RESUMEN
Snake venoms are a complex mixture of proteins and polypeptides that represent a valuable source of potential molecular tools for understanding physiological processes for the development of new drugs. In this study two major PLA2s, named PLA2-I (Asp49) and PLA2-II (Lys49), isolated from the venom of Bothrops diporus from Northeastern Argentina, have shown cytotoxic effects on LM3 murine mammary tumor cells, with PLA2-II-like exhibiting a stronger effect compared to PLA2-I. At sub-cytotoxic levels, both PLA2s inhibited adhesion, migration, and invasion of these adenocarcinoma cells. Moreover, these toxins hindered tubulogenesis in endothelial cells, implicating a potential role in inhibiting tumor angiogenesis. All these inhibitory effects were more pronounced for the catalytically-inactive toxin. Additionally, in silico studies strongly suggest that this PLA2-II-like myotoxin could effectively block fibronectin binding to the integrin receptor, offering a dual advantage over PLA2-I in interacting with the αVß3 integrin. In conclusion, this study reports for the first time, integrating both in vitro and in silico approaches, a comparative analysis of the antimetastatic and antiangiogenic potential effects of two isoforms, an Asp49 PLA2-I and a Lys49 PLA2-II-like, both isolated from Bothrops diporus venom.
Asunto(s)
Bothrops , Venenos de Crotálidos , Fosfolipasas A2 , Animales , Bothrops/metabolismo , Ratones , Fosfolipasas A2/metabolismo , Fosfolipasas A2/química , Fosfolipasas A2/farmacología , Línea Celular Tumoral , Venenos de Crotálidos/química , Movimiento Celular/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Neovascularización Patológica/metabolismo , Adhesión Celular/efectos de los fármacos , Femenino , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/citología , Metástasis de la Neoplasia , Integrina alfaVbeta3/metabolismo , Integrina alfaVbeta3/antagonistas & inhibidores , Fibronectinas/metabolismo , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/química , Humanos , Lisina/química , Lisina/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Neoplasias Mamarias Animales/tratamiento farmacológico , Neoplasias Mamarias Animales/patología , Neoplasias Mamarias Animales/metabolismo , AngiogénesisRESUMEN
INTRODUCTION AND OBJECTIVES: Blood glucose fluctuates severely in the diabetes (DM) and tumor microenvironment. Our previous works have found Hepatitis B virus X protein (HBx) differentially regulated metastasis and apoptosis of hepatoma cells depending on glucose concentration. We here aimed to explore whether HBx played dual roles in the angiogenesis of hepatocellular carcinoma varying on different glucose levels. MATERIALS AND METHODS: We collected conditioned medium from HBx-overexpressing cells cultured with two solubilities of glucose, and then applied to EA.hy926 cells. Alternatively, a co-culture cell system was established with hepatoma cells and EA.hy926 cells. We analyzed the angiogenesis of EA.hy926 cells with CCK8, wound-healing, transwell-migartion and tube formation experiment. ELISA was conducted to detect the secretion levels of angiogenesis-related factors. siRNAs were used to detect the P53-VEGF axis. RESULTS: HBx expressed in hepatoma cells suppressed VEGF secretion, and subsequently inhibited the proliferation, migration and tube formation of EA.hy926 cells in a high glucose condition, while attenuating these in the lower glucose condition. Furthermore, the p53-VEGF axis was required for the dual role of HBx in angiogenesis. Additionally, HBx mainly regulated the nuclear p53. CONCLUSIONS: These data suggest that the dual roles of HBx confer hepatoma cells to remain in a glucose-rich environment and escape from the glucose-low milieu through tumor vessels, promoting liver tumor progression overall. We exclusively revealed the dual role of HBx on the angiogenesis of liver tumors, which may shed new light on the mechanism and management strategy of HBV- and DM-related hepatocellular carcinoma.
Asunto(s)
Carcinoma Hepatocelular , Movimiento Celular , Proliferación Celular , Glucosa , Neoplasias Hepáticas , Neovascularización Patológica , Transducción de Señal , Transactivadores , Proteína p53 Supresora de Tumor , Factor A de Crecimiento Endotelial Vascular , Proteínas Reguladoras y Accesorias Virales , Humanos , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Transactivadores/metabolismo , Transactivadores/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Glucosa/metabolismo , Línea Celular Tumoral , Células Hep G2 , Técnicas de Cocultivo , Virus de la Hepatitis B/genética , Microambiente Tumoral , AngiogénesisRESUMEN
After menstruation the uterine spiral arteries are repaired through angiogenesis. This process is tightly regulated by the paracrine communication between endometrial stromal cells (EnSCs) and endothelial cells. Any molecular aberration in these processes can lead to complications in pregnancy including miscarriage or preeclampsia (PE). Placental growth factor (PlGF) is a known contributing factor for pathological angiogenesis but the mechanisms remain poorly understood. In this study, we investigated whether PlGF contributes to pathological uterine angiogenesis by disrupting EnSCs and endothelial paracrine communication. We observed that PlGF mediates a tonicity-independent activation of nuclear factor of activated T cells 5 (NFAT5) in EnSCs. NFAT5 activated downstream targets including SGK1, HIF-1α and VEGF-A. In depth characterization of PlGF - conditioned medium (CM) from EnSCs using mass spectrometry and ELISA methods revealed low VEGF-A and an abundance of extracellular matrix organization associated proteins. Secreted factors in PlGF-CM impeded normal angiogenic cues in endothelial cells (HUVECs) by downregulating Notch-VEGF signaling. Interestingly, PlGF-CM failed to support human placental (BeWo) cell invasion through HUVEC monolayer. Inhibition of SGK1 in EnSCs improved angiogenic effects in HUVECs and promoted BeWo invasion, revealing SGK1 as a key intermediate player modulating PlGF mediated anti-angiogenic signaling. Taken together, perturbed PlGF-NFAT5-SGK1 signaling in the endometrium can contribute to pathological uterine angiogenesis by negatively regulating EnSCs-endothelial crosstalk resulting in poor quality vessels in the uterine microenvironment. Taken together the signaling may impact on normal trophoblast invasion and thus placentation and, may be associated with an increased risk of complications such as PE.
Asunto(s)
Endometrio , Neovascularización Patológica , Factor de Crecimiento Placentario , Preeclampsia , Proteínas Serina-Treonina Quinasas , Factores de Transcripción , Femenino , Humanos , Embarazo , Endometrio/metabolismo , Endometrio/irrigación sanguínea , Ensayo de Inmunoadsorción Enzimática , Proteínas Inmediatas-Precoces/metabolismo , Neovascularización Patológica/metabolismo , Factor de Crecimiento Placentario/metabolismo , Preeclampsia/metabolismo , Preeclampsia/fisiopatología , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Células del Estroma/metabolismo , Factores de Transcripción/metabolismoRESUMEN
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.
Asunto(s)
Apoptosis , Proliferación Celular , Desoxiadenosinas , Neoplasias , Desoxiadenosinas/farmacología , Desoxiadenosinas/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neovascularización Patológica/tratamiento farmacológicoRESUMEN
Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.
Asunto(s)
Angiotensina II , Leucemia-Linfoma Linfoblástico de Células Precursoras , Sistema Renina-Angiotensina , Humanos , Sistema Renina-Angiotensina/fisiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Angiotensina II/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Transducción de Señal , Angiotensina I/metabolismo , Neovascularización Patológica/metabolismo , Animales , Fragmentos de Péptidos/metabolismoRESUMEN
BACKGROUND: NSCLC is one of the most common causes of death. The hypoxia microenvironment contributes to cancer progression. The purpose was to explore the effects and mechanism of melittin on NSCLC cells in the hypoxic microenvironment. METHODS: NSCLC cell lines (A549 and H1299) were cultured in normoxia or hypoxia conditions with or without melittin treatment. The viability of the cells was detected via MTT assay and the proliferation ability was evaluated by EdU assay. QRT-PCR was performed to evaluate GLUT1, LDHA, HK2, VEGF and LATS2 mRNA levels. Glucose transport was assessed by the 2-NBDG uptake assay. The angiogenesis was determined by the tubule formation assay. The protein expressions of GLUT1, LDHA, HK2, VEGF, LATS2, YAP, p-YAP and HIF-1α were detected via western blotting assay. The tumor formation assay was conducted to examine the roles of melittin and LATS2 in vivo. RESULTS: Melittin inhibited hypoxia-induced cell viability, proliferation, glycolysis and angiogenesis as well as suppressed YAP binding to HIF-1α in NSCLC. Melittin inactivated the YAP/HIF-1α pathway via up-regulation of LATS2, ultimately inhibiting cancer progression of NSCLC. Moreover, melittin suppressed tumor growth via up-regulation of LATS2 in vivo. CONCLUSION: Melittin inactivated the YAP/HIF-1α pathway via up-regulation of LATS2 to contribute to the development of NSCLC. Therefore, melittin is expected to become a potential prognostic drug for the therapy of NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neoplasias Pulmonares , Meliteno , Neovascularización Patológica , Proteínas Serina-Treonina Quinasas , Proteínas Supresoras de Tumor , Regulación hacia Arriba , Proteínas Señalizadoras YAP , Humanos , Proteínas Serina-Treonina Quinasas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/irrigación sanguínea , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Glucólisis/efectos de los fármacos , Proteínas Supresoras de Tumor/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas Señalizadoras YAP/metabolismo , Meliteno/farmacología , Meliteno/uso terapéutico , Línea Celular Tumoral , Factores de Transcripción/metabolismo , Animales , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Transducción de Señal/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fosfoproteínas/metabolismo , AngiogénesisRESUMEN
Tumor hypoxia has been associated with cancer progression, angiogenesis, and metastasis via modifications in the release and cargo composition of extracellular vesicles secreted by tumor cells. Indeed, hypoxic extracellular vesicles are known to trigger a variety of angiogenic responses via different mechanisms. We recently showed that hypoxia promotes endosomal signaling in tumor cells via HIF-1α-dependent induction of the guanine exchange factor ALS2, which activates Rab5, leading to downstream events involved in cell migration and invasion. Since Rab5-dependent signaling is required for endothelial cell migration and angiogenesis, we explored the possibility that hypoxia promotes the release of small extracellular vesicles containing ALS2, which in turn activate Rab5 in recipient endothelial cells leading to pro-angiogenic properties. In doing so, we found that hypoxia promoted ALS2 expression and incorporation as cargo within small extracellular vesicles, leading to subsequent transfer to recipient endothelial cells and promoting cell migration, tube formation, and downstream Rab5 activation. Consequently, ALS2-containing small extracellular vesicles increased early endosome size and number in recipient endothelial cells, which was followed by subsequent sequestration of components of the ß-catenin destruction complex within endosomal compartments, leading to stabilization and nuclear localization of ß-catenin. These events converged in the expression of ß-catenin target genes involved in angiogenesis. Knockdown of ALS2 in donor tumor cells precluded its incorporation into small extracellular vesicles, preventing Rab5-downstream events and endothelial cell responses, which depended on Rab5 activity and guanine exchange factor activity of ALS2. These findings indicate that vesicular ALS2, secreted in hypoxia, promotes endothelial cell events leading to angiogenesis. Finally, these events might explain how tumor angiogenesis proceeds in hypoxic conditions.
Asunto(s)
Movimiento Celular , Vesículas Extracelulares , Factores de Intercambio de Guanina Nucleótido , Transducción de Señal , beta Catenina , Proteínas de Unión al GTP rab5 , Humanos , beta Catenina/metabolismo , Línea Celular Tumoral , Células Endoteliales/metabolismo , Células Endoteliales/patología , Vesículas Extracelulares/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Proteínas de Unión al GTP rab5/metabolismo , Proteínas de Unión al GTP rab5/genéticaRESUMEN
Objective: This study sought to investigate the regulation of long noncoding RNA (lncRNA) XIST on the microRNA (miR)-101-3p/vascular endothelial growth factor A (VEGFA) axis in neovascularization in diabetic retinopathy (DR). Materials and methods: Serum of patients with DR was extracted for the analysis of XIST, miR-101-3p, and VEGFA expression levels. High glucose (HG)-insulted HRMECs and DR model rats were treated with lentiviral vectors. MTT, transwell, and tube formation assays were performed to evaluate cell viability, migration, and angiogenesis, and ELISA was conducted to detect the levels of inflammatory cytokines. Dual-luciferase reporter, RIP, and RNA pull-down experiments were used to validate the relationships among XIST, miR-101-3p, and VEGFA. Results: XIST and VEGFA were upregulated and miR-101-3p was downregulated in serum from patients with DR. XIST knockdown inhibited proliferation, migration, vessel tube formation, and inflammatory responsein HG-treated HRMECs, whereas the above effects were nullified by miR-101-3p inhibition or VEGFA overexpression. miR-101-3p could bind to XIST and VEGFA. XIST promoted DR development in rats by regulating the miR-101-3p/VEGFA axis. Conclusion: LncRNA XIST promotes VEGFA expression by downregulating miR-101-3p, thereby stimulating angiogenesis and inflammatory response in DR.
Asunto(s)
Retinopatía Diabética , MicroARNs , Neovascularización Patológica , ARN Largo no Codificante , Factor A de Crecimiento Endotelial Vascular , ARN Largo no Codificante/genética , Retinopatía Diabética/genética , Retinopatía Diabética/sangre , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Ratas , Humanos , Masculino , Neovascularización Patológica/genética , Ratas Sprague-Dawley , Femenino , Movimiento Celular/genética , Proliferación Celular/genética , Persona de Mediana Edad , Diabetes Mellitus ExperimentalRESUMEN
Phospholipases A2 (PLA2s) from snake venom possess antitumor and antiangiogenic properties. In this study, we evaluated the antimetastatic and antiangiogenic effects of MjTX-II, a Lys49 PLA2 isolated from Bothrops moojeni venom, on lung cancer and endothelial cells. Using in vitro and ex vivo approaches, we demonstrated that MjTX-II reduced cell proliferation and inhibited fundamental processes for lung cancer cells (A549) growth and metastasis, such as adhesion, migration, invasion, and actin cytoskeleton decrease, without significantly interfering with non-tumorigenic lung cells (BEAS-2B). Furthermore, MjTX-II caused cell cycle alterations, increased reactive oxygen species production, modulated the expression of pro- and antiangiogenic genes, and decreased vascular endothelial growth factor (VEGF) expression in HUVECs. Finally, MjTX-II inhibited ex vivo angiogenesis processes in an aortic ring model. Therefore, we conclude that MjTX-II exhibits antimetastatic and antiangiogenic effects in vitro and ex vivo and represents a molecule that hold promise as a pharmacological model for antitumor therapy.
Asunto(s)
Inhibidores de la Angiogénesis , Bothrops , Proliferación Celular , Venenos de Crotálidos , Neoplasias Pulmonares , Animales , Humanos , Inhibidores de la Angiogénesis/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Fosfolipasas A2/farmacología , Movimiento Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Células A549 , Línea Celular Tumoral , Antineoplásicos/farmacología , Neovascularización Patológica/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Serpientes VenenosasRESUMEN
Glioblastomas (GBM) are aggressive tumors known for their heterogeneity, rapid proliferation, treatment resistance, and extensive vasculature. Angiogenesis, the formation of new vessels, involves endothelial cell (EC) migration and proliferation. Various extracellular matrix (ECM) molecules regulate EC survival, migration, and proliferation. Culturing human brain EC (HBMEC) on GBM-derived ECM revealed a decrease in EC numbers compared to controls. Through in silico analysis, we explored ECM gene expression differences between GBM and brain normal glia cells and the impact of GBM microenvironment on EC ECM transcripts. ECM molecules such as collagen alpha chains (COL4A1, COL4A2, p < 0.0001); laminin alpha (LAMA4), beta (LAMB2), and gamma (LAMC1) chains (p < 0.0005); neurocan (NCAN), brevican (BCAN) and versican (VCAN) (p < 0.0005); hyaluronan synthase (HAS) 2 and metalloprotease (MMP) 2 (p < 0.005); MMP inhibitors (TIMP1-4, p < 0.0005), transforming growth factor beta-1 (TGFB1) and integrin alpha (ITGA3/5) (p < 0.05) and beta (ITGB1, p < 0.0005) chains showed increased expression in GBM. Additionally, GBM-influenced EC exhibited elevated expression of COL5A3, COL6A1, COL22A1 and COL27A1 (p < 0.01); LAMA1, LAMB1 (p < 0.001); fibulins (FBLN1/2, p < 0.01); MMP9, HAS1, ITGA3, TGFB1, and wingless-related integration site 9B (WNT9B) (p < 0.01) compared to normal EC. Some of these molecules: COL5A1/3, COL6A1, COL22/27A1, FBLN1/2, ITGA3/5, ITGB1 and LAMA1/B1 (p < 0.01); NCAN, HAS1, MMP2/9, TIMP1/2 and TGFB1 (p < 0.05) correlated with GBM patient survival. In conclusion, this study identified both established and novel ECM molecules regulating GBM angiogenesis, suggesting NCAN and COL27A1 are new potential prognostic biomarkers for GBM.
Asunto(s)
Neoplasias Encefálicas , Matriz Extracelular , Glioblastoma , Neovascularización Patológica , Humanos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Matriz Extracelular/metabolismo , Pronóstico , Células Endoteliales/metabolismo , Microambiente Tumoral/genética , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica , Laminina/metabolismo , Laminina/genética , AngiogénesisRESUMEN
Sesquiterpenes are a class of metabolites derived from plant species with immunomodulatory activity. In this study, we evaluated the effects of treatment with costic acid on inflammation, angiogenesis, and fibrosis induced by subcutaneous sponge implants in mice. One sponge disc per animal was aseptically implanted in the dorsal region of the mice and treated daily with costic acid (at concentrations of 0.1, 1, and 10 µg diluted in 10 µL of 0.5% DMSO) or 0.5% DMSO (control group). After 9 days of treatment, the animals were euthanized, and the implants collected for further analysis. Treatment with costic acid resulted in the reduction of the inflammatory parameters evaluated compared to the control group, with a decrease in the levels of inflammatory cytokines and chemokines (TNF, CXCL-1, and CCL2) and in the activity of MPO and NAG enzymes. Costic acid administration altered the process of mast cell degranulation. We also observed a reduction in angiogenic parameters, such as a decrease in the number of blood vessels, the hemoglobin content, and the levels of VEGF and FGF cytokines. Finally, when assessing implant-induced fibrogenesis, we observed a reduction in the levels of the pro-fibrogenic cytokine TGF-ß1, and lower collagen deposition. The results of this study demonstrate, for the first time, the anti-inflammatory, anti-angiogenic, and anti-fibrotic effects of costic acid in an in vivo model of chronic inflammation and reinforce the therapeutic potential of costic acid.
Asunto(s)
Colágeno , Citocinas , Inflamación , Sesquiterpenos , Animales , Ratones , Sesquiterpenos/farmacología , Sesquiterpenos/aislamiento & purificación , Colágeno/metabolismo , Inflamación/tratamiento farmacológico , Citocinas/metabolismo , Masculino , Fibrosis , Poríferos , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Neovascularización Patológica/tratamiento farmacológico , AngiogénesisRESUMEN
Anti-VEGF (vascular endothelial growth factor) drugs such as aflibercept (AFL) and bevacizumab (BVZ) inhibit pathological neo-angiogenesis and vascular permeability in retinal vascular diseases. As cytokines and growth factors are produced by Müller glial cells under stressful and pathological conditions, we evaluated the in vitro effect of AFL (Eylea®, 0.5 mg/mL) and BVZ (Avastin®, 0.5 mg/mL) on cell viability/metabolism, and cytokine/growth factor production by Müller cells (MIO-M1) under cobalt chloride (CoCl2)-induced hypoxia after 24h, 48h and 72h. Cell viability/metabolism were analyzed by Trypan Blue and MTT assays and cytokine/growth factors in supernatants by Luminex xMAP-based multiplex bead-based immunoassay. Cell viability increased with AFL at 48h and 72h and decreased with BVZ or hypoxia at 24h. BVZ-treated cells showed lower cell viability than AFL at all exposure times. Cell metabolism increased with AFL but decreased with BVZ (72h) and hypoxia (48h and72h). As expected, AFL and BVZ decreased VEGF levels. AFL increased PDGF-BB, IL-6 and TNF-α (24h) and BVZ increased PDGF-BB (72h). Hypoxia reduced IL-1ß, -6, -8, TNF-α and PDGF-BB at 24h, and its suppressive effect was more prominent than AFL (EGF, PDGF-BB, IL-1ß, IL-6, IL-8, and TNF-α) and BVZ (PDGF-BB and IL-6) effects. Hypoxia increased bFGF levels at 48h and 72h, even when combined with anti-VEGFs. However, the stimulatory effect of BVZ predominated over hypoxia for IL-8 and TNF-α (24h), as well as for IL-1ß (72h). Thus, AFL and BVZ exhibit distinct exposure times effects on MIO-M1 cells viability, metabolism, and cytokines/growth factors. Hypoxia and BVZ decreased MIO-M1 cell viability/metabolism, whereas AFL likely induced gliosis. Hypoxia resulted in immunosuppression, and BVZ stimulated inflammation in hypoxic MIO-M1 cells. These findings highlight the complexity of the cellular response as well as the interplay between anti-VEGF treatments and the hypoxic microenvironment.
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Células Ependimogliales , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión , Factor A de Crecimiento Endotelial Vascular , Humanos , Bevacizumab/farmacología , Bevacizumab/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Células Ependimogliales/metabolismo , Supervivencia Celular , Becaplermina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-8/metabolismo , Interleucina-6/metabolismo , Factores de Crecimiento Endotelial Vascular/metabolismo , Citocinas/metabolismo , Hipoxia/metabolismo , Neovascularización Patológica/patología , Inflamación/patologíaRESUMEN
Prostate cancer (PCa) is the second cause of cancer death among men worldwide. Several processes are involved in the development and progression of PCa such as angiogenesis, inflammation and oxidative stress. The present study investigated the effect of short- or long-term Tempol treatment at different stages of prostate adenocarcinoma progression, focusing on angiogenic, proliferative, and stromal remodeling processes in TRAMP mice. The dorsolateral lobe of the prostate of TRAMP mice were evaluated at two different stages of PCa progression; early and late stages. Early stage was again divided into, short- or long-term. 50 mg/kg Tempol dose was administered orally. The results demonstrated that Tempol mitigated the prostate histopathological lesion progressions in the TRAMP mice in all treated groups. However, Tempol increased molecules involved in the angiogenic process such as CD31 and VEGFR2 relative frequencies, particularly in long-term treatment. In addition, Tempol upregulated molecule levels involved in angiogenesis and stromal remodeling process VEGF, TGF-ß1, VE-cadherin and vimentin, particularly, in T8-16 group. Thus, it was concluded that Tempol treatment delayed prostatic lesion progression in the dorsolateral lobe of the TRAMP mice. However, Tempol also led to pro-angiogenic effects and glandular stromal microenvironment imbalance, especially, in the long-term treatment.
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Óxidos N-Cíclicos , Neovascularización Patológica , Neoplasias de la Próstata , Marcadores de Spin , Masculino , Animales , Óxidos N-Cíclicos/farmacología , Óxidos N-Cíclicos/uso terapéutico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/irrigación sanguínea , Neovascularización Patológica/tratamiento farmacológico , Ratones , Progresión de la Enfermedad , AngiogénesisRESUMEN
Tissue-engineered skin represents a helpful strategy for the treatment of deep skin injuries. Nevertheless, these skin substitutes must promote and encourage proper vascularization for a successful graft take. Previous work showed that dermal papilla cells (DPC) favour an earlier neovascularization process of grafted skin substitute contributing to the rapid maturation of the neovascular network, reducing inflammation and favouring extracellular matrix remodelling in nude mice. Based on these results, we studied the influence of DPC and its culture conditions on the different stages of angiogenesis in in vitro models. Here, we showed that DPC cultured as spheres favour the expression of angiogenic factors such as VEGF, FGF2 and angiogenin compared to their monolayer culture. To study the effects of DPC on the different stages of angiogenesis, an in vitro model has been adapted. DPC cultured as spheres significantly enhanced HUVEC migration and tubule formation, indicating the importance of employing physiological culture systems that provide a closer representation of cell behaviour and interactions occurring in vivo. Overall, these results allow us to speculate that the use of DPC spheres in skin substitutes could promote its grafting, vascularization and vascular network maturation through the secretion of angiogenic factors. This approach has great potential to improve clinical outcomes in regenerative medicine and skin wound repair.
Asunto(s)
Angiogénesis , Matriz Extracelular , Animales , Ratones , Ratones Desnudos , Inflamación , Neovascularización PatológicaRESUMEN
BACKGROUND: Studies have suggested that vessels encapsulating tumor clusters (VETC) is a strong predictor of prognosis in patients with hepatocellular carcinoma (HCC). METHODS: A systematic search was conducted in PubMed, Embase, Web of Science, and Scopus databases. Overall survival (OS) and tumor efficacy (TE) were two outcome measures used to evaluate the relationship between VETC and HCC prognosis. Hazard ratios (HR) and their 95% confidence intervals (CI) were used. RESULTS: Thirteen studies with 4429 patients were included in the meta-analysis. The results showed that VETC was significantly associated with both OS (HR 2.00; 95% CI 1.64-2.45) and TE (HR 1.70; 95% CI 1.44-1.99) in HCC patients. Furthermore, recurrence-free survival (RFS) was a stronger indicator of tumor efficacy (HR 1.73; 95% CI 1.44-2.07) than disease-free survival (DFS) (HR 1.69; 95% CI 1.22-2.35). This suggests that VETC-positive HCC has a higher risk of recurrence and a lower survival rate. CONCLUSION: In conclusion, the meta-analysis suggests that VETC is a significant predictor of overall survival and tumor efficacy in HCC patients and may be a valid prognostic indicator.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Humanos , Pronóstico , Recurrencia Local de Neoplasia/patología , Supervivencia sin Enfermedad , Tasa de Supervivencia , Neovascularización Patológica/patologíaRESUMEN
Tumor growth and metastasis require neovascularization, which is dependent on a complex array of factors, such as the production of various pro-angiogenic factors by tumor cells, intercellular signaling, and stromal remodeling. The hypoxic, acidic tumor microenvironment is not only conducive to tumor cell proliferation, but also disrupts the equilibrium of angiogenic factors, leading to vascular heterogeneity, which further promotes tumor development and metastasis. Anti-angiogenic strategies to inhibit tumor angiogenesis has, therefore, become an important focus for anti-tumor therapy. The traditional approach involves the use of anti-angiogenic drugs to inhibit tumor neovascularization by targeting upstream and downstream angiogenesis-related pathways or pro-angiogenic factors, thereby inhibiting tumor growth and metastasis. This review explores the mechanisms involved in tumor angiogenesis and summarizes currently used anti-angiogenic drugs, including monoclonal antibody, and small-molecule inhibitors, as well as the progress and challenges associated with their use in anti-tumor therapy. It also outlines the opportunities and challenges of treating tumors using more advanced anti-angiogenic strategies, such as immunotherapy and nanomaterials.
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Inhibidores de la Angiogénesis , Neoplasias , Neovascularización Patológica , Microambiente Tumoral , Humanos , Neovascularización Patológica/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Neoplasias/irrigación sanguínea , Neoplasias/patología , Inhibidores de la Angiogénesis/uso terapéutico , Inmunoterapia/métodos , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
SUMMARY: Angiogenesis, a process by which new blood vessels are generated from pre-existing ones, is significantly compromised in tumor development, given that due to the nutritional need of tumor cells, pro-angiogenic signals will be generated to promote this process and thus receive the oxygen and nutrients necessary for its development, in addition to being a key escape route for tumor spread. Although there is currently an increase in the number of studies of various anti-angiogenic therapies that help reduce tumor progression, it is necessary to conduct a review of existing studies of therapeutic alternatives to demonstrate their importance.
La angiogénesis, proceso por el cual se generan nuevos vasos sanguíneos a partir de otros preexistentes, se encuentra comprometida de forma importante en el desarrollo tumoral, dado que por necesidad nutritiva de las células tumorales se generarán señales pro angiogénicas para promover este proceso y así recibir el oxígeno y los nutrientes necesarios para su desarrollo, además de ser una ruta de escape clave para la diseminación tumoral. Si bien, actualmente existe un aumento en la cantidad de estudios de diversas terapias anti angiogénicas que ayudan a reducir el avance tumoral, es necesario realizar una revisión de los estudios existentes de alternativas terapéuticas para demostrar su importancia.
Asunto(s)
Humanos , Inhibidores de la Angiogénesis/uso terapéutico , Celecoxib/uso terapéutico , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Ciclooxigenasa 2 , Neoplasias/patología , Antineoplásicos/uso terapéuticoRESUMEN
Dioclea violacea seed mannose-binding lectin (DvL) has attracted considerable attention because of its interesting biological activities, including antitumor, antioxidant, and anti-inflammatory activities. This study evaluated the cytotoxic effect of DvL on tumor and normal cells using the mitochondrial activity reduction (MTT) assay, the carcinogenic and anti-carcinogenic activity by the epithelial tumor test (ETT) in Drosophila melanogaster, and the anti-angiogenic effect by the chick embryo chorioallantoic membrane (CAM) assay. Data demonstrated that DvL promoted strong selective cytotoxicity against tumor cell lines, especially A549 and S180 cells, whereas normal cell lines were weakly affected. Furthermore, DvL did not promote carcinogenesis in D. melanogaster at any concentration tested, but modulated DXR-induced carcinogenesis at the highest concentrations tested. In the CAM and immunohistochemical assays, DvL inhibited sarcoma 180-induced angiogenesis and promoted the reduction of VEGF and TGF-ß levels at all concentrations tested. Therefore, our results demonstrated that DvL is a potent anticancer, anti-angiogenic, and selective cytotoxic agent for tumor cells, suggesting its potential application as a prototype molecule for the development of new drugs with chemoprotective and/or antitumor effects.
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Dioclea , Drosophila melanogaster , Neovascularización Patológica , Animales , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Humanos , Dioclea/química , Embrión de Pollo , Drosophila melanogaster/efectos de los fármacos , Carcinogénesis/efectos de los fármacos , Inhibidores de la Angiogénesis/farmacología , Membrana Corioalantoides/efectos de los fármacos , Membrana Corioalantoides/irrigación sanguínea , Lectinas de Plantas/farmacología , Células A549 , Línea Celular Tumoral , Ratones , AngiogénesisRESUMEN
Angiogenesis is considered one of the hallmarks of cancer, assisting tumor progression and metastasis. The mesoionic compound, MI-D, can induce cell death and provoke cytoskeletal and metabolic changes in cancer cells. Using in vitro and in vivo models, this study aimed to evaluate the effects of MI-D on the viability of human endothelial cells (EC) and its ability to inhibit tumor-induced angiogenesis induced by tumoral cells. For in vitro analysis, colon carcinoma (HT29) and endothelial (EA.hy926) cells were used as the tumoral and angiogenesis models, respectively. To evaluate cytotoxicity, methylene blue viability stain and annexin-V/7AAD tests were performed with both cell types. For the angiogenesis experiments, scratch wound healing and capillary tube-like formation assays were performed with the EC. The in vivo tests were performed with the chorioallantoic membrane (HET-CAM) methodology, wherein gelatin sponge implants containing MI-D (5, 25, and 50 µM), HT29 cells, or both were grafted in the CAM. Our data showed that MI-D induced apoptosis in both endothelial and colon carcinoma cells, with a strong cytotoxic effect on the tumoral lineage. The drug inhibited the EC's migration and capillary-like structure formation in vitro. In the HET-CAM assays, MI-D reduced the number of blood vessels in the membrane when grafted alone and accompanied by tumor cells. In this study, MI-D interfered in important steps of angiogenesis, such as maintenance of endothelial cell viability, migration, formation of capillary-like structures, as well tumor-induced neovascularization, reinforcing the hypothesis that MI-D might act as an inhibitor of angiogenesis, and a potential antitumor agent.
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Antineoplásicos , Carcinoma , Humanos , Células Endoteliales , Angiogénesis , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Movimiento Celular , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Antineoplásicos/uso terapéutico , Carcinoma/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Proliferación CelularRESUMEN
ABSTRACT A 36-year-old black male presented with a progressive loss of visual acuity in both eyes for 7 years. He had a history of tractional retinal detachment in the right eye and vitreous hemorrhage followed by retinal detachment in the left eye. He denied any systemic illness, trauma, or drug abuse. After clinical investigation, he was diagnosed with SC hemoglobinopathy and proliferative sickle cell retinopathy stage V in both eyes.
RESUMO Paciente do sexo masculino, 36 anos, negro, apresentou baixa acuidade visual progressiva em ambos os olhos por 7 anos. Possuía antecedentes de descolamento tracional de retina no olho direito e hemorragia vítrea, seguida de descolamento de retina no olho esquerdo. Negava doenças sistêmicas, trauma ou abuso de drogas. Após investigação clínica, foi diagnosticado com hemoglobinopatia S-C e retinopatia falciforme proliferativa estágio V em ambos os olhos.