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
Ano de defesa: | 2008 |
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Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | |
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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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 |
_version_ |
1817064810144071680 |