RESUMO
Cancer is a health issue causing utmost concern and continuing to be one of the leading causes of mortality worldwide. Effective tumor eradication methods that will improve the prognosis and prolong human life are an important topic in modern medicine. Increasing amounts of evidence indicate that the tumor microenvironment plays a significant role in tumor development and migration. Macrophages are important immune cells that commonly infiltrate the tumor microenvironment. Several studies found that macrophages play different roles in the process of cancer development. This article focuses on the tumor microenvironment and the generation, classification, and function of tumor-associated macrophages as well as their significance for tumor immunotherapy and other aspects, it summarizes nearly 10 years of tumor microenvironment and tumor-associated macrophage research, providing a novel insight for tumor immunotherapy.
Assuntos
Neoplasias/etiologia , Pesquisa , Microambiente Tumoral/fisiologia , Macrófagos Associados a Tumor/fisiologia , Matriz Extracelular/química , Matriz Extracelular/fisiologia , Humanos , Imunoterapia , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Neovascularização Patológica/etiologia , Células Estromais/citologia , Células Estromais/fisiologia , Evasão Tumoral , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/classificação , Macrófagos Associados a Tumor/imunologiaRESUMO
BACKGROUND: The objectives of the present study were to evaluate angiogenesis and mast cell density in oral epithelial dysplasia and oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: This was an observational, retrospective and quantitative study. The samples consisted of 60 tissue specimens from patients with squamous cell carcinoma, epithelial dysplasia and controls (n=20/group). Immunohistochemistry was performed using an anti-tryptase antibody to mast cells and anti-CD31 and anti-CD34 for blood vessels and we count the number of mast cells and determine the percentage of CD31 and CD34 antibody staining (vascular density). RESULTS: The mast cells had lower density in OSCC compared to control and dysplasia (p = 0.009). In angiogenesis, the expression of CD31 showed a higher percentage of blood vessels in OSCC (p < 0.001), however, CD34 showed no difference between groups (p=0.092). The CD31 antibody presented as a high immunostaining in oral mucosa than CD34. CONCLUSIONS: The increased vascularity in squamous cell carcinoma suggests that angiogenesis begins when malignant transformation starts that seems to be inversely associated with the number of mast cells.
Assuntos
Biomarcadores Tumorais/análise , Vasos Sanguíneos/patologia , Carcinogênese/patologia , Carcinoma de Células Escamosas/complicações , Mastócitos/patologia , Neoplasias Bucais/complicações , Neovascularização Patológica/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/imunologia , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Mastócitos/imunologia , Pessoa de Meia-Idade , Neoplasias Bucais/irrigação sanguínea , Neoplasias Bucais/imunologia , Neoplasias Bucais/patologia , Neovascularização Patológica/etiologia , Prognóstico , Estudos RetrospectivosRESUMO
Several studies report the key role of the vascular endothelial growth factor (VEGF) signaling on angiogenesis and on tumor growth. This has led to the development of a number of VEGF-targeted agents to treat cancer patients by disrupting the tumor blood vessel supply. Of them, bevacizumab, an FDA-approved humanized monoclonal antibody against VEGF, is the most promising. Although the use of antibodies targeting the VEGF pathway has shown clinical benefits associated with a reduction in the tumor blood vessel density, the inhibition of VEGF-driven vascular effects is only part of the functional mechanism of these therapeutic agents in the tumor ecosystem. Compelling reports have demonstrated that VEGF confers, in addition to the activation of angiogenesis-related processes, immunosuppressive properties in tumors. It is also known that structural remodeling of the tumor blood vessel bed by anti-VEGF approaches affect the influx and activation of immune cells into tumors, which might influence the therapeutic results. Besides that, part of the therapeutic effects of antiangiogenic antibodies, including their role in the tumor vascular network, might be triggered by Fc receptors in an antigen-independent manner. In this mini-review, we explore the role of VEGF inhibitors in the tumor microenvironment with focus on the immune system, discussing around the functional contribution of both bevacizumab's Fab and Fc domains to the therapeutic results and the combination of bevacizumab therapy with other immune-stimulatory settings, including adjuvant-based vaccine approaches.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Imunológicos/farmacologia , Suscetibilidade a Doenças/imunologia , Neoplasias/etiologia , Neoplasias/metabolismo , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Epitopos/imunologia , Humanos , Imunoglobulina G/farmacologia , Imunoglobulina G/uso terapêutico , Fatores Imunológicos/administração & dosagem , Imunomodulação/efeitos dos fármacos , Modelos Biológicos , Terapia de Alvo Molecular/métodos , Neoplasias/patologia , Neoplasias/terapia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/etiologia , Neovascularização Patológica/metabolismoRESUMO
INTRODUCTION AND OBJECTIVES: Liver cirrhosis is characterized by increased intrahepatic resistance, splanchnic vasodilation/angiogenesis, and formation of portosystemic collateral vessels. Collaterals can cause lethal complications such as gastroesophageal variceal hemorrhage. Homocysteine is linked to vascular dysfunction and angiogenesis and higher levels have been reported in cirrhotic patients. It is also known that folic acid supplementation reverses the effects of homocysteine. However, the treatment effect in cirrhosis has yet to be investigated. MATERIAL AND METHODS: Liver cirrhosis was induced in Sprague-Dawley rats with common bile duct ligation (CBDL). The CBDL rats randomly received (1) vehicle; (2) dl-homocysteine thiolactone (1g/kg/day); (3) dl-homocysteine thiolactone plus folic acid (100mg/kg/day); or (4) folic acid. On the 29th day, hemodynamic parameters, liver and renal biochemistry, protein expressions of proangiogenic factors, mesenteric vascular density and portosystemic shunting were evaluated. RESULTS: In the cirrhotic rats, homocysteine increased mesenteric vascular density and the severity of shunting. It also up-regulated the protein expressions of mesenteric vascular endothelial growth factor (VEGF) and phosphorylated-endothelial nitric oxide synthase (p-eNOS). These effects were reversed by folic acid treatment (P<0.05). CONCLUSION: Folic acid ameliorated the adverse effects of homocysteine in the cirrhotic rats, which may be related to down-regulation of the VEGF-NO signaling pathway.
Assuntos
Circulação Colateral/efeitos dos fármacos , Ácido Fólico/farmacologia , Homocisteína/análogos & derivados , Cirrose Hepática/fisiopatologia , Neovascularização Patológica/induzido quimicamente , Sistema Porta/efeitos dos fármacos , Circulação Esplâncnica/efeitos dos fármacos , Complexo Vitamínico B/farmacologia , Animais , Ducto Colédoco , Hemodinâmica/efeitos dos fármacos , Homocisteína/farmacologia , Ligadura , Cirrose Hepática/complicações , Neovascularização Patológica/etiologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Sistema Porta/patologia , Ratos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Abstract Introduction The human larynx is a very important organ for communication. Many conditions lead to scarring of the vocal folds, decreasing voice quality. Objective We aimed to determine whether fibroblast growth factors (FGFs) may influence tissue integration of grafted fascia into the vocal folds of an animal model. Methods This is an experimental animal study with 12 adult rabbits that were submitted to a grafting fragment obtained from superficial cervical fascia into the vocal fold lamina propria, bilaterally. The right vocal fold was injected with FGFs. The animals were sacrificed after 1 month or 12 months, depending on the group they were assigned to, and a histological analysis of their vocal folds was performed.We analyzed the histological changes (such as the presence of fibrosis and neovascularization) induced by the acute or chronic inflammatory reactions. Results The FGFs induced acute inflammatory changes in all animals after 1 month of the initial experiment. The presence of FGFs triggered more fibrosis than the expected due to the surgical procedure itself when compared with the control side of all animals after 12 months of the initial experiment. Conclusions Fibroblast growth factors alone do not represent a good therapeutic option in phonosurgery, since we observed higher levels of fibrosis in the vocal fold lamina propria. Further studies combining more substances may be necessary to elucidate the best option to be used in this kind of surgery. (AU)
Assuntos
Animais , Prega Vocal/patologia , Fascia Lata/transplante , Fatores de Crescimento de Fibroblastos/farmacologia , Coelhos , Fibrose/etiologia , Doenças da Laringe/congênito , Inflamação/induzido quimicamente , Neovascularização Patológica/etiologiaRESUMO
Abstract Report of a case of Coats disease associated with retinal vasoproliferative tumor in a young female patient with two peripheral vascularized tumors and lipid exudation involving the macula and peripapillary region with serous retinal detachment areas and pre-papillary fibrous proliferation. The proposed and performed treatment was the intravitreal injection of triamcinolone acetonide to decrease the tumor exudation, followed by photocoagulation of the peripheral areas of telangiectasia without subretinal fluid and cryotherapy of the tumors. Despite that this is a rare and difficult to treat combination, in this case report, success was obtained in receding the tumor masses and reapplying the retina, leading to anatomic and visual stabilization.
Resumo Relato de um caso de Doença de Coats associada a tumor vasoproliferativo de retina em uma paciente jovem com duas tumorações vascularizadas periféricas e exsudação lipídica acometendo mácula e região peripapilar com áreas de descolamento de retina seroso e proliferação fibrosa pré-papilar. O tratamento proposto e realizado foi a injeção intra-vítrea de triancinolona para diminuir a exsudação do tumor, seguida de fotocoagulação periférica das áreas de telangiectasia sem fluido subretiniano e criocoagulação dos tumores. Apesar de se tratar de uma associação rara e de difícil tratamento, neste relato de caso, obteve-se êxito em regredir as massas tumorais e reaplicar a retina, levando à estabilização anatômica e visual.
Assuntos
Humanos , Feminino , Adolescente , Neoplasias da Retina/etiologia , Telangiectasia Retiniana/terapia , Neovascularização Patológica/etiologia , Oftalmoscopia , Vasos Retinianos/anormalidades , Descolamento Retiniano/etiologia , Triancinolona/administração & dosagem , Angiofluoresceinografia , Acuidade Visual , Crioterapia/métodos , Exsudatos e Transudatos , Telangiectasia Retiniana/complicações , Telangiectasia Retiniana/diagnóstico por imagem , Injeções Intravítreas , Fundo de Olho , FotocoagulaçãoRESUMO
Eicosanoids are 20-carbon bioactive lipids derived from the metabolism of polyunsaturated fatty acids, which can modulate various biological processes including cell proliferation, adhesion and migration, angiogenesis, vascular permeability and inflammatory responses. In recent years, studies have shown the importance of eicosanoids in the control of physiological and pathological processes associated with several diseases, including cancer. The polyunsaturated fatty acid predominantly metabolized to generate 2-series eicosanoids is arachidonic acid, which is the major n-6 polyunsaturated fatty acid found in animal fat and in the occidental diet. The three main pathways responsible for metabolizing arachidonic acid and other polyunsaturated fatty acids to generate eicosanoids are the cyclooxygenase, lipoxygenase and P450 epoxygenase pathways. Inflammation plays a decisive role in various stages of tumor development including initiation, promotion, invasion and metastasis. This review will focus on studies that have investigated the role of prostanoids and lipoxygenase-derived eicosanoids in the development and progression of different tumors, highlighting the findings that may provide insights into how these eicosanoids can influence cell proliferation, cell migration and the inflammatory process. A better understanding of the complex role played by eicosanoids in both tumor cells and the tumor microenvironment may provide new markers for diagnostic and prognostic purposes and identify new therapeutic strategies in cancer treatment.
Assuntos
Eicosanoides/fisiologia , Ácidos Graxos Insaturados/metabolismo , Inflamação/enzimologia , Neoplasias/patologia , Neovascularização Patológica/etiologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Animais , Ácido Araquidônico/metabolismo , Eicosanoides/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , ProstaglandinasRESUMO
Eicosanoids are 20-carbon bioactive lipids derived from the metabolism of polyunsaturated fatty acids, which can modulate various biological processes including cell proliferation, adhesion and migration, angiogenesis, vascular permeability and inflammatory responses. In recent years, studies have shown the importance of eicosanoids in the control of physiological and pathological processes associated with several diseases, including cancer. The polyunsaturated fatty acid predominantly metabolized to generate 2-series eicosanoids is arachidonic acid, which is the major n-6 polyunsaturated fatty acid found in animal fat and in the occidental diet. The three main pathways responsible for metabolizing arachidonic acid and other polyunsaturated fatty acids to generate eicosanoids are the cyclooxygenase, lipoxygenase and P450 epoxygenase pathways. Inflammation plays a decisive role in various stages of tumor development including initiation, promotion, invasion and metastasis. This review will focus on studies that have investigated the role of prostanoids and lipoxygenase-derived eicosanoids in the development and progression of different tumors, highlighting the findings that may provide insights into how these eicosanoids can influence cell proliferation, cell migration and the inflammatory process. A better understanding of the complex role played by eicosanoids in both tumor cells and the tumor microenvironment may provide new markers for diagnostic and prognostic purposes and identify new therapeutic strategies in cancer treatment.
Assuntos
Humanos , Animais , Eicosanoides/fisiologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Ácidos Graxos Insaturados/metabolismo , Inflamação/enzimologia , Neoplasias/patologia , Neovascularização Patológica/etiologia , Eicosanoides/farmacologia , Prostaglandinas , Ácido Araquidônico/metabolismo , Neoplasias/enzimologia , Neoplasias/tratamento farmacológicoRESUMO
PURPOSE:: To establish and compare protocols of alkaline cauterization for inducing corneal angiogenesis in murine models. METHODS:: Twenty-four adult Wistar rats were distributed into four groups (G1, G2, G3, and G4). The right eye cornea from each rat was cauterized using filter paper (3 mm), soaked in a solution of silver and potassium nitrates (3:1). Cauterization times were 10 (G1 and G4), or 20 seconds (G2 and G3). Cauterized corneas were washed with Ringer's lactate solution. The filter paper was either removed before washing (G1 and G2), or kept on the corneas (G3 and G4). Corneas were photographed at multiple time points (2, 4, 6, 8, 11, 13, and 15 days after the procedure), and neovascularization parameters were assayed. RESULTS:: Neovascularization was observed in 66% of G1 corneas, and 100% of G2, G3, and G4 corneas. On day 15, G1 corneas showed smaller vascularized areas (12.63 ± 12.59%) compared to those in the G3 (41.95 ± 17.32%) and G4 (33 ± 11.74%) (P < 0.05) groups. CONCLUSIONS:: The silver and potassium nitrate solution effectively induced corneal angiogenesis. The G2, G3, and G4 protocols showed excellent reproducibility, and induced vascularization in 100% of corneas.
Assuntos
Cauterização/métodos , Neovascularização da Córnea/etiologia , Modelos Animais de Doenças , Neovascularização Patológica/etiologia , Nitratos , Compostos de Potássio , Prata , Animais , Córnea/irrigação sanguínea , Córnea/cirurgia , Masculino , Ratos Wistar , Valores de Referência , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
Abstract Purpose: To establish and compare protocols of alkaline cauterization for inducing corneal angiogenesis in murine models. Methods: Twenty-four adult Wistar rats were distributed into four groups (G1, G2, G3, and G4). The right eye cornea from each rat was cauterized using filter paper (3 mm), soaked in a solution of silver and potassium nitrates (3:1). Cauterization times were 10 (G1 and G4), or 20 seconds (G2 and G3). Cauterized corneas were washed with Ringer's lactate solution. The filter paper was either removed before washing (G1 and G2), or kept on the corneas (G3 and G4). Corneas were photographed at multiple time points (2, 4, 6, 8, 11, 13, and 15 days after the procedure), and neovascularization parameters were assayed. Results: Neovascularization was observed in 66% of G1 corneas, and 100% of G2, G3, and G4 corneas. On day 15, G1 corneas showed smaller vascularized areas (12.63 ± 12.59%) compared to those in the G3 (41.95 ± 17.32%) and G4 (33 ± 11.74%) (P < 0.05) groups. Conclusions: The silver and potassium nitrate solution effectively induced corneal angiogenesis. The G2, G3, and G4 protocols showed excellent reproducibility, and induced vascularization in 100% of corneas.
Assuntos
Animais , Masculino , Cauterização/métodos , Neovascularização da Córnea/etiologia , Compostos de Potássio , Modelos Animais de Doenças , Neovascularização Patológica/etiologia , Nitratos , Valores de Referência , Fatores de Tempo , Reprodutibilidade dos Testes , Ratos Wistar , Córnea/cirurgia , Córnea/irrigação sanguíneaRESUMO
PURPOSE:: To analyze the effects of injections of intravitreal triamcinolone acetonide (IVTA) and intravitreal bevacizumab (IVB) on the incidence rates of anterior segment neovascularization (ASN) and neovascular glaucoma (NVG) in patients with macular edema secondary to central retinal vein occlusion (CRVO). METHODS:: In this prospective, randomized, double-masked, sham-controlled study, 35 patients with macular edema following CRVO were randomized to intravitreal bevacizumab, intravitreal triamcinolone acetonide, or sham injections during the first 6 months of the study. The primary outcome was the incidence rate of ASN at month 6. The secondary outcomes were the mean changes from baseline in best-corrected visual acuity (BCVA) and central foveal thickness (CFT) on optical coherence tomography over time to month 12. RESULTS:: ASN developed in 8 (22.86%) eyes, including 5 (62.50%) eyes in the sham group and 3 (37.50%) eyes in the IVTA group, during 12 months of fol low-up (p=0.009). BCVA differed significantly (p<0.05) among the groups only at month 1. CFT did not differ significantly (p<0.05) among the groups over 12 months. NVG required surgery and developed in one eye despite laser treatment. CONCLUSION:: Early treatment with intravitreal antivascular endothelial growth factor therapy decreases the rates of ASN and NVG after CRVO.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Bevacizumab/administração & dosagem , Edema Macular/tratamento farmacológico , Neovascularização Patológica/epidemiologia , Triancinolona Acetonida/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Segmento Anterior do Olho/irrigação sanguínea , Anti-Inflamatórios/efeitos adversos , Bevacizumab/efeitos adversos , Método Duplo-Cego , Feminino , Seguimentos , Fóvea Central/fisiopatologia , Glaucoma Neovascular/tratamento farmacológico , Humanos , Incidência , Injeções Intravítreas , Edema Macular/etiologia , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/etiologia , Estudos Prospectivos , Oclusão da Artéria Retiniana/complicações , Oclusão da Artéria Retiniana/tratamento farmacológico , Resultado do Tratamento , Triancinolona Acetonida/efeitos adversos , Acuidade VisualRESUMO
ABSTRACT Purpose: To analyze the effects of injections of intravitreal triamcinolone acetonide (IVTA) and intravitreal bevacizumab (IVB) on the incidence rates of anterior segment neovascularization (ASN) and neovascular glaucoma (NVG) in patients with macular edema secondary to central retinal vein occlusion (CRVO). Methods: In this prospective, randomized, double-masked, sham-controlled study, 35 patients with macular edema following CRVO were randomized to intravitreal bevacizumab, intravitreal triamcinolone acetonide, or sham injections during the first 6 months of the study. The primary outcome was the incidence rate of ASN at month 6. The secondary outcomes were the mean changes from baseline in best-corrected visual acuity (BCVA) and central foveal thickness (CFT) on optical coherence tomography over time to month 12. Results: ASN developed in 8 (22.86%) eyes, including 5 (62.50%) eyes in the sham group and 3 (37.50%) eyes in the IVTA group, during 12 months of fol low-up (p=0.009). BCVA differed significantly (p<0.05) among the groups only at month 1. CFT did not differ significantly (p<0.05) among the groups over 12 months. NVG required surgery and developed in one eye despite laser treatment. Conclusion: Early treatment with intravitreal antivascular endothelial growth factor therapy decreases the rates of ASN and NVG after CRVO.
RESUMO Objetivo: Analisar as taxas de incidência de neovascularização do segmento anterior (NSA) e de glaucoma neovascular (GNV), em pacientes com edema macular secundário a oclusão de veia central da retina (OVCR), em tratamento com injeções intravítreas de triamcinolona (IVTA) ou bevacizumab (IVB). Métodos: Neste estudo prospectivo, randomizado, duplo mascarado e sham controlado, 35 pacientes com edema macular secundário a OVCR foram randomizados para IVB, IVTA ou para o grupo controle (sham), durante os 6 primeiros meses do estudo. O desfecho primário foi a taxa de incidência de NSA no mês 6. Os desfechos secundários foram alterações médias da acuidade visual corrigida (BCVA) e espessura foveal central (EFC) ao exame de tomografia de coerência óptica, até o mês 12. Resultados: NSA ocorreu em oito (22,86%) olhos, cinco (62,50%) olhos no grupo sham e três (37,50%) olhos no grupo tratado com injeções intravítreas de Triamcinolona, Não houve nenhum caso com NSA no grupo tratado com bevacizumab durante 12 meses de acompanhamento (p=0,009). A BCVA apresentou diferença estatisticamente significante (p<0,05) entre os grupos, somente no mês 1. A EFC não apresentou diferenças estatisticamente significantes (p<0,05) entre os grupos ao longo dos 12 meses. GNV ocorreu em um olho apesar do tratamento com laser e este paciente necessitou de intervenção cirúrgica. Conclusão: O tratamento precoce com injeções intravítreas de Anti VEGF podem diminuir as taxas de neovascularização do segmento anterior e glaucoma neovascular após oclusão de veia central da retina.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Triancinolona Acetonida/administração & dosagem , Edema Macular/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Neovascularização Patológica/epidemiologia , Oclusão da Artéria Retiniana/complicações , Acuidade Visual , Glaucoma Neovascular/tratamento farmacológico , Edema Macular/etiologia , Método Duplo-Cego , Incidência , Estudos Prospectivos , Seguimentos , Inibidores da Angiogênese/efeitos adversos , Injeções Intravítreas , Bevacizumab/efeitos adversos , Fóvea Central/fisiopatologia , Segmento Anterior do Olho/irrigação sanguínea , Anti-Inflamatórios/efeitos adversos , Neovascularização Patológica/etiologiaRESUMO
Ovarian hyperstimulation syndrome (OHSS) is a complication of ovarian stimulation with gonadotrophins following human chorionic gonadotrophin (hCG) administration. The relationship between hCG and OHSS is partly mediated via the production of angiogenic factors, such as vascular endothelial growth factor A (VEGFA) and angiopoietins (ANGPTs). Here, we investigated the effect of ANGPT1 inhibition on ovarian angiogenesis in follicular fluid (FF) from women at risk of OHSS, using the chorioallantoic membrane (CAM) of quail embryos as an experimental model. We also analysed cytoskeletal changes and endothelial junction protein expression induced by this FF in the presence or absence of an ANGPT1-neutralising antibody in endothelial cell cultures. The presence of this antibody restored the number of vascular branch points and integrin αvß3 levels in the CAMs to control values. ANGPT1 inhibition in FF from OHSS patients also restored the levels of claudin-5, vascular endothelial cadherin and phosphorylated ß-catenin and partially reversed actin redistribution in endothelial cells. Our findings suggest that ANGPT1 increases pathophysiological angiogenesis in patients at risk of OHSS by acting on tight and adherens junction proteins. Elucidating the mechanisms by which ANGPT1 regulates vascular development and cell-cell junctions in OHSS will contribute to identifying new therapeutic targets for the treatment of human diseases with aberrant vascular leakage.
Assuntos
Junções Aderentes/metabolismo , Angiopoietina-1/metabolismo , Endotélio Vascular/metabolismo , Neovascularização Patológica/etiologia , Folículo Ovariano/metabolismo , Síndrome de Hiperestimulação Ovariana/fisiopatologia , Junções Íntimas/metabolismo , Junções Aderentes/efeitos dos fármacos , Junções Aderentes/patologia , Adulto , Angiopoietina-1/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Argentina/epidemiologia , Bioensaio , Biomarcadores/metabolismo , Linhagem Celular , Células Cultivadas , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Membrana Corioalantoide/metabolismo , Coturnix , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Feminino , Líquido Folicular/citologia , Líquido Folicular/metabolismo , Humanos , Folículo Ovariano/irrigação sanguínea , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/patologia , Síndrome de Hiperestimulação Ovariana/epidemiologia , Síndrome de Hiperestimulação Ovariana/metabolismo , Síndrome de Hiperestimulação Ovariana/patologia , Risco , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/patologiaRESUMO
BACKGROUND: Diagnosis of cardiac masses is still challenging by echocardiography and distinguishing tumors from thrombi has important therapeutical implications. We sought to determine the diagnostic value of real-time perfusion echocardiography (RTPE) for cardiac masses characterization. METHODS: We prospectively studied 86 patients, 23 with malignant tumors (MT), 26 with benign tumors (BT), 33 with thrombi and 6 with pseudotumors who underwent RTPE. Mass perfusion was analyzed qualitatively and blood flow volume (A), blood flow velocity (ß), and microvascular blood flow (A x ß) were determined by quantitative RTPE. RESULTS: Logistic regression models showed that the probability of having a tumor increased by 15.8 times with a peripheral qualitative perfusion pattern, and 34.5 times with a central perfusion pattern, in comparison with the absence of perfusion. Using quantitative RTPE analysis, thrombi group had parameters of blood flow lower than tumor group. A values for thrombi, MT, and BT were 0.1 dB (0.01-0.22), 2.78 dB (1-7) and 2.58 dB (1.44-5), respectively; p < 0.05, while A x ß values were 0.0 dB/s(-1) (0.01-0.14), 2.00 dB/s(-1) (1-6), and 1.18 dB/s(-1) (0.52-3), respectively; p < 0.05. At peak dipyridamole stress, MT had greater microvascular blood volume than BT [A = 4.18 dB (2.14-7.93) versus A = 2.04 dB (1.09-3.55); p < 0.05], but no difference in blood flow [Axß = 2.46 dB/s(-1) (1.42-4.59) versus Axß = 1.55 dB/s [1] (0.51-4.08); p = NS]. An A value >3.28 dB at peak dipyridamole stress predicted MT (AUC = 0.75) and conferred 5.8-times higher chance of being MT rather than BT. CONCLUSION: RTPE demonstrated that cardiac tumors have greater microvascular blood volume and regional blood flow when compared with thrombi. Dipyridamole stress was useful in differentiating MT from BT.
Assuntos
Ecocardiografia/métodos , Neoplasias Cardíacas/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imagem de Perfusão do Miocárdio/métodos , Neovascularização Patológica/diagnóstico por imagem , Trombose/diagnóstico por imagem , Velocidade do Fluxo Sanguíneo , Sistemas Computacionais , Diagnóstico Diferencial , Feminino , Neoplasias Cardíacas/complicações , Neoplasias Cardíacas/fisiopatologia , Humanos , Aumento da Imagem/métodos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/etiologia , Neovascularização Patológica/fisiopatologia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Trombose/fisiopatologiaRESUMO
Accumulating evidence suggests the involvement of stem cells in tumor angiogenesis. Two major types of stem cells frequently discussed in this regard are bone marrow-derived endothelial progenitor cells (EPCs) and tumor-derived cancer stem cells (CSCs). The present review discusses the possibility of a close association between these two cell types that drives the tumor towards metastasis. An exploration of this plausible relationship between EPCs and CSCs is imperative to completely unveil the mechanisms of tumor angiogenesis and develop CSC- and/or EPC-targeted anti-tumor therapies.
Assuntos
Células Endoteliais/fisiologia , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Células-Tronco Neoplásicas/fisiologia , Neovascularização Patológica/etiologia , Células-Tronco/fisiologia , Animais , Células da Medula Óssea/fisiologia , Comunicação Celular , Humanos , Neovascularização Patológica/patologia , Nicho de Células-Tronco/fisiologia , Microambiente TumoralRESUMO
PURPOSE: To investigate the neovascularization after exposure of the external jugular venous endothelium in an experimental model. METHODS: The sample was composed of 60 male rats of Wistar OUT B breed provided by animal colony of the Medicine College of Juazeiro do Norte, weighing 250 to 350 g, aged 90-120 days. Randomized study in OUT B Wistar rats, open, with 60 days duration. The animals were distributed into three groups of 20 specimens and were subjected to the following: Group 1: neck incision with dissection, ligation and section of the external jugular vein. Group 2: neck incision with dissection and ligation of the external jugular vein. Group 3: cervicotomy without dissection of the external jugular vein without ligation or section. The animals were sacrificed, half of them in 30 days and the other half within 60 days. The material in block harvested from the operated site were sectioned and stained for immunohistochemistry with CD34 marker. RESULTS: Neovascularization occurred with level of significance when compared group 1 to group 3 at 30 days (p=0.0076) and the same occurred at 60 days (p=0.0001) (Newman-Keuls test). CONCLUSION: The group with exposure of the venous endothelium showed a significant increase of neovascularization when compared with other groups.
Assuntos
Endotélio Vascular/cirurgia , Veias Jugulares/cirurgia , Neovascularização Patológica/etiologia , Animais , Antígenos CD34/análise , Modelos Animais de Doenças , Imuno-Histoquímica , Ligadura , Masculino , Período Pós-Operatório , Distribuição Aleatória , Ratos Wistar , Fatores de Tempo , Varizes/etiologiaRESUMO
In the adult organism, angiogenesis is restricted to a few physiological conditions. On the other hand, uncontrolled angiogenesis have often been associated to angiogenesis-dependent pathologies. A variety of animal models have been described to provide more quantitative analysis of in vivo angiogenesis and to characterize pro- and antiangiogenic molecules. However, it is still necessary to establish a quantitative, reproducible and specific method for studies of angiogenesis factors and inhibitors. This work aimed to standardize a method for the study of angiogenesis and to investigate the effects of thalidomide on angiogenesis. Sponges of 0.5 x 0.5 x 0.5 cm were implanted in the back of mice groups, control and experimental (thalidomide 200 mg/K/day by gavage). After seven days, the sponges were removed. The dosage of hemoglobin in sponge and in circulation was performed and the ratio between the values was tested using nonparametric Mann-Whitney test. Results have shown that sponge-induced angiogenesis quantitated by ratio between hemoglobin content in serum and in sponge is a helpful model for in vivo studies on angiogenesis. Moreover, it was observed that sponge-induced angiogenesis can be suppressed by thalidomide, corroborating to the validity of the standardized method.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Modelos Animais de Doenças , Neovascularização Patológica/prevenção & controle , Tampões de Gaze Cirúrgicos , Talidomida/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Hemoglobinas/análise , Camundongos , Neovascularização Patológica/etiologia , Neovascularização Patológica/patologiaRESUMO
PURPOSE: To investigate the neovascularization after exposure of the external jugular venous endothelium in an experimental model. METHODS: The sample was composed of 60 male rats of Wistar OUT B breed provided by animal colony of the Medicine College of Juazeiro do Norte, weighing 250 to 350g, aged 90-120 days. Randomized study in OUT B Wistar rats, open, with 60 days duration. The animals were distributed into three groups of 20 specimens and were subjected to the following: Group 1: neck incision with dissection, ligation and section of the external jugular vein. Group 2: neck incision with dissection and ligation of the external jugular vein. Group 3: cervicotomy without dissection of the external jugular vein without ligation or section. The animals were sacrificed, half of them in 30 days and the other half within 60 days. The material in block harvested from the operated site were sectioned and stained for immunohistochemistry with CD34 marker. RESULTS: Neovascularization occurred with level of significance when compared group 1 to group 3 at 30 days (p=0.0076) and the same occurred at 60 days (p=0.0001) (Newman-Keuls test). CONCLUSION: The group with exposure of the venous endothelium showed a significant increase of neovascularization when compared with other groups.
Assuntos
Animais , Masculino , Endotélio Vascular/cirurgia , Veias Jugulares/cirurgia , Neovascularização Patológica/etiologia , /análise , Modelos Animais de Doenças , Imuno-Histoquímica , Ligadura , Período Pós-Operatório , Distribuição Aleatória , Ratos Wistar , Fatores de Tempo , Varizes/etiologiaRESUMO
OBJECTIVE: Angiogenesis depends on a complex interaction between cellular networks and mediators. The endocannabinoid system and its receptors have been shown to play a role in models of inflammation. Here, we investigated whether blockade of cannabinoid receptors may interfere with inflammatory angiogenesis. MATERIALS AND METHODS: Polyester-polyurethane sponges were implanted in C57Bl/6j mice. Animals received doses (3 and 10 mg/kg/daily, s.c.) of the cannabinoid receptor antagonists SR141716A (CB1) or SR144528 (CB2). Implants were collected at days 7 and 14 for cytokines, hemoglobin, myeloperoxidase, and N-acetylglucosaminidase measurements, as indices of inflammation, angiogenesis, neutrophil and macrophage accumulation, respectively. Histological and morphometric analysis were also performed. RESULTS: Cannabinoid receptors expression in implants was detected from day 4 after implantation. Treatment with CB1 or CB2 receptor antagonists reduced cellular influx into sponges at days 7 and 14 after implantation, although CB1 receptor antagonist were more effective at blocking leukocyte accumulation. There was a reduction in TNF-α, VEGF, CXCL1/KC, CCL2/JE, and CCL3/MIP-1α levels, with increase in CCL5/RANTES. Both treatments reduced neovascularization. Dual blockade of cannabinoid receptors resulted in maximum inhibition of inflammatory angiogenesis. CONCLUSIONS: Blockade of cannabinoid receptors reduced leukocyte accumulation, inflammation and neovascularization, suggesting an important role of endocannabinoids in sponge-induced inflammatory angiogenesis both via CB1 and CB2 receptors.
Assuntos
Corpos Estranhos/imunologia , Reação a Corpo Estranho/imunologia , Neovascularização Patológica/imunologia , Receptor CB1 de Canabinoide/imunologia , Receptor CB2 de Canabinoide/imunologia , Animais , Canfanos/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Citocinas/imunologia , Reação a Corpo Estranho/etiologia , Reação a Corpo Estranho/patologia , Leucócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/etiologia , Neovascularização Patológica/patologia , Piperidinas/farmacologia , Poliésteres , Poliuretanos , Pirazóis/farmacologia , Rimonabanto , Pele/imunologiaRESUMO
PURPOSE: To investigate the effect of primary tumorectomy on angiogenesis and pulmonary metastasis in osteosarcoma-bearing nude mice. METHODS: Osteosarcoma was introduced to nude mice via subcutaneous injection of MG-63 cells. One hundred and eighty osteosarcoma-bearing mice were used equally in 3 parallel experiments. The effect of tumorectomy (TR) on the expression of vascular endothelial growth factor (VEGF) and endostatin was investigated by ELISA. Meanwhile, the effect on angiogenesis was evaluated by Matrigel plug assay, and pulmonary metastasis assessed by calculating the metastatic foci. Sham-operation (SO) and untreated (UT) groups served as controls. RESULTS: The VEGF (TR: 79.55 ± 7.82 pg/mL vs. SO: 110.01 ± 5.69 pg/mL, UT: 123.50 ± 10.41 pg/mL; p < 0.01) and endostatin (TR: 47.09 ± 6.22 ng/mL vs. SO: 117.64 ± 7.39 ng/mL, UT: 126.73 ± 6.55 ng/mL; p<0.01) were down-regulated significantly after tumorectomy, and angiogenesis was significantly promoted simultaneously. The incidence of pulmonary metastatic foci was 80.0% in the TR group, 40.0% in the SO group and 35.0% in the UT group. CONCLUSION: Primary tumorectomy can down-regulate the expression of VEGF and endostatin and promote angiogenesis which leads to the acceleration of pulmonary metastasis. These findings imply that anti-angiogenic treatment can be considered after primary tumorectomy.