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Journal of Experimental & Clinical... Mar 2024Tumor angiogenesis inhibitors have been applied for non-small cell lung cancer (NSCLC) therapy. However, the drug resistance hinders their further development....
BACKGROUND
Tumor angiogenesis inhibitors have been applied for non-small cell lung cancer (NSCLC) therapy. However, the drug resistance hinders their further development. Intercellular crosstalk between lung cancer cells and vascular cells was crucial for anti-angiogenenic resistance (AAD). However, the understanding of this crosstalk is still rudimentary. Our previous study showed that Glioma-associated oncogene 1 (Gli1) is a driver of NSCLC metastasis, but its role in lung cancer cell-vascular cell crosstalk remains unclear.
METHODS
Conditioned medium (CM) from Gli1-overexpressing or Gli1-knockdown NSCLC cells was used to educate endothelia cells and pericytes, and the effects of these media on angiogenesis and the maturation of new blood vessels were evaluated via wound healing assays, Transwell migration and invasion assays, tube formation assays and 3D coculture assays. The xenograft model was conducted to establish the effect of Gli1 on tumor angiogenesis and growth. Angiogenic antibody microarray analysis, ELISA, luciferase reporte, chromatin immunoprecipitation (ChIP), bFGF protein stability and ubiquitination assay were performed to explore how Gli1 regulate bFGF expression.
RESULTS
Gli1 overexpression in NSCLC cells enhanced the endothelial cell and pericyte motility required for angiogenesis required for angiogenesis. However, Gli1 knockout in NSCLC cells had opposite effect on this process. bFGF was critical for the enhancement effect on tumor angiogenesis. bFGF treatment reversed the Gli1 knockdown-mediated inhibition of angiogenesis. Mechanistically, Gli1 increased the bFGF protein level by promoting bFGF transcriptional activity and protein stability. Importantly, suppressing Gli1 with GANT-61 obviously inhibited angiogenesis.
CONCLUSION
The Gli1-bFGF axis is crucial for the crosstalk between lung cancer cells and vascular cells. Targeting Gli1 is a potential therapeutic approach for NSCLC angiogenesis.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Pericytes; Zinc Finger Protein GLI1; Angiogenesis; Neovascularization, Pathologic; Cell Movement; Cell Line, Tumor; Cell Proliferation
PubMed: 38493151
DOI: 10.1186/s13046-024-03003-0 -
British Journal of Cancer Dec 2008Evidence from human studies suggests that angiogenesis commences during the pre-malignant stages of cancer. Inhibiting angiogenesis may, therefore, be of potential value... (Review)
Review
Evidence from human studies suggests that angiogenesis commences during the pre-malignant stages of cancer. Inhibiting angiogenesis may, therefore, be of potential value in preventing progression to invasive cancer. Understanding the mechanisms inducing angiogenesis in these lesions and identification of those important in human tumourigenesis are necessary to develop translational strategies that will help realise the goal of angioprevention.
Topics: Animals; Humans; Hypoxia; Neovascularization, Pathologic; Precancerous Conditions; Risk Factors
PubMed: 18941463
DOI: 10.1038/sj.bjc.6604733 -
Frontiers in Immunology 2018Angiogenesis, the process of new blood vessel formation from pre-existing ones, plays a key role in various physiological and pathological conditions. Alteration of the... (Review)
Review
Angiogenesis, the process of new blood vessel formation from pre-existing ones, plays a key role in various physiological and pathological conditions. Alteration of the angiogenic balance, consequent to the deranged production of angiogenic growth factors and/or natural angiogenic inhibitors, is responsible for angiogenesis-dependent diseases, including cancer. Fibroblast growth factor-2 (FGF2) represents the prototypic member of the FGF family, able to induce a complex "angiogenic phenotype" in endothelial cells and a potent neovascular response as the consequence of a tight cross talk between pro-inflammatory and angiogenic signals. The soluble pattern recognition receptor long pentraxin-3 (PTX3) is a member of the pentraxin family produced locally in response to inflammatory stimuli. Besides binding features related to its role in innate immunity, PTX3 interacts with FGF2 and other members of the FGF family via its N-terminal extension, thus inhibiting FGF-mediated angiogenic responses and . Accordingly, PTX3 inhibits the growth and vascularization of FGF-dependent tumors and FGF2-mediated smooth muscle cell proliferation and artery restenosis. Recently, the characterization of the molecular bases of FGF2/PTX3 interaction has allowed the identification of NSC12, the first low molecular weight pan-FGF trap able to inhibit FGF-dependent tumor growth and neovascularization. The aim of this review is to provide an overview of the impact of PTX3 and PTX3-derived molecules on the angiogenic, inflammatory, and tumorigenic activity of FGF2 and their potential implications for the development of more efficacious anti-FGF therapeutic agents to be used in those clinical settings in which FGFs play a pathogenic role.
Topics: Animals; C-Reactive Protein; Fibroblast Growth Factor 2; Humans; Inflammation; Neovascularization, Physiologic; Serum Amyloid P-Component
PubMed: 30349543
DOI: 10.3389/fimmu.2018.02327 -
American Journal of Hematology Nov 2008Tumor vasculature and tumor-associated neo-angiogenesis have recently become major targets for rational drug design of antineoplastic agents. Five such agents with... (Review)
Review
Tumor vasculature and tumor-associated neo-angiogenesis have recently become major targets for rational drug design of antineoplastic agents. Five such agents with angiogenesis inhibiting activity (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have already obtained US Food and Drug Administration approval for clinical use and many others have entered clinical trials. Vascular complications, including venous or arterial thromboembolism and hemorrhage, have emerged as relevant toxicities in several clinical trials with angiogenesis inhibitors. Given the well-known interplay between the blood clotting system, angiogenesis, and tumor growth, a better understanding of the impact of these new drugs on overall hemostatic balance is required. In this brief overview, we discuss the incidence of hemostatic complications, the likely pathogenetic mechanisms involved, and the critical need to establish in randomized clinical trials the usefulness of thrombosis prophylaxis to prevent these complications. Careful documentation of hemostatic complications during treatment with each of the new antiangiogenic drugs is warranted. Further studies are urgently required to better define the causal association of these new agents with hemostatic complications and to establish the best prophylactic strategy.
Topics: Angiogenesis Modulating Agents; Anticoagulants; Humans; Neoplasms; Neovascularization, Pathologic; Thromboembolism
PubMed: 18819092
DOI: 10.1002/ajh.21277 -
International Journal of Molecular... Jan 2020Angiogenesis is a process of generation of de-novo blood vessels from already existing vasculature. It has a crucial role in different physiological process including... (Review)
Review
Angiogenesis is a process of generation of de-novo blood vessels from already existing vasculature. It has a crucial role in different physiological process including wound healing, embryonic development, and tumor growth. The methods by which therapeutic drugs inhibit tumor angiogenesis are termed as anti-angiogenesis cancer therapy. Developments of angiogenic inhibiting drugs have various limitations causing a barrier for successful treatment of cancer, where angiogenesis plays an important role. In this context, investigators developed novel strategies using nanotechnological approaches that have demonstrated inherent antiangiogenic properties or used for the delivery of antiangiogenic agents in a targeted manner. In this present article, we decisively highlight the recent developments of various nanoparticles (NPs) including liposomes, lipid NPs, protein NPs, polymer NPs, inorganic NPs, viral and bio-inspired NPs for potential application in antiangiogenic cancer therapy. Additionally, the clinical perspectives, challenges of nanomedicine, and future perspectives are briefly analyzed.
Topics: Angiogenesis Inhibitors; Animals; Drug Delivery Systems; Humans; Nanomedicine; Nanoparticles; Neoplasms; Neovascularization, Pathologic; Theranostic Nanomedicine
PubMed: 31936832
DOI: 10.3390/ijms21020455 -
Angiogenesis Aug 2021Statins pleiotropically provide additional benefits in reducing atherosclerosis, but their effects on intraplaque angiogenesis (IPA) and hemorrhage (IPH) remain unclear....
OBJECTIVE
Statins pleiotropically provide additional benefits in reducing atherosclerosis, but their effects on intraplaque angiogenesis (IPA) and hemorrhage (IPH) remain unclear. Therefore, we discriminated statin's lipid-lowering dependent and independent effects on IPA and IPH.
APPROACH AND RESULTS
ApoE3*Leiden mice are statin-responsive due to ApoE and LDLR presence, but also allow to titrate plasma cholesterol levels by diet. Therefore, ApoE3*Leiden mice were fed a high-cholesterol-inducing-diet (HCD) with or without atorvastatin (A) or a moderate-cholesterol-inducing-diet (MCD). Mice underwent vein graft surgery to induce lesions with IPA and IPH. Cholesterol levels were significantly reduced in MCD (56%) and HCD + A (39%) compared to HCD with no significant differences between MCD and HCD + A. Both MCD and HCD + A have a similar reduction in vessel remodeling and inflammation comparing to HCD. IPA was significantly decreased by 30% in HCD + A compared to HCD or MCD. Atorvastatin treatment reduced the presence of immature vessels by 34% vs. HCD and by 25% vs. MCD, resulting in a significant reduction of IPH. Atorvastatin's anti-angiogenic capacity was further illustrated by a dose-dependent reduction of ECs proliferation and migration. Cultured mouse aortic-segments lost sprouting capacity upon atorvastatin treatment and became 30% richer in VE-Cadherin expression and pericyte coverage. Moreover, Atorvastatin inhibited ANGPT2 release and decreased VE-Cadherin(Y685)-phosphorylation in ECs.
CONCLUSIONS
Atorvastatin has beneficial effects on vessel remodeling due to its lipid-lowering capacity. Atorvastatin has strong pleiotropic effects on IPA by decreasing the number of neovessels and on IPH by increasing vessel maturation. Atorvastatin improves vessel maturation by inhibiting ANGPT2 release and phospho(Y658)-mediated VE-Cadherin internalization.
Topics: Angiopoietin-2; Animals; Antigens, CD; Apolipoprotein E3; Atorvastatin; Cadherins; Cholesterol, Dietary; Male; Mice; Mice, Mutant Strains; Neovascularization, Pathologic; Plaque, Atherosclerotic
PubMed: 33550461
DOI: 10.1007/s10456-021-09767-9 -
Glia Feb 2019Ischemia-induced angiogenesis contributes to various neuronal and retinal diseases, and often results in neurodegeneration and visual impairment. Current treatments...
Ischemia-induced angiogenesis contributes to various neuronal and retinal diseases, and often results in neurodegeneration and visual impairment. Current treatments involve the use of anti-VEGF agents but are not successful in all cases. In this study we determined that miR-30a-5p is another important mediator of retinal angiogenesis. Using a rodent model of ischemic retinopathy, we show that inhibiting miR-30a-5p reduces neovascularization and promotes tissue repair, through modulation of microglial and endothelial cell cross-talk. miR-30a-5p inhibition results in increased expression of the death receptor Fas and CCL2, to decrease endothelial cell survival and promote microglial migration and phagocytic function in focal regions of ischemic injury. Our data suggest that miR-30a-5p inhibition accelerates tissue repair by enhancing FasL-Fas crosstalk between microglia and endothelial cells, to promote endothelial cell apoptosis and removal of dead endothelial cells. Finally, we found that miR-30a levels were increased in the vitreous of patients with proliferative diabetic retinopathy. Our study identifies a role for miR-30a in the pathogenesis of neovascular retinal disease by modulating microglial and endothelial cell function, and suggests it may be a therapeutic target to treat ischemia-mediated conditions.
Topics: Animals; Animals, Newborn; Apoptosis; Cell Line, Transformed; Cell Proliferation; Chemokine CCL2; Disease Models, Animal; Endothelial Cells; Gene Expression Regulation; Humans; Lectins; Mice; Mice, Inbred C57BL; Mice, Transgenic; MicroRNAs; Microglia; Neovascularization, Pathologic; Neovascularization, Physiologic; RNA Interference; RNA, Messenger; fas Receptor
PubMed: 30484883
DOI: 10.1002/glia.23543 -
Experimental & Molecular Medicine Feb 2021Blinding eye diseases such as corneal neovascularization, proliferative diabetic retinopathy, and age-related macular degeneration are driven by pathological... (Review)
Review
Blinding eye diseases such as corneal neovascularization, proliferative diabetic retinopathy, and age-related macular degeneration are driven by pathological angiogenesis. In cancer, angiogenesis is key for tumor growth and metastasis. Current antiangiogenic treatments applied clinically interfere with the VEGF signaling pathway-the main angiogenic pathway-to inhibit angiogenesis. These treatments are, however, only partially effective in regressing new pathologic vessels, and the disease relapses following cessation of treatment. Moreover, the relapse of pathological angiogenesis can be rapid, aggressive and more difficult to treat than angiogenesis in the initial phase. The manner in which relapse occurs is poorly understood; however, recent studies have begun to shed light on the mechanisms underlying the revascularization process. Hypotheses have been generated to explain the rapid angiogenic relapse and increased resistance of relapsed disease to treatment. In this context, the present review summarizes knowledge of the various mechanisms of disease relapse gained from different experimental models of pathological angiogenesis. In addition, the basement membrane-a remnant of regressed vessels-is examined in detail to discuss its potential role in disease relapse. Finally, approaches for gaining a better understanding of the relapse process are discussed, including prospects for the management of relapse in the context of disease.
Topics: Animals; Basement Membrane; Biomarkers; Collagen; Disease Management; Disease Susceptibility; Endothelium, Vascular; Gene Expression Regulation; Humans; Neovascularization, Pathologic; Recurrence; Signal Transduction
PubMed: 33589713
DOI: 10.1038/s12276-021-00566-2 -
The Journal of Investigative... Dec 2000Matrix metalloproteinases (MMP) are a family of structurally related proteinases most widely recognized for their ability to degrade extracellular matrix, although... (Review)
Review
Matrix metalloproteinases (MMP) are a family of structurally related proteinases most widely recognized for their ability to degrade extracellular matrix, although recent investigations have demonstrated other biologic functions for these enzymes. MMP are typically not constitutively expressed, but are regulated by: (1) cytokines, growth factors, and cell-cell and cell-matrix interactions that control gene expression; (2) activation of their proenzyme form; and (3) the presence of MMP inhibitors [tissue inhibitors of metalloproteinases, (TIMP)]. MMP have important roles in normal processes including development, wound healing, mammary gland, and uterine involution, but are also involved in angiogenesis, tumor growth, and metastasis. Angiogenesis, characteristically defined as the establishment of new vessels from pre-existing vasculature, is required for biologic processes such as wound healing and pathologic processes such as arthritis, tumor growth, and metastasis. Blocking of MMP activity has been studied for potential therapeutic efficacy in controlling such pathologic processes. Synthetic MMP inhibitors, most notably the hydroxymates, have been engineered for this purpose and are presently in clinical trial. These inhibitors may have broad versus specific MMP inhibitory activity. As increased non-matrix degrading capabilities of MMP are recognized, however, i.e., cytokine activation, processing of proteins to molecules of distinct biologic function, it becomes less clear whether the nonselective inhibition of MMP activity for all pathologic processes involving MMP is appropriate. This review focuses upon the contribution of MMP to the process of tumor invasion and angiogenesis, and discusses the design and use of MMP inhibitors as therapeutic agents in these processes.
Topics: Animals; Humans; Matrix Metalloproteinases; Neovascularization, Pathologic; Neovascularization, Physiologic; Skin
PubMed: 11147675
DOI: 10.1046/j.1087-0024.2000.00004.x -
Journal of Nanobiotechnology Feb 2023Wound repair, along with skin appendage regeneration, is challenged by insufficient angiogenesis and neural regeneration. Therefore, promoting both proangiogenic and...
Wound repair, along with skin appendage regeneration, is challenged by insufficient angiogenesis and neural regeneration. Therefore, promoting both proangiogenic and neuro-regenerative therapeutic effects is essential for effective wound repair. However, most therapeutic systems apply these strategies separately or ineffectively. This study investigates the performance of an all-in-one smart dressing (ASD) that integrates angiogenic functional materials and multiple biological factors within a light crosslinked hydrogel, forming a multi-functional dressing capable of facilitating simultaneous micro-vascularization and neural regeneration. The ASD uses a zeolite-imidazolate framework 67 with anchored vanadium oxide (VO@ZIF-67) that allows for the on-demand release of Co with fluctuations in pH at the wound site to stimulate angiogenesis. It can simultaneously release CXCL12, ligustroflavone, and ginsenoside Rg1 in a sustained manner to enhance the recruitment of endogenous mesenchymal stem cells, inhibit senescence, and induce neural differentiation to achieve in situ nerve regeneration. The ASD can stimulate rapid angiogenesis and nerve regeneration within 17 days through multiple angiogenic and neuro-regenerative cues within one dressing. This study provides a proof-of-concept for integrating functional nanomaterials and multiple complementary drugs within a smart dressing for simultaneous angiogenesis and neural regeneration.
Topics: Humans; Skin; Wound Healing; Mesenchymal Stem Cells; Neovascularization, Pathologic; Bandages
PubMed: 36737778
DOI: 10.1186/s12951-023-01787-5