconjugates were characterized in vitro in terms of size, stability in plasma and binding to the target. Quantitative PET imaging and ICP-MS analysis assessed in vivo distribution and specific tumor targeting of tracers. RESULTS The tumor uptake of immunoconjugates was preserved up to 24 h after injection, with high tumor contrast and selective tumor targeting. No major tracer accumulation was observed over time in nonspecific organs. ICP-MS analysis confirmed the antibody specificity after nanoparticle conjugation. CONCLUSION The anti-CD105 antibody conjugation to AuNPs did not greatly affect CD105-dependent tumor uptake and the efficacy of tumor targeting for cancer detection.
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Affiliation(s)
- Linda Karmani
- Biomedical Magnetic Resonance Group (REMA), Louvain Drug Research Institute, Université Catholique de Louvain, Avenue Mounier 73, 1200 Brussels, Belgium
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The type III TGFβ receptor regulates filopodia formation via a Cdc42-mediated IRSp53-N-WASP interaction in epithelial cells. Biochem J 2013; 454:79-89. [PMID: 23750457 DOI: 10.1042/bj20121701] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Cell adhesion and migration are tightly controlled by regulated changes in the actin cytoskeleton. Previously we reported that the TGFβ (transforming growth factor β) superfamily co-receptor, TβRIII (type III TGFβ receptor; also known as βglycan), regulates cell adhesion, migration and invasion, and suppresses cancer progression, in part, through activation of the small GTPase Cdc42 (cell division cycle 42), and Cdc42-dependent alterations to the actin cytoskeleton. In the present study we demonstrate that TβRIII specifically promotes filopodial formation and extension in MCF10A and HMEC (human mammary epithelial cell) mammary epithelial cells. Mechanistically, cell-surface TβRIII and Cdc42 co-localize to filopodial structures and co-complex in a β-arrestin2-dependent, and a TβRI/TβRII-independent manner. The β-arrestin2-mediated interaction between TβRIII and Cdc42 increases complex formation between the Cdc42 effectors IRSp53 with N-WASP (neuronal Wiskott-Aldrich syndrome protein) to increase filopodial formation. We demonstrate a function link between filopodial structures and epithelial cell adhesion as regulated by the TβRIII-Cdc42 interaction. The present studies identify TβRIII as a novel regulator of IRSp53/N-WASP via Cdc42 to regulate filopodial formation and cell adhesion.
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Fukumitsu R, Takagi Y, Yoshida K, Miyamoto S. Endoglin (CD105) is a more appropriate marker than CD31 for detecting microvessels in carotid artery plaques. Surg Neurol Int 2013; 4:132. [PMID: 24231754 PMCID: PMC3815080 DOI: 10.4103/2152-7806.119081] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 08/18/2013] [Indexed: 11/28/2022] Open
Abstract
Background: Microvascular proliferation is a major risk factor for plaque vulnerability in patients with carotid stenosis. There are several vascular endothelial markers such as CD31 and CD105, but it is unclear which marker is most sensitive for microvessels. This study sought to examine the correlations between CD31 and CD105 expression in microvessels on carotid plaques and clinical manifestations. Methods: We studied 13 lesions in 12 patients. The patients underwent carotid endarterectomy and samples were stained for CD31 and CD105. The numbers of microvessels positive for these markers within a field of view were counted. Results: The average numbers of microvessels were 5.8 ± 5.4 for CD31 and 9.2 ± 9.3 for CD105 (P = 0.04). More microvessels were positive for CD105 than there were for CD31 in patients with diabetes mellitus (P = 0.04). Conclusion: In patients with carotid artery stenosis, CD105 is more appropriate than CD31 for detecting microvessels in carotid plaques. In patients with diabetes mellitus, CD105 is significantly more highly expressed in microvessels than CD31.
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Affiliation(s)
- Ryu Fukumitsu
- Department of Neurosurgery, Kyoto University School of Medicine, Kyoto, Japan
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Chakhachiro ZI, Zuo Z, Aladily TN, Kantarjian HM, Cortes JE, Alayed K, Nguyen MH, Medeiros LJ, Bueso-Ramos C. CD105 (endoglin) is highly overexpressed in a subset of cases of acute myeloid leukemias. Am J Clin Pathol 2013; 140:370-8. [PMID: 23955456 DOI: 10.1309/ajcpg8xh7zonakxk] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
OBJECTIVES To assess CD105 (endoglin) expression in 119 acute myeloid leukemia (AML) and 13 control cases using immunohistochemistry. METHODS CD105 expression was assessed retrospectively by using immunohistochemistry in bone marrow specimens. RESULTS CD105 was strongly and diffusely positive in all 9 (100%) AMLs with t(15;17)(q24.1;q21.2), 2 (100%) AMLs with t(8;21)(q22;q22), 1 (100%) AML with t(6;9)(p23;q34), 7 (28%) of 25 AMLs with myelodysplasia-related changes, 1 (33%) of 3 therapy-related AMLs, 3 (16%) of 19 AMLs unclassifiable, 1 (14%) of 7 AMLs with inv(16)(p13.1q22), and 5 (11%) of 45 AMLs not otherwise specified. Uninvolved bone marrow in these cases showed no CD105 expression by erythroid precursors, megakaryocytes, or endothelial or stromal cells. Two of 13 control bone marrow specimens showed partial CD105 positivity in myeloid cells. In 21 strongly CD105+ AML cases tested for the IDH2 mutation, 9 (42%) were mutated (P = .004). CONCLUSIONS These data suggest that CD105 could be a therapeutic target in a subset of patients with AML.
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Affiliation(s)
- Zaher I Chakhachiro
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 072, Houston, TX 77030, USA
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Jin Z, Zhao Z, Cheng Y, Dong M, Zhang X, Wang L, Fan X, Feng X, Mori Y, Meltzer SJ. Endoglin promoter hypermethylation identifies a field defect in human primary esophageal cancer. Cancer 2013; 119:3604-9. [PMID: 23893879 DOI: 10.1002/cncr.28276] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 05/06/2013] [Accepted: 05/13/2013] [Indexed: 01/18/2023]
Abstract
BACKGROUND Endoglin (ENG) is a 180-kilodalton transmembrane glycoprotein that functions as a component of the transforming growth factor-β receptor complex. Recently, ENG promoter hypermethylation was reported in several human cancers. METHODS The authors examined ENG promoter hypermethylation using real-time, quantitative, methylation-specific polymerase chain reaction in 260 human esophageal tissues. RESULTS ENG hypermethylation demonstrated highly discriminative receiver operating characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) from normal esophagus (P<.01). It is interesting to note that ENG normalized methylation values were significantly higher in ESCC compared with normal tissue (P<.01) or EAC (P<.01). The ENG hypermethylation frequency was 46.2% in ESCC and 11.9% in normal esophageal tissue, but increased early and sequentially during EAC-associated neoplastic progression to 13.3% in Barrett metaplasia (BE), 25% in dysplastic BE, and 26.9% in frank EAC. ENG hypermethylation was significantly higher in normal esophageal tissue from patients with ESCC (mean, 0.0186) than in normal tissue from patients with EAC (mean, 0.0117; P<.05). Treatment of KYSE220 ESCC cells with the demethylating agent 5-aza-2'-deoxycytidine was found to reverse ENG methylation and reactivate ENG mRNA expression. CONCLUSIONS Promoter hypermethylation of ENG appears to be a frequent, tissue-specific event in human ESCC and exhibits a field defect with promising biomarker potential for the early detection of ESCC. In addition, ENG hypermethylation occurs in a subset of human EAC, and early during BE-associated esophageal neoplastic progression.
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Affiliation(s)
- Zhe Jin
- Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China; Shenzhen Key Laboratory of Micromolecule Innovative Drugs, Shenzhen, Guangdong, People's Republic of China; Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, People's Republic of China
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Hansen TF, Nielsen BS, Jakobsen A, Sørensen FB. Visualising and quantifying angiogenesis in metastatic colorectal cancer : A comparison of methods and their predictive value for chemotherapy response. Cell Oncol (Dordr) 2013; 36:341-50. [PMID: 23838926 DOI: 10.1007/s13402-013-0139-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2013] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Angiogenesis plays an important role in tumour growth and dissemination. We have recently shown that blood vessel density, determined by image analysis based on microRNA-126 (miRNA-126) in situ hybridization (ISH) in the primary tumours of metastatic colorectal cancers (mCRC), is predictive of chemotherapy response. Here, we evaluated whether more general approaches to determine vessel density in primary tumours are equally predictive of chemotherapy response. METHODS This methodological study was carried out using paraffin embedded tissues from primary tumours of 89 patients with mCRC, who had all been treated with first-line chemotherapy (XELOX). Tissue sections from the deepest invasive tumour front were processed for miRNA-126 ISH and CD34 immunohistochemistry (IHC). Estimates of microvessel density (MVD) were obtained for both miRNA-126 and CD34 by quantitative image analyses (MVDi), vascular area per image (μm²) analyses, and manually counting vessels in vascular hot spots (MVDh). Clinical responses were evaluated according to Response Evaluation Criteria In Solid Tumours (RECIST). RESULTS The MVDi for miRNA-126 showed a significant correlation with treatment response (p=0.01), with a median value of 2,071 μm² (95% CI, 1,505-3,075 μm²) in the responder group compared to 1,337 μm² (95% CI, 1,038-1,499 μm²) in the non-responder group. This difference translated into a significant difference in progression free survival (p=0.01). CONCLUSIONS The methodological assessment of MVD and the molecular vessel marker are both important for the prediction of the chemotherapy response in mCRC. Our findings indicate that MVDi for miRNA-126 represents a powerful estimate and may serve as a clinical biomarker superior to MVDh.
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Pappa CA, Alexandrakis MG, Boula A, Psarakis FE, Kolovou A, Bantouna V, Stavroulaki E, Tsirakis G. Emerging roles of endoglin/CD105 and angiogenic cytokines for disease development and progression in multiple myeloma patients. Hematol Oncol 2013; 31:201-5. [PMID: 23576184 DOI: 10.1002/hon.2044] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Revised: 11/17/2012] [Accepted: 01/14/2013] [Indexed: 12/20/2022]
Abstract
Angiogenesis is an essential process for the expansion of multiple myeloma (MM), in which many angiogenic factors participate. Endoglin (CD105) is a transforming growth factor-β co-receptor, being mainly expressed in angiogenic endothelial cells and has been used as a marker of tumor angiogenesis, having prognostic potential. The aim of the study was to evaluate serum levels of soluble CD105 (sCD105) in MM patients, both during diagnosis and after effective conventional chemotherapy, in the plateau phase, and to correlate them with the clinical stage of the disease, as well as with the known angiogenic factors vascular endothelial growth factor, angiogenin and interleukin-18 (IL-18). Serum levels of the aforementioned factors were measured, by enzyme-linked immunosorbent assay, in 56 newly diagnosed MM patients, in 35 of them who entered plateau phase and in 24 healthy controls. Bone marrow aspirations were also performed in all patients to determine plasma cell infiltration. All measured cytokines were higher in MM patients compared with controls and with advancing disease stage (p < 0.001 for all cases). Furthermore, the values of all factors decreased significantly in the plateau phase (p < 0.001 for all cases). Serum levels of sCD105 correlated with the other angiogenic cytokines, whereas only serum levels of angiogenin had prognostic value for the survival. In conclusion, CD105 and the angiogenic cytokines vascular endothelial growth factor, angiogenin and IL-18, seem to have emerging roles both in angiogenesis and tumor growth in MM.
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Affiliation(s)
- C A Pappa
- Hematology Department, Venizelion Hospital of Heraklion, Greece
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Wittig D, Jászai J, Corbeil D, Funk RHW. Immunohistochemical localization and characterization of putative mesenchymal stem cell markers in the retinal capillary network of rodents. Cells Tissues Organs 2013; 197:344-59. [PMID: 23571553 DOI: 10.1159/000346661] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2012] [Indexed: 11/19/2022] Open
Abstract
Perivascular cells of microvascular niches are the prime candidates for being a reservoire of mesenchymal stem cell (MSC)-like cells in many tissues and organs that could serve as a potential source of cells and a target of novel cell-based therapeutic approaches. In the present study, by utilising typical markers of pericytes (neuronal-glial antigen 2, NG2, a chondroitin sulphate proteoglycan) and those of MSCs (CD146 and CD105) and primitive pluripotent cells (sex-determining region Y-box 2, Sox2), the phenotypic traits and the distribution of murine and rat retinal perivascular cells were investigated in situ. Our findings indicate that retinal microvessels of juvenile rodents are highly covered by NG2-positive branching processes of pericytic (perivascular) cells that are less prominent in mature capillary networks of the adult retina. In the adult rodent retinal vascular bed, NG2 labeling is mainly confined to membranes of the cell body resulting in a pearl-chain-like distribution along the vessels. Retinal pericytes, which were identified by their morphology and NG2 expression, simultaneously express CD146. Furthermore, CD146-positive cells located at small arteriole-to-capillary branching points appear more intensely stained than elsewhere. Evidence for a differential expression of the two markers around capillaries that would hint at a clonal heterogeneity among pericytic cells, however, is lacking. In contrast, the expression of CD105 is exclusively restricted to vascular endothelial cells and Sox2 is detected neither in perivascular nor in endothelial cells. In dissociated retinal cultures, however, simultaneous expression of NG2 and CD105 was observed. Collectively, our data indicate that vascular wall resident retinal pericytes share some phenotypic features (i.e. CD146 expression) with archetypal MSCs, which is even more striking in dissociated retinal cultures (i.e. CD105 expression). These findings might have implications for the treatment of retinal pathologies.
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Affiliation(s)
- Dierk Wittig
- Institute of Anatomy, TU Dresden, Dresden, Germany.
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Paauwe M, ten Dijke P, Hawinkels LJAC. Endoglin for tumor imaging and targeted cancer therapy. Expert Opin Ther Targets 2013; 17:421-35. [PMID: 23327677 DOI: 10.1517/14728222.2013.758716] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Although cancer treatment has evolved substantially in the past decades, cancer-related mortality rates are still increasing. Therapies targeting tumor angiogenesis, crucial for the growth of solid tumors, mainly target vascular endothelial growth factor (VEGF) and have been clinically applied during the last decade. However, these therapies have not met high expectations, which were based on therapeutic efficacy in animal models. This can partly be explained by the upregulation of alternative angiogenic pathways. Therefore, additional therapies targeting other pro-angiogenic pathways are needed. AREAS COVERED The transforming growth factor (TGF)-β signaling pathway plays an important role in (tumor) angiogenesis. Therefore, components of this pathway are interesting candidates for anti-angiogenic therapy. Endoglin, a co-receptor for various TGF-β family members, is specifically overexpressed in tumor vessels and endoglin expression is associated with metastasis and patient survival. Therefore, endoglin might be a good candidate for anti-angiogenic therapy. In this review, we discuss the potential of using endoglin to target the tumor vasculature for imaging and therapeutic purposes. EXPERT OPINION Considering the promising results from various in vitro studies, in vivo animal models and the first clinical trial targeting endoglin, we are convinced that endoglin is a valuable tool for the diagnosis, visualization and ultimately treatment of solid cancers.
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Affiliation(s)
- Madelon Paauwe
- Cancer Genomics Centre Netherlands and Centre for BioMedical Genetics, Department of Molecular Cell Biology, Leiden University Medical Center, Building-2, S1-P, PO-box 9600, 2300 RC Leiden, The Netherlands
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Kaneko T, Arayatrakoollikit U, Yamanaka Y, Ito T, Okiji T. Immunohistochemical and gene expression analysis of stem-cell-associated markers in rat dental pulp. Cell Tissue Res 2012; 351:425-32. [DOI: 10.1007/s00441-012-1539-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2012] [Accepted: 11/23/2012] [Indexed: 02/07/2023]
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Berndt S, Blacher S, Munaut C, Detilleux J, d'Hauterive SP, Huhtaniemi I, Evain‐Brion D, Noël A, Fournier T, Foidart J. Hyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF‐β receptor activation. FASEB J 2012; 27:1309-21. [DOI: 10.1096/fj.12-213686] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Sarah Berndt
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche en Santé (UMRS)‐767ParisFrance
- Université Paris Descartes, Sorbonne Paris CitéParisFrance
- PremUP FondationParisFrance
| | - Silvia Blacher
- Laboratory of Tumor and Development BiologyGroupe Interdisciplinaire de Génoprotéomique Appliqué‐Cancer (GIGA‐Cancer)LiègeBelgium
| | - Carine Munaut
- Laboratory of Tumor and Development BiologyGroupe Interdisciplinaire de Génoprotéomique Appliqué‐Cancer (GIGA‐Cancer)LiègeBelgium
| | - Julien Detilleux
- Laboratory of Tumor and Development BiologyGroupe Interdisciplinaire de Génoprotéomique Appliqué‐Cancer (GIGA‐Cancer)LiègeBelgium
| | - Sophie Perrier d'Hauterive
- Center of ImmunologyUniversity of LiègeLiègeBelgium
- Department of Obstetrics and GynecologyCentre Hospitalier Regional (CHR)LiègeBelgium
| | - Ilpo Huhtaniemi
- Institute of Reproductive and Developmental BiologyImperial College LondonLondonUK
| | - Danièle Evain‐Brion
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche en Santé (UMRS)‐767ParisFrance
- Université Paris Descartes, Sorbonne Paris CitéParisFrance
- PremUP FondationParisFrance
| | - Agnès Noël
- Laboratory of Tumor and Development BiologyGroupe Interdisciplinaire de Génoprotéomique Appliqué‐Cancer (GIGA‐Cancer)LiègeBelgium
| | - Thierry Fournier
- Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche en Santé (UMRS)‐767ParisFrance
- Université Paris Descartes, Sorbonne Paris CitéParisFrance
- PremUP FondationParisFrance
| | - Jean‐Michel Foidart
- Laboratory of Tumor and Development BiologyGroupe Interdisciplinaire de Génoprotéomique Appliqué‐Cancer (GIGA‐Cancer)LiègeBelgium
- Department of Obstetrics and GynecologyCentre Hospitalier Regional (CHR)LiègeBelgium
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GVHD after allogeneic haematopoietic SCT for AML: angiogenesis, vascular endothelial growth factor and VEGF receptor expression in the BM. Bone Marrow Transplant 2012; 48:715-21. [PMID: 23085826 DOI: 10.1038/bmt.2012.200] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
There is increasing evidence suggesting that both angiogenesis and endothelial injury are involved in GVHD. To study the dynamics of angiogenesis, we examined 26 patients with AML who had undergone allogeneic haematopoietic SCT. All were in CR and had either acute GVHD (aGVHD) or chronic GVHD (cGVHD). We performed immunohistochemical studies of BM microvessel density (MVD) using Abs against vascular-endothelial (VE)-cadherin, CD34 and CD105, and expression of vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2. At the time of diagnosis, the MVD in AML patients was higher than that in the normal controls, and the MVD decreased after induction chemotherapy. Patients with aGVHD had a significantly higher MVD than patients without aGVHD. Conversely, patients with cGVHD did not have a significantly different MVD. In previous aGVHD, we also found more VEGF+ megakaryocytes. XY FISH in sex-mismatched patients showed that the BM blood vessels consisted mainly of recipient endothelial cells. Taken together, these results suggest that new vessel formation and the VEGF/VEGFR system are involved in aGVHD.
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Todorović-Raković N, Vujasinović T, Abu Rabi Z. Selection of clinically useful angiogenesis-related biomarkers: an update. Int J Biol Markers 2012; 27:e65-e81. [PMID: 22307386 DOI: 10.5301/jbm.2012.8989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2011] [Indexed: 11/20/2022]
Abstract
Angiogenesis is a complex phenomenon that involves interaction between growth factors/cytokines and their receptors, and proteolytic enzymes and their inhibitors, which, in addition to and in accordance with their main roles, act together during this multistep process. Cancer angiogenesis is specific, because the same factors that enable angiogenesis are involved in the process of carcinogenesis. The aim of this review was to analyze the current knowledge regarding the significance of selected biomarkers in cancer angiogenesis, with emphasis on their prognostic value in the circulation.
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Affiliation(s)
- Nataša Todorović-Raković
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Belgrade - Serbia.
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Lionello M, Staffieri A, Marioni G. Potential prognostic and therapeutic role for angiogenesis markers in laryngeal carcinoma. Acta Otolaryngol 2012; 132:574-82. [PMID: 22497582 DOI: 10.3109/00016489.2011.652308] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Angiogenesis is a hallmark of cancer, fundamental to its growth. The 'angiogenic switch' occurs when pro-angiogenic factors are not balanced by anti-angiogenic factors. A correlation between angiogenic properties and oncological prognosis (for laryngeal squamous cell carcinoma (LSCC) too) was first hypothesized in the 1990s. An exhaustive literature review was performed to investigate available data on angiogenesis markers and their biological role and therapeutic potential in LSCC. The prognostic significance of microvascular density in LSCC was investigated with endothelial targets, e.g. CD105, CD34, and CD31. Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), VEGF receptor 2, angiogenin, hypoxia-inducible factor 1, and other biological markers were also studied. Only anti-EGFR therapy has been approved by the USFood and Drug Administration (FDA) for head and neck carcinoma in recent years, while several agents interfering with VEGF and its receptors are being studied. Experimental findings indicate that anti-CD105 monoclonal antibodies efficiently inhibit tumor angiogenesis. There are two main ways to approach the vascular profile of solid malignancies: by inhibiting new vessel formation (anti-angiogenic therapy) or selectively damaging neoplastic vessels (vascular targeting therapy). In advanced LSCC, both these strategies seem promising and warrant further preclinical and clinical investigation.
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Affiliation(s)
- Marco Lionello
- Department of Neurosciences, Otolaryngology Section, University of Padova, Padova, Italy
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Tsirakis G, Pappa CA, Spanoudakis M, Chochlakis D, Alegakis A, Psarakis FE, Stratinaki M, Stathopoulos EN, Alexandrakis MG. Clinical significance of sCD105 in angiogenesis and disease activity in multiple myeloma. Eur J Intern Med 2012; 23:368-73. [PMID: 22560388 DOI: 10.1016/j.ejim.2012.01.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2011] [Revised: 12/03/2011] [Accepted: 01/31/2012] [Indexed: 11/30/2022]
Abstract
BACKGROUND Τhe importance of angiogenesis in malignancies' growth is well recognized. CD105 (Endoglin), a proliferation-associated glycoprotein, is a powerful marker of neovascularization. Elevated amounts of soluble CD105 (sCD105) have been identified in selected solid tumors. The aim of the study was to estimate circulating levels of sCD105 and soluble transforming growth factor-β(1) (sTGF-β(1)), in multiple myeloma (MM) patients, to determine their significance in tumor progression and to investigate the correlation between sCD105 and markers of disease activity. METHODS We studied 50 newly diagnosed MM patients. Twenty-five of them were also investigated in plateauphase. Twenty patients with monoclonal gammopathy of undetermined significance (MGUS) were enrolled in this study. As control group 28 healthy persons were studied. We determined sCD105, sTGF-β(1) and interleukin-6 (IL-6) in the serum, Ki-67 proliferation index (Ki-67 PI) expression and microvascular density(MVD) in bone marrow with immunohistochemistry. RESULTS The mean concentrations of sCD105 and IL-6 were higher in MM and MGUS patients compared to controls, whereas serum levels of sTGF-β(1) were lower in MM patients compared to MGUS patients and controls. sCD105 levels, were significantly different among disease stages, with higher values in advanced stages. It was found that sCD105 correlated with Ki-67 PI, MVD and IL-6. CONCLUSIONS CD105 seems to play an important role in angiogenesis and tumor progression. Circulating levels of sCD105 could detect patients with more advanced disease and might help in evaluating the response to treatment.
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Affiliation(s)
- G Tsirakis
- Department of Hematology, University Hospital of Heraklion, Heraklion, Crete, Greece
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Rau KM, Huang CC, Chiu TJ, Chen YY, Lu CC, Liu CT, Pei SN, Wei YC. Neovascularization evaluated by CD105 correlates well with prognostic factors in breast cancers. Exp Ther Med 2012; 4:231-236. [PMID: 23139713 DOI: 10.3892/etm.2012.594] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2012] [Accepted: 05/21/2012] [Indexed: 12/21/2022] Open
Abstract
Angiogenesis is critical for the growth, invasion and metastasis of cancers. Extensive neovascularization and tumor thrombus also correlate with a poor prognosis in breast cancer (BC). Although anti-angiogenic agents have been the therapies of choice for BC, in particular for triple-negative BCs, predictive markers for anti-angiogenic agents are lacking. Microvascular density (MVD) is commonly used to assess the neovascularization in tumors. Compared with pan-endothelial markers such as CD31, CD34 and von Willebrand factor (vWF), CD105 has a higher specificity for MVD in tumor tissues. In this study, we aimed to determine the prognostic value of CD105 in BCs. Paraffin-embedded tissue blocks from 201 BC patients were formed into tissue microarrays. Evaluation of MVD revealed that a median of 11 microvessels determined by CD105 staining correlated significantly with the pathological characteristics of BCs and also with the survival of patients. The expression of CD105 correlated inversely with hormone receptor (HR) expression but positively with Her-2 expression. Univariate analysis indicated that CD105 is a superior predictor of disease-free survival (DFS) in stage I and II diseases; multivariate analysis indicated that only hormone receptors (HRs) are suitable for predicting overall survival (OS) in stage III disease. These findings reveal for the first time that MVD measured by CD105 staining correlates positively with Her-2 expression but negatively with HR expression. The significance of MVD on OS is more apparent in early stage BCs. CD105 has the potential to be used as a predictive marker for anti-angiogenic agents; the targeting of CD105 may also be a potential anticancer strategy.
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Affiliation(s)
- Kun-Ming Rau
- Department of Internal Medicine, Division of Hematology-Oncology, and ; Chang Gung University, College of Medicine, Tao-Yuan
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