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1.
Scand J Immunol ; 90(4): e12800, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31241785

RESUMO

Lymphatic malformations (LMs) are disfiguring congenital anomalies characterized by aberrant growth of lymphatic vessels. They are broadly categorized histopathologically as macrocystic and microcystic. Although sclerotherapy has shown some success in the treatment of macrocystic malformations, there has been less progress with developing treatment strategies for microcystic malformations. In this study, we characterized lymphatic endothelial cells isolated from lymphatic and lymphaticovenous malformations. When compared to cells from normal lymphatic vessels, we found that the primary cultured malformed cells are morphologically different and also exhibited differences in binding, proliferation, migration and tube formation. Transcriptome analysis identified several genes whose expression was substantially higher in malformed compared to normal lymphatic endothelium, including DIRAS3 and FOXF1. Further analysis of LM tissue samples revealed distinguishing gene expression patterns that could pave the way to understanding the molecular pathogenesis of LMs. Based on gene expression signatures, we propose a new hypothesis that the subtype of localized LMs could be formed because of disruptions in lymph node development.


Assuntos
Linfonodos/crescimento & desenvolvimento , Anormalidades Linfáticas/genética , Vasos Linfáticos/patologia , Transcriptoma , Movimento Celular/genética , Proliferação de Células/genética , Células Cultivadas , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Linfonodos/embriologia , Cultura Primária de Células , Ligação Proteica , Análise Serial de Tecidos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas rho de Ligação ao GTP/genética
2.
Nature ; 459(7250): 1126-30, 2009 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-19458618

RESUMO

The incidence of many cancer types is significantly reduced in individuals with Down's syndrome, and it is thought that this broad cancer protection is conferred by the increased expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21. One such gene is Down's syndrome candidate region-1 (DSCR1, also known as RCAN1), which encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signalling by the calcineurin pathway. Here we show that DSCR1 is increased in Down's syndrome tissues and in a mouse model of Down's syndrome. Furthermore, we show that the modest increase in expression afforded by a single extra transgenic copy of Dscr1 is sufficient to confer significant suppression of tumour growth in mice, and that such resistance is a consequence of a deficit in tumour angiogenesis arising from suppression of the calcineurin pathway. We also provide evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis. These data provide a mechanism for the reduced cancer incidence in Down's syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals.


Assuntos
Síndrome de Down/genética , Inositol/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Animais , Calcineurina/metabolismo , Proteínas de Ligação ao Cálcio , Catecóis , Células Cultivadas , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Síndrome de Down/metabolismo , Células Endoteliais/metabolismo , Dosagem de Genes/genética , Humanos , Camundongos , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Quinases Dyrk
3.
Proc Natl Acad Sci U S A ; 109(28): 11306-11, 2012 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-22733742

RESUMO

Antiangiogenesis therapy has become a vital part of the armamentarium against cancer. Hypertension is a dose-limiting toxicity for VEGF inhibitors. Thus, there is a pressing need to address the associated adverse events so these agents can be better used. The hypertension may be mediated by reduced NO bioavailability resulting from VEGF inhibition. We proposed that the hypertension may be prevented by coadministration with endostatin (ES), an endogenous angiogenesis inhibitor with antitumor effects shown to increase endothelial NO production in vitro. We determined that Fc-conjugated ES promoted NO production in endothelial and smooth muscle cells. ES also lowered blood pressure in normotensive mice and prevented hypertension induced by anti-VEGF antibodies. This effect was associated with higher circulating nitrate levels and was absent in eNOS-knockout mice, implicating a NO-mediated mechanism. Retrospective study of patients treated with ES in a clinical trial revealed a small but significant reduction in blood pressure, suggesting that the findings may translate to the clinic. Coadministration of ES with VEGF inhibitors may offer a unique strategy to prevent drug-related hypertension and enhance antiangiogenic tumor suppression.


Assuntos
Pressão Sanguínea/fisiologia , Endostatinas/metabolismo , Hipertensão/metabolismo , Hipertensão/prevenção & controle , Óxido Nítrico/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/farmacologia , Animais , Anticorpos/química , Ensaios Clínicos Fase II como Assunto , Feminino , Coração/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/prevenção & controle
4.
Proc Natl Acad Sci U S A ; 109(22): 8699-704, 2012 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-22589302

RESUMO

The mechanisms underlying tumor dormancy have been elusive and not well characterized. We recently published an experimental model for the study of human tumor dormancy and the role of angiogenesis, and reported that the angiogenic switch was preceded by a local increase in VEGF-A and basic fibroblast growth factor. In this breast cancer xenograft model (MDA-MB-436 cells), analysis of differentially expressed genes revealed that heat shock protein 27 (HSP27) was significantly up-regulated in angiogenic cells compared with nonangiogenic cells. The effect of HSP27 down-regulation was further evaluated in cell lines, mouse models, and clinical datasets of human patients with breast cancer and melanoma. Stable down-regulation of HSP27 in angiogenic tumor cells was followed by long-term tumor dormancy in vivo. Strikingly, only 4 of 30 HSP27 knockdown xenograft tumors initiated rapid growth after day 70, in correlation with a regain of HSP27 protein expression. Significantly, no tumors escaped from dormancy without HSP27 expression. Down-regulation of HSP27 was associated with reduced endothelial cell proliferation and decreased secretion of VEGF-A, VEGF-C, and basic fibroblast growth factor. Conversely, overexpression of HSP27 in nonangiogenic cells resulted in expansive tumor growth in vivo. By clinical validation, strong HSP27 protein expression was associated with markers of aggressive tumors and decreased survival in patients with breast cancer and melanoma. An HSP27-associated gene expression signature was related to molecular subgroups and survival in breast cancer. Our findings suggest a role for HSP27 in the balance between tumor dormancy and tumor progression, mediated by tumor-vascular interactions. Targeting HSP27 might offer a useful strategy in cancer treatment.


Assuntos
Neoplasias da Mama/metabolismo , Regulação para Baixo , Proteínas de Choque Térmico HSP27/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Animais , Western Blotting , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Feminino , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP27/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos SCID , Neovascularização Patológica/genética , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Transplante Heterólogo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator C de Crescimento do Endotélio Vascular/genética , Fator C de Crescimento do Endotélio Vascular/metabolismo
5.
Am J Pathol ; 183(3): 987-95, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23831329

RESUMO

Diabetes mellitus is a disease with considerable morbidity and mortality worldwide. Breakdown of the blood-retinal barrier and leakage from the retinal vasculature leads to diabetic macular edema, an important cause of vision loss in patients with diabetes. Although epidemiologic studies and randomized clinical trials suggest that glycemic control plays a major role in the development of vascular complications of diabetes, insulin therapies for control of glucose metabolism cannot prevent long-term retinal complications. The phenomenon of temporary paradoxical worsening of diabetic macular edema after insulin treatment has been observed in a number of studies. In prospective studies on non-insulin-dependent (type 2) diabetes mellitus patients, a change in treatment from oral drugs to insulin was often associated with a significant increased risk of retinopathy progression and visual impairment. Although insulin therapies are critical for regulation of the metabolic disease, their role in the retina is controversial. In this study with diabetic mice, insulin treatment resulted in increased vascular leakage apparently mediated by betacellulin and signaling via the epidermal growth factor (EGF) receptor. In addition, treatment with EGF receptor inhibitors reduced retinal vascular leakage in diabetic mice on insulin. These findings provide unique insight into the role of insulin signaling in mediating retinal effects in diabetes and open new avenues for therapeutics to treat the retinal complications of diabetes mellitus.


Assuntos
Vasos Sanguíneos/patologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Fator de Crescimento Epidérmico/metabolismo , Substâncias Protetoras/metabolismo , Transdução de Sinais , Proteínas ADAM/metabolismo , Proteína ADAM10 , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Betacelulina , Vasos Sanguíneos/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Humanos , Insulina/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Edema Macular/metabolismo , Edema Macular/patologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Proteínas Quinases/farmacologia , Retina , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/metabolismo
6.
Nature ; 453(7198): 1117-21, 2008 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-18469803

RESUMO

Despite intense investigation, mechanisms that facilitate the emergence of the pre-eclampsia phenotype in women are still unknown. Placental hypoxia, hypertension, proteinuria and oedema are the principal clinical features of this disease. It is speculated that hypoxia-driven disruption of the angiogenic balance involving vascular endothelial growth factor (VEGF)/placenta-derived growth factor (PLGF) and soluble Fms-like tyrosine kinase-1 (sFLT-1, the soluble form of VEGF receptor 1) might contribute to some of the maternal symptoms of pre-eclampsia. However, pre-eclampsia does not develop in all women with high sFLT-1 or low PLGF levels, and it also occurs in some women with low sFLT-1 and high PLGF levels. Moreover, recent experiments strongly suggest that several soluble factors affecting the vasculature are probably elevated because of placental hypoxia in the pre-eclamptic women, indicating that upstream molecular defect(s) may contribute to pre-eclampsia. Here we show that pregnant mice deficient in catechol-O-methyltransferase (COMT) show a pre-eclampsia-like phenotype resulting from an absence of 2-methoxyoestradiol (2-ME), a natural metabolite of oestradiol that is elevated during the third trimester of normal human pregnancy. 2-ME ameliorates all pre-eclampsia-like features without toxicity in the Comt(-/-) pregnant mice and suppresses placental hypoxia, hypoxia-inducible factor-1alpha expression and sFLT-1 elevation. The levels of COMT and 2-ME are significantly lower in women with severe pre-eclampsia. Our studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder.


Assuntos
Catecol O-Metiltransferase/deficiência , Estradiol/análogos & derivados , Estradiol/deficiência , Pré-Eclâmpsia/metabolismo , 2-Metoxiestradiol , Albuminas/análise , Animais , Pressão Sanguínea , Catecol O-Metiltransferase/análise , Catecol O-Metiltransferase/genética , Creatinina/urina , Modelos Animais de Doenças , Estradiol/sangue , Estradiol/urina , Feminino , Humanos , Hipertensão , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células Matadoras Naturais/imunologia , Tamanho da Ninhada de Vivíparos , Masculino , Camundongos , Placenta/enzimologia , Placenta/patologia , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/enzimologia , Pré-Eclâmpsia/urina , Gravidez , Proteinúria , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
7.
Cancer Cell ; 7(3): 251-61, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15766663

RESUMO

Angiogenesis inhibitors, such as TNP-470 and the nontoxic HPMA copolymer-TNP-470 (caplostatin), are emerging as a class of anticancer drugs. We report that TNP-470 and caplostatin inhibit vascular hyperpermeability of tumor blood vessels as well as that induced in mouse skin by different mediators. Treatment with TNP-470 or angiostatin for 3 days was sufficient to reduce permeability of tumor blood vessels, delayed-type hypersensitivity, and pulmonary edema induced by IL-2. TNP-470 also inhibited VPF/VEGF-induced phosphorylation of VEGFR-2, calcium influx, and RhoA activation in endothelial cells. These results identify an activity of TNP-470, that of inhibiting vessel hyperpermeability. This activity likely contributes to TNP-470's antiangiogenic effect and suggests that caplostatin can be used in the treatment of cancer and inflammation.


Assuntos
Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Capilares/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Angiostatinas/farmacologia , Animais , Cálcio/metabolismo , Capilares/metabolismo , Capilares/ultraestrutura , Permeabilidade Capilar/fisiologia , Movimento Celular/efeitos dos fármacos , Cicloexanos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/ultraestrutura , Feminino , Hipersensibilidade Tardia , Interleucina-2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Neoplasias/patologia , O-(Cloroacetilcarbamoil)fumagilol , Edema Pulmonar/induzido quimicamente , Pele/irrigação sanguínea , Pele/efeitos dos fármacos , Pele/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
8.
Nat Rev Cancer ; 2(10): 727-39, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12360276

RESUMO

Angiogenesis inhibitors are a new class of drugs, for which the general rules involving conventional chemotherapy might not apply. The successful translation of angiogenesis inhibitors to clinical application depends partly on the transfer of expertise from scientists who are familiar with the biology of angiogenesis to clinicians. What are the most common questions that clinicians ask as they begin to test angiogenesis inhibitors in cancer clinical trials?


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias/tratamento farmacológico , Movimento Celular , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos , Genes p53/genética , Humanos , Interferon-alfa/uso terapêutico , Neovascularização Patológica , Talidomida/uso terapêutico
9.
Angiogenesis ; 15(2): 265-73, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22402885

RESUMO

Platelets sequester angiogenesis regulatory proteins which suggests an avenue for developing biomarkers to monitor disease. We describe a comparison of angiogenesis regulatory proteins found in platelets of colorectal cancer patients and normal controls. Platelet and plasma content of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF), platelet factor 4 (PF4), thrombospondin-1 (TSP-1) and endostatin in 35 patients with colon cancer were compared with 84 age-matched healthy controls using ELISAs. We standardized the platelet preparation procedure, introduced process controls and normalized the respective protein levels to platelet numbers using an actin ELISA. Statistically significant differences were found in the median levels of VEGF, PF4 and PDGF in platelets of patients with cancer compared to healthy individuals. Platelet concentrations in cancer patients versus controls were: VEGF 1.3 versus 0.6 pg/10(6), PF4 18.5 versus 9.4 ng/10(6), and PDGF 34.1 versus 21.0 pg/10(6). Multivariable logistic regression analysis indicated that PDGF, PF4 and VEGF were independent predictors of colorectal carcinoma and as a set provided statistically significant discrimination (area under the curve = 0.893, P < .0001). No significant differences were detected for bFGF, endostatin, or TSP-1. Reference Change Value analysis determined that the differences seen were not clinically significant. Plasma levels yielded no correlations.


Assuntos
Neoplasias Colorretais/sangue , Neovascularização Patológica/sangue , Fator Plaquetário 4/sangue , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Neoplasias Colorretais/patologia , Feminino , Fator 2 de Crescimento de Fibroblastos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Trombospondina 1/sangue
10.
Am J Pathol ; 178(4): 1782-91, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21435458

RESUMO

Endometriosis is a debilitating disease characterized by the growth of ectopic endometrial tissue. It is widely accepted that angiogenesis plays an integral part in the establishment and growth of endometriotic lesions. Recent data from a variety of angiogenesis-dependent diseases suggest a critical role of bone marrow-derived endothelial progenitor cells (EPCs) in neovascularization. In this study we examined the blood levels of EPCs and mature circulating endothelial cells in a mouse model of surgically induced endometriosis. Fluorescence-activated cell sorting analysis revealed elevated levels of EPCs in the blood of mice with endometriosis compared with control subject that underwent a sham operation. EPC concentrations positively correlated with the amount of endometriotic tissue and peaked 1 to 4 days after induction of disease. In a green fluorescent protein bone marrow transplant experiment we found green fluorescent protein-positive endothelial cells incorporated into endometriotic lesions but not eutopic endometrium, as revealed by flow cytometry and immunohistochemistry. Finally, treatment of endometriosis-bearing mice with the angiogenesis inhibitor Lodamin, an oral nontoxic formulation of TNP-470, significantly decreased EPC levels while suppressing lesion growth. Taken together, our data indicate an important role for bone marrow-derived endothelial cells in the pathogenesis of endometriosis and support the potential clinical use of anti-angiogenic therapy as a novel treatment modality for this disease.


Assuntos
Endometriose/sangue , Células Endoteliais/citologia , Células-Tronco/citologia , Administração Oral , Inibidores da Angiogênese/farmacologia , Animais , Transplante de Medula Óssea , Separação Celular , Cicloexanos/farmacologia , Modelos Animais de Doenças , Endometriose/patologia , Feminino , Citometria de Fluxo , Proteínas de Fluorescência Verde/metabolismo , Imuno-Histoquímica/métodos , Camundongos , Camundongos Endogâmicos C57BL , O-(Cloroacetilcarbamoil)fumagilol , Sesquiterpenos/farmacologia , Regulação para Cima
11.
Blood ; 115(22): 4605-13, 2010 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-20086246

RESUMO

The sequential events leading to tumor progression include a switch to the angiogenic phenotype, dependent on a shift in the balance between positive and negative angiogenic regulators produced by tumor and stromal cells. Although the biologic properties of many angiogenesis regulatory proteins have been studied in detail, the mechanisms of their transport and delivery in vivo during pathologic angiogenesis are not well understood. Here, we demonstrate that expression of one of the most potent angiogenesis inhibitors, thrombospondin-1, is up-regulated in the platelets of tumor-bearing mice. We establish that this up-regulation is a consequence of both increased levels of thrombospondin-1 mRNA in megakaryocytes, as well as increased numbers of megakaryocytes in the bone marrow of tumor-bearing mice. Through the use of mouse tumor models and bone marrow transplantations, we show that platelet-derived thrombospondin-1 is a critical negative regulator during the early stages of tumor angiogenesis. Collectively, our data suggest that the production and delivery of the endogenous angiogenesis inhibitor thrombospondin-1 by platelets may be a critical host response to suppress tumor growth through inhibiting tumor angiogenesis. Further, this work implicates the use of thrombospondin-1 levels in platelets as an indicator of tumor growth and regression.


Assuntos
Plaquetas/fisiologia , Neovascularização Patológica , Trombospondina 1/fisiologia , Animais , Sequência de Bases , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Lewis/sangue , Carcinoma Pulmonar de Lewis/irrigação sanguínea , Carcinoma Pulmonar de Lewis/genética , Linhagem Celular Tumoral , Primers do DNA/genética , Megacariócitos/metabolismo , Melanoma Experimental/sangue , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Trombopoese , Trombospondina 1/sangue , Trombospondina 1/deficiência , Trombospondina 1/genética
12.
Pediatr Res ; 71(2): 168-78, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22258128

RESUMO

INTRODUCTION: We investigated the use of dietary omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) in the treatment of neuroblastoma both as a sole agent and in combination with sunitinib, a broad-spectrum tyrosine kinase receptor inhibitor. RESULTS: Substitution of all dietary fat with menhaden oil (ω-3 PUFA rich) resulted in a 40-70% inhibition of tumor growth and a statistically significant difference in the levels of several PUFAs (18:2 ω-6, 20:4 ω-6, 22:4 ω-6, 20:5 ω-3) as compared with a control diet. Furthermore, tumors from animals on the ω-3 fatty acid (FA)-enriched diet had an elevated triene/tetraene ratio suggestive of a change in local eicosanoid metabolism in these tissues similar to that seen with essential fatty acid deficiency. The ω-3 FA-enriched diet also decreased tumor-associated inflammatory cells and induced mitochondrial changes suggestive of mitochondrial damage. Combination treatment with sunitinib resulted in further reduction in tumor proliferation and microvessel density. DISCUSSION: These findings suggest a potential role for ω-3 PUFAs in the combination treatment of neuroblastoma. METHODS: We used a murine model of orthotopic and subcutaneous human neuroblastoma and diets that differ in the FA content to define the optimal dietary ω-3/omega-6 (ω-6) FA ratio required for the inhibition of these tumors.


Assuntos
Inibidores da Angiogênese/farmacologia , Proliferação de Células/efeitos dos fármacos , Dieta , Ácidos Graxos Ômega-3/administração & dosagem , Óleos de Peixe/administração & dosagem , Indóis/farmacologia , Neuroblastoma/dietoterapia , Neuroblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Animais , Ácido Araquidônico/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ácidos Graxos Ômega-3/metabolismo , Óleos de Peixe/metabolismo , Humanos , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos SCID , Microvasos/efeitos dos fármacos , Microvasos/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Neuroblastoma/irrigação sanguínea , Neuroblastoma/enzimologia , Neuroblastoma/patologia , Sunitinibe , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Cancer Cell ; 1(2): 113-5, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12086868
14.
Cancer Cell ; 3(5): 497-509, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12781367

RESUMO

Mitochondria are the powerhouse of the cell and their disruption leads to cell death. We have used a peptide trivalent arsenical, 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO), to inactivate the adenine nucleotide translocator (ANT) that exchanges matrix ATP for cytosolic ADP across the inner mitochondrial membrane and is the key component of the mitochondrial permeability transition pore (MPTP). GSAO triggered Ca(2+)-dependent MPTP opening by crosslinking Cys(160) and Cys(257) of ANT. GSAO treatment caused a concentration-dependent increase in superoxide levels, ATP depletion, mitochondrial depolarization, and apoptosis in proliferating, but not growth-quiescent, endothelial cells. Endothelial cell proliferation drives new blood vessel formation, or angiogenesis. GSAO inhibited angiogenesis in the chick chorioallantoic membrane and in solid tumors in mice. Consequently, GSAO inhibited tumor growth in mice with no apparent toxicity at efficacious doses.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Arsenicais/uso terapêutico , Células Endoteliais/metabolismo , Amarelo de Eosina-(YS)/análogos & derivados , Mitocôndrias/efeitos dos fármacos , Neovascularização Patológica , Translocador 1 do Nucleotídeo Adenina/metabolismo , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Aorta/citologia , Apoptose , Biotina/farmacologia , Cálcio/metabolismo , Cálcio/farmacologia , Bovinos , Divisão Celular , Sobrevivência Celular , Embrião de Galinha , Citosol/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/uso terapêutico , Amarelo de Eosina-(YS)/farmacologia , Feminino , Imuno-Histoquímica , Canais Iônicos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos SCID , Microscopia de Fluorescência , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial , Poro de Transição de Permeabilidade Mitocondrial , Modelos Químicos , Peptídeos/química , Fatores de Tempo
15.
Biochem Biophys Res Commun ; 409(3): 562-6, 2011 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-21605550

RESUMO

An angiogenesis inhibitor named Beta-35 has been identified and purified from the conditioned medium of mouse pancreatic ß cells tumor cells. Beta-35 has a molecular weight of 35 kDa and inhibits DNA synthesis of bovine capillary endothelial cells at a half-maximal concentration of approximately 5 nM. It shows anti-angiogenic activity in the chick embryo chorioallantoic membrane at a dose of about 1 µg/embryo. Amino acid microsequencing and mass spectrometric analysis of the purified protein demonstrate that Beta-35 contains the first 314 residues of the N-terminal sequence of bovine transferrin. We have cloned and expressed this protein in Escherichia coli using the corresponding gene segment of Beta-35 contained in the cDNA of human transferrin. The recombinant protein of Beta-35 shows significant anti-tumor activity at a dose of 5mg/kg/day against human pancreatic cancer or melanoma implanted subcutaneously in SCID mice.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Transferrina/uso terapêutico , Sequência de Aminoácidos , Inibidores da Angiogênese/genética , Inibidores da Angiogênese/isolamento & purificação , Animais , Bovinos , Linhagem Celular Tumoral , Clonagem Molecular , Meios de Cultivo Condicionados/química , Meios de Cultivo Condicionados/farmacologia , Humanos , Melanoma/irrigação sanguínea , Melanoma/tratamento farmacológico , Camundongos , Camundongos SCID , Dados de Sequência Molecular , Transplante de Neoplasias , Neoplasias Pancreáticas/metabolismo , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/isolamento & purificação , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêutico , Transferrina/genética , Transferrina/isolamento & purificação
16.
Blood ; 114(9): 1987-98, 2009 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-19465692

RESUMO

Angiostatin, a proteolytic fragment of plasminogen, is a potent endogenous antiangiogenic agent. The molecular mechanisms governing angiostatin's antiangiogenic and antitumor effects are not well understood. Here, we report the identification of mitochondrial compartment as the ultimate target of angiostatin. After internalization of angiostatin into the cell, at least 2 proteins within the mitochondria bind this molecule: malate dehydrogenase, a member of Krebs cycle, and adenosine triphosphate synthase. In vitro and in vivo studies revealed differential regulation of key prosurvival and angiogenesis-related proteins in angiostatin-treated tumors and tumor-endothelium. Angiostatin induced apoptosis via down-regulation of mitochondrial BCL-2. Angiostatin treatment led to down-regulation of c-Myc and elevated levels of another key antiangiogenic protein, thrombospondin-1, reinforcing its antitumor and antiangiogenic effects. Further evidence is provided for reduced recruitment and infiltration of bone marrow-derived macrophages in angiostatin-treated tumors. The observed effects of angiostatin were restricted to the tumor site and were not observed in other major organs of the mice, indicating unique tumor specific bioavailability. Together, our data suggest mitochondria as a novel target for antiangiogenic therapy and provide mechanistic insights to the antiangiogenic and antitumor effects of angiostatin.


Assuntos
Inibidores da Angiogênese/farmacologia , Angiostatinas/fisiologia , Apoptose , Regulação da Expressão Gênica , Mitocôndrias/metabolismo , Animais , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Humanos , Masculino , Camundongos , Camundongos SCID , Modelos Biológicos , Neoplasias/terapia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
17.
Blood ; 113(12): 2835-42, 2009 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-19036702

RESUMO

Clinical trials with antiangiogenic agents have not been able to validate plasma or serum levels of angiogenesis regulators as reliable markers of cancer presence or therapeutic response. We recently reported that platelets contain numerous proteins that regulate angiogenesis. We now show that accumulation of angiogenesis regulators in platelets of animals bearing malignant tumors exceeds significantly their concentration in plasma or serum, as well as their levels in platelets from non-tumor-bearing animals. This process is selective, as platelets do not take up a proportional amount of other plasma proteins (eg, albumin), even though these may be present at higher concentrations. We also find that VEGF-enriched Matrigel pellets implanted subcutaneously into mice or the minute quantities of VEGF secreted by microscopic subcutaneous tumors (0.5-1 mm(3)) result in an elevation of VEGF levels in platelets, without any changes in its plasma levels. The profile of other angiogenesis regulatory proteins (eg, platelet-derived growth factor, basic fibroblast growth factor) sequestered by platelets also reflects the presence of tumors in vivo before they can be macroscopically evident. The ability of platelets to selectively take up angiogenesis regulators in cancer-bearing hosts may have implications for the diagnosis and management of many angiogenesis-related diseases and provide a guide for antiangiogenic therapies.


Assuntos
Proteínas Angiogênicas/sangue , Plaquetas/metabolismo , Neovascularização Patológica/sangue , Difosfato de Adenosina/farmacologia , Animais , Linhagem Celular Tumoral/transplante , Colágeno , Combinação de Medicamentos , Implantes de Medicamento , Endostatinas/sangue , Fator 2 de Crescimento de Fibroblastos/sangue , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Laminina , Lipossarcoma/sangue , Lipossarcoma/irrigação sanguínea , Lipossarcoma/metabolismo , Lipossarcoma/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Ativação Plaquetária/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/análise , Proteoglicanas , Proteômica , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Trombina/farmacologia , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacocinética , Fator A de Crescimento do Endotélio Vascular/farmacologia
18.
Nat Med ; 10(3): 255-61, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14981512

RESUMO

Angiogenesis is crucial for tumor growth. Angiogenesis inhibitors, such as O-(chloracetyl-carbamoyl) fumagillol (TNP-470), are thus emerging as a new class of anticancer drugs. In clinical trials, TNP-470 slowed tumor growth in patients with metastatic cancer. However, at higher doses necessary for tumor regression, many patients experienced neurotoxicity. We therefore synthesized and characterized a water-soluble conjugate of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, Gly-Phe-Leu-Gly linker and TNP-470. This conjugate accumulated selectively in tumor vessels because of the enhanced permeability and retention (EPR) effect. HPMA copolymer-TNP-470 substantially enhanced and prolonged the activity of TNP-470 in vivo in tumor and hepatectomy models. Polymer conjugation prevented TNP-470 from crossing the blood-brain barrier (BBB) and decreased its accumulation in normal organs, thereby avoiding drug-related toxicities. Treatment with TNP-470 caused weight loss and neurotoxic effects in mice, whereas treatment with the conjugate did not. This new approach for targeting angiogenesis inhibitors specifically to the tumor vasculature may provide a new strategy for the rational design of cancer therapies.


Assuntos
Inibidores da Angiogênese/metabolismo , Antineoplásicos/metabolismo , Metacrilatos/metabolismo , Neovascularização Patológica , Sesquiterpenos/metabolismo , Inibidores da Angiogênese/química , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Barreira Hematoencefálica , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Embrião de Galinha , Cicloexanos , Células Endoteliais/metabolismo , Humanos , Fígado/fisiologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/patologia , Metacrilatos/química , Metacrilatos/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos SCID , Estrutura Molecular , O-(Cloroacetilcarbamoil)fumagilol , Polímeros , Regeneração/fisiologia , Sesquiterpenos/química , Sesquiterpenos/uso terapêutico
19.
Dig Dis Sci ; 56(10): 2792-801, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21735086

RESUMO

BACKGROUND: Despite recent advances and better understanding of the etiology and the pathogenesis of gastrointestinal ulcer diseases, e.g., duodenal ulcer, the molecular events leading to ulcer development, delayed healing, and recurrence remain poorly elucidated. AIMS: After we found that duodenal ulcers did not heal despite increased levels of vascular endothelial growth factor (VEGF), we tested the hypothesis that an imbalance in angiogenic VEGF and anti-angiogenic endostatin and angiostatin might be important in the development and delayed healing of experimental duodenal ulcers. METHODS: Levels of VEGF, endostatin, and angiostatin, and the expression and activity of related matrix metalloproteinases (MMP) 2 and 9 were measured in scrapings of rat proximal duodenal mucosa in the early and late stages of chemically induced duodenal ulceration. Furthermore, animals were treated with recombinant endostatin and MMP 2 inhibitor to test the relationship between MMP2 and endostatin and their involvement in healing of experimental duodenal ulcers. RESULTS: A concurrent increase of duodenal VEGF, endostatin, and angiostatin was noted during duodenal ulceration. Endostatin treatment aggravated duodenal ulcer. Levels of MMP2, but not MMP9, were increased. Inhibition of MMP2 reduced levels of endostatin and angiostatin, and attenuated duodenal ulcers. CONCLUSIONS: Increased levels of endostatin and angiostatin induced by MMP2 delayed healing of duodenal ulcers despite concurrently increased VEGF. Thus, an inappropriate angiogenic response or "angiogenic imbalance" may be an important new mechanism in ulcer development and impaired healing.


Assuntos
Angiostatinas/metabolismo , Úlcera Duodenal/metabolismo , Endostatinas/metabolismo , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/fisiologia , Animais , Cisteamina/efeitos adversos , Modelos Animais de Doenças , Úlcera Duodenal/induzido quimicamente , Úlcera Duodenal/fisiopatologia , Inibidores Enzimáticos/farmacologia , Feminino , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/fisiopatologia , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz , Neovascularização Patológica/fisiopatologia , Nitrilas/efeitos adversos , Ratos , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo
20.
Drug Resist Updat ; 13(1-2): 16-28, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20061178

RESUMO

Within three decades, anti-angiogenic therapy has rapidly evolved into an integral component of current standard anti-cancer treatment. Anti-angiogenic therapy has fulfilled a number of its earlier proposed promises. The universality of this approach is demonstrated by the broad spectrum of malignant and benign tumor entities, as well as non-neoplastic diseases, that are currently treated with anti-angiogenic agents. In contrast to tumor cell targeting therapies, the development of acquired drug resistance (e.g., via mutations in growth factor receptor signaling genes) has not been described yet for the principal target of anti-angiogenic therapy--the tumor endothelium. Moreover, the tumor endothelium has emerged as a critical target of conventional cancer therapies, such as chemotherapy and radiotherapy. The presumption that tumor growth and metastasis are angiogenesis-dependent implies that the number of potential targets of an anti-cancer therapy could be reduced to those that stimulate the angiogenesis process. Therefore, the set of endogenous angiogenesis stimulants might constitute an "Achilles heel" of cancer. Direct targeting of tumor endothelium via, e.g., endogenous angiogenesis inhibitors poses another promising but clinically less explored therapeutic strategy. Indeed, the majority of current anti-angiogenic approaches block the activity of a single or at most a few pro-angiogenic proteins secreted by tumor cells or the tumor stroma. Based on our systems biology work on the angiogenic switch, we predicted that the redundancy of angiogenic signals might limit the efficacy of anti-angiogenic monotherapies. In support of this hypothesis, emerging experimental evidence suggests that tumors may become refractory or even evade the inhibition of a single pro-angiogenic pathway via compensatory upregulation of alternative angiogenic factors. Here, we discuss current concepts and propose novel strategies to overcome tumor evasion of anti-angiogenic therapy. We believe that early detection of tumors, prediction of tumor evasive mechanisms and rational design of anti-angiogenic combinations will direct anti-angiogenic therapy towards its ultimate goal--the conversion of cancer to a dormant, chronic, manageable disease.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/prevenção & controle , Neoplasias/tratamento farmacológico , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Terapia Combinada/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Modelos Biológicos , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos
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