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Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis

ABSTRACT: We asked whether combining Notch and VEGF blockade would enhance suppression of tumor angiogenesis and growth, using the NGP neuroblastoma model. NGP tumors were engineered to express a Notch1 decoy construct (N1D), which restricts Notch signaling, and then treated with either the anti-VEGF antibody bevacizumab or vehicle. Combining Notch and VEGF blockade led to blood vessel regression, increasing endothelial cell apoptosis and disrupting pericyte coverage of endothelial cells. Combined Notch and VEGF blockade did not affect tumor weight, but did additively reduce tumor viability. Our results indicate that Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis, and show that concurrent blockade disrupts primary tumor vasculature and viability further than inhibition of either pathway alone.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48880 | GEO | 2013/12/01

SECONDARY ACCESSION(S): PRJNA212114

REPOSITORIES: GEO

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Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis

Project description:We asked whether combining Notch and VEGF blockade would enhance suppression of tumor angiogenesis and growth, using the NGP neuroblastoma model. NGP tumors were engineered to express a Notch1 decoy construct (N1D), which restricts Notch signaling, and then treated with either the anti-VEGF antibody bevacizumab or vehicle. Combining Notch and VEGF blockade led to blood vessel regression, increasing endothelial cell apoptosis and disrupting pericyte coverage of endothelial cells. Combined Notch and VEGF blockade did not affect tumor weight, but did additively reduce tumor viability. Our results indicate that Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis, and show that concurrent blockade disrupts primary tumor vasculature and viability further than inhibition of either pathway alone. 6 neuroblastoma tumors were transfected with Notch1 decoy, 6 with Notch1 decoy and treated with bevacizumab, 6 tumors treated with bevacizumab, and 6 control tumors were profiled by human 133A 2.0 arrays

2013-12-01 | E-GEOD-48880 | biostudies-arrayexpress

Hutchinson2016 - Vascular phenotype identification and anti-angiogenic treatment recommendation

Project description:This is a spatially averaged multiscale mathematical model of tumor angiogenesis. The model describes the dynamics of VEGF, Ang1, Ang2, and PDGF, coupled with those of mature and immature endothelial cells and pericyte cells.

2019-11-13 | MODEL1911130007 | BioModels

Effect of VEGF on expressions of C2H2 zinc finger proteins in human umbilical vein endothelial cells.

Project description:Angiogenic homeostasis is maintained by a balance between vascular endothelial growth factor (VEGF) and Notch signalling in endothelial cells (ECs). We screened for molecules that might mediate the coupling of VEGF signal transduction with down-regulation of Notch signalling, and identified B-cell chronic lymphocytic leukemia/lymphoma6-associated zinc finger protein (BAZF). BAZF was induced by VEGF-A in ECs to bind to the Notch signalling factor CBF1, and to promote the degradation of CBF1 through polyubiquitination in a CBF1-cullin3 (CUL3) E3 ligase complex. BAZF disruption in vivo decreased endothelial tip cell number and filopodia protrusion, and markedly abrogated vascular plexus formation in the mouse retina, overlapping the retinal phenotype seen in response to Notch activation. Further, impaired angiogenesis and capillary remodeling were observed in skin-wounded BAZF-/- mice. We therefore propose that BAZF supports angiogenic sprouting via BAZF-CUL3-based polyubiquitination-dependent degradation of CBF1 to down-regulate Notch signalling. Human umbilical vein endothelial cells were stimulated with recombinant human VEGF165 for 0, 1, 2, 6, 12, 24 and 48 hours.

2012-03-25 | E-GEOD-35171 | biostudies-arrayexpress

MicroRNA expression in HMVECs: control vs. VEGF-treated vs. PEDF/VEGF-treated

Project description:MicroRNA expression profiling of human microvascular endothelial cells (HMVECs) treated with either vascular endothelial growth factor (VEGF) only or in combination with the natural angiogenesis inhibitor pigment epithelial-derived factor (PEDF). Originally we were interested in the microRNA-mediated regulation of angiogenesis by the endogenous anti-angiogenic PEDF. To identify the microRNAs involved in PEDF signaling in activated endothelial cells, we compared the levels of microRNAs in non-treated microvascular endothelial cells, cells treated with VEGF, and cells treated with a combination of VEGF and PEDF. After treatment, total RNA content was isolated and sent for analysis to LC Sciences, LLC. They performed expression profiling and completed statistical analysis, based on which we confirmed the regulation of one of the microRNAs, mir-27b. In the following experiments, we identified the targets of mir-27b relevant for angiogenesis and confirmed our findings in zebrafish and mouse models. The manuscript describes the key role of mir-27b in determination of the endothelial tip cell fate and venous differentiation by regulating Notch ligand Delta-like ligand 4 (Dll4) and Sprouty homologue 2 (Spry2). Three-condition experiment: untreated (control) HMVECs vs. VEGF-treated HMVECs vs. PEDF/VEGF-treated HMVECs.

2011-12-31 | E-GEOD-34735 | biostudies-arrayexpress

Effect of VEGF on expressions of C2H2 zinc finger proteins in human umbilical vein endothelial cells.

2012-03-25 | GSE35171 | GEO

Regulation of Angiogenesis by EZH2

Project description:While VEGF-targeted therapies are showing promise in clinical studies, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homologue 2 (EZH2) expression in either tumor cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation and indicates the presence of a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin 1 (VASH1). EZH2 silencing in the tumor-associated endothelial cells resulted in inhibition of angiogenesis mediated by reactivation of VASH1, and reduced ovarian cancer growth. Combined, these data provide a new understanding of the regulation of tumor angiogenesis and support the potential for targeting EZH2 as a novel therapeutic approach. Pre-clinical study, DNA microarray (Illumina HumanHT-12)

2010-10-12 | E-GEOD-20381 | biostudies-arrayexpress

Placental growth factor mediates pathological uterine vasculature by activating the NFAT5-SGK1 mechano-signaling axis in the endometrium: Implications for pre-eclampsia development.

Project description:After menstruation the uterine spiral arteries are repaired through angiogenesis. This process is tightly regulated by the paracrine communication between endometrial stromal cells (EnSCs) and endothelial cells. Any molecular aberration in these processes can lead to complications in pregnancy including miscarriage or pre-eclampsia (PE). Placental growth factor (PlGF) can increase cell stiffness contributing to pathological angiogenesis but the biomechanisms remain poorly understood. In this study, we investigated whether PlGF contributes to pathological uterine vasculature by disrupting EnSCs and endothelial paracrine communication. We observed that PlGF mediates a tonicity-independent activation of nuclear factor of activated T cells 5 (NFAT5) in EnSCs. NFAT5 activated downstream targets including SGK1, HIF-1α and VEGF-A. In depth characterization of PlGF - conditioned medium (CM) from EnSCs using mass spectrometry and ELISA methods revealed low VEGF-A and an abundance of extracellular matrix organization associated proteins. Secreted factors in PlGF-CM impeded normal angiogenic cues in endothelial cells (HUVECs) by downregulating Notch-VEGF signalling. Interestingly, PlGF-CM failed to support human placental (BeWo) cell invasion through HUVEC monolayer. Inhibition of SGK1 in EnSCs improved angiogenic effects in HUVECs and promoted BeWo invasion, revealing SGK1 as a key intermediate player modulating PlGF mediated anti-angiogenic signalling. Taken together, perturbed PlGF-NFAT5-SGK1 mechano-signaling in the endometrium can contribute to pathological uterine angiogenesis by negatively regulating EnSCs -endothelial crosstalk resulting in poor quality vessels in the uterine microenvironment. Taken together the signaling may impact on normal trophoblast invasion and thus placentation and, may be associated with an increased risk of complications such as PE.

2024-10-17 | PXD051697 | Pride

BMP/Taz-Hippo signaling modulates VEGF-mediated angiogenesis

Project description:The BMP/TGFβ-Smad, Notch and VEGF signaling guides formation of endothelial tip and stalk cells. However, the crosstalk of bone morphogenetic proteins (BMPs) and vascular endothelial growth factor receptor 2 (VEGFR2) signaling has remained largely unknown. We demonstrate that BMP family members regulate VEGFR2 and Notch signaling, and act via TAZ-Hippo signaling pathway. BMPs were found to be regulated after VEGF gene transfer in C57/Bl6 mice and in a porcine myocardial ischemia model. BMPs 2/4/6 were identified as endothelium-specific targets of VEGF. BMP2 modulated VEGF-mediated endothelial sprouting via Delta like Canonical Notch Ligand 4 (DLL4). BMP6 modulated VEGF signaling by regulating VEGFR2 expression and acted via Hippo signaling effector TAZ, known to regulate cell survival/proliferation, and to be dysregulated in cancer. In a matrigel plug assay in nude mice BMP6 was further demonstrated to induce angiogenesis. BMP6 is the first member of BMP family found to directly regulate both Hippo signaling and neovessel formation. It may thus serve as a target in pro/anti-angiogenic therapies.

2020-10-07 | GSE82106 | GEO

Transcription profiling of HUVEC cells following treatment with angiogenesis trigger, VEGF or a more general mitogenic growth factor, EGF

Project description:Angiogenesis is defined as the formation of new capillaries by sprouting from preexisting vessels. It is mainly triggered by vascular endothelial growth factor (VEGF) and occurs in the adult primarily in wound healing processes or in pathologic tumor vessel growth. To identify genes specifically triggered by VEGF and involved in the process of angiogenesis, we utilized Affymetrix microarrays hybridized with cRNA of human umbilical vein endothelial cells (HUVEC) stimulated with either the main trigger of angiogenesis, VEGF or a more general mitogenic growth factor, EGF. This was done under the assumption that, in comparison to EGF, VEGF would induce an additional set of genes not solely required for cell division but necessary for angiogenesis. The obtained data revealed that in HUVEC VEGF induces a large repertoire of genes, the majority of which are not or significantly less induced by EGF. Experiment Overall Design: HUVEC, quiescent by maintaining dense cultures in complete medium for four days without change of medium were stimulted with 100ng of VEGF or 50ng of EGF for 30, 60, 150 and 360 minutes and total RNA was isolated using Trizol.

2009-07-03 | E-GEOD-10778 | biostudies-arrayexpress

Inhibition of Notch4 with Novel Neutralizing Antibodies Reduces Tumor Growth in Multiple Tumor Types and Targets Endothelium and Tumor Associated Macrophages in a Mouse Breast Cancer Model [RiboTag RNA-seq]

Project description:Endothelial Notch signaling is critical for tumor angiogenesis. Notch1 blockade reduces tumor vessel function but causes vascular dysfunction, hypoxia, and gastrointestinal toxicity. Notch4 expression is restricted to developing vasculature, where it promotes angiogenesis. Unlike other Notch proteins, Notch4 has rarely been targeted therapeutically. We developed highly specific Notch4-blocking antibodies, 6-3-A6 and humanized E7011, allowing therapeutic targeting of Notch4 in tumor models. E7011 treatment significantly delayed tumor growth and impaired tumor vessel perfusion in mouse models of breast, skin, and lung tumors. In a mouse orthotopic breast cancer model, Notch4 expression was confined to endothelial cells, but E7011 treatment significantly increased tumor-associated macrophages and increased macrophage expression of anti-tumor genes. Liposomal clodronate-mediated macrophage depletion reversed the anti-tumor effects of E7011, demonstrating that Notch4 supports tumor growth via angiocrine signaling to tumor macrophages. We conclude that targeting Notch4 alters tumor vessel function and tumor associated macrophage phenotype, leading to tumor inhibition.

2024-08-08 | GSE241629 | GEO

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