Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta à radioterapia em gliomas

Detalhes bibliográficos
Autor(a) principal: Gehring, Marina Petersen
Data de Publicação: 2016
Tipo de documento: Tese
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações da PUC_RS
Texto Completo: http://tede2.pucrs.br/tede2/handle/tede/6652
Resumo: Gliomas represent the most common class of malignant tumors of the central nervous system being the most aggressive, and lethal brain tumors in primary brain tumors. Among the treatments, radiation is one of the most used therapies, but the intrinsic radioresistance of these tumors remains a critical problem in the management of these patients. Currently it is known that the effect of radiation extends beyond the directly cytotoxicity caused in tumor cells. Radiation therapy appears to induce an immunogenic cell death that among the features is ATP release. The ATP can cause cytotoxicity via P2X7 receptor and also acts as a sign of damage activating the immune system. The ATP can be hydrolyzed by enzymes of the purinergic system, among them the ectonucleotidase CD39, to adenosine, which has an opposite effect to ATP, causing immunosuppression. The radiation-induced ATP release and the ability of this nucleotide in modulate immune responses raised the hypothesis about the purinergic signaling participation in the tumor and immune cells response to radiation. Therefore, this study investigated: i) the role of ectonucleotidase CD39/NTPDase1 in the radiation-induced immune response in gliomas, ii) the importance of ATP-P2X7 receptor in the gliomas response to radiotherapy. Using knockout mice for CD39/NTPDase1, we observed that the deletion of this enzyme combined with radiotherapy significantly reduced the immunosuppressive cells Tregs in the tumor and spleen, attenuated the infiltration of myeloid derived suppressor cells caused by radiation and increased CCR7 expression in splenic dendritic cells and macrophages, indicating the presence of freshly mobilized antigen presenting cells available to differentiate in immune-effector cells that sustain a more prolonged antigen-specific T-cell–mediated immune response. Thereby, showing that blocking the activity of CD39/NTPDase1 can control immunosuppressive mechanisms generated by the tumor and promises to improve the radiotherapy response. Furthermore, in this study we observed that radiation actives the P2X7 receptor and by silencing this receptor on the GL261 glioma cell line, we have shown that radiotherapy is less efficient in vivo when compared with mice injected with GL261 WT cells, which constitutively express the P2X7 receptor. We also showed that patients with glioma that overexpress the P2X7 receptor, showed a better response to radiotherapy, revealing the importance of the expression of this receptor on glioma cells as a useful marker to analyze the tumor sensitivity to radiation and a successful radiotherapy response. In summary, our data shed light on the purinergic signaling for modulating the radiotherapy response in gliomas.
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spelling Morrone, Fernanda Bueno462.631.280-20http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4707416P4020.647.450-41http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4203373P6Gehring, Marina Petersen2016-05-10T11:19:25Z2016-01-11http://tede2.pucrs.br/tede2/handle/tede/6652Gliomas represent the most common class of malignant tumors of the central nervous system being the most aggressive, and lethal brain tumors in primary brain tumors. Among the treatments, radiation is one of the most used therapies, but the intrinsic radioresistance of these tumors remains a critical problem in the management of these patients. Currently it is known that the effect of radiation extends beyond the directly cytotoxicity caused in tumor cells. Radiation therapy appears to induce an immunogenic cell death that among the features is ATP release. The ATP can cause cytotoxicity via P2X7 receptor and also acts as a sign of damage activating the immune system. The ATP can be hydrolyzed by enzymes of the purinergic system, among them the ectonucleotidase CD39, to adenosine, which has an opposite effect to ATP, causing immunosuppression. The radiation-induced ATP release and the ability of this nucleotide in modulate immune responses raised the hypothesis about the purinergic signaling participation in the tumor and immune cells response to radiation. Therefore, this study investigated: i) the role of ectonucleotidase CD39/NTPDase1 in the radiation-induced immune response in gliomas, ii) the importance of ATP-P2X7 receptor in the gliomas response to radiotherapy. Using knockout mice for CD39/NTPDase1, we observed that the deletion of this enzyme combined with radiotherapy significantly reduced the immunosuppressive cells Tregs in the tumor and spleen, attenuated the infiltration of myeloid derived suppressor cells caused by radiation and increased CCR7 expression in splenic dendritic cells and macrophages, indicating the presence of freshly mobilized antigen presenting cells available to differentiate in immune-effector cells that sustain a more prolonged antigen-specific T-cell–mediated immune response. Thereby, showing that blocking the activity of CD39/NTPDase1 can control immunosuppressive mechanisms generated by the tumor and promises to improve the radiotherapy response. Furthermore, in this study we observed that radiation actives the P2X7 receptor and by silencing this receptor on the GL261 glioma cell line, we have shown that radiotherapy is less efficient in vivo when compared with mice injected with GL261 WT cells, which constitutively express the P2X7 receptor. We also showed that patients with glioma that overexpress the P2X7 receptor, showed a better response to radiotherapy, revealing the importance of the expression of this receptor on glioma cells as a useful marker to analyze the tumor sensitivity to radiation and a successful radiotherapy response. In summary, our data shed light on the purinergic signaling for modulating the radiotherapy response in gliomas.Os gliomas representam a classe mais comum de tumores malignos do sistema nervoso central, sendo o tumor cerebral mais agressivo e letal entre os tumores cerebrais primários. Dentre os tratamentos, a radiação é uma das terapias mais utilizadas, porém a radiorresistência intrínseca destes tumores continua a ser um problema crítico na gestão de destes pacientes. Atualmente, sabe-se que o efeito da radiação se estende além da citotoxicidade direta causada nas células tumorais. A radioterapia parece induzir uma morte celular imunogênica, que entre as características está a liberação de ATP. O ATP pode causar citotoxicidade através do receptor P2X7 e também atua como um sinal de dano celular ativando o sistema imune. O ATP pode ser hidrolisado por enzimas do sistema purinérgico, dentre elas a ectonucleotidase CD39/NTPDase1, à adenosina, que tem um efeito aposto ao ATP, causando imunossupressão. A secreção de ATP induzida pela radioterapia e a capacidade deste nucleotídeo em modular a resposta imune, levantou a hipótese da participação da sinalização purinérgica na resposta de células tumorais à radiação e na resposta imune induzida pela radioterapia. Portanto, neste estudo visou-se investigar: i) o papel da ectonucleotidase CD39/NTPDase1 na resposta imune induzida pela radioterapia em gliomas, ii) a importância da via ATP-receptor P2X7 na resposta de gliomas à radioterapia. Através de camundongos knockout para a enzima CD39/NTPDase1, observamos que a deleção desta enzima combinada com a radioterapia reduziu significativamente as células imunossupressoras Tregs no tumor e no baço, atenuou a infiltração de células mieloides supressoras causada pela radiação, e aumentou a expressão de CCR7 em células dentríticas e macrófagos localizados no baço, indicando a presença células apresentadoras de antígeno recémmobilizadas e disponíveis para se diferenciarem em células imunes efetoras que sustentam uma resposta imune mais prolongada mediada por células T antígeno específicas. Deste modo, mostrou-se que o bloqueio da atividade da CD39/NTPDase1 pode controlar mecanismos imunossupressores gerados pelo tumor e promete melhorar a resposta à radioterapia. Além disso, neste estudo observou-se que a radioterapia ativa o receptor P2X7 e através do silenciamento deste receptor na linhagem de glioma GL261, demonstramos que a radioterapia foi pouco eficiente in vivo, quando comparado com camundongos injetados com a GL261 WT, que expressa constitutivamente o receptor P2X7. Também demonstramos que pacientes com glioma que expressaram mais o receptor P2X7, apresentaram uma melhor resposta a radioterapia, revelando a importância da expressão deste receptor em células de glioma como um marcador útil para analisar a sensibilidade tumoral à radioterapia e para uma resposta bem-sucedida à radioterapia. Em suma, nossos dados lançam luz sobre a sinalização purinérgica para a modulação da resposta à radioterapia em gliomas.Submitted by Setor de Tratamento da Informação - BC/PUCRS (tede2@pucrs.br) on 2016-05-10T11:19:25Z No. of bitstreams: 1 TES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf: 5818535 bytes, checksum: 5b089589ca820b17117fd0c8e9d1cc90 (MD5)Made available in DSpace on 2016-05-10T11:19:25Z (GMT). No. of bitstreams: 1 TES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf: 5818535 bytes, checksum: 5b089589ca820b17117fd0c8e9d1cc90 (MD5) Previous issue date: 2016-01-11Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESapplication/pdfhttp://tede2.pucrs.br:80/tede2/retrieve/164789/TES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf.jpgporPontifícia Universidade Católica do Rio Grande do SulPrograma de Pós-Graduação em Biologia Celular e MolecularPUCRSBrasilFaculdade de BiociênciasTRIFOSFATO DE ADENOSINAGLIOMASRADIOTERAPIABIOLOGIA CELULARBIOLOGIA MOLECULARCIENCIAS BIOLOGICAS::BIOLOGIA GERALPapel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta à radioterapia em gliomasinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesis819824693009663736060060060060036528317262667714-16345593859312446972075167498588264571info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da PUC_RSinstname:Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS)instacron:PUC_RSTHUMBNAILTES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf.jpgTES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf.jpgimage/jpeg3655http://tede2.pucrs.br/tede2/bitstream/tede/6652/4/TES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf.jpgae9686f1d4c362bf054d32502f1e2517MD54TEXTTES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf.txtTES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf.txttext/plain397815http://tede2.pucrs.br/tede2/bitstream/tede/6652/3/TES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf.txt4c445c973309f7d9ae2e995306b52f9aMD53ORIGINALTES_MARINA_PETERSEN_GEHRING_COMPLETO.pdfTES_MARINA_PETERSEN_GEHRING_COMPLETO.pdfapplication/pdf5818535http://tede2.pucrs.br/tede2/bitstream/tede/6652/2/TES_MARINA_PETERSEN_GEHRING_COMPLETO.pdf5b089589ca820b17117fd0c8e9d1cc90MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-8610http://tede2.pucrs.br/tede2/bitstream/tede/6652/1/license.txt5a9d6006225b368ef605ba16b4f6d1beMD51tede/66522016-05-10 12:01:12.299oai:tede2.pucrs.br:tede/6652QXV0b3JpemHDp8OjbyBwYXJhIFB1YmxpY2HDp8OjbyBFbGV0csO0bmljYTogQ29tIGJhc2Ugbm8gZGlzcG9zdG8gbmEgTGVpIEZlZGVyYWwgbsK6OS42MTAsIGRlIDE5IGRlIGZldmVyZWlybyBkZSAxOTk4LCBvIGF1dG9yIEFVVE9SSVpBIGEgcHVibGljYcOnw6NvIGVsZXRyw7RuaWNhIGRhIHByZXNlbnRlIG9icmEgbm8gYWNlcnZvIGRhIEJpYmxpb3RlY2EgRGlnaXRhbCBkYSBQb250aWbDrWNpYSBVbml2ZXJzaWRhZGUgQ2F0w7NsaWNhIGRvIFJpbyBHcmFuZGUgZG8gU3VsLCBzZWRpYWRhIGEgQXYuIElwaXJhbmdhIDY2ODEsIFBvcnRvIEFsZWdyZSwgUmlvIEdyYW5kZSBkbyBTdWwsIGNvbSByZWdpc3RybyBkZSBDTlBKIDg4NjMwNDEzMDAwMi04MSBiZW0gY29tbyBlbSBvdXRyYXMgYmlibGlvdGVjYXMgZGlnaXRhaXMsIG5hY2lvbmFpcyBlIGludGVybmFjaW9uYWlzLCBjb25zw7NyY2lvcyBlIHJlZGVzIMOgcyBxdWFpcyBhIGJpYmxpb3RlY2EgZGEgUFVDUlMgcG9zc2EgYSB2aXIgcGFydGljaXBhciwgc2VtIMO0bnVzIGFsdXNpdm8gYW9zIGRpcmVpdG9zIGF1dG9yYWlzLCBhIHTDrXR1bG8gZGUgZGl2dWxnYcOnw6NvIGRhIHByb2R1w6fDo28gY2llbnTDrWZpY2EuCg==Biblioteca Digital de Teses e Dissertaçõeshttp://tede2.pucrs.br/tede2/PRIhttps://tede2.pucrs.br/oai/requestbiblioteca.central@pucrs.br||opendoar:2016-05-10T15:01:12Biblioteca Digital de Teses e Dissertações da PUC_RS - Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS)false
dc.title.por.fl_str_mv Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta à radioterapia em gliomas
title Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta à radioterapia em gliomas
spellingShingle Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta à radioterapia em gliomas
Gehring, Marina Petersen
TRIFOSFATO DE ADENOSINA
GLIOMAS
RADIOTERAPIA
BIOLOGIA CELULAR
BIOLOGIA MOLECULAR
CIENCIAS BIOLOGICAS::BIOLOGIA GERAL
title_short Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta à radioterapia em gliomas
title_full Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta à radioterapia em gliomas
title_fullStr Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta à radioterapia em gliomas
title_full_unstemmed Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta à radioterapia em gliomas
title_sort Papel do receptor P2X7 e da enzima CD39/NTPDASE1 na resposta à radioterapia em gliomas
author Gehring, Marina Petersen
author_facet Gehring, Marina Petersen
author_role author
dc.contributor.advisor1.fl_str_mv Morrone, Fernanda Bueno
dc.contributor.advisor1ID.fl_str_mv 462.631.280-20
dc.contributor.advisor1Lattes.fl_str_mv http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4707416P4
dc.contributor.authorID.fl_str_mv 020.647.450-41
dc.contributor.authorLattes.fl_str_mv http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4203373P6
dc.contributor.author.fl_str_mv Gehring, Marina Petersen
contributor_str_mv Morrone, Fernanda Bueno
dc.subject.por.fl_str_mv TRIFOSFATO DE ADENOSINA
GLIOMAS
RADIOTERAPIA
BIOLOGIA CELULAR
BIOLOGIA MOLECULAR
topic TRIFOSFATO DE ADENOSINA
GLIOMAS
RADIOTERAPIA
BIOLOGIA CELULAR
BIOLOGIA MOLECULAR
CIENCIAS BIOLOGICAS::BIOLOGIA GERAL
dc.subject.cnpq.fl_str_mv CIENCIAS BIOLOGICAS::BIOLOGIA GERAL
description Gliomas represent the most common class of malignant tumors of the central nervous system being the most aggressive, and lethal brain tumors in primary brain tumors. Among the treatments, radiation is one of the most used therapies, but the intrinsic radioresistance of these tumors remains a critical problem in the management of these patients. Currently it is known that the effect of radiation extends beyond the directly cytotoxicity caused in tumor cells. Radiation therapy appears to induce an immunogenic cell death that among the features is ATP release. The ATP can cause cytotoxicity via P2X7 receptor and also acts as a sign of damage activating the immune system. The ATP can be hydrolyzed by enzymes of the purinergic system, among them the ectonucleotidase CD39, to adenosine, which has an opposite effect to ATP, causing immunosuppression. The radiation-induced ATP release and the ability of this nucleotide in modulate immune responses raised the hypothesis about the purinergic signaling participation in the tumor and immune cells response to radiation. Therefore, this study investigated: i) the role of ectonucleotidase CD39/NTPDase1 in the radiation-induced immune response in gliomas, ii) the importance of ATP-P2X7 receptor in the gliomas response to radiotherapy. Using knockout mice for CD39/NTPDase1, we observed that the deletion of this enzyme combined with radiotherapy significantly reduced the immunosuppressive cells Tregs in the tumor and spleen, attenuated the infiltration of myeloid derived suppressor cells caused by radiation and increased CCR7 expression in splenic dendritic cells and macrophages, indicating the presence of freshly mobilized antigen presenting cells available to differentiate in immune-effector cells that sustain a more prolonged antigen-specific T-cell–mediated immune response. Thereby, showing that blocking the activity of CD39/NTPDase1 can control immunosuppressive mechanisms generated by the tumor and promises to improve the radiotherapy response. Furthermore, in this study we observed that radiation actives the P2X7 receptor and by silencing this receptor on the GL261 glioma cell line, we have shown that radiotherapy is less efficient in vivo when compared with mice injected with GL261 WT cells, which constitutively express the P2X7 receptor. We also showed that patients with glioma that overexpress the P2X7 receptor, showed a better response to radiotherapy, revealing the importance of the expression of this receptor on glioma cells as a useful marker to analyze the tumor sensitivity to radiation and a successful radiotherapy response. In summary, our data shed light on the purinergic signaling for modulating the radiotherapy response in gliomas.
publishDate 2016
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