The Experts below are selected from a list of 4299 Experts worldwide ranked by ideXlab platform
Ji-liang Li - One of the best experts on this subject based on the ideXlab platform.
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Role of Delta-like 4 in Jagged1-induced tumour angiogenesis and tumour growth
Oncotarget, 2017Co-Authors: Chern Ein Oon, Esther Bridges, Helen Sheldon, Richard C. A. Sainson, Adrian Jubb, Russell Leek, Francesca Buffa, Adrian L Harris, Helen Turley, Ji-liang LiAbstract:// Chern Ein Oon 1,2 , Esther Bridges 1 , Helen Sheldon 1 , Richard C. A. Sainson 1 , Adrian Jubb 1 , Helen Turley 1 , Russell Leek 1 , Francesca Buffa 1 , Adrian L. Harris 1,* and Ji-Liang Li 1,3,* 1 Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK 2 Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang, Malaysia 3 Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth PL6 8BU, UK * These authors are joint senior authors Correspondence to: Ji-Liang Li, email: // Keywords : Notch signalling, DLL4, JAG1, angiogenesis, bevacizumab Received : January 23, 2017 Accepted : March 11, 2017 Published : April 08, 2017 Abstract Delta-like 4 (DLL4) and Jagged1 (JAG1) are two key Notch ligands implicated in tumour angiogenesis. They were shown to have opposite effects on mouse retinal and adult regenerative angiogenesis. In tumours, both ligands are upregulated but their relative effects and interactions in tumour biology, particularly in tumour response to therapeutic intervention are unclear. Here we demonstrate that DLL4 and JAG1 displayed equal potency in stimulating Notch target genes in HMEC-1 endothelial cells but had opposing effects on sprouting angiogenesis in vitro . Mouse DLL4 or JAG1 expressed in glioblastoma cells decreased tumour cell proliferation in vitro but promoted tumour growth in vivo . mDLL4-expressing tumours showed fewer but larger vessels whereas mJAG1-tumours produced more vessels. In both tumour types pericyte coverage was decreased but the vessels were more perfused. Both ligands increased tumour resistance towards anti-VEGF therapy but the resistance was higher in mDLL4-tumours versus mJAG1-tumours. However, their sensitivity to the therapy was restored by blocking Notch signalling with dibenzazepine. Importantly, anti-DLL4 antibody blocked the effect of JAG1 on tumour growth and increased vessel branching in vivo . The mechanism behind the differential responsiveness was due to a positive feedback loop for DLL4-Notch signalling, rendering DLL4 more dominant in activating Notch signalling in the tumour microenvironment. We concluded that DLL4 and JAG1 promote tumour growth by modulating tumour angiogenesis via different mechanisms. JAG1 is not antagonistic but utilises DLL4 in tumour angiogenesis. The results suggest that anti-JAG1 therapy should be explored in conjunction with anti-DLL4 treatment in developing anti-Notch therapies in clinics.
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targeting DLL4 in tumors shows preclinical activity but potentially significant toxicity
Future Oncology, 2010Co-Authors: Ji-liang Li, Adrian Jubb, Adrian L HarrisAbstract:Evaluation of: Yan M, Callahan CA, Beyer JC et al.: Chronic DLL4 blockade induces vascular neoplasms. Nature 463, E6–E7 (2010). Delta-like ligand 4 (DLL4) is a Notch ligand that is critical in the formation of a functional vascular network in tumors. Blockade of DLL4-mediated Notch signaling strikingly increases nonproductive angiogenesis, but significantly inhibits tumor growth in preclinical mouse models. Thus, DLL4 has emerged as an attractive target for cancer therapy. Anti-DLL4 antibodies have recently entered clinical trials. However, the potential toxic effects of anti-DLL4 are poorly understood. In this article, Yan et al. reported that chronic DLL4 blockade abnormally activates endothelial cells, causes pathological changes of multiple organs and induces vascular neoplasms. The findings need confirmation in further studies using different tumor-bearing animals but, nevertheless, raise important safety concerns regarding the use of anti-DLL4 agents and warrant monitoring for these effects in clini...
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nuclear and membrane expression of the angiogenesis regulator delta like ligand 4 DLL4 in normal and malignant human tissues
Histopathology, 2009Co-Authors: Juan Carlos Martinez, Richard C. A. Sainson, Ji-liang Li, Adrian L Harris, Helen Turley, Marcus M Muller, Graham Steers, Ludovine Choteau, Francesco Pezzella, Kevin C GatterAbstract:AIMS: Delta-like ligand 4 (DLL4) is one of five known Notch ligands in mammals and interacts predominantly with Notch 1. DLL4 is induced by vascular endothelial growth factor (VEGF) and acts downstream of VEGF as a 'brake' on VEGF-induced vessel growth, forming an autoregulatory negative feedback loop inactivating VEGF. This action was believed to occur only in vascular development, raising hopes that DLL4 could be a specific drug target for controlling vessel growth in tumours and other pathological conditions. Our aim was to pursue this by raising a monoclonal antibody to the internal domain of DLL4 and assess its distribution in normal and malignant tissues in comparison with antibodies against the external domain of DLL4. METHODS AND RESULTS: The anti-DLL4 monoclonal antibody was raised using conventional mouse hybridoma techniques. The antibody has been fully characterized by Western blotting and transfectant immunostaining. It has also been comprehensively compared with other antibodies against both the internal and external domains of DLL4. The antigen is widely expressed on human tissues not only on endothelium but also on epithelium and stromal cells. Indeed, in our comprehensive survey only pulmonary alveoli failed to express DLL4. Of a wide range of malignancies, most also expressed DLL4 on tumour cells with a predominantly cytoplasmic pattern, although a number also displayed nuclear positivity. CONCLUSIONS: Contrary to previous beliefs, DLL4 is widely distributed in tissues other than vessels including many malignancies. Furthermore, the molecule is internalized on binding its receptor and often transported to the nucleus. These findings raise many interesting possibilities for further study of DLL4 and its potential as a therapeutic target.
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regulation of multiple angiogenic pathways by DLL4 and notch in human umbilical vein endothelial cells
Microvascular Research, 2008Co-Authors: Laura S Harrington, Richard C. A. Sainson, Ji-liang Li, Cassin Kimmel Williams, Jennifer M Taylor, Adrian L HarrisAbstract:Abstract The Notch ligand, DLL4, is essential for angiogenesis during embryonic vascular development and is involved in tumour angiogenesis. Several recent publications demonstrated that blockade of DLL4 signalling inhibits tumour growth, suggesting that it may constitute a good candidate for anti-cancer therapy. In order to understand the role of DLL4 at the cellular level, we performed an analysis of DLL4-regulated genes in HUVECs. The genes identified included several angiogenic signalling pathways, such as VEGF, FGF and HGF. In particular we identified downregulation (VEGFR2, placenta growth factor PlGF) of VEGF pathway components resulting in the overall effect of limiting the response of HUVEC to VEGF. However extensive upregulation of VEGFR1 was observed allowing continued response to its ligand PlGF but the soluble form of the VEGFR1, sVEGFR1 was also upregulated. PlGF enhanced tubulogenesis of HUVEC suggesting that downregulation of PlGF and upregulation of VEGFR1 including sVEGFR1 are important mechanisms by which DLL4 attenuates PlGF and VEGF signalling. DLL4-stimulated HUVECs had impaired ERK activation in response to VEGF and HGF indicating that DLL4 signalling negatively regulates these pathways. DLL4 expression reduced vessel sprout length in a 3D tubulogenesis assay confirming that DLL4 signalling inhibits angiogenesis. Altogether, our data suggest that DLL4 expression acts as a switch from the proliferative phase of angiogenesis to the maturation and stabilisation phase by blocking endothelial cell proliferation and allowing induction of a more mature, differentiated phenotype. The regulation of sVEGFR1 provides a novel mechanism for DLL4 signalling to regulate cells at distance, not just in adjacent cells.
Adrian L Harris - One of the best experts on this subject based on the ideXlab platform.
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Role of Delta-like 4 in Jagged1-induced tumour angiogenesis and tumour growth
Oncotarget, 2017Co-Authors: Chern Ein Oon, Esther Bridges, Helen Sheldon, Richard C. A. Sainson, Adrian Jubb, Russell Leek, Francesca Buffa, Adrian L Harris, Helen Turley, Ji-liang LiAbstract:// Chern Ein Oon 1,2 , Esther Bridges 1 , Helen Sheldon 1 , Richard C. A. Sainson 1 , Adrian Jubb 1 , Helen Turley 1 , Russell Leek 1 , Francesca Buffa 1 , Adrian L. Harris 1,* and Ji-Liang Li 1,3,* 1 Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK 2 Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang, Malaysia 3 Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth PL6 8BU, UK * These authors are joint senior authors Correspondence to: Ji-Liang Li, email: // Keywords : Notch signalling, DLL4, JAG1, angiogenesis, bevacizumab Received : January 23, 2017 Accepted : March 11, 2017 Published : April 08, 2017 Abstract Delta-like 4 (DLL4) and Jagged1 (JAG1) are two key Notch ligands implicated in tumour angiogenesis. They were shown to have opposite effects on mouse retinal and adult regenerative angiogenesis. In tumours, both ligands are upregulated but their relative effects and interactions in tumour biology, particularly in tumour response to therapeutic intervention are unclear. Here we demonstrate that DLL4 and JAG1 displayed equal potency in stimulating Notch target genes in HMEC-1 endothelial cells but had opposing effects on sprouting angiogenesis in vitro . Mouse DLL4 or JAG1 expressed in glioblastoma cells decreased tumour cell proliferation in vitro but promoted tumour growth in vivo . mDLL4-expressing tumours showed fewer but larger vessels whereas mJAG1-tumours produced more vessels. In both tumour types pericyte coverage was decreased but the vessels were more perfused. Both ligands increased tumour resistance towards anti-VEGF therapy but the resistance was higher in mDLL4-tumours versus mJAG1-tumours. However, their sensitivity to the therapy was restored by blocking Notch signalling with dibenzazepine. Importantly, anti-DLL4 antibody blocked the effect of JAG1 on tumour growth and increased vessel branching in vivo . The mechanism behind the differential responsiveness was due to a positive feedback loop for DLL4-Notch signalling, rendering DLL4 more dominant in activating Notch signalling in the tumour microenvironment. We concluded that DLL4 and JAG1 promote tumour growth by modulating tumour angiogenesis via different mechanisms. JAG1 is not antagonistic but utilises DLL4 in tumour angiogenesis. The results suggest that anti-JAG1 therapy should be explored in conjunction with anti-DLL4 treatment in developing anti-Notch therapies in clinics.
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targeting DLL4 in tumors shows preclinical activity but potentially significant toxicity
Future Oncology, 2010Co-Authors: Ji-liang Li, Adrian Jubb, Adrian L HarrisAbstract:Evaluation of: Yan M, Callahan CA, Beyer JC et al.: Chronic DLL4 blockade induces vascular neoplasms. Nature 463, E6–E7 (2010). Delta-like ligand 4 (DLL4) is a Notch ligand that is critical in the formation of a functional vascular network in tumors. Blockade of DLL4-mediated Notch signaling strikingly increases nonproductive angiogenesis, but significantly inhibits tumor growth in preclinical mouse models. Thus, DLL4 has emerged as an attractive target for cancer therapy. Anti-DLL4 antibodies have recently entered clinical trials. However, the potential toxic effects of anti-DLL4 are poorly understood. In this article, Yan et al. reported that chronic DLL4 blockade abnormally activates endothelial cells, causes pathological changes of multiple organs and induces vascular neoplasms. The findings need confirmation in further studies using different tumor-bearing animals but, nevertheless, raise important safety concerns regarding the use of anti-DLL4 agents and warrant monitoring for these effects in clini...
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nuclear and membrane expression of the angiogenesis regulator delta like ligand 4 DLL4 in normal and malignant human tissues
Histopathology, 2009Co-Authors: Juan Carlos Martinez, Richard C. A. Sainson, Ji-liang Li, Adrian L Harris, Helen Turley, Marcus M Muller, Graham Steers, Ludovine Choteau, Francesco Pezzella, Kevin C GatterAbstract:AIMS: Delta-like ligand 4 (DLL4) is one of five known Notch ligands in mammals and interacts predominantly with Notch 1. DLL4 is induced by vascular endothelial growth factor (VEGF) and acts downstream of VEGF as a 'brake' on VEGF-induced vessel growth, forming an autoregulatory negative feedback loop inactivating VEGF. This action was believed to occur only in vascular development, raising hopes that DLL4 could be a specific drug target for controlling vessel growth in tumours and other pathological conditions. Our aim was to pursue this by raising a monoclonal antibody to the internal domain of DLL4 and assess its distribution in normal and malignant tissues in comparison with antibodies against the external domain of DLL4. METHODS AND RESULTS: The anti-DLL4 monoclonal antibody was raised using conventional mouse hybridoma techniques. The antibody has been fully characterized by Western blotting and transfectant immunostaining. It has also been comprehensively compared with other antibodies against both the internal and external domains of DLL4. The antigen is widely expressed on human tissues not only on endothelium but also on epithelium and stromal cells. Indeed, in our comprehensive survey only pulmonary alveoli failed to express DLL4. Of a wide range of malignancies, most also expressed DLL4 on tumour cells with a predominantly cytoplasmic pattern, although a number also displayed nuclear positivity. CONCLUSIONS: Contrary to previous beliefs, DLL4 is widely distributed in tissues other than vessels including many malignancies. Furthermore, the molecule is internalized on binding its receptor and often transported to the nucleus. These findings raise many interesting possibilities for further study of DLL4 and its potential as a therapeutic target.
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regulation of multiple angiogenic pathways by DLL4 and notch in human umbilical vein endothelial cells
Microvascular Research, 2008Co-Authors: Laura S Harrington, Richard C. A. Sainson, Ji-liang Li, Cassin Kimmel Williams, Jennifer M Taylor, Adrian L HarrisAbstract:Abstract The Notch ligand, DLL4, is essential for angiogenesis during embryonic vascular development and is involved in tumour angiogenesis. Several recent publications demonstrated that blockade of DLL4 signalling inhibits tumour growth, suggesting that it may constitute a good candidate for anti-cancer therapy. In order to understand the role of DLL4 at the cellular level, we performed an analysis of DLL4-regulated genes in HUVECs. The genes identified included several angiogenic signalling pathways, such as VEGF, FGF and HGF. In particular we identified downregulation (VEGFR2, placenta growth factor PlGF) of VEGF pathway components resulting in the overall effect of limiting the response of HUVEC to VEGF. However extensive upregulation of VEGFR1 was observed allowing continued response to its ligand PlGF but the soluble form of the VEGFR1, sVEGFR1 was also upregulated. PlGF enhanced tubulogenesis of HUVEC suggesting that downregulation of PlGF and upregulation of VEGFR1 including sVEGFR1 are important mechanisms by which DLL4 attenuates PlGF and VEGF signalling. DLL4-stimulated HUVECs had impaired ERK activation in response to VEGF and HGF indicating that DLL4 signalling negatively regulates these pathways. DLL4 expression reduced vessel sprout length in a 3D tubulogenesis assay confirming that DLL4 signalling inhibits angiogenesis. Altogether, our data suggest that DLL4 expression acts as a switch from the proliferative phase of angiogenesis to the maturation and stabilisation phase by blocking endothelial cell proliferation and allowing induction of a more mature, differentiated phenotype. The regulation of sVEGFR1 provides a novel mechanism for DLL4 signalling to regulate cells at distance, not just in adjacent cells.
Richard C. A. Sainson - One of the best experts on this subject based on the ideXlab platform.
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Role of Delta-like 4 in Jagged1-induced tumour angiogenesis and tumour growth
Oncotarget, 2017Co-Authors: Chern Ein Oon, Esther Bridges, Helen Sheldon, Richard C. A. Sainson, Adrian Jubb, Russell Leek, Francesca Buffa, Adrian L Harris, Helen Turley, Ji-liang LiAbstract:// Chern Ein Oon 1,2 , Esther Bridges 1 , Helen Sheldon 1 , Richard C. A. Sainson 1 , Adrian Jubb 1 , Helen Turley 1 , Russell Leek 1 , Francesca Buffa 1 , Adrian L. Harris 1,* and Ji-Liang Li 1,3,* 1 Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK 2 Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang, Malaysia 3 Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth PL6 8BU, UK * These authors are joint senior authors Correspondence to: Ji-Liang Li, email: // Keywords : Notch signalling, DLL4, JAG1, angiogenesis, bevacizumab Received : January 23, 2017 Accepted : March 11, 2017 Published : April 08, 2017 Abstract Delta-like 4 (DLL4) and Jagged1 (JAG1) are two key Notch ligands implicated in tumour angiogenesis. They were shown to have opposite effects on mouse retinal and adult regenerative angiogenesis. In tumours, both ligands are upregulated but their relative effects and interactions in tumour biology, particularly in tumour response to therapeutic intervention are unclear. Here we demonstrate that DLL4 and JAG1 displayed equal potency in stimulating Notch target genes in HMEC-1 endothelial cells but had opposing effects on sprouting angiogenesis in vitro . Mouse DLL4 or JAG1 expressed in glioblastoma cells decreased tumour cell proliferation in vitro but promoted tumour growth in vivo . mDLL4-expressing tumours showed fewer but larger vessels whereas mJAG1-tumours produced more vessels. In both tumour types pericyte coverage was decreased but the vessels were more perfused. Both ligands increased tumour resistance towards anti-VEGF therapy but the resistance was higher in mDLL4-tumours versus mJAG1-tumours. However, their sensitivity to the therapy was restored by blocking Notch signalling with dibenzazepine. Importantly, anti-DLL4 antibody blocked the effect of JAG1 on tumour growth and increased vessel branching in vivo . The mechanism behind the differential responsiveness was due to a positive feedback loop for DLL4-Notch signalling, rendering DLL4 more dominant in activating Notch signalling in the tumour microenvironment. We concluded that DLL4 and JAG1 promote tumour growth by modulating tumour angiogenesis via different mechanisms. JAG1 is not antagonistic but utilises DLL4 in tumour angiogenesis. The results suggest that anti-JAG1 therapy should be explored in conjunction with anti-DLL4 treatment in developing anti-Notch therapies in clinics.
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new mechanism for notch signaling to endothelium at a distance by delta like 4 incorporation into exosomes
Blood, 2010Co-Authors: Helen Sheldon, Richard C. A. Sainson, Russell Leek, Helen Turley, Emily Heikamp, Rebecca Dragovic, Peter H Thomas, Mariola J Edelmann, Benedikt M Kessler, I L SargentAbstract:Notch signaling is an evolutionary conserved pathway that is mediated by cell-cell contact. It is involved in a variety of developmental processes and has an essential role in vascular development and angiogenesis. Delta-like 4 (DLL4) is a Notch ligand that is up-regulated during angiogenesis. It is expressed in endothelial cells and regulates the differentiation between tip cells and stalk cells of neovasculature. Here, we present evidence that DLL4 is incorporated into endothelial exosomes. It can also be incorporated into the exosomes of tumor cells that overexpress DLL4. These exosomes can transfer the DLL4 protein to other endothelial cells and incorporate it into their cell membrane, which results in an inhibition of Notch signaling and a loss of Notch receptor. Transfer of DLL4 was also shown in vivo from tumor cells to host endothelium. Addition of DLL4 exosomes confers a tip cell phenotype on the endothelial cell, which results in a high DLL4/Notch-receptor ratio, low Notch signaling, and filopodia formation. This was further evidenced by increased branching in a tube-formation assay and in vivo. This reversal in phenotype appears to enhance vessel formation and is a new form of signaling for Notch ligands that expands their signaling potential beyond cell-cell contact.
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nuclear and membrane expression of the angiogenesis regulator delta like ligand 4 DLL4 in normal and malignant human tissues
Histopathology, 2009Co-Authors: Juan Carlos Martinez, Richard C. A. Sainson, Ji-liang Li, Adrian L Harris, Helen Turley, Marcus M Muller, Graham Steers, Ludovine Choteau, Francesco Pezzella, Kevin C GatterAbstract:AIMS: Delta-like ligand 4 (DLL4) is one of five known Notch ligands in mammals and interacts predominantly with Notch 1. DLL4 is induced by vascular endothelial growth factor (VEGF) and acts downstream of VEGF as a 'brake' on VEGF-induced vessel growth, forming an autoregulatory negative feedback loop inactivating VEGF. This action was believed to occur only in vascular development, raising hopes that DLL4 could be a specific drug target for controlling vessel growth in tumours and other pathological conditions. Our aim was to pursue this by raising a monoclonal antibody to the internal domain of DLL4 and assess its distribution in normal and malignant tissues in comparison with antibodies against the external domain of DLL4. METHODS AND RESULTS: The anti-DLL4 monoclonal antibody was raised using conventional mouse hybridoma techniques. The antibody has been fully characterized by Western blotting and transfectant immunostaining. It has also been comprehensively compared with other antibodies against both the internal and external domains of DLL4. The antigen is widely expressed on human tissues not only on endothelium but also on epithelium and stromal cells. Indeed, in our comprehensive survey only pulmonary alveoli failed to express DLL4. Of a wide range of malignancies, most also expressed DLL4 on tumour cells with a predominantly cytoplasmic pattern, although a number also displayed nuclear positivity. CONCLUSIONS: Contrary to previous beliefs, DLL4 is widely distributed in tissues other than vessels including many malignancies. Furthermore, the molecule is internalized on binding its receptor and often transported to the nucleus. These findings raise many interesting possibilities for further study of DLL4 and its potential as a therapeutic target.
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regulation of multiple angiogenic pathways by DLL4 and notch in human umbilical vein endothelial cells
Microvascular Research, 2008Co-Authors: Laura S Harrington, Richard C. A. Sainson, Ji-liang Li, Cassin Kimmel Williams, Jennifer M Taylor, Adrian L HarrisAbstract:Abstract The Notch ligand, DLL4, is essential for angiogenesis during embryonic vascular development and is involved in tumour angiogenesis. Several recent publications demonstrated that blockade of DLL4 signalling inhibits tumour growth, suggesting that it may constitute a good candidate for anti-cancer therapy. In order to understand the role of DLL4 at the cellular level, we performed an analysis of DLL4-regulated genes in HUVECs. The genes identified included several angiogenic signalling pathways, such as VEGF, FGF and HGF. In particular we identified downregulation (VEGFR2, placenta growth factor PlGF) of VEGF pathway components resulting in the overall effect of limiting the response of HUVEC to VEGF. However extensive upregulation of VEGFR1 was observed allowing continued response to its ligand PlGF but the soluble form of the VEGFR1, sVEGFR1 was also upregulated. PlGF enhanced tubulogenesis of HUVEC suggesting that downregulation of PlGF and upregulation of VEGFR1 including sVEGFR1 are important mechanisms by which DLL4 attenuates PlGF and VEGF signalling. DLL4-stimulated HUVECs had impaired ERK activation in response to VEGF and HGF indicating that DLL4 signalling negatively regulates these pathways. DLL4 expression reduced vessel sprout length in a 3D tubulogenesis assay confirming that DLL4 signalling inhibits angiogenesis. Altogether, our data suggest that DLL4 expression acts as a switch from the proliferative phase of angiogenesis to the maturation and stabilisation phase by blocking endothelial cell proliferation and allowing induction of a more mature, differentiated phenotype. The regulation of sVEGFR1 provides a novel mechanism for DLL4 signalling to regulate cells at distance, not just in adjacent cells.
Dusan Djokovic - One of the best experts on this subject based on the ideXlab platform.
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Endothelial DLL4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo.
BMC Cancer, 2017Co-Authors: Alexandre Trindade, Dusan Djokovic, Joana Gigante, Liliana Mendonça, Antonio DuarteAbstract:Background The inhibition of Delta-like 4 (DLL4)/Notch signaling has been shown to result in excessive, nonfunctional vessel proliferation and significant tumor growth suppression. However, safety concerns emerged with the identification of side effects resulting from chronic DLL4/Notch blockade. Alternatively, we explored the endothelial DLL4 overexpression using different mouse tumor models.
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combination of DLL4 notch and ephrin b2 ephb4 targeted therapy is highly effective in disrupting tumor angiogenesis
BMC Cancer, 2010Co-Authors: Dusan Djokovic, Alexandre Trindade, Joana Gigante, Marina Badenes, Lilliana Silva, Xiuqing Li, Ming Gong, Valery Krasnoperov, Parkash S Gill, Antonio DuarteAbstract:DLL4/Notch and Ephrin-B2/EphB4 pathways play critical roles in tumor vessel development and maturation. This study evaluates the efficacy of the inhibition of both signaling pathways, alone and in combination, in reducing the growth of an autochthonous mouse tumor and assesses potential adverse effects. We used the transgenic RIP1-Tag2 tumor model to study the effects of 1) inhibition of DLL4/Notch by either DLL4 allelic deletion or use of a soluble extracellular DLL4 (sDLL4), 2) inhibition of Ephrin-B2/EphB4 signaling by a soluble extracellular EphB4 fused to albumin (sEphB4-Alb), and 3) inhibition of both pathways by sEphB4-Alb combined with either DLL4 allelic deletion or sDLL4. To investigate adverse effects, we used inducible endothelial-specific DLL4 knock-out mice, treated with sEphB4-Alb, and carried out histopathological analysis. DLL4 allele deletion or soluble DLL4 treatment resulted in increased tumor vessel density, reduced mural cell recruitment and vessel perfusion which resulted in reduced tumor size. The soluble EphB4 instead reduced vessel density and vessel perfusion, leading to reduction of tumor size. Greater efficacy was observed when sEphB4-Alb was combined with either DLL4 allele deletion or sDLL4 in regards to tumor size, vessel perfusion and mural cell recruitment. Induced endothelial specific DLL4 loss-of-function caused hepatic vascular alterations, which were prevented by concomitant sEphB4-Alb treatment. Combination targeting of DLL4/Notch and Ephrin-B2/EphB4 has potential for clinical investigation, providing cumulative efficacy and increased safety over DLL4/Notch inhibition alone.
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Combination of DLL4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis
BMC Cancer, 2010Co-Authors: Dusan Djokovic, Alexandre Trindade, Joana Gigante, Marina Badenes, Lilliana Silva, Xiuqing Li, Ming Gong, Valery Krasnoperov, Parkash S GillAbstract:DLL4/Notch and Ephrin-B2/EphB4 pathways play critical roles in tumor vessel development and maturation. This study evaluates the efficacy of the inhibition of both signaling pathways, alone and in combination, in reducing the growth of an autochthonous mouse tumor and assesses potential adverse effects. We used the transgenic RIP1-Tag2 tumor model to study the effects of 1) inhibition of DLL4/Notch by either DLL4 allelic deletion or use of a soluble extracellular DLL4 (sDLL4), 2) inhibition of Ephrin-B2/EphB4 signaling by a soluble extracellular EphB4 fused to albumin (sEphB4-Alb), and 3) inhibition of both pathways by sEphB4-Alb combined with either DLL4 allelic deletion or sDLL4. To investigate adverse effects, we used inducible endothelial-specific DLL4 knock-out mice, treated with sEphB4-Alb, and carried out histopathological analysis. DLL4 allele deletion or soluble DLL4 treatment resulted in increased tumor vessel density, reduced mural cell recruitment and vessel perfusion which resulted in reduced tumor size. The soluble EphB4 instead reduced vessel density and vessel perfusion, leading to reduction of tumor size. Greater efficacy was observed when sEphB4-Alb was combined with either DLL4 allele deletion or sDLL4 in regards to tumor size, vessel perfusion and mural cell recruitment. Induced endothelial specific DLL4 loss-of-function caused hepatic vascular alterations, which were prevented by concomitant sEphB4-Alb treatment. Combination targeting of DLL4/Notch and Ephrin-B2/EphB4 has potential for clinical investigation, providing cumulative efficacy and increased safety over DLL4/Notch inhibition alone.
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inhibition of DLL4 mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion
Blood, 2007Co-Authors: Jeffrey S Scehnet, Dusan Djokovic, Alexandre Trindade, Valery Krasnoperov, Weidong Jiang, Ram S Kumar, Rui BeneditoAbstract:Vascular development is dependent on various growth factors and certain modifiers critical for providing arterial or venous identity, interaction with the surrounding stroma and tissues, hierarchic network formation, and recruitment of pericytes. Notch receptors and ligands (Jagged and Delta-like) play a critical role in this process in addition to VEGF. DLL4 is one of the Notch ligands that regulates arterial specification and maturation events. In the current study, we have shown that loss of function by either targeted allele deletion or use of a soluble form of DLL4 extracellular domain leads to inhibition of Notch signaling, resulting in increased vascular proliferation but defective maturation. Newly forming vessels have thin caliber, a markedly reduced vessel lumen, markedly reduced pericyte recruitment, and deficient vascular perfusion. sDLL4 similarly induced defective vascular response in tumor implants leading to reduced tumor growth. Interference with DLL4-Notch signaling may be particularly desirable in tumors that have highly induced DLL4-Notch pathway.
Alexandre Trindade - One of the best experts on this subject based on the ideXlab platform.
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Endothelial DLL4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo.
BMC Cancer, 2017Co-Authors: Alexandre Trindade, Dusan Djokovic, Joana Gigante, Liliana Mendonça, Antonio DuarteAbstract:Background The inhibition of Delta-like 4 (DLL4)/Notch signaling has been shown to result in excessive, nonfunctional vessel proliferation and significant tumor growth suppression. However, safety concerns emerged with the identification of side effects resulting from chronic DLL4/Notch blockade. Alternatively, we explored the endothelial DLL4 overexpression using different mouse tumor models.
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DLL4 notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models
Development, 2013Co-Authors: Brunella Cristofaro, Alexandre Trindade, Antonio Duarte, Marcella Faria, Steven Suchting, Aurelie S Leroyer, Ann C Zovein, Luisa M Iruelaarispe, Nathalie Kubis, Daniel HenrionAbstract:SUMMARY Arteriogenesis requires growth of pre-existing arteriolar collateral networks and determines clinical outcome in arterial occlusive diseases. Factors responsible for the development of arteriolar collateral networks are poorly understood. The Notch ligand Delta- like 4 (DLL4) promotes arterial differentiation and restricts vessel branching. We hypothesized that DLL4 may act as a genetic determinant of collateral arterial networks and functional recovery in stroke and hind limb ischemia models in mice. Genetic loss- and gain-of-function approaches in mice showed that DLL4-Notch signaling restricts pial collateral artery formation by modulating arterial branching morphogenesis during embryogenesis. Adult DLL4 +/− mice showed increased pial collateral numbers, but stroke volume upon middle cerebral artery occlusion was not reduced compared with wild-type littermates. Likewise, DLL4 +/− mice showed reduced blood flow conductance after femoral artery occlusion, and, despite markedly increased angiogenesis, tissue ischemia was more severe. In peripheral arteries, loss of DLL4 adversely affected excitation-contraction coupling in arterial smooth muscle in response to vasopressor agents and arterial vessel wall adaption in response to increases in blood flow, collectively contributing to reduced flow reserve. We conclude that DLL4-Notch signaling modulates native collateral formation by acting on vascular branching morphogenesis during embryogenesis. DLL4 furthermore affects tissue perfusion by acting on arterial function and structure. Loss of DLL4 stimulates collateral formation and angiogenesis, but in the context of ischemic diseases such beneficial effects are overruled by adverse functional changes, demonstrating that ischemic recovery is not solely determined by collateral number but rather by vessel functionality.
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bone marrow derived endothelial progenitors expressing delta like 4 DLL4 regulate tumor angiogenesis
PLOS ONE, 2011Co-Authors: Carla Real, Hideo Yagita, Alexandre Trindade, Antonio Duarte, Leonor Remédio, Francisco Caiado, Catia Igreja, Cristina Borges, Perpetua Pintodoo, Sergio DiasAbstract:Neo-blood vessel growth (angiogenesis), which may involve the activation of pre-existing endothelial cells (EC) and/or the recruitment of bone marrow-derived vascular precursor cells (BM-VPC), is essential for tumor growth. Molecularly, besides the well established roles for Vascular endothelial growth factor (VEGF), recent findings show the Notch signalling pathway, in particular the ligand Delta-like 4 (DLL4), is also essential for adequate tumor angiogenesis; DLL4 inhibition results in impaired, non-functional, angiogenesis and reduced tumor growth. However, the role of BM-VPC in the setting of Notch pathway modulation was not addressed and is the subject of the present report. Here we show that SDF-1 and VEGF, which are produced by tumors, increase DLL4 expression on recruited BM-VPC. Mechanistically, BM-VPC activated, in a DLL4-dependent manner, a transcriptional program on mature EC suggestive of EC activation and stabilization. BM-VPC induced ICAM-2 and Fibronectin expression on EC, an effect that was blocked by a DLL4-specific neutralizing antibody. In vivo, transplantation of BM-VPC with decreased DLL4 into tumor-bearing mice resulted in the formation of microvessels with decreased pericyte coverage and reduced fibronectin expression. Consequently, transplantation of BM-VPC with decreased DLL4 resulted in impaired tumor angiogenesis, increased tumor hypoxia and apoptosis, and decreased tumor growth. Taken together, our data suggests that DLL4 expression by BM-VPC affects their communication with tumor vessel endothelial cells, thereby modulating tumor angiogenesis by affecting vascular stability.
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combination of DLL4 notch and ephrin b2 ephb4 targeted therapy is highly effective in disrupting tumor angiogenesis
BMC Cancer, 2010Co-Authors: Dusan Djokovic, Alexandre Trindade, Joana Gigante, Marina Badenes, Lilliana Silva, Xiuqing Li, Ming Gong, Valery Krasnoperov, Parkash S Gill, Antonio DuarteAbstract:DLL4/Notch and Ephrin-B2/EphB4 pathways play critical roles in tumor vessel development and maturation. This study evaluates the efficacy of the inhibition of both signaling pathways, alone and in combination, in reducing the growth of an autochthonous mouse tumor and assesses potential adverse effects. We used the transgenic RIP1-Tag2 tumor model to study the effects of 1) inhibition of DLL4/Notch by either DLL4 allelic deletion or use of a soluble extracellular DLL4 (sDLL4), 2) inhibition of Ephrin-B2/EphB4 signaling by a soluble extracellular EphB4 fused to albumin (sEphB4-Alb), and 3) inhibition of both pathways by sEphB4-Alb combined with either DLL4 allelic deletion or sDLL4. To investigate adverse effects, we used inducible endothelial-specific DLL4 knock-out mice, treated with sEphB4-Alb, and carried out histopathological analysis. DLL4 allele deletion or soluble DLL4 treatment resulted in increased tumor vessel density, reduced mural cell recruitment and vessel perfusion which resulted in reduced tumor size. The soluble EphB4 instead reduced vessel density and vessel perfusion, leading to reduction of tumor size. Greater efficacy was observed when sEphB4-Alb was combined with either DLL4 allele deletion or sDLL4 in regards to tumor size, vessel perfusion and mural cell recruitment. Induced endothelial specific DLL4 loss-of-function caused hepatic vascular alterations, which were prevented by concomitant sEphB4-Alb treatment. Combination targeting of DLL4/Notch and Ephrin-B2/EphB4 has potential for clinical investigation, providing cumulative efficacy and increased safety over DLL4/Notch inhibition alone.
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Combination of DLL4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis
BMC Cancer, 2010Co-Authors: Dusan Djokovic, Alexandre Trindade, Joana Gigante, Marina Badenes, Lilliana Silva, Xiuqing Li, Ming Gong, Valery Krasnoperov, Parkash S GillAbstract:DLL4/Notch and Ephrin-B2/EphB4 pathways play critical roles in tumor vessel development and maturation. This study evaluates the efficacy of the inhibition of both signaling pathways, alone and in combination, in reducing the growth of an autochthonous mouse tumor and assesses potential adverse effects. We used the transgenic RIP1-Tag2 tumor model to study the effects of 1) inhibition of DLL4/Notch by either DLL4 allelic deletion or use of a soluble extracellular DLL4 (sDLL4), 2) inhibition of Ephrin-B2/EphB4 signaling by a soluble extracellular EphB4 fused to albumin (sEphB4-Alb), and 3) inhibition of both pathways by sEphB4-Alb combined with either DLL4 allelic deletion or sDLL4. To investigate adverse effects, we used inducible endothelial-specific DLL4 knock-out mice, treated with sEphB4-Alb, and carried out histopathological analysis. DLL4 allele deletion or soluble DLL4 treatment resulted in increased tumor vessel density, reduced mural cell recruitment and vessel perfusion which resulted in reduced tumor size. The soluble EphB4 instead reduced vessel density and vessel perfusion, leading to reduction of tumor size. Greater efficacy was observed when sEphB4-Alb was combined with either DLL4 allele deletion or sDLL4 in regards to tumor size, vessel perfusion and mural cell recruitment. Induced endothelial specific DLL4 loss-of-function caused hepatic vascular alterations, which were prevented by concomitant sEphB4-Alb treatment. Combination targeting of DLL4/Notch and Ephrin-B2/EphB4 has potential for clinical investigation, providing cumulative efficacy and increased safety over DLL4/Notch inhibition alone.