scholarly journals Novel Targets and Entities Inducing Cellular Apoptosis and Anti-Angiogenic Activity in Retinoblastoma Management

BioMedica ◽  
2021 ◽  
Vol 37 (2) ◽  
pp. 76-85
Author(s):  
Zirwa Abdul Rauf ◽  
Muhammad Hamza Zahid ◽  
Feng Guo ◽  
Zaigui Wang
Keyword(s):  
Side Effects ◽  
Pediatric Cancer ◽  
External Beam Radiotherapy ◽  
Beta Catenin ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Rb1 Gene ◽  
Cellular Apoptosis ◽  
Endothelial Growth Factor ◽  
Kinase Pathway

<p>Retinoblastoma (Rb) represents a primary pediatric cancer, which if left untreated can invade to the nervous system that primarily occurs due to loss of the RB1 gene. Several clinically available therapies are used for the management of risk factors associated with Rb including chemotherapy, brachytherapy, external beam radiotherapy etc. However, each treatment has its own side effects. To meet with the best approach in order to minimize these side effects, novel targeted therapies have been developed that inhibit tumor in an angiogenic-dependent manner. This review provides the insights about some targets and the pharmaceuticals with their possible mechanism of action that targets angiogenesis and induces apoptosis. The targets include activation of p53 via controlling mouse double minute homolog 2, survivin, and thrombospondin-1. Entities described in this review include 5-aminoimidazole-4-carboxamide ribonucleotide, niclosamide, bevacizumab, aflibercept, genistein and quercetin and their potential in treating Rb. Also, the signaling pathways that are affected in response to these drugs like activated protein kinase pathway, Wnt/&beta;-catenin pathway, vascular endothelial growth factor and its receptors has also been discussed.</p>

scholarly journals eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Takeshi Ninchoji ◽  
Dominic T Love ◽  
Ross O Smith ◽  
Marie Hedlund ◽  
Dietmar Vestweber ◽  
...  
Keyword(s):  
No Synthase ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Ocular Diseases ◽  
Oxygen Induced Retinopathy ◽  
No Formation ◽  
Therapy Development ◽  
Endothelial Growth Factor ◽  
Deutsche Forschungsgemeinschaft

Background:Hypoxia and consequent production of vascular endothelial growth factor A (VEGFA) promote blood vessel leakiness and edema in ocular diseases. Anti-VEGFA therapeutics may aggravate hypoxia; therefore, therapy development is needed.Methods:Oxygen-induced retinopathy was used as a model to test the role of nitric oxide (NO) in pathological neovascularization and vessel permeability. Suppression of NO formation was achieved chemically using L-NMMA, or genetically, in endothelial NO synthase serine to alanine (S1176A) mutant mice.Results:Suppression of NO formation resulted in reduced retinal neoangiogenesis. Remaining vascular tufts exhibited reduced vascular leakage through stabilized endothelial adherens junctions, manifested as reduced phosphorylation of vascular endothelial (VE)-cadherin Y685 in a c-Src-dependent manner. Treatment with a single dose of L-NMMA in established retinopathy restored the vascular barrier and prevented leakage.Conclusions:We conclude that NO destabilizes adheren junctions, resulting in vascular hyperpermeability, by converging with the VEGFA/VEGFR2/c-Src/VE-cadherin pathway.Funding:This study was supported by the Swedish Cancer foundation (19 0119 Pj ), the Swedish Research Council (2020-01349), the Knut and Alice Wallenberg foundation (KAW 2020.0057) and a Fondation Leducq Transatlantic Network of Excellence Grant in Neurovascular Disease (17 CVD 03). KAW also supported LCW with a Wallenberg Scholar grant (2015.0275). WCS was supported by Grants R35 HL139945, P01 HL1070205, AHA MERIT Award. DV was supported by grants from the Deutsche Forschungsgemeinschaft, SFB1450, B03, and CRU342, P2.

scholarly journals HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1α (HIF-1α) Synthesis: Novel Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor Expression

2001 ◽  
Vol 21 (12) ◽  
pp. 3995-4004 ◽  
Author(s):  
Erik Laughner ◽  
Panthea Taghavi ◽  
Kelly Chiles ◽  
Patrick C. Mahon ◽  
Gregg L. Semenza
Keyword(s):  
Breast Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Cancer Cells ◽  
Half Life ◽  
Hypoxia Inducible Factor ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Her2 Signaling ◽  
Endothelial Growth Factor

ABSTRACT Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator composed of HIF-1α and HIF-1β subunits. Several dozen HIF-1 targets are known, including the gene encoding vascular endothelial growth factor (VEGF). Under hypoxic conditions, HIF-1α expression increases as a result of decreased ubiquitination and degradation. The tumor suppressors VHL (von Hippel-Lindau protein) and p53 target HIF-1α for ubiquitination such that their inactivation in tumor cells increases the half-life of HIF-1α. Increased phosphatidylinositol 3-kinase (PI3K) and AKT or decreased PTEN activity in prostate cancer cells also increases HIF-1α expression by an undefined mechanism. In breast cancer, increased activity of the HER2 (also known as neu) receptor tyrosine kinase is associated with increased tumor grade, chemotherapy resistance, and decreased patient survival. HER2 has also been implicated as an inducer of VEGF expression. Here we demonstrate that HER2 signaling induced by overexpression in mouse 3T3 cells or heregulin stimulation of human MCF-7 breast cancer cells results in increased HIF-1α protein and VEGF mRNA expression that is dependent upon activity of PI3K, AKT (also known as protein kinase B), and the downstream kinase FRAP (FKBP-rapamycin-associated protein). In contrast to other inducers of HIF-1 expression, heregulin stimulation does not affect the half-life of HIF-1α but instead stimulates HIF-1α synthesis in a rapamycin-dependent manner. The 5′-untranslated region of HIF-1α mRNA directs heregulin-inducible expression of a heterologous protein. These data provide a molecular basis for VEGF induction and tumor angiogenesis by heregulin-HER2 signaling and establish a novel mechanism for the regulation of HIF-1α expression.

scholarly journals Neuropilin-1 Mediates Collapsin-1/Semaphorin III Inhibition of Endothelial Cell Motility

1999 ◽  
Vol 146 (1) ◽  
pp. 233-242 ◽  
Author(s):  
Hua-Quan Miao ◽  
Shay Soker ◽  
Leonard Feiner ◽  
José Luis Alonso ◽  
Jonathan A. Raper ◽  
...  
Keyword(s):  
Binding Sites ◽  
Aortic Ring ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Binding Assays ◽  
Angiogenesis Assay ◽  
Neuropilin 1 ◽  
Endothelial Growth Factor ◽  
Neuronal Guidance

Neuropilin-1 (NRP1) is a receptor for two unrelated ligands with disparate activities, vascular endothelial growth factor-165 (VEGF165), an angiogenesis factor, and semaphorin/collapsins, mediators of neuronal guidance. To determine whether semaphorin/collapsins could interact with NRP1 in nonneuronal cells, the effects of recombinant collapsin-1 on endothelial cells (EC) were examined. Collapsin-1 inhibited the motility of porcine aortic EC (PAEC) expressing NRP1 alone; coexpressing KDR and NRP1 (PAEC/KDR/NRP1), but not parental PAEC; or PAEC expressing KDR alone. The motility of PAEC expressing NRP1 was inhibited by 65–75% and this inhibition was abrogated by anti-NRP1 antibody. In contrast, VEGF165 stimulated the motility of PAEC/KDR/NRP1. When VEGF165 and collapsin-1 were added simultaneously to PAEC/KDR/NRP1, dorsal root ganglia (DRG), and COS-7/NRP1 cells, they competed with each other in EC motility, DRG collapse, and NRP1-binding assays, respectively, suggesting that the two ligands have overlapping NRP1 binding sites. Collapsin-1 rapidly disrupted the formation of lamellipodia and induced depolymerization of F-actin in an NRP1-dependent manner. In an in vitro angiogenesis assay, collapsin-1 inhibited the capillary sprouting of EC from rat aortic ring segments. These results suggest that collapsin-1 can inhibit EC motility as well as axon motility, that these inhibitory effects on motility are mediated by NRP1, and that VEGF165 and collapsin-1 compete for NRP1-binding sites.

Characterization of the vasculogenic block in the absence of vascular endothelial growth factor-A

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 1979-1987 ◽  
Author(s):  
Victoria L. Bautch ◽  
Sambra D. Redick ◽  
Aaron Scalia ◽  
Marco Harmaty ◽  
Peter Carmeliet ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Embryonic Stem ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Vegf Signaling ◽  
Homozygous Mutant ◽  
Endothelial Growth Factor ◽  
Rna Levels

Abstract Vascular endothelial growth factor (VEGF) signaling is required for both differentiation and proliferation of vascular endothelium. Analysis of differentiated embryonic stem cells with one or both VEGF-A alleles deleted showed that both the differentiation and the expansion of endothelial cells are blocked during vasculogenesis. Blood island formation was reduced by half in hemizygous mutant VEGF cultures and by 10-fold in homozygous mutant VEGF cultures. Homozygous mutant cultures could be partially rescued by the addition of exogenous VEGF. RNA levels for the endothelial adhesion receptors ICAM-2 and PECAM were reduced in homozygous mutant cultures, but ICAM-2 RNA levels decreased substantially, whereas PECAM RNA levels remained at hemizygous levels. The quantitative data correlated with the antibody staining patterns because cells that were not organized into vessels expressed PECAM but not ICAM-2. These PECAM+ cell clumps accumulated in mutant cultures as vessel density decreased, suggesting that they were endothelial cell precursors blocked from maturation. A subset of PECAM+ cells in clumps expressed stage-specific embryonic antigen-1 (SSEA-1), and all were ICAM-2(−) and CD34(−), whereas vascular endothelial cells incorporated into vessels were PECAM(+), ICAM-2(+), CD34(+), and SSEA-1(−). Analysis of flk-1 expression indicated that a subset of vascular precursor cells coexpressed PECAM and flk-1. These data suggest that VEGF signaling acts in a dose-dependent manner to affect both a specific differentiation step and the subsequent expansion of endothelial cells.

Vascular endothelial growth factor synergistically enhances bone morphogenetic protein-4-dependent lymphohematopoietic cell generation from embryonic stem cells in vitro

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2275-2283 ◽  
Author(s):  
Naoki Nakayama ◽  
Jae Lee ◽  
Laura Chiu
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Bone Morphogenetic Protein ◽  
Es Cells ◽  
Embryonic Stem ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Morphogenetic Protein ◽  
Endothelial Growth Factor

Abstract The totipotent mouse embryonic stem (ES) cell is known to differentiate into cells expressing the β-globin gene when stimulated with bone morphogenetic protein (BMP)-4. Here, we demonstrate that BMP-4 is essential for generating both erythro-myeloid colony-forming cells (CFCs) and lymphoid (B and NK) progenitor cells from ES cells and that vascular endothelial growth factor (VEGF) synergizes with BMP-4. The CD45+ myelomonocytic progenitors and Ter119+ erythroid cells began to be detected with 0.5 ng/mL BMP-4, and their levels plateaued at approximately 2 ng/mL. VEGF alone weakly elevated the CD34+ cell population though no lymphohematopoietic progenitors were induced. However, when combined with BMP-4, 2 to 20 ng/mL VEGF synergistically augmented the BMP-4-dependent generation of erythro-myeloid CFCs and lymphoid progenitors from ES cells, which were enriched in CD34+ CD31lo and CD34+CD45− cell populations, respectively, in a dose-dependent manner. Furthermore, during the 7 days of in vitro differentiation, BMP-4 was required within the first 4 days, whereas VEGF was functional after the action of BMP-4 (in the last 3 days). Thus, VEGF is a synergistic enhancer for the BMP-4-dependent differentiation processes, and it seems to be achieved by the ordered action of the 2 factors.

Wnt5a Expression Is Associated With the Tumor Proliferation and the Stromal Vascular Endothelial Growth Factor—An Expression in Non–Small-Cell Lung Cancer

2005 ◽  
Vol 23 (34) ◽  
pp. 8765-8773 ◽  
Author(s):  
Cheng-long Huang ◽  
Dage Liu ◽  
Jun Nakano ◽  
Shinya Ishikawa ◽  
Keiichi Kontani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Squamous Cell ◽  
Squamous Cell Carcinomas ◽  
Proliferation Index ◽  
Beta Catenin ◽  
Vascular Endothelial ◽  
Small Cell Lung ◽  
Ki 67 ◽  
Wnt5a Expression ◽  
Endothelial Growth Factor

Purpose The Wnt gene family encodes the multifunctional signaling glycoproteins. We performed the present study to investigate the clinical significance of Wnt5a expression in non–small-cell lung cancer (NSCLC). Patients and Methods One hundred twenty-three patients with NSCLC who had undergone resection were investigated. Real-time quantitative reverse transcriptase polymerase chain reaction was performed to evaluate the Wnt5a gene expression. Immunohistochemistry was performed to investigate the Wnt5a protein expression, the Ki-67 proliferation index, tumor angiogenesis, and the expression of beta-catenin and vascular endothelial growth factor-A (VEGF-A). Results Wnt5a gene expression in squamous cell carcinoma was significantly higher than that in adenocarcinoma (P < .0001). There was a significant correlation between the normalized Wnt5a gene expression ratio and the intratumoral Wnt5a protein expression (r = 0.729; P < .0001). The intratumoral Wnt5a expression was significantly correlated with the Ki-67 proliferation index (r = 0.708; P < .0001). In contrast, no correlation was observed between the intratumoral Wnt5a expression and tumor angiogenesis. Furthermore, the intratumoral Wnt5a expression was significantly correlated with the stromal expression of beta-catenin (r = 0.729; P < .0001) and VEGF-A (r = 0.661; P < .0001). In addition, the stromal VEGF-A expression was also correlated with Ki-67 proliferation (r = 0.627; P < .0001). Cox regression analyses demonstrated Wnt5a status to be a significant prognostic factor for NSCLC patients (P = .0193), especially for patients with squamous cell carcinomas (P = .0491). Conclusion The present study revealed that an overexpression of Wnt5a could produce more aggressive NSCLC, especially in squamous cell carcinomas, during tumor progression.

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