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Cancer Treatment and Research... 2021Angiogenesis plays an important role in the development of cancer since it allows for the delivery of oxygen, nutrients, and growth factors as well as tumor... (Review)
Review
Angiogenesis plays an important role in the development of cancer since it allows for the delivery of oxygen, nutrients, and growth factors as well as tumor dissemination to distant organs. Inhibition of angiogenesis is an important strategy for the prevention of multiple solid tumors that depend on cutting or at least reducing the blood supply to tumor micro-regions, resulting in pan-hypoxia and pan-necrosis within solid tumor tissues. These drugs are an important part of treatment for some types of cancer. As a stand-alone therapy, inhibition of tumor angiogenesis can arrest or halt tumor growth, but will not eliminate the tumor. Therefore, anti-angiogenic drugs in combinations with another anti-cancer treatment method, like chemotherapy, lead to being critical for optimum cancer patient outcomes. Over the last two decades, investigations have been made to improve the efficacy of anti-angiogenic drugs, recognize their potential in drug interactions, and come up with plausible explanations for possible treatment resistance. This review will offer an overview of the varying concepts of tumor angiogenesis, several important angiogenic factors; focus on the role of anti-angiogenesis strategies in cancer treatment.
Topics: Humans; Immunotherapy; Neoplasms; Neovascularization, Pathologic
PubMed: 34147821
DOI: 10.1016/j.ctarc.2021.100422 -
Pathology, Research and Practice Jan 2024Cancer remains the primary cause of mortality in developed nations. Although localized tumors can be effectively addressed through surgery, radiotherapy, and other... (Review)
Review
Cancer remains the primary cause of mortality in developed nations. Although localized tumors can be effectively addressed through surgery, radiotherapy, and other targeted methods, drug efficacy often wanes in the context of metastatic diseases. As a result, significant efforts are being made to develop drugs capable of not only inhibiting tumor growth but also impeding the metastasis of malignant tumors, with a focus on hindering their migration to adjacent organs. Cancer stem cells metastasize via blood and lymphatic vessels, exhibiting a high mutation rate, significant variability, and a predisposition to drug resistance. In contrast, endothelial cells, being less prone to mutation, are less likely to give rise to drug-resistant clones. Furthermore, the direct contact of circulating anti-angiogenic drugs with vascular endothelial cells expedites their therapeutic impact. Hence, anti-angiogenesis targeted therapy assumes a pivotal role in cancer treatment. This paper provides a succinct overview of the molecular mechanisms governing the interaction between cancer stem cells and angiogenesis.
Topics: Humans; Neovascularization, Pathologic; Endothelial Cells; Angiogenesis; Neoplasms; Neoplastic Stem Cells
PubMed: 38160481
DOI: 10.1016/j.prp.2023.155064 -
International Journal of Molecular... Apr 2022A co-culture assay with human umbilical vein endothelial cells (HUVECs) and normal human dermal fibroblasts (NHDFs) was used to study whether selected angiogenesis...
A co-culture assay with human umbilical vein endothelial cells (HUVECs) and normal human dermal fibroblasts (NHDFs) was used to study whether selected angiogenesis inhibitors were able to inhibit differentiation and network formation of HUVECs in vitro. The effect of the inhibitors was determined by the morphology and the calculated percentage area covered by HUVECs. Neutralizing VEGF with avastin and polyclonal goat anti-VEGF antibody and inhibiting VEGFR2 with sorafenib and vatalanib resulted in the formation of HUVEC clusters of variable sizes as a result of inhibited EC differentiation. Furthermore, numerous inhibitors of the VEGF signaling pathways were tested for their effect on the growth and differentiation of HUVECs. The effects of these inhibitors did not reveal a cluster morphology, either individually or when combined to block VEGFR2 downstream pathways. Only the addition of -methyl--bromolevamisole revealed a similar morphology as when targeting VEGF and VEGFR2, meaning it may have an inhibitory influence directly on VEGFR signaling. Additionally, several nuclear receptor ligands and miscellaneous compounds that might affect EC growth and differentiation were tested, but only dexamethasone gave rise to cluster formation similarly to VEGF-neutralizing compounds. These results point to a link between angiogenesis, HUVEC differentiation and glucocorticoid receptor activation.
Topics: Angiogenesis Inhibitors; Cell Movement; Cell Proliferation; Human Umbilical Vein Endothelial Cells; Humans; Neovascularization, Physiologic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 35457095
DOI: 10.3390/ijms23084277 -
Trends in Endocrinology and Metabolism:... Aug 2020Angiogenesis is crucial for the development of the blood vasculature during embryogenesis, but also contributes to cancer and other diseases. While therapeutic targeting... (Review)
Review
Angiogenesis is crucial for the development of the blood vasculature during embryogenesis, but also contributes to cancer and other diseases. While therapeutic targeting of endothelial cells (ECs) through growth factor inhibition is limited by insufficient efficacy and resistance, a new paradigm for modulating angiogenesis by targeting EC metabolism has emerged. Findings from the past decade highlight how ECs adapt their metabolism to proliferate or migrate during vessel sprouting, or to maintain the vascular barrier and protect themselves against oxidative stress in the high-oxygen environment they are exposed to in healthy conditions. We overview key endothelial metabolic pathways underlying the different EC phenotypes, as well as potential opportunities for targeting EC metabolism in therapeutic settings.
Topics: Animals; Endothelial Cells; Humans; Neovascularization, Pathologic; Neovascularization, Physiologic; Oxidative Stress
PubMed: 32622584
DOI: 10.1016/j.tem.2020.05.009 -
Lung Cancer (Amsterdam, Netherlands) Aug 2023The chemotherapy drugs for NSCLC often face the consequences of treatment failure due to acquired drug resistance. Tumor chemotherapy resistance is often accompanied by...
AIMS
The chemotherapy drugs for NSCLC often face the consequences of treatment failure due to acquired drug resistance. Tumor chemotherapy resistance is often accompanied by angiogenesis. Here, we aimed to investigate the effect and underlying mechanisms of ADAM-17 inhibitor ZLDI-8 we found before on angiogenesis and vasculogenic mimicry(VM) in drug-resistant NSCLC.
MAIN METHODS
The tube formation assay was used to evaluate angiogenesis and VM. Migration and invasion were assessed with transwell assays in the co-culture condition. To explore the underlying mechanisms of how ZLDI-8 inhibited tubes formation, ELISA assay and western blot assay were preformed. The effects of ZLDI-8 on angiogenesis in vivo were investigated in Matrigel plug, CAM and Rat aortic ring assays.
KEY FINDINGS
In the present study, ZLDI-8 significantly inhibited the tube formation of human umbilical vein endothelial cells (HUVECs) in either normal medium or in tumor supernatants. Furthermore, ZLDI-8 also inhibited VM tubes formation of A549/Taxol cells. In the co-culture assay, the interaction between lung cancer cells and HUVECs promotes increased cell migration and invasion, while ZLDI-8 eliminates this promotion. Moreover, the VEGF secretion were decreased by ZLDI-8 and the expression of Notch1, Dll4, HIF1α and VEGF were inhibited by ZLDI-8. In addition, ZLDI-8 can inhibit blood vessel formation in the Matrigel plug, CAM and Rat aortic ring assays.
SIGNIFICANCE
ZLDI-8 inhibits angiogenesis and VM in drug-resistant NSCLC through suppressing Notch1-HIF1α-VEGF signaling pathway. This study lays the foundation for the discovery of drugs that inhibit angiogenesis and VM in drug resistant NSCLC.
Topics: Humans; Rats; Animals; Lung Neoplasms; Endothelial Cells; Vascular Endothelial Growth Factor A; Cell Line, Tumor; Neovascularization, Pathologic; Carcinoma, Non-Small-Cell Lung; Cell Movement; Human Umbilical Vein Endothelial Cells
PubMed: 37364397
DOI: 10.1016/j.lungcan.2023.107279 -
International Angiology : a Journal of... Dec 2018Competitive inhibition of endothelial nitric oxide synthase (eNOS) is the main biological effect of asymmetric dimethylarginine (ADMA), i.e. the methylated derivative of... (Review)
Review
Competitive inhibition of endothelial nitric oxide synthase (eNOS) is the main biological effect of asymmetric dimethylarginine (ADMA), i.e. the methylated derivative of L-arginine. The resulting low level of NO is becoming one of the elements of pathogenesis of numerous cardiovascular disorders, mainly related to atherosclerosis, but also other metabolic diseases including type 2 diabetes. It appears that a high level of ADMA is not only a marker of pathological conditions such as chronic kidney failure, but also a significant factor which damages the endothelium. Despite multiple studies, the mechanisms of reducing the level of ADMA, which would allow to inhibit the progression of cardiovascular diseases and effective treatment, e.g. by means of L-arginine supplementation or medicines which are lowering ADMA levels, are still unclear. Perhaps, linking ADMA with the processes of new blood cell formation (angiogenesis) will allow us to explain these multifactor mechanisms.
Topics: Animals; Arginine; Atherosclerosis; Cardiovascular Diseases; Endothelial Cells; Humans; Neovascularization, Pathologic; Neovascularization, Physiologic; Plaque, Atherosclerotic; Signal Transduction; Up-Regulation
PubMed: 30256050
DOI: 10.23736/S0392-9590.18.04017-8 -
Cells Aug 2020Previously, we demonstrated that the homeoprotein Msx1 interaction with p53 inhibited tumor growth by inducing apoptosis. However, Msx1 can exert its tumor suppressive...
Previously, we demonstrated that the homeoprotein Msx1 interaction with p53 inhibited tumor growth by inducing apoptosis. However, Msx1 can exert its tumor suppressive effect through the inhibition of angiogenesis since growth of the tumor relies on sufficient blood supply from the existing vessels to provide oxygen and nutrients for tumor growth. We hypothesized that the inhibition of tumor growth by Msx1 might be due to the inhibition of angiogenesis. Here, we explored the role of Msx1 in angiogenesis. Overexpression of Msx1 in HUVECs inhibited angiogenesis, and silencing of Msx1 by siRNA abrogated its anti-angiogenic effects. Furthermore, forced expression of Msx1 in mouse muscle tissue inhibited vessel sprouting, and application of an Ad-Msx1-transfected conditioned medium onto the chicken chorioallantoic membrane (CAM) led to a significant inhibition of new vessel formation. To explore the underlying mechanism of Msx1-mediated angiogenesis, yeast two-hybrid screening was performed, and we identified PIASy (protein inhibitor of activated STAT Y) as a novel Msx1-interacting protein. We mapped the homeodomain of Msx1 and the C-terminal domain of PIASy as respective interacting domains. Consistent with its anti-angiogenic function, overexpression of Msx1 suppressed the reporter activity of VEGF. Interestingly, PIASy stabilized Msx1 protein, whereas deletion of the Msx1-interacting domain in PIASy abrogated the inhibition of tube formation and the stabilization of Msx1 protein. Our findings suggest the functional importance of PIASy-Msx1 interaction in Msx1-mediated angiogenesis inhibition.
Topics: Animals; Chick Embryo; Human Umbilical Vein Endothelial Cells; Humans; MSX1 Transcription Factor; Mice; Mice, Inbred BALB C; Neovascularization, Physiologic; Poly-ADP-Ribose Binding Proteins; Protein Binding; Protein Inhibitors of Activated STAT; Vascular Endothelial Growth Factor A
PubMed: 32784646
DOI: 10.3390/cells9081854 -
Current Drug Metabolism 2017Angiogenesis is an essential physiological process for growth and maintenance of the body. Especially its role becomes indispendable during the embryonic development... (Review)
Review
BACKGROUND
Angiogenesis is an essential physiological process for growth and maintenance of the body. Especially its role becomes indispendable during the embryonic development stage but lacks in adults with some exceptions like while wound repair and menstrual cycle. It is a tightly regulated process and relies on the cascade of several molecular signaling pathways with the involvement of many effectors like vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF) etc.
METHODS
Related literature/ information were retrieved, analyzed and compiled from the online published resources available in Medline, Pubmed, Pubmed Central, Science Direct and other scientific databases.
RESULTS
Excessive angiogenesis leads to disorders like tumor, atherosclerosis, rheumatoid arthritis, diabetic retinopathy, endometriosis, psoriasis, and adiposity. While, reduced angiogenesis also results in several ailments like cardiac ischemia, low capillary density in brain of Alzheimer's patients and delayed wound healing. Therefore, both angio-proliferative and anti-angiogenic approaches may be of use in developing novel therapeutics. Bacterial toxins are known for modulating the process of angiogenesis by mimicking pro-angiogenic factors and/ or competing with them. Furthermore, they inactivate the receptors or keep them in ON status, hence can be used to treat angiogenic disorders. The ease in handling, cultivation and manipulating the toxins structure has enabled the use of bacteria as an ideal choice for novel therapeutic developments.
CONCLUSION
This review intends to elucidate the molecular mechanisms through which certain bacteria may alter the level of angiogenesis and consequently can work as therapeutics against angiogenic disorders.
Topics: Angiogenesis Inhibitors; Animals; Bacterial Toxins; Humans; Neovascularization, Pathologic
PubMed: 28901253
DOI: 10.2174/1389200218666170911150948 -
Current Rheumatology Reviews 2021Endostatin by its therapeutic value against rheumatoid arthritis has recently gained significant interest in biomedical science. A recent study revealed that various... (Review)
Review
BACKGROUND
Endostatin by its therapeutic value against rheumatoid arthritis has recently gained significant interest in biomedical science. A recent study revealed that various approaches have been made to prevent rheumatoid arthritis by either controlling or inhibiting the progression of angiogenesis.
OBJECTIVE
The main objective of the current manuscript is to enumerate the intrinsic role of endostatin in rheumatoid arthritis.
METHODS
A thorough and detailed review of literature from the papers published from the year 1997-2019 was studied for the preparation of the current article.
RESULTS
Endostatin is one such agent of the subfamily of ECM called as multiplexins obtained from proteolytic cleavage of XVIII and its carboxylic terminal fragments and is known for its antiangiogenic and antiproliferative property. The exact mechanism of endostatin is still unclear, but it acts by downregulating or inhibiting the responses of various factors, including Id1, Id3, matrix metalloproteinase, and Nuclear factor Kappa B that are liable for angiogenesis. The mutual effects on adipogenesis and angiogenesis, endostatin inhibits dietary-induced obesity and its related metabolic disorders, such as insulin resistance, glucose intolerance, and hepatic steatosis.
CONCLUSION
The present review demonstrates the intrinsic usage of endostatin as a novel molecule in rheumatoid arthritis. It focuses on the status of the therapeutic potential of endostatin in inhibiting the activity of angiogenesis is also very well explored.
Topics: Arthritis, Rheumatoid; Endostatins; Humans; Neovascularization, Pathologic
PubMed: 32348230
DOI: 10.2174/1573397115666191127141801 -
Experimental Eye Research Sep 2023Proliferative diabetic retinopathy (PDR) adversely affects visual function. Extracellular matrix proteins (ECM) contribute significantly to the development of PDR. A...
Proliferative diabetic retinopathy (PDR) adversely affects visual function. Extracellular matrix proteins (ECM) contribute significantly to the development of PDR. A Disintegrin and Metalloproteinase with Thrombospondin motifs 5 (ADAMTS5) is a member of ECM proteins. ADAMTS5 participates in angiogenesis and inflammation in diverse diseases. However, the role of ADAMTS5 in PDR remains elusive. Multiplex beam array technology was used to analyze vitreous humor of PDR patients and normal people. ELISA and Western blot were used to detect the expression of ADAMTS5, PEDF and autophagy related factors. Immunofluorescence assay was used to mark the expression and localization of ADAMTS5 and PEDF. The neovascularization was detected by tube formation test. Our results revealed that ADAMTS5 expression was increased in the vitreous humor of PDR patients and oxygen-induced retinopathy (OIR) mice retinas. Inhibiting ADAMTS5 alleviated pathological angiogenesis and upregulated PEDF expression in the OIR mice. In addition, ADAMTS5 inhibited PEDF secretion in ARPE-19 cells in vitro studies, thereby inhibiting the migration of HMEC-1. Mechanically, ADAMTS5 promoted the autophagic degradation of PEDF. Collectively, inhibition of ADAMTS5 during OIR suppresses pathological angiogenesis. Our study provides a new approach for resolving pathological angiogenesis in PDR.
Topics: Animals; Mice; Autophagy; Diabetes Mellitus; Diabetic Retinopathy; Eye Proteins; Neovascularization, Pathologic; Retinal Diseases; Retinal Neovascularization; Serpins
PubMed: 37490993
DOI: 10.1016/j.exer.2023.109597