ABSTRACT
Multiple myeloma (MM) is a neoplastic condition resulting from the uncontrolled expansion of B-cell-derived plasma cells. The importance of angiogenesis in MM development has also been demonstrated. Extracellular vesicles (EVs) have vital functions in interactions between neighboring cells, such as angiogenesis. The objective of this in vitro study was to examine the transfection and angiogenesis effects of MM-EVs on endothelial cells (ECs) upon treatment with Tetrahydroisoquinoline (THIQ) as a bioactive organic compound derivative from isoquinoline. Following treatment of multiple myeloma cells (U266) with THIQ, MM-EVs were harvested and transmigrated to human umbilical vein endothelial cells (HUVEC) in a co-culture model. EVs transmigration was traced by flow cytometry. Correspondingly, the expression of angiogenic genes and/or proteins in U266 cells and HUVECs was measured by RT-PCR and ELISA methods. Likewise, the proliferation and migration of HUVECs treated with THIQ-treated MM-EVs were visualized and estimated by performing both tube formation and scratch wound healing methods. Surprisingly, the anti-angiogenic effect of THIQ-treated MM-EVs was evident by the decreased expression of CD34, VEGFR2, and IL-6 at the mRNA and/or protein levels after internalization of MM-EVs in HUVEC. Finally, tube formation and scratch wound healing experiments showed inhibition of HUVEC cell proliferation and migration by THIQ-treated MM-EVs compared to control MM-EVs. MM-EVs derived from THIQ-treated myeloma cells (U266) inhibited angiogenesis in HUVECs. This phenomenon is coordinated by the internalized THIQ-treated MM-EVs in HUVECs, and ultimately the reduction of angiogenic factors and inhibition of tube formation and scratch wound healing.
Subject(s)
Cell Movement , Extracellular Vesicles , Human Umbilical Vein Endothelial Cells , Multiple Myeloma , Neovascularization, Pathologic , Tetrahydroisoquinolines , Humans , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Multiple Myeloma/pathology , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Extracellular Vesicles/metabolism , Extracellular Vesicles/drug effects , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/metabolism , Tetrahydroisoquinolines/pharmacology , Cell Movement/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Coculture Techniques , Angiogenesis Inhibitors/pharmacology , AngiogenesisABSTRACT
This review explores the pivotal role of angiogenesis in breast cancer progression and treatment. It covers biomarkers, imaging techniques, therapeutic approaches, resistance mechanisms, and clinical implications. Key topics include Vascular Endothelial Growth Factors, angiopoietins, microRNA signatures, and circulating endothelial cells as biomarkers, along with Magnetic Resonance Imaging, Computed Tomography Angiography, Ultrasound, and Positron Emission Tomography for imaging. Therapeutic strategies targeting VEGF, tyrosine kinase inhibitors, and the intersection of angiogenesis with immunotherapy are discussed. Challenges such as resistance mechanisms and personalized medicine approaches are addressed. Clinical implications, prognostic value, and the future direction of angiogenesis-targeted therapies are highlighted. The article concludes with reflections on the transformative potential of understanding angiogenesis.
Subject(s)
Breast Neoplasms , Neovascularization, Pathologic , Female , Humans , Angiogenesis/drug effects , Angiogenesis/physiopathology , Angiogenesis Inhibitors/therapeutic use , Breast Neoplasms/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/physiopathologyABSTRACT
BACKGROUND: Endometriosis is associated with a wide variety of signs and symptoms and can lead to infertility, embryo death, and even miscarriage. Although the exact pathogenesis and etiology of endometriosis is still unclear, it has been shown that it has a chronic inflammatory nature and angiogenesis is also involved in it. OBJECTIVE: This review aims to explore the role of inflammation and angiogenesis in endometriosis and suggest a potential treatment targeting these pathways. FINDINGS: Among the pro-inflammatory cytokines, studies have shown solid roles for interleukin 1ß (IL-ß), IL-6, and tumor necrosis factor α (TNF-α) in the pathogenesis of this condition. Other than inflammation, angiogenesis, the formation of new blood vessels from pre-existing capillaries, is also involved in the pathogenesis of endometriosis. Among angiogenic factors, vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α), transforming growth factor ß1 (TGF-ß1), and matrix metalloproteinases (MMPs) are more essential in the pathogenesis of endometriosis. Interestingly, it has been shown that inflammation and angiogenesis share some similar pathways with each other that could be potentially targeted for treatment of diseases caused by these two processes. Cannabidiol (CBD) is a non-psychoactive member of cannabinoids which has well-known and notable anti-inflammatory and antiangiogenic properties. This agent has been shown to decrease IL-1ß, IL-6, TNF-α, VEGF, TGFß, and MMPs in different animal models of diseases. CONCLUSION: It seems that CBD could be a possible treatment for endometriosis due to its anti-inflammatory and antiangiogenic activity, however, further studies are needed.
Subject(s)
Cannabidiol , Endometriosis , Inflammation , Neovascularization, Pathologic , Endometriosis/drug therapy , Endometriosis/pathology , Female , Humans , Cannabidiol/therapeutic use , Cannabidiol/pharmacology , Neovascularization, Pathologic/drug therapy , Inflammation/drug therapy , Animals , Cytokines/metabolism , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Angiogenesis Inhibitors/therapeutic use , Angiogenesis Inhibitors/pharmacology , AngiogenesisABSTRACT
With the escalating incidence and mortality rates of cancer, there is an ever-growing emphasis on the research of anticancer drugs. Cordycepin, the primary nucleoside antibiotic isolated from Cordyceps militaris, has emerged as a remarkable agent for cancer prevention and treatment. Functioning as a natural targeted antitumor drug, cordycepin assumes an increasingly pivotal role in cancer therapy. This review elucidates the mechanisms of cordycepin in inhibiting tumor cell proliferation, inducing apoptosis, as well as its capabilities in suppressing angiogenesis and metastasis. Moreover, the immunomodulatory effects of cordycepin in cancer treatment are explored. Additionally, the current status, challenges, and future prospects of cordycepin application in clinical trials are briefly discussed. The objective is to provide a valuable reference for the utilization of cordycepin in cancer treatment.
Subject(s)
Apoptosis , Cell Proliferation , Deoxyadenosines , Neoplasms , Deoxyadenosines/pharmacology , Deoxyadenosines/therapeutic use , Humans , Neoplasms/drug therapy , Cell Proliferation/drug effects , Apoptosis/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Neovascularization, Pathologic/drug therapyABSTRACT
Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.
Subject(s)
Natriuretic Peptide, C-Type , Neovascularization, Pathologic , Tumor Microenvironment , Animals , Neovascularization, Pathologic/drug therapy , Natriuretic Peptide, C-Type/pharmacology , Natriuretic Peptide, C-Type/therapeutic use , Mice , Humans , Tumor Microenvironment/drug effects , Cell Line, Tumor , Neoplasms/drug therapy , Neoplasms/pathology , Neoplasms/blood supply , Immunity/drug effectsABSTRACT
BACKGROUND: Eplerenone is a selective aldosterone receptor blocker that is effective in preventing the progression of chroinic kidney disease (CKD). However, its mechanism and role in CKD pregnancy still remain uncertain. The aim of this study was to evaluate whether eplerenone could attenuated the fibrosis of unilateral ureteral obstruction (UUO) pregnant rats' contralateral kidney, improved pregnancy outcome and explore its therapeutic mechanisms. METHODS: A pregnancy rat model of UUO established, female Wistar rats were randomly assigned into sham-operated group (Sham group),sham-operated combined pregnancy group (SP group), unilateral ureteral obstruction combined pregnancy group (UUO + Pregnancy group), unilateral ureteral obstruction combined pregnancy, administered eplerenone (UUO + Pregnancy+Eplerenone group). On the 18th day of pregnancy, the rats were placed in a metabolic cage, 24 h urine was collected and stored at -80 °C. Next day, all animals were euthanized, and serum was collected by centrifugation and stored at -20 °C. Then the right kidney was extracted, a part of the kidney was placed in 4% paraformaldehyde for morphology, immunohistochemical staining, and immunofluorescence staining, and the other part was placed in a - 80 °C refrigerator for RNA and protein extraction. In vitro, HUVECs was treated with aldosterone, progesterone and estradiol, VEGFA and its receptor blocker bevacizumab. The ability of proliferation, migration and tubularization of HUVECs was detected by CCK-8, scratch wound assay and endothelial tube formation assay. And the co-expression of CD34 and α-SMA of HUVECs was detected by Flow cytometry. RESULTS: Immunofluorescence results showed that the co-expression of CD34 and α-SMA increased in the UUO + Pregnancy group was significantly increased. The expression of SGK-1, TGFß-1, Smad2, Smad3, VEGF-A, VEGFR2, CD34, α-SMA and Collagen I was significantly higher in the kidneys of the UUO + Pregnancy group compared to the Sham group and SP group. Eplerenone inhibited the expression of those results. In vitro, the ability of proliferation, migration and tubularization was increased after treated with aldosterone, aldosterone with progesterone and estradiol or VEGFA. Similarly, the expression of α-SMA on the surface of HUVECs treated with aldosterone, aldosterone with progesterone and estradiol were increased, while eplerenone supressed its expression. CONCLUSION: Eplerenone inhibits renal angiogenesis by blocking the SGK-1/TGFß signal transduction pathway, thereby inhibiting the phenotypic transformation of endothelial cells, slowing down renal fibrosis, and reducing kidney damage caused by pregnancy.
Subject(s)
Eplerenone , Immediate-Early Proteins , Kidney , Protein Serine-Threonine Kinases , Rats, Wistar , Renal Insufficiency, Chronic , Transforming Growth Factor beta , Animals , Female , Pregnancy , Eplerenone/pharmacology , Eplerenone/therapeutic use , Rats , Immediate-Early Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/pathology , Kidney/metabolism , Kidney/pathology , Kidney/drug effects , Transforming Growth Factor beta/metabolism , Signal Transduction/drug effects , Humans , Human Umbilical Vein Endothelial Cells/metabolism , Cell Proliferation/drug effects , Spironolactone/pharmacology , Spironolactone/analogs & derivatives , Spironolactone/therapeutic use , Ureteral Obstruction/metabolism , Ureteral Obstruction/drug therapy , Ureteral Obstruction/pathology , Ureteral Obstruction/complications , Mineralocorticoid Receptor Antagonists/pharmacology , Mineralocorticoid Receptor Antagonists/therapeutic use , Vascular Endothelial Growth Factor A/metabolism , Cell Movement/drug effects , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/drug therapy , AngiogenesisABSTRACT
BACKGROUND: Cirrhosis leads to portal hypertension (PHT), affecting survival with limited treatment options. This study investigated Imperatorin (IMP), a furanocoumarin with anti-inflammatory and hypotensive properties, for its therapeutic role and mechanisms in cirrhotic PHT. METHODS: Hepatic stellate cells (HSCs) inhibition by IMP was evaluated using LX-2 cell line. Rat cirrhosis was induced via CCl4 for 16 weeks. Experimental group were orally administered IMP (15/25 mg/kg/day) for 4 weeks. We subsequently examined portal pressure (PP), cirrhosis, inflammation, angiogenesis, and vascular remodeling. Network pharmacology was employed for mechanistic insights. RESULTS: IMP significantly inhibited the fibrogenesis in HSCs and suppressed cell viability. CCl4 exposure induced cirrhosis, inflammation, angiogenesis, vascular remodeling and PHT. IMP significantly reduced PP from 22.85 ± 3.88 mmHg to 6.67 ± 0.6 mmHg, diminished collagen deposition and pro-fibrotic factor expression, alleviated inflammation, and improved liver function. Vessel wall thickness in superior mesenteric arteries was restored, and intra-/extrahepatic angiogenesis was inhibited via VEGF and vWF. Furthermore, IMP induced sinusoidal vasodilation by upregulating eNOS and GCH1. Enrichment analysis indicated that IMP was involved in various biological processes associated with cirrhosis, such as the regulation of blood pressure, tissue remodeling, response to inflammation, and regulation of angiogenesis, etc. Additionally, IMP suppressed hepatic expression of TGF-ß both in vitro and in vivo, which was further supported by KEGG analysis. CONCLUSION: Our research demonstrated that IMP significantly mitigated cirrhosis PHT by reducing hepatic fibrosis and inflammation, curbing angiogenesis and vascular remodeling, and promoting vasodilation. This protective mechanism appears to be facilitated through the downregulation of TGF-ß.
Subject(s)
Carbon Tetrachloride , Furocoumarins , Hepatic Stellate Cells , Hypertension, Portal , Liver Cirrhosis , Vascular Remodeling , Furocoumarins/pharmacology , Furocoumarins/therapeutic use , Animals , Hypertension, Portal/drug therapy , Hypertension, Portal/physiopathology , Vascular Remodeling/drug effects , Hepatic Stellate Cells/drug effects , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Male , Rats , Liver Cirrhosis/drug therapy , Liver Cirrhosis/pathology , Liver Cirrhosis/metabolism , Liver Cirrhosis/chemically induced , Humans , Rats, Sprague-Dawley , Cell Line , Signal Transduction/drug effects , Network Pharmacology , Neovascularization, Pathologic/drug therapy , Liver/drug effects , Liver/pathology , Liver/metabolism , Liver/blood supplyABSTRACT
Insufficient angiogenic stimulation and dysregulated glycolipid metabolism in senescent vascular endothelial cells (VECs) constitute crucial features of vascular aging. Concomitantly, the generation of excess senescence-associated secretory phenotype (SASP) and active immune-inflammatory responses propagates within injured vessels, tissues, and organs. Until now, targeted therapies that efficiently rectify phenotypic abnormalities in senescent VECs have still been lacking. Here, we constructed a Pd/hCeO2-BMS309403@platelet membrane (PCBP) nanoheterostructured capsule system loaded with fatty acid-binding protein 4 (FABP4) inhibitors and modified with platelet membranes and investigated its therapeutic role in aged mice. PCBP showed significant maintenance in aged organs and demonstrated excellent biocompatibility. Through cyclic tail vein administration, PCBP extended the lifespan and steadily ameliorated abnormal phenotypes in aged mice, including SASP production, immune and inflammatory status, and age-related metabolic disorders. In senescent ECs, PCBP mediated the activation of vascular endothelial growth factor (VEGF) signaling and glycolysis and inhibition of FABP4 by inducing the synthesis of hypoxia-inducible factor-1α, thereby reawakening neovascularization and restoring glycolipid metabolic homeostasis. In conclusion, the PCBP nanocapsule system provides a promising avenue for interventions against aging-induced dysfunction.
Subject(s)
Aging , Nanocapsules , Animals , Mice , Aging/metabolism , Nanocapsules/chemistry , Humans , Mice, Inbred C57BL , Glycolipids/chemistry , Glycolipids/metabolism , Cellular Senescence/drug effects , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , AngiogenesisABSTRACT
Vasculogenic mimicry (VM) serves as a vascular-like channel that provides important substances for tumor growth and is a primary factor in glioblastoma (GBM) drug resistance. Human Antigen R (HuR)-an mRNA-binding protein-is highly expressed in GBM, closely related to tumor progression, and deemed a potential drug target. Although some small-molecule compounds have been identified to disrupt HuR binding to target mRNA, they remain in the preclinical research stage, suggesting the need for further validation and development of HuR inhibitors. In our study, we aim to screen for potential HuR inhibitors and investigate their efficacy and molecular mechanisms in GBM. We employed the fluorescence polarization method to identify HuR inhibitors from a natural compound library, confirming the efficacy of juglone in effectively inhibiting the binding of HuR to AREVegf-a. Further validation of the binding of juglone to HuR at the protein level was conducted through electrophoretic mobility shift analysis, surface plasmon resonance, and molecular docking. Furthermore, juglone demonstrated inhibitory effects on glioma growth and VM formation in vitro and in vivo. Moreover, it was observed that juglone reversed epithelial-mesenchymal transition by inhibiting the VEGF-A/VEGFR2/AKT/SNAIL signaling pathway. Finally, we established the capability of juglone to target HuR in U251 cells through HuR knockdown, mRNA stability, and cell thermal shift assays. Therefore, this study identifies juglone as a novel HuR inhibitor, potentially offering promise as a lead compound for anti-VM therapy in GBM by targeting HuR. Abbreviations: AKT, protein kinase B; ARE, adenine-and uridine-rich elements; CETSA, cellular thermal shift assay; DMEM, Dulbecco's modified Eagle's medium; ELISA, enzyme linked immune sorbent assay; EMSA, electrophoretic mobility shift assay; EMT, epithelial mesenchymal transition; FP, fluorescence polarization; GBM, glioblastoma; HTS, high-throughput screening; HuR, human antigen R; IF, Immunofluorescence; PAS, periodic acid-Schiff; PI3K, phosphoinositide-3 kinase; qRT-PCR, quantitative real-time PCR; RRMs, RNA recognition motifs; SPR, surface plasmon resonance. TMZ, temozolomide; VM, vasculogenic mimicry; VEGF-A, Vascular endothelial growth factor-A; VEGFR2, Vascular endothelial growth factor receptor-2.
Subject(s)
ELAV-Like Protein 1 , Naphthoquinones , Vascular Endothelial Growth Factor A , Humans , ELAV-Like Protein 1/metabolism , ELAV-Like Protein 1/genetics , ELAV-Like Protein 1/antagonists & inhibitors , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Naphthoquinones/pharmacology , Animals , Mice , Cell Line, Tumor , Mice, Nude , Glioma/metabolism , Glioma/drug therapy , Glioma/pathology , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Gene Expression Regulation, Neoplastic/drug effects , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Mice, Inbred BALB C , Xenograft Model Antitumor Assays/methodsABSTRACT
BACKGROUND AND PURPOSE: The poor delivery of drugs to infiltrating tumor cells contributes to therapeutic failure in glioblastoma. During the early phase of an anti-angiogenic treatment, a remodeling of the tumor vasculature could occur, leading to a more functional vessel network that could enhance drug delivery. However, the restructuration of blood vessels could increase the proportion of normal endothelial cells that could be a barrier for the free diffusion of drugs. The net balance, in favor or not, of a better delivery of compounds during the course of an antiangiogenic treatment remains to be established. This study explored whether cediranib and thalidomide could modulate perfusion and vessel permeability in the brain U87 tumor mouse model. METHODS: The dynamic evolution of the diffusion of agents outside the tumor core using the fluorescent dye Evans Blue in histology and Gd-DOTA using dynamic contrast-enhanced (DCE)-MRI. CD31 labelling of endothelial cells was used to measure the vascular density. RESULTS AND INTERPRETATION: Cediranib and thalidomide effectively reduced tumor size over time. The accessibility of Evans Blue outside the tumor core continuously decreased over time. The vascular density was significantly decreased after treatment while the proportion of normal vessels remained unchanged over time. In contrast to histological studies, DCE-MRI did not tackle any significant change in hemodynamic parameters, in the core or margins of the tumor, whatever the parameter used or the pharmacokinetic model used. While cediranib and thalidomide were effective in decreasing the tumor size, they were ineffective in transiently increasing the delivery of agents in the core and the margins of the tumor.
Subject(s)
Angiogenesis Inhibitors , Brain Neoplasms , Glioblastoma , Quinazolines , Thalidomide , Glioblastoma/drug therapy , Glioblastoma/pathology , Glioblastoma/blood supply , Thalidomide/pharmacology , Thalidomide/therapeutic use , Animals , Angiogenesis Inhibitors/pharmacology , Mice , Quinazolines/pharmacology , Quinazolines/pharmacokinetics , Quinazolines/therapeutic use , Humans , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Magnetic Resonance Imaging , Xenograft Model Antitumor Assays , Capillary Permeability/drug effects , Mice, Nude , Cell Line, Tumor , IndolesABSTRACT
BACKGROUND: Long-term anti-angiogenesis leads to pruned vasculature, densely deposited extracellular matrix (ECM), and consequently reduced chemotherapy delivery in esophagogastric cancer (EGC). To address this issue, we evaluated the efficacy of adding a hyaluronidase or a NO-donor to the regimen of chemotherapy and anti-angiogenic drugs. METHODS: A patient-derived EGC xenograft model was developed. Grafted mice were randomly assigned to four experimental groups and one control group. The experimental groups received DC101, a murine angiogenesis inhibitor, and nab-paclitaxel (NPTX), with the addition of hyaluronidase (PEGPH20), or NO-donor (nitroglycerine, NTG), or their combination, respectively. We compared tumor growth during 17 days of treatment. We performed immunohistochemistry for ECM components hyaluronan (HA) and collagen, CD31 for endothelial cells, and γH2AX for DNA damage. The positively stained areas were quantified, and vessel diameters were measured using QuPath software. RESULTS: Prolonged DC101 treatment induced deposition of HA (p<0.01) and collagen (p<0.01). HA was effectively degraded by PEGPH20 (p<0.001), but not by NTG as expected. Both PEGPH20 (p<0.05) and NTG (p<0.01) dilated vessels collapsed in response to long-term DC101 treatment. However, only PEGPH20 (rather than NTG) was found to significantly inhibit tumor growth (p<0.05) in combination with NPTX and DC101. CONCLUSIONS: These findings suggest that the mechanical barrier of HA is the major reason responsible for the resistance developed during prolonged anti-angiogenesis in EGC. Incorporating PEGPH20 into the existing treatment regimen is promising to improve outcomes for patients with EGC.
Subject(s)
Albumins , Angiogenesis Inhibitors , Esophageal Neoplasms , Hyaluronoglucosaminidase , Neovascularization, Pathologic , Paclitaxel , Stomach Neoplasms , Xenograft Model Antitumor Assays , Animals , Paclitaxel/pharmacology , Paclitaxel/administration & dosage , Paclitaxel/therapeutic use , Hyaluronoglucosaminidase/administration & dosage , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/pathology , Humans , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/administration & dosage , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Albumins/pharmacology , Albumins/administration & dosage , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Mice , Hyaluronic Acid/pharmacology , Mice, Nude , Female , Angiogenesis , Antibodies, MonoclonalABSTRACT
BACKGROUND/AIM: Malignant melanoma is a tumor with a poor prognosis that can metastasize distally at an early stage. Terrein, a metabolite produced by Aspergillus terreus, suppresses the expression of angiogenin, an angiogenic factor. However, the pharmacological effects of natural terrein have not been elucidated, because only a small amount of terrein can be extracted from large fungal cultures. In this study, we investigated the antineoplastic effects of terrein on human malignant melanoma cells and its underlying mechanisms. MATERIALS AND METHODS: Human malignant melanoma cell lines were cultured in the presence of terrein and analyzed. Angiogenin production was evaluated using ELISA. Ribosome biosynthesis was evaluated using silver staining of the nucleolar organizer region. Intracellular signaling pathways were analyzed using western blotting. Malignant melanoma cells were transplanted subcutaneously into the backs of nude mice. The tumors were removed at 5 weeks and analyzed histopathologically. RESULTS: Terrein inhibited angiogenin expression, proliferation, migration, invasion, and ribosome biosynthesis in malignant melanoma cells. Terrein was shown to inhibit tumor growth and angiogenesis in animal models. CONCLUSION: This study demonstrated that terrein has anti-tumor effects against malignant melanoma. Furthermore, chemically synthesized non-natural terrein can be mass-produced and serve as a novel potential anti-tumor drug candidate.
Subject(s)
Cell Proliferation , Melanoma , Mice, Nude , Ribonuclease, Pancreatic , Humans , Animals , Melanoma/drug therapy , Melanoma/metabolism , Melanoma/pathology , Ribonuclease, Pancreatic/metabolism , Mice , Cell Proliferation/drug effects , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Xenograft Model Antitumor Assays , Cell Movement/drug effects , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Gene Expression Regulation, Neoplastic/drug effects , CyclopentanesABSTRACT
This study aimed to explore advances in biomarkers related to anti-angiogenic therapy in patients with non-small cell lung cancer (NSCLC), thereby enhancing treatment selection, advancing personalized and precision medicine to improve treatment outcomes and patient survival rates. This article reviews key discoveries in predictive biomarkers for anti-angiogenic therapy in NSCLC in recent years, such as (1) liquid biopsy predictive biomarkers: studies have identified activated circulating endothelial cells (aCECs) via liquid biopsy as potential predictive biomarkers for the efficacy of anti-angiogenic therapy; (2) imaging biomarkers: advanced imaging technologies, such as dynamic contrast-enhanced integrated magnetic resonance positron emission tomography (MR-PET), are used to assess tumor angiogenesis in patients with NSCLC and evaluate the clinical efficacy of anti-angiogenic drugs; (3) genetic predictive biomarkers: research has explored polymorphisms of Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1) and vascular endothelial growth factor-A (VEGF-A), as well as how plasma levels of VEGF-A can predict the outcomes and prognosis of patients with non-squamous NSCLC undergoing chemotherapy combined with bevacizumab. Despite progress in identifying biomarkers related to anti-angiogenic therapy, several challenges remain, including limitations in clinical trials, heterogeneity in NSCLC, and technical hurdles. Future research will require extensive clinical validation and in-depth mechanistic studies to fully exploit the potential of these biomarkers for personalized treatment.
Subject(s)
Angiogenesis Inhibitors , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/blood , Angiogenesis Inhibitors/therapeutic use , Neovascularization, Pathologic/drug therapy , PrognosisABSTRACT
Angiogenesis, primarily mediated by vascular endothelial growth factor (VEGF), is a fundamental step in the progression and metastasis of head and neck squamous cell carcinoma (HNSCC). Traditional anti-angiogenic therapies that target the VEGF pathway have shown promise but are often associated with significant side effects and variable efficacy due to the complexity of the angiogenic signaling pathway. This review highlights the potential of a specific VEGF splice form, VEGF165b, as an innovative therapeutic target for HNSCC. VEGF165b, unlike standard VEGF, is a natural inhibitor that binds to VEGF receptors without triggering pro-angiogenic signaling. Its distinct molecular structure and behavior suggest ways to modulate angiogenesis. This concept is particularly relevant when studying HNSCC, as introducing VEGF165b's anti-angiogenic properties offers a novel approach to understanding and potentially influencing the disease's dynamics. The review synthesizes experimental evidence suggesting the efficacy of VEGF165b in inhibiting tumor-induced angiogenesis and provides insight into a novel therapeutic strategy that could better manage HNSCC by selectively targeting aberrant vascular growth. This approach not only provides a potential pathway for more targeted and effective treatment options but also opens the door to a new paradigm in anti-angiogenic therapy with the possibility of reduced systemic toxicity. Our investigation is reshaping the future of HNSCC treatment by setting the stage for future research on VEGF splice variants as a tool for personalized medicine.
Subject(s)
Head and Neck Neoplasms , Neovascularization, Pathologic , Squamous Cell Carcinoma of Head and Neck , Vascular Endothelial Growth Factor A , Humans , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/metabolism , Squamous Cell Carcinoma of Head and Neck/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/pathology , Angiogenesis Inhibitors/therapeutic use , Angiogenesis Inhibitors/pharmacology , Protein Isoforms/genetics , Protein Isoforms/metabolism , Animals , Signal Transduction/drug effectsABSTRACT
Blood vessels in tumors are often dysfunctional. This impairs the delivery of therapeutic agents to and distribution among the cancer cells. Subsequently, treatment efficacy is reduced, and dose escalation can increase adverse effects on non-malignant tissues. The dysfunctional vessel phenotypes are attributed to aberrant pro-angiogenic signaling, and anti-angiogenic agents can ameliorate traits of vessel dysfunctionality. However, they simultaneously reduce vessel density and thereby impede drug delivery and distribution. Exploring possibilities to improve vessel functionality without compromising vessel density in the tumor microenvironment, we evaluated transcription factors (TFs) involved in epithelial-mesenchymal transition (EMT) as potential targets. Based on similarities between EMT and angiogenic activation of endothelial cells, we hypothesized that these TFs, Snai1 in particular, might serve as key regulators of vessel dysfunctionality. In vitro, experiments demonstrated that Snai1 (similarly Slug and Twist1) regulates endothelial permeability, permissiveness for tumor cell transmigration, and tip/stalk cell formation. Endothelial-specific, heterozygous knock-down of Snai1 in mice improved vascular quality in implanted tumors. This resulted in better oxygenation and reduced metastasis. Notably, the tumors in Snai1KD mice responded significantly better to chemotherapeutics as drugs were transported into the tumors at strongly increased rates and more homogeneously distributed. Thus, we demonstrate that restoring vessel homeostasis without affecting vessel density is feasible in malignant tumors. Combining such vessel re-engineering with anti-cancer drugs allows for strategic treatment approaches that reduce treatment toxicity on non-malignant tissues.
Subject(s)
Epithelial-Mesenchymal Transition , Neovascularization, Pathologic , Snail Family Transcription Factors , Snail Family Transcription Factors/metabolism , Snail Family Transcription Factors/genetics , Animals , Humans , Mice , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Epithelial-Mesenchymal Transition/drug effects , Epithelial-Mesenchymal Transition/genetics , Neoplasms/drug therapy , Neoplasms/pathology , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/blood supply , Cell Line, Tumor , Tumor Microenvironment/drug effects , Human Umbilical Vein Endothelial Cells , Endothelial Cells/metabolism , Endothelial Cells/pathology , Endothelial Cells/drug effects , Angiogenesis Inhibitors/pharmacology , FemaleABSTRACT
Breast cancer, as a highly prevalent cancer among women, is one of the main causes of female mortality due to cancer. There is a need for more treatment options to improve the survival time of breast cancer patients. Metastasis to distant organs is a standard indicator of advanced breast cancer and a primary cause of breast cancer mortality, making the control of breast cancer metastasis crucial. Targeted therapy, with its advantages of precision, high effectiveness, and minimal side effects, has garnered significant attention as a hot research topic in breast cancer treatment. Among these therapies, anti-angiogenic therapy aim to inhibit tumor angiogenesis, control tumor growth, and reduce metastasis. Additionally, anti-angiogenic therapy can restructure the tumor vasculature, enhancing the effectiveness of other anti-cancer drugs. Lenvatinib, an orally available small molecule multi-targeted tyrosine kinase inhibitor, exerts its anti-tumor effects mainly by inhibiting tumor angiogenesis and tumor cell proliferation. It has been approved for the treatment of thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma. Due to its multi-targeted nature, lenvatinib not only has direct anti-tumor effects but also possesses immunomodulatory activity, which can enhance the tumor immune response. This makes it a promising candidate for a broad range of cancers. Recent studies have explored the role of lenvatinib in breast cancer, including its various mechanisms of action and its use as a monotherapy or in combination to control breast cancer progression. This review will summarize the molecular mechanisms and research progress of lenvatinib in breast cancer treatment, discussing its potential applications and therapeutic prospects in managing breast cancer.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Phenylurea Compounds , Quinolines , Humans , Quinolines/therapeutic use , Phenylurea Compounds/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Female , Antineoplastic Agents/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Neovascularization, Pathologic/drug therapy , Angiogenesis Inhibitors/therapeutic useABSTRACT
This pre-clinical study was designed to demonstrate how vascular disrupting agents (VDAs) should be administered, either alone or when combined with radiation in clinically relevant fractionated radiation schedules, for the optimal anti-tumor effect. CDF1 mice, implanted in the right rear foot with a 200 mm3 murine C3H mammary carcinoma, were injected with various doses of the most potent VDA drug, combretastatin A-1 phosphate (CA1P), under different schedules. Tumors were also locally irradiated with single-dose, or stereotactic (3 × 5-20 Gy) or conventional (30 × 2 Gy) fractionation schedules. Tumor growth and control were the endpoints used. Untreated tumors had a tumor growth time (TGT5; time to grow to 5 times the original treatment volume) of around 6 days. This increased with increasing drug doses (5-100 mg/kg). However, with single-drug treatments, the maximum TGT5 was only 10 days, yet this increased to 19 days when injecting the drug on a weekly basis or as three treatments in one week. CA1P enhanced radiation response regardless of the schedule or interval between the VDA and radiation. There was a dose-dependent increase in radiation response when the combined with a single, stereotactic, or conventional fractionated irradiation, but these enhancements plateaued at around a drug dose of 25 mg/kg. This pre-clinical study demonstrated how VDAs should be combined with clinically applicable fractionated radiation schedules for the optimal anti-tumor effect, thus suggesting the necessary pre-clinical testing required to ultimately establish VDAs in clinical practice.
Subject(s)
Dose Fractionation, Radiation , Animals , Mice , Female , Stilbenes/pharmacology , Stilbenes/administration & dosage , Mice, Inbred C3H , Neovascularization, Pathologic/radiotherapy , Neovascularization, Pathologic/drug therapy , Cell Line, Tumor , Mammary Neoplasms, Experimental/radiotherapy , Mammary Neoplasms, Experimental/blood supply , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/pathologyABSTRACT
A literature search was conducted to review papers on the results of studies of clear cell renal cancer (CCRC) vascularization. Numerous data on the relationship between tumor pathogenesis and its vascularization have been revealed, which indicates the multifactorial nature of CCRC development and the significant role of angiogenesis in this process. It should be taken into account that patients with CCRC may have impaired vessel formation even before tumor development. To evaluate normal and pathologic angiogenesis, a pathohistologic study using immunohistochemistry is certainly necessary. Due to the significant role of angiogenesis in the development and course of CCRC, the use of drugs that suppress the formation of the vascular network in the tumor is relevant and advisable. To date, many drugs have been developed and introduced into clinical practice to inhibit angiogenesis. However, such drugs have not lived up to the expectations placed due to the frequent and rapidly developing drug resistance. Timely detection of pre-tumor and tumor processes, as well as effective treatment of cancer, including CCRC, is possible only with close cooperation between pathomorphologists and oncologists.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Neovascularization, Pathologic , Humans , Kidney Neoplasms/pathology , Kidney Neoplasms/blood supply , Kidney Neoplasms/drug therapy , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/drug therapy , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/blood supply , Carcinoma, Renal Cell/drug therapy , Angiogenesis Inhibitors/therapeutic use , Angiogenesis Inhibitors/pharmacology , AngiogenesisABSTRACT
Endothelial Notch signaling is critical for tumor angiogenesis. Notch1 blockade can interfere with tumor vessel function but causes tissue hypoxia and gastrointestinal toxicity. Notch4 is primarily expressed in endothelial cells, where it may promote angiogenesis; however, effective therapeutic targeting of Notch4 has not been successful. We developed highly specific Notch4-blocking antibodies, 6-3-A6 and humanized E7011, allowing therapeutic targeting of Notch4 to be assessed in tumor models. Notch4 was expressed in tumor endothelial cells in multiple cancer models, and endothelial expression was associated with response to E7011/6-3-A6. Anti-Notch4 treatment significantly delayed tumor growth in mouse models of breast, skin, and lung cancers. Enhanced tumor inhibition occurred when anti-Notch4 treatment was used in combination with chemotherapeutics. Endothelial transcriptomic analysis of murine breast tumors treated with 6-3-A6 identified significant changes in pathways of vascular function but caused only modest change in canonical Notch signaling. Analysis of early and late treatment timepoints revealed significant differences in vessel area and perfusion in response to anti-Notch4 treatment. We conclude that targeting Notch4 improves tumor growth control through endothelial intrinsic mechanisms. SIGNIFICANCE: A first-in-class anti-Notch4 agent, E7011, demonstrates strong antitumor effects in murine tumor models including breast carcinoma. Endothelial Notch4 blockade reduces perfusion and vessel area.
Subject(s)
Antibodies, Neutralizing , Neovascularization, Pathologic , Receptor, Notch4 , Animals , Receptor, Notch4/metabolism , Mice , Humans , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/metabolism , Female , Antibodies, Neutralizing/pharmacology , Antibodies, Neutralizing/therapeutic use , Cell Line, Tumor , Signal Transduction/drug effects , Xenograft Model Antitumor Assays , Disease Models, Animal , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Cell Proliferation/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolismABSTRACT
BACKGROUND: Vascular Endothelial Growth Factor Receptors (VEGFR1 and VEGFR2) are tyrosine kinase receptors expressed on endothelial cells and tumor vessels and play an important role in angiogenesis. In this study, three repeats of VEGFR1 and VEGFR2 binding peptide (VGB3) were genetically fused to the truncated diphtheria toxin (TDT), and its in vitro activity was evaluated. METHODS: The recombinant construct (TDT-triVGB3) was expressed in bacteria cells and purified with nickel affinity chromatography. The binding capacity and affinity of TDT-triVGB3 were evaluated using the enzyme-linked immunosorbent assay. The inhibitory activity of TDT-triVGB3 on viability, migration, and tube formation of human endothelial cells was evaluated using MTT, migration, and tube formation assays. RESULTS: TDT-triVGB3 selectively detected VEGFR1 and VEGFR2 with high affinity in an enzyme- linked immunosorbent assay and significantly inhibited viability, migration, and tube formation of human endothelial cells. CONCLUSION: The developed TDT-triVGB3 is potentially a novel agent for targeting VEGFR1/ VEGFR2 over-expressing cancer cells.