Estudo da indoleamina 2,3-dioxigenase 1 no câncer de bexiga: correlação com parâmetros clinicopatológicos, relação com BCG e sua inibição química
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da Uninove |
Texto Completo: | http://bibliotecatede.uninove.br/handle/tede/2763 |
Resumo: | Bladder cancer (BC) has a high rate of recurrence and progression even after TUR associated with BCG immunotherapy. Indoleamine 2,3-dioxigenase 1 (IDO) is an immunomodulatory enzyme implied in the immune escape and progression of several types of cancer, acting through signaling pathways, such as GCN2 (general control nonderepressible 2) and AHR (aryl hydrocarbon receptor). Because it is strongly induced by interferon-gamma, a BCG-induced cytokine, IDO may be responsible for part of the progression of BC after conventional treatment. The inhibition of IDO becomes attractive, but the effect of inhibitors over its pathways in BC is not known. The objectives were: (i) to verify if the IDO is associated with the progression of the BC; (ii) verify whether BCG induces IDO in the BC; and (ii) check if two usual IDO inhibitors interfere with the GNC2 and AHR pathways in the BC. Biopsies from 155 patients with BC were selected for the study, 88 with non-muscle-invasive BC (NMI) and 67 with muscle-invasive BC (MI). Immunohistochemistry for IDO was performed to correlate its expression with clinicopathological data acquired from medical records. The effect of BCG on the expression of IDO was investigated in culture of human lines of BC and in in vivo model, evaluating it by means of immunohistochemistry and real-time PCR. Inhibitors of IDO 1-methyl-D-tryptophan (MT) and INCB024360 (INCB) were evaluated in cell culture and MT in animal model. The inhibition of IDO was measured by measuring L-quinurenine in the supernatant and the activation of the GCN2 and AHR pathways by real-time PCR for CHOP and CYP1A1, respectively. As a result, the expression of IDO correlates positively with the progression of the BC (grade and stage). The use of BCG had no effect on the expression of IDO, either in culture or in animal model. The evaluated inhibitors were effective in inhibiting IDO, but MT induced the AHR pathway triggered by IDO, as an agonist. In conclusion, (i) the IDO has the potential to assist in the prognosis of BC, as it is associated with advanced degree and stage of BC; (ii) BCG does not directly induce the expression of IDO in BC, remaining as a safe adjuvant treatment; (iii) between the two IDO inhibitors evaluated, the INCB is promising, while MT offers risk for activating the AHR pathway, a pathway recognized as a potential for tumor escape and progression. |
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Dellê, Humbertohttp://lattes.cnpq.br/7435662740477057Dellê, Humbertohttp://lattes.cnpq.br/7435662740477057Dalboni, Maria Aparecidahttp://lattes.cnpq.br/9818040147487320Marcos, Rodrigo Labathttp://lattes.cnpq.br/2964112163504080Moreno, Maria Carolina Ramoshttp://lattes.cnpq.br/1778359865832303Matheus, Luiz Henrique Gomes2021-11-18T19:44:21Z2020-03-23Matheus, Luiz Henrique Gomes. Estudo da indoleamina 2,3-dioxigenase 1 no câncer de bexiga: correlação com parâmetros clinicopatológicos, relação com BCG e sua inibição química. 2020. 98 f. Tese( Programa de Mestrado em Medicina) - Universidade Nove de Julho, São Paulo.http://bibliotecatede.uninove.br/handle/tede/2763Bladder cancer (BC) has a high rate of recurrence and progression even after TUR associated with BCG immunotherapy. Indoleamine 2,3-dioxigenase 1 (IDO) is an immunomodulatory enzyme implied in the immune escape and progression of several types of cancer, acting through signaling pathways, such as GCN2 (general control nonderepressible 2) and AHR (aryl hydrocarbon receptor). Because it is strongly induced by interferon-gamma, a BCG-induced cytokine, IDO may be responsible for part of the progression of BC after conventional treatment. The inhibition of IDO becomes attractive, but the effect of inhibitors over its pathways in BC is not known. The objectives were: (i) to verify if the IDO is associated with the progression of the BC; (ii) verify whether BCG induces IDO in the BC; and (ii) check if two usual IDO inhibitors interfere with the GNC2 and AHR pathways in the BC. Biopsies from 155 patients with BC were selected for the study, 88 with non-muscle-invasive BC (NMI) and 67 with muscle-invasive BC (MI). Immunohistochemistry for IDO was performed to correlate its expression with clinicopathological data acquired from medical records. The effect of BCG on the expression of IDO was investigated in culture of human lines of BC and in in vivo model, evaluating it by means of immunohistochemistry and real-time PCR. Inhibitors of IDO 1-methyl-D-tryptophan (MT) and INCB024360 (INCB) were evaluated in cell culture and MT in animal model. The inhibition of IDO was measured by measuring L-quinurenine in the supernatant and the activation of the GCN2 and AHR pathways by real-time PCR for CHOP and CYP1A1, respectively. As a result, the expression of IDO correlates positively with the progression of the BC (grade and stage). The use of BCG had no effect on the expression of IDO, either in culture or in animal model. The evaluated inhibitors were effective in inhibiting IDO, but MT induced the AHR pathway triggered by IDO, as an agonist. In conclusion, (i) the IDO has the potential to assist in the prognosis of BC, as it is associated with advanced degree and stage of BC; (ii) BCG does not directly induce the expression of IDO in BC, remaining as a safe adjuvant treatment; (iii) between the two IDO inhibitors evaluated, the INCB is promising, while MT offers risk for activating the AHR pathway, a pathway recognized as a potential for tumor escape and progression.O câncer de bexiga (CB) apresenta alta taxa de recorrência e progressão mesmo após RTU associada à imunoterapia com BCG. A indoleamina 2,3-dioxigenase 1 (IDO) é uma enzima imunomoduladora implicada no escape imunológico e progressão de diversos tipos de câncer, agindo por meio de vias de sinalização, tais como GCN2 (general control nondrepressible 2) e AHR (aryl hydrocarbon receptor). Por ser fortemente induzida por interferon-gama, uma citocina induzida por BCG, a IDO pode ser responsável por parte da progressão do CB após o tratamento convencional. A inibição da IDO torna-se atraente, porém o efeito dos inibidores sobre as suas vias no CB não é conhecido. Os objetivos foram: (i) verificar se a IDO está associada com a progressão do CB; (ii) verificar se o BCG induz IDO no CB; e (ii) verificar se dois inibidores usuais da IDO interferem nas vias GNC2 e AHR no CB. Biópsias de 155 pacientes com CB foram selecionadas para o estudo, sendo 88 com CB não músculo-invasivo (NMI) e 67 com CB músculo-invasivo (MI). Imunohistoquímica para IDO foi realizada para correlacionar sua expressão com os dados clinicopatológicos adquiridos dos prontuários. O efeito do BCG sobre a expressão de IDO foi investigado em cultura de linhagens humanas de CB e em modelo in vivo, avaliando-a por meio de imunohistoquímica e PCR em tempo real. Os inibidores da IDO 1-metil-D-triptofano (MT) e INCB024360 (INCB) foram avaliados em cultura de células e o MT em modelo animal. A inibição da IDO foi aferida pela mensuração de L-quinurenina no sobrenadante e a ativação das vias GCN2 e AHR por meio de PCR em tempo real para CHOP e CYP1A1, respectivamente. Como resultados, a expressão de IDO correlaciona-se positivamente com progressão do CB (grau e estádio). Já o uso de BCG não exerceu efeito sobre a expressão de IDO, tanto em cultura como em modelo animal. Os inibidores avaliados foram eficazes em inibir a IDO, porém o MT induziu a via AHR acionada pela IDO, como um agonista. Como conclusão, (i) a IDO tem potencial para auxiliar no prognóstico do CB, pois associa-se com grau e estagio avançados de CB; (ii) o BCG não induz diretamente a expressão de IDO no CB, mantendo-se como um tratamento adjuvante seguro; (iii) entre os dois inibidores da IDO avaliados, o INCB mostra-se promissor, enquanto o MT oferece risco por acionar a via AHR, uma via reconhecida como potencializadora de escape e progressão tumorais.Submitted by Nadir Basilio (nadirsb@uninove.br) on 2021-11-18T19:44:21Z No. of bitstreams: 1 Luiz Henrique Gomes Matheus.pdf: 2644993 bytes, checksum: b311ff61c9f945e8ba5726083bc80490 (MD5)Made available in DSpace on 2021-11-18T19:44:21Z (GMT). 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dc.title.por.fl_str_mv |
Estudo da indoleamina 2,3-dioxigenase 1 no câncer de bexiga: correlação com parâmetros clinicopatológicos, relação com BCG e sua inibição química |
dc.title.alternative.eng.fl_str_mv |
Study of indoleamine 2,3-dioxygenase in bladder cancer: correlation with clinicopathological parameters, relationship with BCG and its chemical inhibition |
title |
Estudo da indoleamina 2,3-dioxigenase 1 no câncer de bexiga: correlação com parâmetros clinicopatológicos, relação com BCG e sua inibição química |
spellingShingle |
Estudo da indoleamina 2,3-dioxigenase 1 no câncer de bexiga: correlação com parâmetros clinicopatológicos, relação com BCG e sua inibição química Matheus, Luiz Henrique Gomes Indoleamina 2,3-dioxigenase 1 BCG receptor de hidrocarboneto de arila Indoleamine 2,3-dioxygenase 1 BCG aryl hydrocarbon receptor CIENCIAS DA SAUDE |
title_short |
Estudo da indoleamina 2,3-dioxigenase 1 no câncer de bexiga: correlação com parâmetros clinicopatológicos, relação com BCG e sua inibição química |
title_full |
Estudo da indoleamina 2,3-dioxigenase 1 no câncer de bexiga: correlação com parâmetros clinicopatológicos, relação com BCG e sua inibição química |
title_fullStr |
Estudo da indoleamina 2,3-dioxigenase 1 no câncer de bexiga: correlação com parâmetros clinicopatológicos, relação com BCG e sua inibição química |
title_full_unstemmed |
Estudo da indoleamina 2,3-dioxigenase 1 no câncer de bexiga: correlação com parâmetros clinicopatológicos, relação com BCG e sua inibição química |
title_sort |
Estudo da indoleamina 2,3-dioxigenase 1 no câncer de bexiga: correlação com parâmetros clinicopatológicos, relação com BCG e sua inibição química |
author |
Matheus, Luiz Henrique Gomes |
author_facet |
Matheus, Luiz Henrique Gomes |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Dellê, Humberto |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/7435662740477057 |
dc.contributor.referee1.fl_str_mv |
Dellê, Humberto |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/7435662740477057 |
dc.contributor.referee2.fl_str_mv |
Dalboni, Maria Aparecida |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/9818040147487320 |
dc.contributor.referee3.fl_str_mv |
Marcos, Rodrigo Labat |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/2964112163504080 |
dc.contributor.referee4.fl_str_mv |
Moreno, Maria Carolina Ramos |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/1778359865832303 |
dc.contributor.author.fl_str_mv |
Matheus, Luiz Henrique Gomes |
contributor_str_mv |
Dellê, Humberto Dellê, Humberto Dalboni, Maria Aparecida Marcos, Rodrigo Labat Moreno, Maria Carolina Ramos |
dc.subject.por.fl_str_mv |
Indoleamina 2,3-dioxigenase 1 BCG receptor de hidrocarboneto de arila |
topic |
Indoleamina 2,3-dioxigenase 1 BCG receptor de hidrocarboneto de arila Indoleamine 2,3-dioxygenase 1 BCG aryl hydrocarbon receptor CIENCIAS DA SAUDE |
dc.subject.eng.fl_str_mv |
Indoleamine 2,3-dioxygenase 1 BCG aryl hydrocarbon receptor |
dc.subject.cnpq.fl_str_mv |
CIENCIAS DA SAUDE |
description |
Bladder cancer (BC) has a high rate of recurrence and progression even after TUR associated with BCG immunotherapy. Indoleamine 2,3-dioxigenase 1 (IDO) is an immunomodulatory enzyme implied in the immune escape and progression of several types of cancer, acting through signaling pathways, such as GCN2 (general control nonderepressible 2) and AHR (aryl hydrocarbon receptor). Because it is strongly induced by interferon-gamma, a BCG-induced cytokine, IDO may be responsible for part of the progression of BC after conventional treatment. The inhibition of IDO becomes attractive, but the effect of inhibitors over its pathways in BC is not known. The objectives were: (i) to verify if the IDO is associated with the progression of the BC; (ii) verify whether BCG induces IDO in the BC; and (ii) check if two usual IDO inhibitors interfere with the GNC2 and AHR pathways in the BC. Biopsies from 155 patients with BC were selected for the study, 88 with non-muscle-invasive BC (NMI) and 67 with muscle-invasive BC (MI). Immunohistochemistry for IDO was performed to correlate its expression with clinicopathological data acquired from medical records. The effect of BCG on the expression of IDO was investigated in culture of human lines of BC and in in vivo model, evaluating it by means of immunohistochemistry and real-time PCR. Inhibitors of IDO 1-methyl-D-tryptophan (MT) and INCB024360 (INCB) were evaluated in cell culture and MT in animal model. The inhibition of IDO was measured by measuring L-quinurenine in the supernatant and the activation of the GCN2 and AHR pathways by real-time PCR for CHOP and CYP1A1, respectively. As a result, the expression of IDO correlates positively with the progression of the BC (grade and stage). The use of BCG had no effect on the expression of IDO, either in culture or in animal model. The evaluated inhibitors were effective in inhibiting IDO, but MT induced the AHR pathway triggered by IDO, as an agonist. In conclusion, (i) the IDO has the potential to assist in the prognosis of BC, as it is associated with advanced degree and stage of BC; (ii) BCG does not directly induce the expression of IDO in BC, remaining as a safe adjuvant treatment; (iii) between the two IDO inhibitors evaluated, the INCB is promising, while MT offers risk for activating the AHR pathway, a pathway recognized as a potential for tumor escape and progression. |
publishDate |
2020 |
dc.date.issued.fl_str_mv |
2020-03-23 |
dc.date.accessioned.fl_str_mv |
2021-11-18T19:44:21Z |
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dc.identifier.citation.fl_str_mv |
Matheus, Luiz Henrique Gomes. Estudo da indoleamina 2,3-dioxigenase 1 no câncer de bexiga: correlação com parâmetros clinicopatológicos, relação com BCG e sua inibição química. 2020. 98 f. Tese( Programa de Mestrado em Medicina) - Universidade Nove de Julho, São Paulo. |
dc.identifier.uri.fl_str_mv |
http://bibliotecatede.uninove.br/handle/tede/2763 |
identifier_str_mv |
Matheus, Luiz Henrique Gomes. Estudo da indoleamina 2,3-dioxigenase 1 no câncer de bexiga: correlação com parâmetros clinicopatológicos, relação com BCG e sua inibição química. 2020. 98 f. Tese( Programa de Mestrado em Medicina) - Universidade Nove de Julho, São Paulo. |
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http://bibliotecatede.uninove.br/handle/tede/2763 |
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