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1.
Biomed Res Int ; 2021: 3291762, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34631879

RESUMO

Primary central nervous system lymphoma (PCNSL) is a rare lymphoma, and the disease course is often aggressive with poor prognosis outcomes. PCNSL undergoes germinal center reactions and impairs B-cell maturation. However, angiogenesis is also involved in the tumorigenesis and progression of PCNSL. This study investigated the effects of the tumor microenvironment and angiogenesis-associated genomic alterations on the outcomes of PCNSL. The analysis also evaluated the influence of treatment modality and timing on PCNSL survival using partial least squares variance-based path modeling (PLS-PM). PLS-PM can be used to evaluate the complex relationship between prognostic variables and disease outcomes with a small sample of measurements and structural models. A total of 19 immunocompetent PCNSL samples were analyzed by exome sequencing. Our results suggest that the timing of radiotherapy and mutations of ROBO1 and KAT2B are potential indicators of PCNSL outcomes and may be affected by baseline characteristics such as age and sex. Our results also showed that patients with no mutations of ROBO1 and KAT2B, SubRT subgroup showed favorable survival outcomes compared with no SubRT subgroup in short-term follow-up. All SubRT patients have received high-dose methotrexate induction chemotherapy in the initial treatment. Therefore, initial induction chemotherapy combined with subsequent radiotherapy might improve survival outcomes in PCNSL patients who have no ROBO1 and KAT2B somatic mutations in short-term follow-up. The overall findings suggest that the tumor microenvironment and angiogenesis-associated genomic alterations and treatment modalities are potential indicators of overall survival and may be affected by the baseline characteristics of PCNSL patients.


Assuntos
Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma/sangue , Linfoma/tratamento farmacológico , Neovascularização Patológica/patologia , Microambiente Tumoral , Idoso , Análise Mutacional de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Análise dos Mínimos Quadrados , Masculino , Mutação/genética , Resultado do Tratamento
2.
BMC Med Imaging ; 20(1): 62, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32517711

RESUMO

BACKGROUND: Diffusion and perfusion MRI can invasively define physical properties and angiogenic features of tumors, and guide the individual treatment. The purpose of this study was to investigate whether the diffusion and perfusion MRI parameters of primary central nervous system lymphomas (PCNSLs) are related to the tumor locations. METHODS: We retrospectively reviewed the diffusion, perfusion, and conventional MRI of 68 patients with PCNSLs at different locations (group 1: cortical gray matter, group 2: white matter, group 3: deep gray matter). Relative maximum cerebral blood volume (rCBVmax) from perfusion MRI, minimum apparent diffusion coefficients (ADCmin) from DWI of each group were calculated and compared by one-way ANOVA test. In addition, we compared the mean apparent diffusion coefficients (ADCmean) in three different regions of control group. RESULTS: The rCBVmax of PCNSLs yielded the lowest value in the white matter group, and the highest value in the cortical gray matter group (P < 0.001). However, the ADCmin of each subgroup was not statistically different. The ADCmean of each subgroup in control group was not statistically different. CONCLUSION: Our study confirms that rCBVmax of PCNSLs are related to the tumor location, and provide simple but effective information for guiding the clinical practice of PCNSLs.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Linfoma/diagnóstico por imagem , Angiografia por Ressonância Magnética/métodos , Adulto , Idoso , Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Volume Sanguíneo Cerebral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
3.
Med Sci Monit ; 25: 3321-3328, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31055591

RESUMO

BACKGROUND This study aimed to compare the magnetic resonance imaging (MRI) findings of primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS) with delayed contrast enhancement and histological microvessel density (MVD). T1-weighted and T2-weighted contrast-enhanced and non-enhanced brain imaging were used. CNS lymphoma tissue was evaluated using primary antibodies to endothelial cells and smooth muscle cells, and histochemical staining for reticulin fibers and basement membrane, which allowed quantification of the MVD. MATERIAL AND METHODS Twenty-one patients with histologically confirmed primary DLBCL of the CNS underwent pre-contrast-enhanced and postcontrast-enhanced MRI. Histology of the CNS lymphoma tissue included immunohistochemical staining with antibodies to CD34 for vascular endothelial cells and alpha smooth muscle actin (ASMA) for vascular smooth muscle cells, and histochemical staining included periodic acid-Schiff (PAS) and silver staining for reticulin fibers to evaluate microvessel density (MVD). RESULTS In primary DLBCL of the CNS, a positive correlation was found between the degree of necrosis and the size of the lymphoma (r=0.546, P=0.01). Delayed imaging enhancement was significantly correlated with the number of mature vessels, MVD, basement membrane, and reticulin fibers (r=0.593, 0.466, 0.446 and 0.497, respectively). Standardized ß regression coefficient analysis showed that the MVD, PAS-positive structures, the number of mature vessels, and reticulin fibers, were significantly associated with delayed enhancement on MRI (ß values, 0.425, 0.409, 0.295, and 0.188, respectively). CONCLUSIONS In primary DLBCL of the CNS, delayed imaging enhancement on MRI may be due to reduced neovascularization and vascular infiltration by lymphoma cells.


Assuntos
Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/patologia , Adulto , Idoso , Neoplasias do Sistema Nervoso Central/patologia , Meios de Contraste , Feminino , Humanos , Aumento da Imagem/métodos , Contagem de Linfócitos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/patologia , Estudos Retrospectivos
4.
Exp Neurol ; 299(Pt B): 326-333, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28911884

RESUMO

Research of various diseases of the nervous system has shown that VEGF has direct neuroprotective effects in the central and peripheral nervous systems, and indirect effects on improving neuronal vessel perfusion which leads to nerve protection. In the tumors of the nervous system, VEGF plays a critical role in tumor angiogenesis and tumor progression. The effect of anti-VEGF treatment on nerve protection and function has been recently reported - by normalizing the tumor vasculature, anti-VEGF treatment is able to relieve nerve edema and deliver oxygen more efficiently into the nerve, thus reducing nerve damage and improving nerve function. This review aims to summarize the divergent roles of VEGF in diseases of the nervous system and the recent findings of anti-VEGF therapy in nerve damage/regeneration and function in tumors, specifically, in Neurofibromatosis type 2 associated schwannomas.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , Neurofibromatose 2 , Neuroma Acústico/tratamento farmacológico , Neoplasias do Sistema Nervoso Periférico/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Hipóxia Celular/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Modelos Animais de Doenças , Progressão da Doença , Humanos , Proteínas de Neoplasias/fisiologia , Neovascularização Patológica/etiologia , Regeneração Nervosa/efeitos dos fármacos , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/fisiopatologia , Neuroma Acústico/irrigação sanguínea , Neuroma Acústico/genética , Neoplasias do Sistema Nervoso Periférico/irrigação sanguínea , Nervo Isquiático/irrigação sanguínea , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiopatologia , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/fisiologia
5.
Brain Tumor Pathol ; 33(3): 200-8, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26951238

RESUMO

Hemangiopericytoma (HPC) is a highly vascularized mesenchymal tumor. Local recurrence and distant metastasis are common features of HPC. Considering the remarkable hyper-vasculature phenotype of HPC, we assumed that dysregulated angiogenic signaling pathways were involved in HPC. The key components of angiogenic signaling pathways including VEGF-VEGF-R2, EphrinB2-EphB4 and DLL4-Notch were examined by real-time RT-PCR, Western blotting and immunostaining in 17 surgical specimens of HPC patients and in 6 controls. A significant upregulation of VEGF and VEGF-R2 associated with elevated levels of p-Akt and proliferating cell nuclear antigen (PCNA) was detected in HPC. Moreover, a dramatic increase in the mRNA and protein expression of EphB4 and its downstream factor p-Erk1/2 was found in HPC. A massive activation of core-components of DLL4-Notch signaling was detected in HPC. Double-immunofluorescent staining confirmed the expression of these upregulated key factors in the endothelial cells of tumor vessels. The present study identified the activation of multiple and crucial angiogenic signaling pathways, which could function individually and/or synergistically to stimulate angiogenesis in HPC and eventually contribute to tumor growth and progression. Our findings emphasize the importance to target multiple angiogenic signaling pathways when an anti-angiogenic therapy is considered for this highly vascularized tumor.


Assuntos
Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Neoplasias do Sistema Nervoso Central/genética , Hemangiopericitoma/irrigação sanguínea , Hemangiopericitoma/genética , Neovascularização Patológica/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Ativação Transcricional/genética , Ativação Transcricional/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Proteínas de Ligação ao Cálcio , Neoplasias do Sistema Nervoso Central/patologia , Progressão da Doença , Efrina-B2/genética , Efrina-B2/fisiologia , Feminino , Hemangiopericitoma/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Receptor EphB4/genética , Receptor EphB4/fisiologia , Receptores Notch/genética , Receptores Notch/fisiologia , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/fisiologia
7.
Cell Mol Life Sci ; 72(16): 3069-82, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25943307

RESUMO

Because tumors require a vascular supply for their survival and growth, angiogenesis is considered an important therapeutic target in most human cancers including cancer of the central nervous system. Antiangiogenic therapy has focused on inhibitors of the vascular endothelial growth factor (VEGF) signaling pathway. VEGF pathway-targeted drugs have shown therapeutic efficacy in several CNS tumors and have been tried most frequently in glioblastoma. These therapies, however, have been less effective than anticipated as some patients do not respond to therapy and some receive only modest benefit. Underlying this suboptimal response are multiple mechanisms of drug resistance involving changes in both tumor cells and their microenvironment. In this review, we discuss the multiple proposed mechanisms by which neurological tumors evolve to become resistant to antiangiogenic therapies. A better understanding of these mechanisms, their context, and their interplay will likely facilitate improvements in pharmacological strategies for the targeted treatment of neurological tumors.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Microambiente Celular , Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neovascularização Patológica/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Humanos , Modelos Biológicos
8.
Brain Tumor Pathol ; 32(1): 41-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25433721

RESUMO

Chemokines are peptides that function as chemoattractant cytokines in cell activation, differentiation and trafficking. Endothelin B receptor (ETBR) is a receptor for endothelin, which is known to function as a vasoconstrictor. In the present study, to clarify the immune escape mechanism of primary central nervous system lymphomas (PCNSLs), the expression of ETBR and of subsets of chemokines (CXCL12, 13) in 24 PCNSLs was investigated. CXCL12 was expressed by lymphoma cells in different resident brain cell populations in 22/24 cases. CXCL13 expression was identified in tumor cells in 19/24 cases, but was only expressed by tumor cells and by proliferating vascular endothelial cells. In addition, tumor-infiltrated lymphocytes (TILs) accumulated in areas with expression of chemokines, particularly of CXCL13. ETBR expression was detected in 12/24 cases. Positive ETBR cases were associated with a paucity of TILs, particularly of cytotoxic T cells, whereas negative ETBR cases were associated with an abundance of TILs. The combined data indicate that CXCL12 and CXCL13 up-regulation may be differently linked to the development of PCNSLs and to the accumulation of TILs. In addition, ETBR expression by lymphoma and endothelial cells may mediate trafficking of TILs, which may explain the immune escape processes of PCNSLs.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/imunologia , Quimiocina CXCL12/fisiologia , Quimiocina CXCL13/fisiologia , Linfoma/genética , Linfoma/imunologia , Receptor de Endotelina B/fisiologia , Evasão Tumoral/genética , Microambiente Tumoral/genética , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Neoplasias do Sistema Nervoso Central/patologia , Quimiocina CXCL12/genética , Quimiocina CXCL13/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Receptor de Endotelina B/genética , Regulação para Cima
9.
Methods Mol Biol ; 1135: 25-34, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24510852

RESUMO

Current antiangiogenic therapies have led to the observation that such agents can lead to improved tumor vessel structure and function termed "vascular normalization" which reduces tumor burden. However, vessel normalization is a transient process, and patients often develop resistance/poor response to anti-vascular strategies that remains an important clinical challenge. Therefore, increasing effort has been made to better understand the cellular and molecular mechanisms of vascular normalization and its contribution to immunomodulation. Herein, we summarize the recent effort to better understand the cellular and molecular mechanisms of vascular normalization with a focus on preclinical genetic models. These studies remain important directions for a mechanistic understanding of the complexities of the maintenance of BBB integrity and the impact of its breakdown on tumor dissemination and pharmaco-distribution of therapeutics.


Assuntos
Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Neovascularização Fisiológica , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/uso terapêutico , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/imunologia , Artérias Cerebrais/metabolismo , Artérias Cerebrais/fisiopatologia , Resistencia a Medicamentos Antineoplásicos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Humanos , Microvasos/metabolismo , Microvasos/fisiopatologia , Neovascularização Patológica/patologia , Neovascularização Patológica/fisiopatologia , Distribuição Tecidual , Evasão Tumoral
10.
J Cell Sci ; 127(Pt 4): 701-7, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24481819

RESUMO

Loss-of-function mutations in genes encoding KRIT1 (also known as CCM1), CCM2 (also known as OSM and malcavernin) or PDCD10 (also known as CCM3) cause cerebral cavernous malformations (CCMs). These abnormalities are characterized by dilated leaky blood vessels, especially in the neurovasculature, that result in increased risk of stroke, focal neurological defects and seizures. The three CCM proteins can exist in a trimeric complex, and each of these essential multi-domain adaptor proteins also interacts with a range of signaling, cytoskeletal and adaptor proteins, presumably accounting for their roles in a range of basic cellular processes including cell adhesion, migration, polarity and apoptosis. In this Cell Science at a Glance article and the accompanying poster, we provide an overview of current models of CCM protein function focusing on how known protein-protein interactions might contribute to cellular phenotypes and highlighting gaps in our current understanding.


Assuntos
Neoplasias do Sistema Nervoso Central/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Permeabilidade Capilar , Proteínas de Transporte/metabolismo , Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Hemangioma Cavernoso do Sistema Nervoso Central/irrigação sanguínea , Humanos , Proteína KRIT1 , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Proteínas rho de Ligação ao GTP/metabolismo
11.
Curr Oncol Rep ; 16(4): 380, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24510742

RESUMO

Malignant gliomas are the most common primary brain tumor found in adults. Unfortunately, the prognosis for these type of tumors remains dismal despite aggressive treatment with surgical resection, radiation and chemotherapy. Therefore, therapeutics aimed at disrupting the angiogenesis of these tumors is being utilized in to improve survival outcomes and quality of life. This paper reviews the history of antiangiogenic agents in malignant gliomas, discusses the FDA approval of bevacizumab as monotherapy in recurrent glioblastoma and the subsequent controversy, and analyzes the most recent newly diagnosed trials of RTOG 0825 and AVAglio. Additionally, the results of the latest trials with antiangiogenic agents and possible biomarkers are reviewed. Multiple questions remain regarding the potential benefit of antiangiogenic treatments in patients with glioblastoma. Future clinical trials should be designed to learn more about these drugs, to optimize their future use.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Glioma/irrigação sanguínea , Neovascularização Patológica/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Ensaios Clínicos como Assunto , Glioma/tratamento farmacológico , Humanos
12.
Cell Tissue Res ; 354(2): 409-30, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23963648

RESUMO

The extracellular matrix (ECM) protein tenascin-C (TN-C) is upregulated within glioma tissues and cultured glioma cell lines. TN-C possesses a multi-modular structure and a variety of functional properties have been reported for its domains. We describe five novel monoclonal antibodies identifying different domains of TN-C. The epitopes for these antibodies were investigated by using recombinantly expressed fibronectin type III domains of TN-C. The biological effects of TN-C fragments on glioma cell proliferation and adhesion were analyzed. The expression pattern of TN-C in human glioma tissue sections and in glioma cell lines was studied with the novel library of monoclonal antibodies. The immunocytochemical analyses of the established human glioma cell lines U-251-MG, U-373-MG and U-87-MG revealed distinct staining patterns for each antibody. Robust expression of TN-C was found within the tumor mass of surgery specimens from glioblastoma. In many cases, the expression of this ECM molecule was clearly associated with blood vessels, particularly with microvessels. Three of the new antibodies highlighted individual TN-C-expressing single cells in glioma tissues. The effect of TN-C domains on glioma cells was examined by a BrdU-proliferation assay and an adhesion assay. Short fragments of constitutively expressed TN-C-domains did not exert significant effects on the proliferation of glioma cells, whereas the intact molecule increased cell division rates. In contrast, the long fragment TNfnALL containing all of the FNIII domains of TN-C decreased proliferation. Additionally, we found strong differences between the adhesion-influencing properties of the recombinant fragments on glioma cells.


Assuntos
Neoplasias Encefálicas/irrigação sanguínea , Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Glioma/irrigação sanguínea , Tenascina/análise , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Regulação Neoplásica da Expressão Gênica , Glioblastoma/irrigação sanguínea , Glioblastoma/genética , Glioblastoma/patologia , Glioma/genética , Glioma/patologia , Humanos , Imuno-Histoquímica , Tenascina/genética
13.
Exp Cell Res ; 319(15): 2350-9, 2013 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-23911990

RESUMO

Rap1 signaling is important for both major processes of vessel formation: vasculogenesis, or de novo vessel formation, and angiogenesis, sprouting of new vessels from pre-existing ones. We provide an overview of genetic studies in mice and zebrafish and discuss some of the proposed underlying mechanisms derived from cellular models, with particular emphasis on Rap1's role in angiogenesis, maintenance of endothelial barrier and connection with cerebral cavernous malformation (CCM), a neurological deficit that leads to seizures and lethal stroke. Lastly, we provide a brief summary of studies in cardiac and smooth muscle cells, where the Epac-Rap1 signaling axis is emerging as an important regulator of contractility.


Assuntos
Vasos Sanguíneos/metabolismo , Neoplasias do Sistema Nervoso Central/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Transdução de Sinais , Proteínas rap1 de Ligação ao GTP/metabolismo , Animais , Vasos Sanguíneos/patologia , Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Células Endoteliais/patologia , Endotélio Vascular/patologia , Regulação da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/irrigação sanguínea , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Camundongos , Morfogênese , Neovascularização Patológica , Neovascularização Fisiológica , Peixe-Zebra , Proteínas rap1 de Ligação ao GTP/genética
14.
J Cereb Blood Flow Metab ; 33(5): 780-6, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23486297

RESUMO

Cerebral blood volume (CBV) measurement complements conventional magnetic resonance imaging (MRI) to indicate pathologies in the central nervous system (CNS). Dynamic susceptibility contrast (DSC) perfusion imaging is limited by low resolution and distortion. Steady-state (SS) imaging may provide higher resolution CBV maps but was not previously possible in patients. We tested the feasibility of clinical SS-CBV measurement using ferumoxytol, a nanoparticle blood pool contrast agent. SS-CBV measurement was analyzed at various ferumoxytol doses and compared with DSC-CBV using gadoteridol. Ninety nine two-day MRI studies were acquired in 65 patients with CNS pathologies. The SS-CBV maps showed improved contrast to noise ratios, decreased motion artifacts at increasing ferumoxytol doses. Relative CBV (rCBV) values obtained in the thalamus and tumor regions indicated good consistency between the DSC and SS techniques when the higher dose (510 mg) ferumoxytol was used. The SS-CBV maps are feasible using ferumoxytol in a clinical dose of 510 mg, providing higher resolution images with comparable rCBV values to the DSC technique. Physiologic imaging using nanoparticles will be beneficial in visualizing CNS pathologies with high vascularity that may or may not correspond with blood-brain barrier abnormalities.


Assuntos
Determinação do Volume Sanguíneo/métodos , Encéfalo/irrigação sanguínea , Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Meios de Contraste , Nanopartículas de Magnetita , Volume Sanguíneo , Encéfalo/patologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/patologia , Neoplasias do Sistema Nervoso Central/patologia , Circulação Cerebrovascular , Gadolínio , Compostos Heterocíclicos , Humanos , Compostos Organometálicos
17.
J Exp Med ; 209(9): 1611-27, 2012 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-22908324

RESUMO

Endothelial Wnt/ß-catenin signaling is necessary for angiogenesis of the central nervous system and blood-brain barrier (BBB) differentiation, but its relevance for glioma vascularization is unknown. In this study, we show that doxycycline-dependent Wnt1 expression in subcutaneous and intracranial mouse glioma models induced endothelial Wnt/ß-catenin signaling and led to diminished tumor growth, reduced vascular density, and normalized vessels with increased mural cell attachment. These findings were corroborated in GL261 glioma cells intracranially transplanted in mice expressing dominant-active ß-catenin specifically in the endothelium. Enforced endothelial ß-catenin signaling restored BBB characteristics, whereas inhibition by Dkk1 (Dickkopf-1) had opposing effects. By overactivating the Wnt pathway, we induced the Wnt/ß-catenin-Dll4/Notch signaling cascade in tumor endothelia, blocking an angiogenic and favoring a quiescent vascular phenotype, indicated by induction of stalk cell genes. We show that ß-catenin transcriptional activity directly regulated endothelial expression of platelet-derived growth factor B (PDGF-B), leading to mural cell recruitment thereby contributing to vascular quiescence and barrier function. We propose that reinforced Wnt/ß-catenin signaling leads to inhibition of angiogenesis with normalized and less permeable vessels, which might prove to be a valuable therapeutic target for antiangiogenic and edema glioma therapy.


Assuntos
Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Neoplasias do Sistema Nervoso Central/metabolismo , Glioma/irrigação sanguínea , Glioma/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proteínas de Ligação ao Cálcio , Neoplasias do Sistema Nervoso Central/patologia , Endotélio Vascular/metabolismo , Feminino , Fatores de Transcrição Forkhead/genética , Glioma/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Gradação de Tumores , Neovascularização Patológica , Proteínas Proto-Oncogênicas c-sis/genética , Proteína Wnt1/genética , Proteína Wnt1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Microvasc Res ; 84(1): 34-43, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22465694

RESUMO

INTRODUCTION: Alterations of microvasculature are integral to CNS neoplasia, and a diagnostic feature of high-grade gliomas. The objectives of this study were two fold: First, to correlate morphometrically measured microvessel density (MVD), microvessel caliber (VC), and percentage of total microvessel area (%TVA) with WHO histologic grade in various types of primary CNS tumors. Second, to evaluate if such a correlation could be further refined by using mathematical derivatives of measured parameters namely coefficient of variation of VC (COofVC), microvessel cross-sectional area (VCSA), and percentage of total VCSA (%TVCSA). MATERIALS AND METHODS: Various microvessel parameters were assessed in a variety of 30 primary CNS tumors as consecutively encountered in routine surgical pathology practice including gliomas, meningiomas and others by image morphometry using CD34-immunostained sections. We introduced a novel method of effectively determining VC. Results were correlated with tumor type and grade. Appropriate statistical analysis was performed. RESULTS: Microvessel characteristics, especially VC (p<0.0022), VCSA (p<0.0164), CVofVC (p<0.0001), %TVCSA (p<0.0002) and %TVA (p<0.0003) of tumors were significantly greater than normal tissue. MVD increased in all tumors, excepting meningiomas, and was significantly higher in gliomas (p<0.0062). MVD showed negative correlation with VC (r=-0.808) and VCSA (r=-0.848) in the normal brain but was less significant in tumors. Unlike tumors, caliber distribution of microvessels in normal brain was noted to follow a Gaussian pattern. Histological grades of tumors showed positive correlation with MVD (r=0.547), VC (r=0.606), CVofVC (r=0.623), VCSA (r=0.485), %TVCSA (r=0.783) and %TVA (r=0.603). Calculated scores, estimated from multiple regressions of vessel parameters, correlated well with histological grade, with S2 (calculated using all measured as well as mathematically derived microvessel parameters) being better than S1 (calculated using measured parameters: MVD and VC). CONCLUSION: Tumor grades positively correlated with all microvessel parameters, with %TVCSA displaying the best. The correlation of %TVA with tumor grade was weaker than %TVCSA mainly due to the impact of MVD. These findings emphasize the value of VC as effectively measured using our novel method and best illustrated by its derivative %TVCSA (an indicator of blood flow), in addition to the well-recognized value of MVD in tumor prognostication. Multiple regressions of microvessel parameters provided the best correlation with grade. Morphometric analysis of microvessels in CNS tumor facilitates a better understanding of the tumor grade, tumor progression and overall prognosis.


Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Glioma/patologia , Meningioma/patologia , Microvasos/patologia , Adolescente , Adulto , Idoso , Antígenos CD34/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Criança , Glioma/irrigação sanguínea , Humanos , Processamento de Imagem Assistida por Computador , Meningioma/irrigação sanguínea , Microvasos/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Adulto Jovem
19.
Leuk Res ; 36(3): 369-76, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21924771

RESUMO

Lack of suitable mouse models for central nervous system (CNS)-associated leukemias has hindered mechanism-guided development of therapeutics. By transplanting retrovirus-transformed mouse erythroleukemia cells into syngeneic mice, we developed a new animal model of meningeal leukemia associated with rapid paralysis. Necropsy revealed massive proliferation of the leukemic cells in the bone marrow (BM) followed by pathological angiogenesis and invasion of the leukemic cells into the meninges of the CNS. Further analysis demonstrated that the erythroleukemia cells secreted high levels of VEGF and preferentially adhered in vitro to fibronectin. This unique animal model for meningeal leukemia should facilitate studies of engraftment and proliferation of leukemic cells in the BM and their invasion of the CNS as well as pre-clinical evaluation of experimental therapeutics for CNS-associated leukemias.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Leucemia Eritroblástica Aguda/fisiopatologia , Leucemia Experimental/patologia , Neoplasias Meníngeas/patologia , Retroviridae/genética , Animais , Biomarcadores Tumorais/genética , Western Blotting , Adesão Celular , Proliferação de Células , Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Neoplasias do Sistema Nervoso Central/etiologia , Ensaio de Imunoadsorção Enzimática , Fibronectinas/metabolismo , Perfilação da Expressão Gênica , Integrina alfa5beta1/metabolismo , Leucemia Experimental/etiologia , Neoplasias Meníngeas/irrigação sanguínea , Neoplasias Meníngeas/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Análise de Sequência com Séries de Oligonucleotídeos , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Eur J Cancer ; 48(5): 772-81, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22100902

RESUMO

No literature data are available concerning the expression of aquaporin-4 in primary central nervous system lymphomas and the relationship between aquaporin-4 expression and the morphological characteristics of blood vessels. Here, we have investigated this relationship in 24 human diffuse large B-cell primary central nervous system lymphomas by means of immunocytochemistry and confocal laser microscopy. Results have shown that: (i) a high aquaporin-4 expression correlated with a high Ki-67 index and aquaporin-4 marked tumour and endothelial cells in cytoplasm and plasma membranes, while aquaporin-4 expression was low in tumour areas with a low Ki-67 index where few tumour cells were positive to aquaporin-4, and endothelial cells showed aquaporin-4 expression on their abluminal side. (ii) Different type of cells participated in vessels formation: CD20(+) tumour cells and factor VIII(+) endothelial cells; aquaporin-4(+) tumour cells and CD31(+) endothelial cells; CD20(+) and aquaporin-4(+) tumour cells; glial fibrillary acidid protein(+) endothelial cells surrounded by glial fibrillary acidic protein(+) tumour cells. Overall, these data suggest the importance of aquaporin-4 in primary central nervous system lymphomas due to its involvement in cerebral oedema formation and resolution and tumour cell migratory activity, and have documented that tumour microvasculature in lymphomas is extremely heterogeneous, confirming the importance of neoangiogenesis in the pathogenesis of lymphomas.


Assuntos
Aquaporina 4/biossíntese , Neoplasias do Sistema Nervoso Central/metabolismo , Células Endoteliais/metabolismo , Linfoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Processos de Crescimento Celular/fisiologia , Neoplasias do Sistema Nervoso Central/irrigação sanguínea , Neoplasias do Sistema Nervoso Central/patologia , Células Endoteliais/patologia , Feminino , Humanos , Imuno-Histoquímica , Linfoma/patologia , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Fenótipo
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