Avaliação imuno-histoquímica da expressão das proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada em neurofibromas e tumores malignos da bainha do nervo periférico: correlação clínico-patológica

Detalhes bibliográficos
Ano de defesa: 2008
Autor(a) principal: Cunha, Karin Soares Gonçalves
Orientador(a): Não Informado pela instituição
Banca de defesa: Não Informado pela instituição
Tipo de documento: Tese
Tipo de acesso: Acesso aberto
Idioma: por
Instituição de defesa: Programa de Pós-graduação em Patologia
Patologia
Programa de Pós-Graduação: Não Informado pela instituição
Departamento: Não Informado pela instituição
País: Não Informado pela instituição
Palavras-chave em Português:
Link de acesso: https://app.uff.br/riuff/handle/1/18270
Resumo: Malignant peripheral nerve sheath tumors are rare and highly aggressive neoplasms. Neurofibromatosis type 1, a syndrome caused by mutations in the NF1 gene, is the major risk factor for the development of these tumors. Malignant peripheral nerve sheath tumors may appear de novo or may develop from the transformation of a benign neural neoplasm, mainly from a plexiform neurofibroma, which occurs almost exclusively in Neurofibromatosis type 1 patients. Nowadays, the knowledge of the factors involved in the oncogenesis of malignant peripheral nerve sheath tumors is still modest. It is believed that the loss of heterozygosity of NF1 gene is sufficient for the development of neurofibromas, but studies have been demonstrated that the pathogenesis of malignant peripheral nerve sheath tumors is a multistage process, involving many molecular alterations in addition to biallelic inactivation of NF1 gene. Many authors have been evaluated alterations in cell proliferation control genes, but the knowledge of apoptosis alterations in these tumors is still scarce. With the aim to evaluate the expression of apoptosis-associated proteins in malignant peripheral nerve sheath tumors, the immunoreactivity of p53, Bcl-2, Bcl-x and cleaved caspase-3 proteins was investigated in 28 malignant peripheral nerve sheath tumors, using tissue microarray, and compared with their immunoreactivity in 38 neurofibromas. The correlation of the expression of these proteins with clinicopathological features and prognosis of malignant peripheral nerve sheath tumors was also investigated. P53, Bcl-2, Bcl-x and cleaved caspase-3 proteins were expressed in 64,3%, 78,6%, 75,0% and 100% of malignant peripheral nerve sheath tumors, respectively, and in 2,6%, 32,4%, 43,2% and 100% of neurofibromas, respectively. Comparing the immunopositive cases, malignant perihperal nerve sheath tumores showed higher positivity indexes for Bcl-2, Bcl-x and cleaved caspase-3 than neurofibromas. In neurofibromas, cleaved caspase-3 expression was only observed in the nucleus of the cells, whereas 50% of malignant peripheral nerve sheath tumors showed nuclear expression and the other 50% expressed cleaved caspase-3 in the nucleus and in the cytoplasm of the cells. There was a correlation between the cytoplasmatic expression of cleaved caspase-3 and the high histological grade, high mitotic index and necrosis. In multivariate Cox analysis, necrosis was an independent predictor factor for lower overall survival and high positivity index for cleaved caspase-3 was an independent risk factor for worse disease-free survival. Our results suggest that alterations of p53, Bcl-2, Bcl-x and cleaved caspase-3 expression are possibly associated to the development of malignant peripheral nerve sheath tumors
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spelling Avaliação imuno-histoquímica da expressão das proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada em neurofibromas e tumores malignos da bainha do nervo periférico: correlação clínico-patológicaTumores malignos da bainha do nervo periféricoNeurofibromasNeurofibromatose Tipo 1Proteína p53Proteína Bcl-2Proteína Bcl-xCaspase-3 clivadaimunohistoquímicaNeurofibromaMalignant peripheral nerve sheath tumorapoptosisp53 proteinBcl-2 proteinBcl-x proteinCleaved caspase-3ImmunohistochemistryCNPQ::CIENCIAS DA SAUDE::MEDICINA::ANATOMIA PATOLOGICA E PATOLOGIA CLINICAMalignant peripheral nerve sheath tumors are rare and highly aggressive neoplasms. Neurofibromatosis type 1, a syndrome caused by mutations in the NF1 gene, is the major risk factor for the development of these tumors. Malignant peripheral nerve sheath tumors may appear de novo or may develop from the transformation of a benign neural neoplasm, mainly from a plexiform neurofibroma, which occurs almost exclusively in Neurofibromatosis type 1 patients. Nowadays, the knowledge of the factors involved in the oncogenesis of malignant peripheral nerve sheath tumors is still modest. It is believed that the loss of heterozygosity of NF1 gene is sufficient for the development of neurofibromas, but studies have been demonstrated that the pathogenesis of malignant peripheral nerve sheath tumors is a multistage process, involving many molecular alterations in addition to biallelic inactivation of NF1 gene. Many authors have been evaluated alterations in cell proliferation control genes, but the knowledge of apoptosis alterations in these tumors is still scarce. With the aim to evaluate the expression of apoptosis-associated proteins in malignant peripheral nerve sheath tumors, the immunoreactivity of p53, Bcl-2, Bcl-x and cleaved caspase-3 proteins was investigated in 28 malignant peripheral nerve sheath tumors, using tissue microarray, and compared with their immunoreactivity in 38 neurofibromas. The correlation of the expression of these proteins with clinicopathological features and prognosis of malignant peripheral nerve sheath tumors was also investigated. P53, Bcl-2, Bcl-x and cleaved caspase-3 proteins were expressed in 64,3%, 78,6%, 75,0% and 100% of malignant peripheral nerve sheath tumors, respectively, and in 2,6%, 32,4%, 43,2% and 100% of neurofibromas, respectively. Comparing the immunopositive cases, malignant perihperal nerve sheath tumores showed higher positivity indexes for Bcl-2, Bcl-x and cleaved caspase-3 than neurofibromas. In neurofibromas, cleaved caspase-3 expression was only observed in the nucleus of the cells, whereas 50% of malignant peripheral nerve sheath tumors showed nuclear expression and the other 50% expressed cleaved caspase-3 in the nucleus and in the cytoplasm of the cells. There was a correlation between the cytoplasmatic expression of cleaved caspase-3 and the high histological grade, high mitotic index and necrosis. In multivariate Cox analysis, necrosis was an independent predictor factor for lower overall survival and high positivity index for cleaved caspase-3 was an independent risk factor for worse disease-free survival. Our results suggest that alterations of p53, Bcl-2, Bcl-x and cleaved caspase-3 expression are possibly associated to the development of malignant peripheral nerve sheath tumorsTumores malignos da bainha do nervo periférico são neoplasias raras e altamente agressivas. O maior fator de risco para o desenvolvimento destes tumores é a presença da síndrome Neurofibromatose tipo 1, causada por mutações no gene NF1. Os tumores malignos da bainha do nervo periférico podem surgir de novo ou a partir da transformação maligna de uma neoplasia neural benigna, principalmente o neurofibroma plexiforme, que acontece quase que exclusivamente em pacientes com Neurofibromatose tipo 1. Atualmente, o conhecimento sobre os fatores envolvidos na oncogênese dos tumores malignos da bainha do nervo periférico ainda é pequeno. Embora se acredite que a perda da heterozigosidade do gene NF1 seja o suficiente para o surgimento dos neurofibromas, estudos têm demonstrado que o desenvolvimento dos tumores malignos da bainha do nervo periférico, associados ou não à Neurofibromatose tipo 1, é um processo de vários estágios, envolvendo um número variado de alterações moleculares em adição à inativação bialélica do gene NF1. Muitos trabalhos têm avaliado alterações em genes controladores da proliferação celular, porém o conhecimento da alteração da apoptose nestes tumores é escasso. Com o objetivo de avaliar a expressão de proteínas associadas à apoptose nos tumores malignos da bainha do nervo periférico, foi investigada a imunorreatividade, utilizando o tissue microarray, para as proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada em 28 tumores malignos da bainha do nervo periférico e os resultados comparados com a expressão destas proteínas em 38 neurofibromas. A correlação da expressão das proteínas estudadas com os dados clínico-patológicos e o prognóstico dos tumores malignos da bainha do nervo periférico também foi investigada. As proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada foram expressas em 64,3%, 78,6%, 75,0% e 100% dos tumores malignos da bainha do nervo periférico, respectivamente, e em 2,6%, 32,4% 43,2% e 100% dos neurofibromas. Comparando os casos imunopositivos, os tumores malignos da bainha do nervo periférico apresentaram maiores índices de positividade para as proteínas Bcl-2, Bcl-x e caspase-3 clivada do que os neurofibromas. A expressão da caspase-3 clivada foi observada apenas no núcleo dos neurofibromas, enquanto que 50% dos tumores malignos da bainha do nervo periférico apresentaram imunomarcação nuclear e a outra metade expressaram a proteína no núcleo e citoplasma. Observou-se correlação entre a presença de marcação citoplasmática da caspase-3 clivada e o alto grau histopatológico, alto índice mitótico e necrose nos tumores malignos da bainha do nervo periférico. A presença de necrose também estava correlacionada com uma menor sobrevida total e o alto índice de positividade para a caspase-3 clivada mostrou-se um fator preditor importante para menor sobrevida livre de doença, na análise multivariada de Cox. Nossos resultados sugerem que a alteração da expressão das proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada estão possivelmente associadas com o desevolvimento dos tumores malignos da bainha do nervo periférico.Programa de Pós-graduação em PatologiaPatologiaLopes, Vânia SilamiCPF:99985743122http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4793225Y6Moura Neto, Rodrigo Soares deCPF:02817006022http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4781261J7Geller, MauroCPF:79528160522http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4788915E8Rochael, Mayra CarrijoCPF:43455321122http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4797553J7Canedo, Nathalie Henriques SilvaCPF:82400405022http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4795406Y9Oliveira, Carlos Alberto Basilio deCPF:02305000222http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4787042E6Carakushansky, GersonCPF:71641827122http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4783548P4Peryassú, Marcius AchiaméCPF:79481711222http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4584942Y3Cunha, Karin Soares Gonçalves2021-03-10T20:44:05Z2009-03-312021-03-10T20:44:05Z2008-07-02info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttps://app.uff.br/riuff/handle/1/18270porCC-BY-SAinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da Universidade Federal Fluminense (RIUFF)instname:Universidade Federal Fluminense (UFF)instacron:UFF2021-03-10T20:44:05Zoai:app.uff.br:1/18270Repositório InstitucionalPUBhttps://app.uff.br/oai/requestriuff@id.uff.bropendoar:21202024-08-19T10:55:02.345468Repositório Institucional da Universidade Federal Fluminense (RIUFF) - Universidade Federal Fluminense (UFF)false
dc.title.none.fl_str_mv Avaliação imuno-histoquímica da expressão das proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada em neurofibromas e tumores malignos da bainha do nervo periférico: correlação clínico-patológica
title Avaliação imuno-histoquímica da expressão das proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada em neurofibromas e tumores malignos da bainha do nervo periférico: correlação clínico-patológica
spellingShingle Avaliação imuno-histoquímica da expressão das proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada em neurofibromas e tumores malignos da bainha do nervo periférico: correlação clínico-patológica
Cunha, Karin Soares Gonçalves
Tumores malignos da bainha do nervo periférico
Neurofibromas
Neurofibromatose Tipo 1
Proteína p53
Proteína Bcl-2
Proteína Bcl-x
Caspase-3 clivada
imunohistoquímica
Neurofibroma
Malignant peripheral nerve sheath tumor
apoptosis
p53 protein
Bcl-2 protein
Bcl-x protein
Cleaved caspase-3
Immunohistochemistry
CNPQ::CIENCIAS DA SAUDE::MEDICINA::ANATOMIA PATOLOGICA E PATOLOGIA CLINICA
title_short Avaliação imuno-histoquímica da expressão das proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada em neurofibromas e tumores malignos da bainha do nervo periférico: correlação clínico-patológica
title_full Avaliação imuno-histoquímica da expressão das proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada em neurofibromas e tumores malignos da bainha do nervo periférico: correlação clínico-patológica
title_fullStr Avaliação imuno-histoquímica da expressão das proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada em neurofibromas e tumores malignos da bainha do nervo periférico: correlação clínico-patológica
title_full_unstemmed Avaliação imuno-histoquímica da expressão das proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada em neurofibromas e tumores malignos da bainha do nervo periférico: correlação clínico-patológica
title_sort Avaliação imuno-histoquímica da expressão das proteínas p53, Bcl-2, Bcl-x e caspase-3 clivada em neurofibromas e tumores malignos da bainha do nervo periférico: correlação clínico-patológica
author Cunha, Karin Soares Gonçalves
author_facet Cunha, Karin Soares Gonçalves
author_role author
dc.contributor.none.fl_str_mv Lopes, Vânia Silami
CPF:99985743122
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4793225Y6
Moura Neto, Rodrigo Soares de
CPF:02817006022
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4781261J7
Geller, Mauro
CPF:79528160522
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4788915E8
Rochael, Mayra Carrijo
CPF:43455321122
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4797553J7
Canedo, Nathalie Henriques Silva
CPF:82400405022
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4795406Y9
Oliveira, Carlos Alberto Basilio de
CPF:02305000222
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4787042E6
Carakushansky, Gerson
CPF:71641827122
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4783548P4
Peryassú, Marcius Achiamé
CPF:79481711222
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4584942Y3
dc.contributor.author.fl_str_mv Cunha, Karin Soares Gonçalves
dc.subject.por.fl_str_mv Tumores malignos da bainha do nervo periférico
Neurofibromas
Neurofibromatose Tipo 1
Proteína p53
Proteína Bcl-2
Proteína Bcl-x
Caspase-3 clivada
imunohistoquímica
Neurofibroma
Malignant peripheral nerve sheath tumor
apoptosis
p53 protein
Bcl-2 protein
Bcl-x protein
Cleaved caspase-3
Immunohistochemistry
CNPQ::CIENCIAS DA SAUDE::MEDICINA::ANATOMIA PATOLOGICA E PATOLOGIA CLINICA
topic Tumores malignos da bainha do nervo periférico
Neurofibromas
Neurofibromatose Tipo 1
Proteína p53
Proteína Bcl-2
Proteína Bcl-x
Caspase-3 clivada
imunohistoquímica
Neurofibroma
Malignant peripheral nerve sheath tumor
apoptosis
p53 protein
Bcl-2 protein
Bcl-x protein
Cleaved caspase-3
Immunohistochemistry
CNPQ::CIENCIAS DA SAUDE::MEDICINA::ANATOMIA PATOLOGICA E PATOLOGIA CLINICA
description Malignant peripheral nerve sheath tumors are rare and highly aggressive neoplasms. Neurofibromatosis type 1, a syndrome caused by mutations in the NF1 gene, is the major risk factor for the development of these tumors. Malignant peripheral nerve sheath tumors may appear de novo or may develop from the transformation of a benign neural neoplasm, mainly from a plexiform neurofibroma, which occurs almost exclusively in Neurofibromatosis type 1 patients. Nowadays, the knowledge of the factors involved in the oncogenesis of malignant peripheral nerve sheath tumors is still modest. It is believed that the loss of heterozygosity of NF1 gene is sufficient for the development of neurofibromas, but studies have been demonstrated that the pathogenesis of malignant peripheral nerve sheath tumors is a multistage process, involving many molecular alterations in addition to biallelic inactivation of NF1 gene. Many authors have been evaluated alterations in cell proliferation control genes, but the knowledge of apoptosis alterations in these tumors is still scarce. With the aim to evaluate the expression of apoptosis-associated proteins in malignant peripheral nerve sheath tumors, the immunoreactivity of p53, Bcl-2, Bcl-x and cleaved caspase-3 proteins was investigated in 28 malignant peripheral nerve sheath tumors, using tissue microarray, and compared with their immunoreactivity in 38 neurofibromas. The correlation of the expression of these proteins with clinicopathological features and prognosis of malignant peripheral nerve sheath tumors was also investigated. P53, Bcl-2, Bcl-x and cleaved caspase-3 proteins were expressed in 64,3%, 78,6%, 75,0% and 100% of malignant peripheral nerve sheath tumors, respectively, and in 2,6%, 32,4%, 43,2% and 100% of neurofibromas, respectively. Comparing the immunopositive cases, malignant perihperal nerve sheath tumores showed higher positivity indexes for Bcl-2, Bcl-x and cleaved caspase-3 than neurofibromas. In neurofibromas, cleaved caspase-3 expression was only observed in the nucleus of the cells, whereas 50% of malignant peripheral nerve sheath tumors showed nuclear expression and the other 50% expressed cleaved caspase-3 in the nucleus and in the cytoplasm of the cells. There was a correlation between the cytoplasmatic expression of cleaved caspase-3 and the high histological grade, high mitotic index and necrosis. In multivariate Cox analysis, necrosis was an independent predictor factor for lower overall survival and high positivity index for cleaved caspase-3 was an independent risk factor for worse disease-free survival. Our results suggest that alterations of p53, Bcl-2, Bcl-x and cleaved caspase-3 expression are possibly associated to the development of malignant peripheral nerve sheath tumors
publishDate 2008
dc.date.none.fl_str_mv 2008-07-02
2009-03-31
2021-03-10T20:44:05Z
2021-03-10T20:44:05Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://app.uff.br/riuff/handle/1/18270
url https://app.uff.br/riuff/handle/1/18270
dc.language.iso.fl_str_mv por
language por
dc.rights.driver.fl_str_mv CC-BY-SA
info:eu-repo/semantics/openAccess
rights_invalid_str_mv CC-BY-SA
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Programa de Pós-graduação em Patologia
Patologia
publisher.none.fl_str_mv Programa de Pós-graduação em Patologia
Patologia
dc.source.none.fl_str_mv reponame:Repositório Institucional da Universidade Federal Fluminense (RIUFF)
instname:Universidade Federal Fluminense (UFF)
instacron:UFF
instname_str Universidade Federal Fluminense (UFF)
instacron_str UFF
institution UFF
reponame_str Repositório Institucional da Universidade Federal Fluminense (RIUFF)
collection Repositório Institucional da Universidade Federal Fluminense (RIUFF)
repository.name.fl_str_mv Repositório Institucional da Universidade Federal Fluminense (RIUFF) - Universidade Federal Fluminense (UFF)
repository.mail.fl_str_mv riuff@id.uff.br
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