scholarly journals Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis

2013 ◽  
Vol 210 (10) ◽  
pp. 1937-1945 ◽  
Author(s):  
Adriana Soler ◽  
Helena Serra ◽  
Wayne Pearce ◽  
Ana Angulo ◽  
Julie Guillermet-Guibert ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Tumor Hypoxia ◽  
Tumor Stroma ◽  
Vascular Density ◽  
Vascular Endothelial ◽  
Therapeutic Opportunity ◽  
Endothelial Growth Factor ◽  
Nonfunctional Tumor

Understanding the direct, tumor cell–intrinsic effects of PI 3-kinase (PI3K) has been a key focus of research to date. Here, we report that cancer cell–extrinsic PI3K activity, mediated by the p110α isoform of PI3K, contributes in an unexpected way to tumor angiogenesis. In syngeneic mouse models, inactivation of stromal p110α led to increased vascular density, reduced vessel size, and altered pericyte coverage. This increased vascularity lacked functionality, correlating with enhanced tumor hypoxia and necrosis, and reduced tumor growth. The role of p110α in tumor angiogenesis is multifactorial, and includes regulation of proliferation and DLL4 expression in endothelial cells. p110α in the tumor stroma is thus a regulator of vessel formation, with p110α inactivation giving rise to nonfunctional angiogenesis, which can stunt tumor growth. This type of vascular aberration differs from vascular endothelial growth factor–centered antiangiogenesis therapies, which mainly lead to vascular pruning. Inhibition of p110α may thus offer a new antiangiogenic therapeutic opportunity in cancer.

Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis

2005 ◽  
Vol 23 (5) ◽  
pp. 1011-1027 ◽  
Author(s):  
Daniel J. Hicklin ◽  
Lee M. Ellis
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Anti Vegf ◽  
Vegf Pathway ◽  
Endothelial Growth Factor

New blood vessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastatic dissemination. Hence, the molecular basis of tumor angiogenesis has been of keen interest in the field of cancer research. The vascular endothelial growth factor (VEGF) pathway is well established as one of the key regulators of this process. The VEGF/VEGF-receptor axis is composed of multiple ligands and receptors with overlapping and distinct ligand-receptor binding specificities, cell-type expression, and function. Activation of the VEGF-receptor pathway triggers a network of signaling processes that promote endothelial cell growth, migration, and survival from pre-existing vasculature. In addition, VEGF mediates vessel permeability, and has been associated with malignant effusions. More recently, an important role for VEGF has emerged in mobilization of endothelial progenitor cells from the bone marrow to distant sites of neovascularization. The well-established role of VEGF in promoting tumor angiogenesis and the pathogenesis of human cancers has led to the rational design and development of agents that selectively target this pathway. Studies with various anti-VEGF/VEGF-receptor therapies have shown that these agents can potently inhibit angiogenesis and tumor growth in preclinical models. Recently, an anti-VEGF antibody (bevacizumab), when used in combination with chemotherapy, was shown to significantly improve survival and response rates in patients with metastatic colorectal cancer and thus, validate VEGF pathway inhibitors as an important new treatment modality in cancer therapy.

The Role of Vascular Endothelial Growth Factor in Tumor Angiogenesis

1998 ◽  
pp. 305-318
Author(s):  
Georg Breier ◽  
Annette Damert ◽  
Sabine Blum ◽  
Ernst Reichmann ◽  
Karl H. Plate ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tumor Angiogenesis ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

scholarly journals Role of Peroxisome Proliferator-Activated Receptor Alpha in the Control of Cyclooxygenase 2 and Vascular Endothelial Growth Factor: Involvement in Tumor Growth

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
Raquel Grau ◽  
Manuel D. Díaz-Muñoz ◽  
Cristina Cacheiro-Llaguno ◽  
Manuel Fresno ◽  
Miguel A. Iñiguez
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Cell Growth ◽  
Tumor Growth ◽  
Peroxisome Proliferator ◽  
Vascular Endothelial ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cox 2 ◽  
Endothelial Growth Factor

A growing body of evidence indicates that PPAR (peroxisome proliferator-activated receptor)αagonists might have therapeutic usefulness in antitumoral therapy by decreasing abnormal cell growth, and reducing tumoral angiogenesis. Most of the anti-inflammatory and antineoplastic properties of PPAR ligands are due to their inhibitory effects on transcription of a variety of genes involved in inflammation, cell growth and angiogenesis. Cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF) are crucial agents in inflammatory and angiogenic processes. They also have been significantly associated to cell proliferation, tumor growth, and metastasis, promoting tumor-associated angiogenesis. Aberrant expression of VEGF and COX-2 has been observed in a variety of tumors, pointing to these proteins as important therapeutic targets in the treatment of pathological angiogenesis and tumor growth. This review summarizes the current understanding of the role of PPARαand its ligands in the regulation of COX-2 and VEGF gene expression in the context of tumor progression.

Small extracellular vesicles containing miR-486-5p promote angiogenesis after myocardial infarction in mice and nonhuman primates

2021 ◽  
Vol 13 (584) ◽  
pp. eabb0202
Author(s):  
Qingju Li ◽  
Yinchuan Xu ◽  
Kaiqi Lv ◽  
Yingchao Wang ◽  
Zhiwei Zhong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Extracellular Vesicles ◽  
Nonhuman Primates ◽  
Target Genes ◽  
Cardiac Fibroblasts ◽  
Vascular Density ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Stem cell–derived small extracellular vesicles (sEVs) promote angiogenesis after myocardial infarction (MI). However, the components of sEVs that contribute to these effects and the safety and efficiency of engineered sEV treatment for MI remain unresolved. Here, we observed improved cardiac function, enhanced vascular density, and smaller infarct size in mice treated with the sEVs from hypoxia-preconditioned (HP) mesenchymal stem cells (MSCs) (HP-sEVs) than in mice treated with normoxia-preconditioned (N) MSCs (N-sEVs). MicroRNA profiling revealed a higher abundance of miR-486-5p in HP-sEVs than in N-sEVs, and miR-486-5p inactivation abolished the benefit of HP-sEV treatment, whereas miR-486-5p up-regulation enhanced the benefit of N-sEV treatment. Matrix metalloproteinase 19 (MMP19) abundance was lower in HP-sEV–treated than N-sEV–treated mouse hearts but was enriched in cardiac fibroblasts (CFs), and Mmp19 was identified as one of the target genes of miR-486-5p. Conditioned medium from CFs that overexpressed miR-486-5p or silenced MMP19 increased the angiogenic activity of endothelial cells; however, medium from CFs that simultaneously overexpressed Mmp19 and miR-486-5p abolished this effect. Mmp19 silencing in CFs reduced the cleavage of extracellular vascular endothelial growth factor (VEGF). Furthermore, miR-486-5p–overexpressing N-sEV treatment promoted angiogenesis and cardiac recovery without increasing arrhythmia complications in a nonhuman primate (NHP) MI model. Collectively, this study highlights the key role of sEV miR-486-5p in promoting cardiac angiogenesis via fibroblastic MMP19-VEGFA cleavage signaling. Delivery of miR-486-5p–engineered sEVs safely enhanced angiogenesis and cardiac function in an NHP MI model and may promote cardiac repair.

Wogonin Inhibits Angiogenesis Via a c-Myc/Hif-1α–dependent Pathway in Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5238-5238 ◽  
Author(s):  
Rong Fu ◽  
Qinglong Guo ◽  
Yan Chen ◽  
Huihui Song ◽  
Baoan Chen
Keyword(s):  
Multiple Myeloma ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Conflicts Of Interest ◽  
Tumor Promotion ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor ◽  
Dependent Pathway

Abstract Wogonin, a plant-derived flavone, has been shown to inhibit tumor angiogenesis. Angiogenesis is associated with multiple myeloma (MM) progression. However, the mechanisms that Wogonin inhibits angiogenesis in MM microenvironment are not well known. In this study, we investigated Wogonin inhibited tumor angiogenesis that correlated with the inhibition the secretion of vascular endothelial growth factor (VEGF) in MM cells. The c-Myc/Hif-1α–dependent pathway was essential to regulate MM cell-mediated angiogenesis and contributed to tumor growth. Wogonin inhibited c-Myc activation and down-regulated the expression of c-Myc and Hif-1α. Functionally, based on transient knockdowns and overexpression, our data delineate Wogonin inhibited VEGF production and secretion mediating tumor angiogenesis via c-Myc/Hif-1α–dependent pathway. Our data, therefore, identify Wogonin as a novel anti-angiogenesis compound to inhibit tumor promotion in MM. Disclosures No relevant conflicts of interest to declare.

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