Tumor growth and metastasis rely on tumor vascular network for the adequate supply of oxygen and nutrients. Tumor angiogenesis relies on a highly complex program of growth factor signaling, ...endothelial cell (EC) proliferation, extracellular matrix (ECM) remodeling, and stromal cell interactions. Numerous pro-angiogenic drivers have been identified, the most important of which is the vascular endothelial growth factor (VEGF). The importance of pro-angiogenic inducers in tumor growth, invasion and extravasation make them an excellent therapeutic target in several types of cancers. Hence, the number of anti-angiogenic agents developed for cancer treatment has risen over the past decade, with at least eighty drugs being investigated in preclinical studies and phase I-III clinical trials. To date, the most common approaches to the inhibition of the VEGF axis include the blockade of VEGF receptors (VEGFRs) or ligands by neutralizing antibodies, as well as the inhibition of receptor tyrosine kinase (RTK) enzymes. Despite promising preclinical results, anti-angiogenic monotherapies led only to mild clinical benefits. The minimal benefits could be secondary to primary or acquired resistance, through the activation of alternative mechanisms that sustain tumor vascularization and growth. Mechanisms of resistance are categorized into VEGF-dependent alterations, non-VEGF pathways and stromal cell interactions. Thus, complementary approaches such as the combination of these inhibitors with agents targeting alternative mechanisms of blood vessel formation are urgently needed. This review provides an updated overview on the pathophysiology of angiogenesis during tumor growth. It also sheds light on the different pro-angiogenic and anti-angiogenic agents that have been developed to date. Finally, it highlights the preclinical evidence for mechanisms of angiogenic resistance and suggests novel therapeutic approaches that might be exploited with the ultimate aim of overcoming resistance and improving clinical outcomes for patients with cancer.
The vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been shown to play major roles not only in physiological but also in most pathological angiogenesis, such as cancer. VEGF ...belongs to the PDGF supergene family characterized by 8 conserved cysteines and functions as a homodimer structure. VEGF-A regulates angiogenesis and vascular permeability by activating 2 receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk1 in mice). On the other hand, VEGF-C/VEGF-D and their receptor, VEGFR-3 (Flt-4), mainly regulate lymphangiogenesis. The VEGF family includes other interesting variants, one of which is the virally encoded VEGF-E and another is specifically expressed in the venom of the habu snake (Trimeresurus flavoviridis). VEGFRs are distantly related to the PDGFR family; however, they are unique with respect to their structure and signaling system. Unlike members of the PDGFR family that strongly stimulate the PI3K-Akt pathway toward cell proliferation, VEGFR-2, the major signal transducer for angiogenesis, preferentially utilizes the PLCγ-PKC-MAPK pathway for signaling. The VEGF-VEGFR system is an important target for anti-angiogenic therapy in cancer and is also an attractive system for pro-angiogenic therapy in the treatment of neuronal degeneration and ischemic diseases.
Vascular endothelial growth factor (VEGF) is a pleiotropic growth factor that binds a broad spectrum of cell types and regulates diverse cellular processes, including angiogenesis, growth and ...survival. However, it is technically difficult to quantify VEGF-cell binding activity because of reversible nature of ligand-receptor interactions. Here we used T7 bacteriophage display to quantify and compare binding activity of three human VEGF-A (hVEGF) isoforms, including hVEGF111, 165 and 206. All three isoforms bound equally well to immobilized aflibercept, a decoy VEGF receptor. hVEGF111-Phage exhibited minimal binding to immobilized heparan sulfate, whereas hVEGF206-Phage and hVEGF165-Phage had the highest and intermediate binding to heparan, respectively. In vitro studies revealed that all three isoforms bound to human umbilical vein endothelial cells (HUVECs), HEK293 epithelial and SK-N-AS neuronal cells. hVEGF111-Phage has the lowest binding activity, while hVEGF206-Phage has the highest binding. hVEGF206-Phage was the most sensitive to detect VEGF-cell binding, albeit with the highest background binding to SK-N-AS cells. These results suggest that hVEGF206-Phage is the best-suited isoform to quantify VEGF-cell binding even though VEGF165 is the most biologically active. Furthermore, this study demonstrates the utility of T7 phage display as a platform for rapid and convenient ligand-cell binding quantification with pros and cons discussed.
•A method to quickly quantify VEGF binding to cells, receptor and heparan.•All three VEGF isoforms, including VEGF111, 165 and 206, can be readily quantified.•VEGF206 isoform shows the highest binding to cells and heparan sulfate.•VEGF165 isoform has the intermediate binding to cells and heparan.•VEGF111 isoform show the lowest binding to cells and heparan.
Background
Ischemic stroke is a serious cerebrovascular disease with high morbidity and disability. Zinc accumulation has been shown to play a vital role in neuronal death and blood–brain barrier ...damage following ischemia in acute stage. However, almost nothing is known about whether zinc is involved in neurological recovery in ischemic prolonged period. This study investigates whether zinc promotes neurological recovery through astrocytes‐induced angiogenesis during ischemic repair phase.
Methods
Sprague–Dawley rats were subjected to 2 h ischemia/14, 21, and 28 days reperfusion by middle cerebral artery occlusion, then administered ZnCl2 (10 mg/kg) via intraperitoneally daily from 7 days to tissue collection to observe brain tissue morphology, neurological function recovery by cortical width index, Adhesive removal test, and Forelimb placing test. Angiogenesis, astrocyte activation, and HIF‐1α/VEGF pathway were assessed via Western blot, immunofluorescence, and BrdU method in vivo and in vitro.
Results
The results showed that zinc significantly alleviated brain atrophy and improved neurological function recovery during the cerebral ischemia repair stage. Zinc significantly increased the protein levels of HIF‐1α, VEGF‐A, and VEGF‐R2 in astrocytes, and promoted angiogenesis during cerebral ischemia repair. In vitro and in vivo studies confirmed that zinc promoted angiogenesis via the astrocyte‐mediated HIF‐1α/VEGF signaling pathway.
Conclusions
Zinc significantly improves neurological function recovery during the cerebral ischemia repair stage, providing new evidence supporting zinc as a potential therapeutic target for ischemic stroke by promoting astrocyte induced angiogenesis.
Zinc can alleviate cerebral ischemia atrophy and promote neurological function recovery during cerebral ischemia repair stage.
Zinc promoted angiogenesis via astrocyte‐mediated HIF‐1α/VEGF signaling pathway.
Zinc may serve as a potential therapeutic target for the treatment of functional.
Intravitreal anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular age-related macular degeneration (NVAMD). However, many patients suffer from ...incomplete response to anti-VEGF therapy (IRT), which is defined as (1) persistent (plasma) fluid exudation; (2) unresolved or new hemorrhage; (3) progressive lesion fibrosis; and/or (4) suboptimal vision recovery. The first three of these collectively comprise the problem of persistent disease activity (PDA) in spite of anti-VEGF therapy. Meanwhile, the problem of suboptimal vision recovery (SVR) is defined as a failure to achieve excellent functional visual acuity of 20/40 or better in spite of sufficient anti-VEGF treatment. Thus, incomplete response to anti-VEGF therapy, and specifically PDA and SVR, represent significant clinical unmet needs.
In this review, we will explore PDA and SVR in NVAMD, characterizing the clinical manifestations and exploring the pathobiology of each. We will demonstrate that PDA occurs most frequently in NVAMD patients who develop high-flow CNV lesions with arteriolarization, in contrast to patients with capillary CNV who are highly responsive to anti-VEGF therapy. We will review investigations of experimental CNV and demonstrate that both types of CNV can be modeled in mice. We will present and consider a provocative hypothesis: formation of arteriolar CNV occurs via a distinct pathobiology, termed neovascular remodeling (NVR), wherein blood-derived macrophages infiltrate the incipient CNV lesion, recruit bone marrow-derived mesenchymal precursor cells (MPCs) from the circulation, and activate MPCs to become vascular smooth muscle cells (VSMCs) and myofibroblasts, driving the development of high-flow CNV with arteriolarization and perivascular fibrosis. In considering SVR, we will discuss the concept that limited or poor vision in spite of anti-VEGF may not be caused simply by photoreceptor degeneration but instead may be associated with photoreceptor synaptic dysfunction in the neurosensory retina overlying CNV, triggered by infiltrating blood-derived macrophages and mediated by Müller cell activation Finally, for each of PDA and SVR, we will discuss current approaches to disease management and treatment and consider novel avenues for potential future therapies.
•Incomplete response to anti-VEGF therapy: significant unmet need in neovascular AMD.•Persistent disease activity (PDA) caused by macrophage-driven neovascular remodeling.•Suboptimal vision response (SVR) is caused by photoreceptor synaptic dysfunction.•Novel therapies for neovascular AMD will need to address problems of PDA and SVR.
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