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Seminars in Cancer Biology Dec 1992Progress in our understanding of tumour angiogenesis and an appreciation of the marked differences between quiescent and proliferating endothelium are revealing new... (Review)
Review
Progress in our understanding of tumour angiogenesis and an appreciation of the marked differences between quiescent and proliferating endothelium are revealing new strategies for anticancer therapy. This article outlines these strategies and critically assesses their chances of success.
Topics: Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 1283702
DOI: No ID Found -
Arteriosclerosis, Thrombosis, and... Sep 2006Angiogenesis, the process by which new blood vessels develop from a pre-existing vascular network, is essential for normal development and in certain physiological... (Review)
Review
Angiogenesis, the process by which new blood vessels develop from a pre-existing vascular network, is essential for normal development and in certain physiological states. Inadequate or excessive angiogenesis has been incriminated in a number of pathologic states. For example, vaso-occlusive disease arising from atherosclerosis can lead to ischemia, a situation in which enhanced angiogenesis would be beneficial. Conversely, overzealous angiogenesis can contribute to tumor development and in this case inhibition of angiogenesis is desirable. Thus, strategies to induce or inhibit angiogenesis are of considerable therapeutic interest.
Topics: Animals; Humans; Neovascularization, Physiologic; Transcription, Genetic
PubMed: 16778118
DOI: 10.1161/01.ATV.0000232542.42968.e3 -
Angiogenesis Aug 2021Angiogenesis plays a critical role in both physiological responses and disease pathogenesis. Excessive angiogenesis can promote neoplastic diseases and retinopathies,... (Review)
Review
Angiogenesis plays a critical role in both physiological responses and disease pathogenesis. Excessive angiogenesis can promote neoplastic diseases and retinopathies, while inadequate angiogenesis can lead to aberrant perfusion and impaired wound healing. Transforming growth factor β activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, is a key modulator involved in a range of cellular functions including the immune responses, cell survival and death. TAK1 is activated in response to various stimuli such as proinflammatory cytokines, hypoxia, and oxidative stress. Emerging evidence has recently suggested that TAK1 is intimately involved in angiogenesis and mediates pathogenic processes related to angiogenesis. Several detailed mechanisms by which TAK1 regulates pathological angiogenesis have been clarified, and potential therapeutics targeting TAK1 have emerged. In this review, we summarize recent studies of TAK1 in angiogenesis and discuss the crosstalk between TAK1 and signaling pathways involved in pathological angiogenesis. We also discuss the approaches for selectively targeting TAK1 and highlight the rationales of therapeutic strategies based on TAK1 inhibition for the treatment of pathological angiogenesis.
Topics: Animals; Drug Delivery Systems; Humans; MAP Kinase Kinase Kinases; Neovascularization, Pathologic; Signal Transduction
PubMed: 33973075
DOI: 10.1007/s10456-021-09787-5 -
Annals of Medicine 2008The adventitia and the outer layers of media of an atherosclerosis-prone arterial wall are vascularized by vasa vasorum. Upon growth of an atherosclerotic lesion in the... (Review)
Review
The adventitia and the outer layers of media of an atherosclerosis-prone arterial wall are vascularized by vasa vasorum. Upon growth of an atherosclerotic lesion in the intima, neovascular sprouts originating from the adventitial vasa vasorum enter the lesion, the local proangiogenic micromilieu in the lesion being created by intramural hypoxia, by increased intramural oxidant stress, and by inflammatory cell infiltration (macrophages, T cells and mast cells). The angiogenic factors present in the lesions include various growth factors, chemokines, cytokines, proteinases, and several other factors possessing direct or indirect angiogenic activities, while the current list of antiangiogenic factors is smaller. An imbalance between endogenous inducers and inhibitors of angiogenesis, with a predominance of the former ones, is essential for the development of neovessels during the progression of the lesion. By providing oxygen and nutrients to the cells of atherosclerotic lesions, neovascularization initially tends to prevent cellular death and so contributes to plaque growth and stabilization. However, the inflammatory cells may induce rupture of the fragile neovessels, and so cause intraplaque hemorrhage and ensuing plaque destabilization. Pharmacological inhibition of angiogenesis in atherosclerotic plaques with ensuing inhibition of lesion progression has been achieved in animal models, but clinical studies aiming at regulation of angiogenesis in the atherosclerotic arterial wall can be designed only after we have reached a firm conclusion about the role of angiogenesis at various stages of lesion development--good or bad.
Topics: Animals; Atherosclerosis; Cell Death; Clinical Trials as Topic; Disease Models, Animal; Disease Progression; Humans; Inflammation; Neovascularization, Pathologic; Vasa Vasorum
PubMed: 18608127
DOI: 10.1080/07853890802186913 -
Carcinogenesis Feb 2007Melanotransferrin (MTf), the membrane-bound human melanoma antigen p97, binds to plasminogen and stimulates its activation, thus regulating a crucial step involved in...
Melanotransferrin (MTf), the membrane-bound human melanoma antigen p97, binds to plasminogen and stimulates its activation, thus regulating a crucial step involved in angiogenesis. In our study, a truncated soluble form of MTf (sMTf) inhibits, in a dose-dependent manner, the in vitro tubulogenesis of human umbilical vessel endothelial cells (HUVEC) induced by media conditioned with MTf-expressing cells. Following these results, we used the in vivo Matrigel plug angiogenesis assay to investigate whether truncated sMTf could inhibit neovascularization in mice. We found that basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and MTf-expressing cells strongly stimulate in vivo Matrigel neovascularization. However, subcutaneous (s.c.) administration of truncated sMTf inhibits both bFGF- and VEGF- as well as human melanoma SK-Mel-28-induced angiogenesis. This inhibition was dependent on the truncated sMTf concentration and reached maximal inhibition at 40 mg/kg/week. Furthermore, we found that a single s.c. injection of truncated sMTf into nude mice at 5 mg/kg produced a maximal blood concentration of approximately 40 nM, which is comparable with the level required to inhibit in vitro HUVEC tubulogenesis. Overall, our results strongly suggest that s.c. administration of truncated sMTf may provide a novel therapeutic strategy for the treatment of angiogenesis-related disorders.
Topics: Angiogenesis Inhibitors; Antigens, Neoplasm; Cells, Cultured; Fibrinolysin; Fibroblast Growth Factor 2; Humans; Melanoma-Specific Antigens; Neoplasm Proteins; Neovascularization, Pathologic; Recombinant Proteins; Solubility; Vascular Endothelial Growth Factor A
PubMed: 16857721
DOI: 10.1093/carcin/bgl123 -
British Journal of Pharmacology Jan 2015Opioid systems mainly regulate physiological functions such as pain, emotional tone and reward circuitry in neural tissues (brain and spinal cord). These systems are... (Review)
Review
UNLABELLED
Opioid systems mainly regulate physiological functions such as pain, emotional tone and reward circuitry in neural tissues (brain and spinal cord). These systems are also found in extraneural tissues (ganglia, gut, spleen, stomach, lung, pancreas, liver, heart, blood and blood vessels), and recent studies have elucidated their roles in various organs. The current review focuses on the roles of opioid systems in blood vessels, especially angiogenesis, during development and tumour malignancy. The balance between endogenous activators and inhibitors of angiogenesis delicately maintains a normally quiescent vasculature to sustain homeostasis. Disturbance of this balance causes pathogenic angiogenesis and, especially in tumours, several activators such as VEGF are highly expressed in the tumour microenvironment and strongly induce tumour angiogenesis, the so-called angiogenic switch. Recently, we demonstrated that κ opioid receptor agonists function as anti-angiogenic factors, which impede the angiogenic switch, in vascular development and tumour angiogenesis by inhibiting the expression of receptors for VEGF. In clinical medicine, angiogenesis inhibitors that target VEGF signalling such as bevacizumab are used as anti-cancer drugs. Although therapies that inhibit tumour angiogenesis have been highly successful for tumour therapy, most patients eventually develop resistance to this anti-angiogenic therapy. Thus, we must identify novel targets for anti-angiogenic agents to sustain inhibition of angiogenesis for tumour therapy. The regulation of responses to κ opioid receptor ligands could be useful for controlling vascular formation under physiological conditions and in cancers, and thus could offer therapeutic benefits beyond the relief of pain.
LINKED ARTICLES
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
Topics: Angiogenesis Inhibitors; Animals; Humans; Ligands; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Receptors, Opioid, kappa
PubMed: 24417697
DOI: 10.1111/bph.12573 -
Angiogenesis 2005Angiogenesis is a complex process involving coordinated steps of endothelial cell activation, proliferation, migration, tube formation and capillary sprouting with...
Angiogenesis is a complex process involving coordinated steps of endothelial cell activation, proliferation, migration, tube formation and capillary sprouting with participation of intracellular signaling pathways. Regulation of angiogenesis carries tremendous potential for cancer therapy. Our earlier studies showed that vitamin D-binding protein-macrophage activating factor (DBP-maf) acts as a potent anti-angiogenic factor and inhibits tumor growth in vivo. The goal of this investigation was to understand the effect of DBP-maf on human endothelial cell (HEC) and the mechanism of angiogenesis inhibition. DBP-maf inhibited human endothelial cell (HEC) proliferation by inhibiting DNA synthesis (IC(50) = 7.8 +/- 0.15 microg/ml). DBP-maf significantly induced S- and G0/G1-phase arrest in HEC in 72 h. DBP-maf potently blocked VEGF-induced migration, tube-formation of HEC in a dose dependent manner. In addition, DBP-maf inhibited growth factor-induced microvessel sprouting in rat aortic ring assay. Moreover, DBP-maf inhibited VEGF signaling by decreasing VEGF-mediated phosphorylation of VEGFR-2 and ERK1/2, a downstream target of VEGF signaling cascade. However, Akt activation was not affected. These studies collectively demonstrate that DBP-maf inhibits angiogenesis by blocking critical steps such as HEC proliferation, migration, tube formation and microvessel sprouting. DBP-maf exerts its effect by inhibiting VEGR-2 and ERK1/2 signaling cascades. Understanding the cellular and molecular mechanisms of anti-endothelial activity of DBP-maf will allow us to develop it as an angiogenesis targeting novel drug for tumor therapy.
Topics: Cell Migration Inhibition; Cell Proliferation; Cells, Cultured; DNA Replication; Down-Regulation; Endothelial Cells; Endothelium, Vascular; G1 Phase; Growth Inhibitors; Humans; Macrophage-Activating Factors; Microvessels; Mitogen-Activated Protein Kinases; Neovascularization, Pathologic; Phosphorylation; S Phase; Vascular Endothelial Growth Factor A; Vitamin D-Binding Protein
PubMed: 16400520
DOI: 10.1007/s10456-005-9024-7 -
Experimental Eye Research Dec 2014Natural products are characterized by high chemical diversity and biochemical specificity; therefore, they are appealing as lead compounds for drug discovery. Given the... (Review)
Review
Natural products are characterized by high chemical diversity and biochemical specificity; therefore, they are appealing as lead compounds for drug discovery. Given the importance of angiogenesis to many pathologies, numerous natural products have been explored as potential anti-angiogenic drugs. Ocular angiogenesis underlies blinding eye diseases such as retinopathy of prematurity (ROP) in children, proliferative diabetic retinopathy (DR) in adults of working age, and age-related macular degeneration (AMD) in the elderly. Despite the presence of effective therapy in many cases, these diseases are still a significant health burden. Anti-VEGF biologics are the standard of care, but may cause ocular or systemic side effects after intraocular administration and patients may be refractory. Many anti-angiogenic compounds inhibit tumor growth and metastasis alone or in combination therapy, but a more select subset of them has been tested in the context of ocular neovascular diseases. Here, we review the promise of natural products as anti-angiogenic agents, with a specific focus on retinal and choroidal neovascularization. The multifunctional curcumin and the chalcone isoliquiritigenin have demonstrated promising anti-angiogenic effects in mouse models of DR and choroidal neovascularization (CNV) respectively. The homoisoflavanone cremastranone and the flavonoid deguelin have been shown to inhibit ocular neovascularization in more than one disease model. The isoflavone genistein and the flavone apigenin on the other hand are showing potential in the prevention of retinal and choroidal angiogenesis with long-term administration. Many other products with anti-angiogenic potential in vitro such as the lactone withaferin A, the flavonol quercetin, and the stilbenoid combretastatin A4 are awaiting investigation in different ocular disease-relevant animal models. These natural products may serve as lead compounds for the design of more specific, efficacious, and affordable drugs with minimal side effects.
Topics: Angiogenesis Inhibitors; Animals; Biological Products; Eye Diseases; Humans; Neovascularization, Pathologic
PubMed: 25304218
DOI: 10.1016/j.exer.2014.10.002 -
Japanese Journal of Clinical Oncology Nov 2007Sangivamycin, an antibiotic with anti-tumor and anti-herpes virus activities by inhibiting both DNA/RNA synthesis and protein kinase C activity, was reported to suppress...
BACKGROUND
Sangivamycin, an antibiotic with anti-tumor and anti-herpes virus activities by inhibiting both DNA/RNA synthesis and protein kinase C activity, was reported to suppress selectively DNA synthesis and growth of human umbilical vein endothelial cells and their tube formation in vitro. Here, to address the potential clinical use of sangivamycin in future, we investigated its anti-angiogenic effect in in vivo chicken chorioallantoic membrane (CAM) and mouse dorsal air sac (DAS) assays, and investigated underlying mechanism.
METHODS
The effect of sangivamycin on blood vessel formation in CAM was observed under the microscope after treating for two days. For DAS assays, chambers fulfilled with tumor cells were implanted beneath mouse dorsal skin. After the mice were administered with sangivamycin, tumor-induced angiogenesis was observed under the microscope. The effect of sangivamycin on ATP synthesis on the endothelial cell surface was assayed by measuring ATP production with bioluminescence assay.
RESULTS
Sangivamycin suppressed angiogenesis within CAM down to 94-71%, which was partially blocked by simultaneous addition of a 40-fold excess of adenosine. Sangivamycin also inhibited tumor-angiogenesis in the DAS assay by 61%, and suppressed ATP production on the endothelial cell surface by 75%.
CONCLUSION
Sangivamycin inhibits the in vivo angiogenesis within CAM and tumor-induced angiogenesis within mouse dorsal skin, at least in part via inhibiting endothelial cell surface ATP metabolism in addition to inhibition of DNA/RNA synthesis and/or protein kinase C activity, suggesting a potential clinical use of sangivamycin as a novel anti-cancer reagent capable of targeting not only cancer cells but also endothelial cells.
Topics: Air Sacs; Angiogenesis Inhibitors; Animals; Antibiotics, Antineoplastic; Cell Line; Chickens; Chorioallantoic Membrane; Endothelium; Female; Mice; Mice, Inbred ICR; Mitochondrial Proton-Translocating ATPases; Neovascularization, Pathologic; Neovascularization, Physiologic; Pyrimidine Nucleosides; Xenograft Model Antitumor Assays
PubMed: 17956898
DOI: 10.1093/jjco/hym115 -
Advanced Science (Weinheim,... Feb 2024Chemotherapy is widely used to treat colorectal cancer (CRC). Despite its substantial benefits, the development of drug resistance and adverse effects remain...
Chemotherapy is widely used to treat colorectal cancer (CRC). Despite its substantial benefits, the development of drug resistance and adverse effects remain challenging. This study aimed to elucidate a novel role of glucagon in anti-cancer therapy. In a series of in vitro experiments, glucagon inhibited cell migration and tube formation in both endothelial and tumor cells. In vivo studies demonstrated decreased tumor blood vessels and fewer pseudo-vessels in mice treated with glucagon. The combination of glucagon and chemotherapy exhibited enhanced tumor inhibition. Mechanistic studies demonstrated that glucagon increased the permeability of blood vessels, leading to a pronounced disruption of vessel morphology. Signaling pathway analysis identified a VEGF/VEGFR-dependent mechanism whereby glucagon attenuated angiogenesis through its receptor. Clinical data analysis revealed a positive correlation between elevated glucagon expression and chemotherapy response. This is the first study to reveal a role for glucagon in inhibiting angiogenesis and vascular mimicry. Additionally, the delivery of glucagon-encapsulated PEGylated liposomes to tumor-bearing mice amplified the inhibition of angiogenesis and vascular mimicry, consequently reinforcing chemotherapy efficacy. Collectively, the findings demonstrate the role of glucagon in inhibiting tumor vessel network and suggest the potential utility of glucagon as a promising predictive marker for patients with CRC receiving chemotherapy.
Topics: Humans; Animals; Mice; Glucagon; Neovascularization, Pathologic; Colorectal Neoplasms; Signal Transduction; Cell Line, Tumor
PubMed: 38072640
DOI: 10.1002/advs.202307271