Potencial prognóstico da expressão das proteínas imunomoduladoras IDO, CD39 e CD73 na progressão do câncer de bexiga
Autor(a) principal: | |
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Data de Publicação: | 2021 |
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/2986 |
Resumo: | Introduction: Bladder cancer (BC) is the second most common tumor of the urinary system. Although 75% of cases have an initial non-muscle-invasive presentation (NMIBC) and can be treated curatively with organ preservation through endoscopic resection, about 75% present with recurrence and 20% progress to the muscle-invasive form (MIBC). Immunotherapy with intravesical BCG is used as an adjuvant therapy and reduces tumor recurrence and progression by 50%, but the other half of the cases will still have a recurrence of the neoplasm. MIBC, on the other hand, is treated by radical cystectomy and neoadjuvant chemotherapy, but at this stage the treatment has high perioperative morbidity and the 5-year survival is only 50%. The promising results of immunotherapies have encouraged new targets. Indoleamine 2,3-dioxygenase (IDO) is an enzyme that has immunomodulatory action in important physiological mechanisms, preventing an exacerbated response of the immune system. IDO is also expressed in tumors where it acts by inhibiting lymphocytic activity and thus promoting immune escape. CD39 and CD73 proteins also have immunosuppressive action and, like IDO, they have oncogenic action, as they favor the immune escape of the neoplastic cell. Although the role of IDO, CD39 and CD73 is not yet fully established, the expression of these molecules may have prognostic potential in BC. Objectives: To evaluate the protein expression of IDO, CD73 and CD39 in surgical specimens of CBNMI and CBMI and to correlate with clinicopathological parameters. Material and methods: We retrospectively selected 88 patients with NIMBC treated by endoscopic resection and adjuvant BCG who had or did not have disease recurrence during the postoperative follow-up at Hospital Brigadeiro between 2012 and 2017. We also evaluated the expression of these markers in a series of 77 patients with CBMI treated by radical cystectomy at the same time and location. Protein expression was evaluated semiquantitatively by immunohistochemistry in Tissue Micro Array containing three samples per case. We correlated the expression of these proteins with tumor grade, pathological stage, recurrence, smoking, treatment and disease progression. Results: Of the 162 patients who offered viable samples, 129 were men (79.6%) and 33 were women (20.4%). Most were elderly (70.4%>65 years old) and smokers (79.5%). As for the histological grade, 74% of the patients were of high grade and 26% of low grade. The high expression of IDO1 correlated with an early stage (NMIBC x MIBC) and with patients undergoing TUR (RTU x CR) (p<0.001). The high expression of CD39 was associated with NMIBC (p<0.001), the lower grade stage (Ta, T1 x T2, T3 and T4) and the RTU treatment (RTU x CR) (p<0.001). Regarding CD73, no clinical-pathological characteristics were associated. However, when combined with CD39 expression, low expression of CD39 and CD73 was associated with advanced BC. Regarding the treatment, the high expression of both was present in patients submitted to TUR in contrast to the low expression of both in the CR (p<0.001). Finally, the analysis of the correlation between the association of IDO, CD39 and CD73 expression proved to be significant (p<0.002). Conclusion: We propose that the analysis of IDO, CD39 and CD73 enzymes may be complementary biomarkers in the prognosis of BC. |
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Dellê, Humbertohttp://lattes.cnpq.br/7435662740477057Dellê, Humbertohttp://lattes.cnpq.br/7435662740477057Rodrigues, Maria Fernanda Setúbal Destrohttp://lattes.cnpq.br/7153553682954852Zamuner, Stella Reginahttp://lattes.cnpq.br/1935805744318404Moreno, Ana Carolina Ramoshttp://lattes.cnpq.br/3582028585601108http://lattes.cnpq.br/4488806265506200Ferreira, Janaina Mendes2022-07-21T14:19:13Z2021-03-24Ferreira, Janaina Mendes. Potencial prognóstico da expressão das proteínas imunomoduladoras IDO, CD39 e CD73 na progressão do câncer de bexiga. 2021. 81 f. Tese( Programa de Mestrado em Medicina) - Universidade Nove de Julho, São Paulo.http://bibliotecatede.uninove.br/handle/tede/2986Introduction: Bladder cancer (BC) is the second most common tumor of the urinary system. Although 75% of cases have an initial non-muscle-invasive presentation (NMIBC) and can be treated curatively with organ preservation through endoscopic resection, about 75% present with recurrence and 20% progress to the muscle-invasive form (MIBC). Immunotherapy with intravesical BCG is used as an adjuvant therapy and reduces tumor recurrence and progression by 50%, but the other half of the cases will still have a recurrence of the neoplasm. MIBC, on the other hand, is treated by radical cystectomy and neoadjuvant chemotherapy, but at this stage the treatment has high perioperative morbidity and the 5-year survival is only 50%. The promising results of immunotherapies have encouraged new targets. Indoleamine 2,3-dioxygenase (IDO) is an enzyme that has immunomodulatory action in important physiological mechanisms, preventing an exacerbated response of the immune system. IDO is also expressed in tumors where it acts by inhibiting lymphocytic activity and thus promoting immune escape. CD39 and CD73 proteins also have immunosuppressive action and, like IDO, they have oncogenic action, as they favor the immune escape of the neoplastic cell. Although the role of IDO, CD39 and CD73 is not yet fully established, the expression of these molecules may have prognostic potential in BC. Objectives: To evaluate the protein expression of IDO, CD73 and CD39 in surgical specimens of CBNMI and CBMI and to correlate with clinicopathological parameters. Material and methods: We retrospectively selected 88 patients with NIMBC treated by endoscopic resection and adjuvant BCG who had or did not have disease recurrence during the postoperative follow-up at Hospital Brigadeiro between 2012 and 2017. We also evaluated the expression of these markers in a series of 77 patients with CBMI treated by radical cystectomy at the same time and location. Protein expression was evaluated semiquantitatively by immunohistochemistry in Tissue Micro Array containing three samples per case. We correlated the expression of these proteins with tumor grade, pathological stage, recurrence, smoking, treatment and disease progression. Results: Of the 162 patients who offered viable samples, 129 were men (79.6%) and 33 were women (20.4%). Most were elderly (70.4%>65 years old) and smokers (79.5%). As for the histological grade, 74% of the patients were of high grade and 26% of low grade. The high expression of IDO1 correlated with an early stage (NMIBC x MIBC) and with patients undergoing TUR (RTU x CR) (p<0.001). The high expression of CD39 was associated with NMIBC (p<0.001), the lower grade stage (Ta, T1 x T2, T3 and T4) and the RTU treatment (RTU x CR) (p<0.001). Regarding CD73, no clinical-pathological characteristics were associated. However, when combined with CD39 expression, low expression of CD39 and CD73 was associated with advanced BC. Regarding the treatment, the high expression of both was present in patients submitted to TUR in contrast to the low expression of both in the CR (p<0.001). Finally, the analysis of the correlation between the association of IDO, CD39 and CD73 expression proved to be significant (p<0.002). Conclusion: We propose that the analysis of IDO, CD39 and CD73 enzymes may be complementary biomarkers in the prognosis of BC.Introdução: O câncer de bexiga (CB) é o segundo tumor mais comum do sistema urinário. Embora 75% dos casos tenham apresentação inicial não músculo-invasiva (CBNMI) e possam ser tratados curativamente com preservação do órgão através da ressecção endoscópica, cerca de 75% apresentam recorrência e 20% evoluem para a forma músculo-invasiva (CBMI). A imunoterapia com BCG intravesical é utilizada como terapia adjuvante e reduz em 50% a recorrência e a progressão tumoral, porém a outra metade dos casos ainda apresentará a recidiva da neoplasia. Já o CBMI é tratado pela cistectoma radical e quimioterapia neoadjuvante, porém nesse estádio o tratamento apresenta alta morbidade peri-operatória e a sobrevida em 5 anos é de apenas 50%. Os resultados promissores de imunoterapias têm incentivado novos alvos. A indoleamina 2,3-dioxigenase (IDO) é uma enzima que apresenta ação imunomoduladora em mecanismos fisiológicos importantes evitando resposta exacerbada do sistema imune. A IDO também é expressa em tumores onde atua inibindo atividade linfocitária e promovendo assim o escape imunológico. As proteínas CD39 e CD73 também apresentam ação imunossupressora e assim como a IDO têm ação oncogênica, por favorecer o escape imunológico da célula neoplásica. Embora o papel da IDO, CD39 e CD73 ainda não esteja plenamente estabelecido, a expressão destas moléculas possam ter potencial no prognóstico no CB. Objetivos: Avaliar a expressão proteica da IDO, CD73 e CD39 em espécimes cirúrgicos de CBNMI e CBMI e correlacionar com parâmetros clinicopatológicos. Material e métodos: Selecionamos retrospectivamente 88 pacientes com CBNMI tratados por ressecção endoscópica e BCG adjuvante que apresentaram ou não recidiva da doença durante o seguimento pós-operatório no Hospital Brigadeiro entre 2012 e 2017. Avaliamos também a expressão destes marcadores em série de 77 pacientes com CBMI tratados por cistectomia radical no mesmo período e local. A expressão proteica foi avaliada semiquantitativamente por imunohistoquímica em Tissue Micro Array contendo três amostras por caso. Correlacionamos a expressão destas proteínas com o grau tumoral, o estádio patológico, recidiva, tabagismo, tratamento e progressão da doença. Resultados: Dos 162 pacientes que ofereceram amostras viáveis, 129 eram homens (79,6%) e 33 eram mulheres (20,4%). A maioria era formada por idosos (70,4%>65 anos) e fumantes (79,5%). Quanto ao grau histológico, 74% dos pacientes eram de alto grau e 26% de baixo grau. A alta expressão de IDO1 correlacionou-se com um estadio precoce (CBNMI x CBMI) e com pacientes submetidos à RTU (RTU x CR) (p<0,001). A alta expressão de CD39 foi associada ao CBMNI (p<0,001), ao estadio de menor grau (Ta, T1 x T2, T3 e T4) e ao tratamento RTU (RTU x CR) (p<0,001). Em relação à CD73, não foram associadas características clínico-patológicas. No entanto, quando combinado à expressão de CD39, a baixa expressão de CD39 e CD73 foi associada à CB avançada. Em relação ao tratamento, a alta expressão de ambas se apresentou nos pacientes submetidos a RTU em contraste com a baixa expressão de ambas no CR (p<0,001). Por fim a análise da correlação entre a associação da expressão de IDO, CD39 e CD73 demonstrou-se significativa (p<0,002). Conclusão: Propomos que a análise das enzimas IDO, CD39 e CD73, podem ser biomarcadores complementares no prognóstico do CB.Submitted by Nadir Basilio (nadirsb@uninove.br) on 2022-07-21T14:19:13Z No. of bitstreams: 1 Janaina Mendes Ferreira.pdf: 1394108 bytes, checksum: 4d3bc50d7e26a01d9f1f36e7a8721073 (MD5)Made available in DSpace on 2022-07-21T14:19:13Z (GMT). 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dc.title.por.fl_str_mv |
Potencial prognóstico da expressão das proteínas imunomoduladoras IDO, CD39 e CD73 na progressão do câncer de bexiga |
dc.title.alternative.eng.fl_str_mv |
Prognostic potential of the immunomodulatory proteins IDO, CD39 and CD73 in the progression of bladder cancer |
title |
Potencial prognóstico da expressão das proteínas imunomoduladoras IDO, CD39 e CD73 na progressão do câncer de bexiga |
spellingShingle |
Potencial prognóstico da expressão das proteínas imunomoduladoras IDO, CD39 e CD73 na progressão do câncer de bexiga Ferreira, Janaina Mendes IDO CD39 CD73 carcinoma de bexiga biomarcadores prognóstico IDO CD39 CD73 bladder carcinoma biomarkers prognosis CIENCIAS DA SAUDE |
title_short |
Potencial prognóstico da expressão das proteínas imunomoduladoras IDO, CD39 e CD73 na progressão do câncer de bexiga |
title_full |
Potencial prognóstico da expressão das proteínas imunomoduladoras IDO, CD39 e CD73 na progressão do câncer de bexiga |
title_fullStr |
Potencial prognóstico da expressão das proteínas imunomoduladoras IDO, CD39 e CD73 na progressão do câncer de bexiga |
title_full_unstemmed |
Potencial prognóstico da expressão das proteínas imunomoduladoras IDO, CD39 e CD73 na progressão do câncer de bexiga |
title_sort |
Potencial prognóstico da expressão das proteínas imunomoduladoras IDO, CD39 e CD73 na progressão do câncer de bexiga |
author |
Ferreira, Janaina Mendes |
author_facet |
Ferreira, Janaina Mendes |
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 |
Rodrigues, Maria Fernanda Setúbal Destro |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/7153553682954852 |
dc.contributor.referee3.fl_str_mv |
Zamuner, Stella Regina |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/1935805744318404 |
dc.contributor.referee4.fl_str_mv |
Moreno, Ana Carolina Ramos |
dc.contributor.referee4Lattes.fl_str_mv |
http://lattes.cnpq.br/3582028585601108 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/4488806265506200 |
dc.contributor.author.fl_str_mv |
Ferreira, Janaina Mendes |
contributor_str_mv |
Dellê, Humberto Dellê, Humberto Rodrigues, Maria Fernanda Setúbal Destro Zamuner, Stella Regina Moreno, Ana Carolina Ramos |
dc.subject.por.fl_str_mv |
IDO CD39 CD73 carcinoma de bexiga biomarcadores prognóstico |
topic |
IDO CD39 CD73 carcinoma de bexiga biomarcadores prognóstico IDO CD39 CD73 bladder carcinoma biomarkers prognosis CIENCIAS DA SAUDE |
dc.subject.eng.fl_str_mv |
IDO CD39 CD73 bladder carcinoma biomarkers prognosis |
dc.subject.cnpq.fl_str_mv |
CIENCIAS DA SAUDE |
description |
Introduction: Bladder cancer (BC) is the second most common tumor of the urinary system. Although 75% of cases have an initial non-muscle-invasive presentation (NMIBC) and can be treated curatively with organ preservation through endoscopic resection, about 75% present with recurrence and 20% progress to the muscle-invasive form (MIBC). Immunotherapy with intravesical BCG is used as an adjuvant therapy and reduces tumor recurrence and progression by 50%, but the other half of the cases will still have a recurrence of the neoplasm. MIBC, on the other hand, is treated by radical cystectomy and neoadjuvant chemotherapy, but at this stage the treatment has high perioperative morbidity and the 5-year survival is only 50%. The promising results of immunotherapies have encouraged new targets. Indoleamine 2,3-dioxygenase (IDO) is an enzyme that has immunomodulatory action in important physiological mechanisms, preventing an exacerbated response of the immune system. IDO is also expressed in tumors where it acts by inhibiting lymphocytic activity and thus promoting immune escape. CD39 and CD73 proteins also have immunosuppressive action and, like IDO, they have oncogenic action, as they favor the immune escape of the neoplastic cell. Although the role of IDO, CD39 and CD73 is not yet fully established, the expression of these molecules may have prognostic potential in BC. Objectives: To evaluate the protein expression of IDO, CD73 and CD39 in surgical specimens of CBNMI and CBMI and to correlate with clinicopathological parameters. Material and methods: We retrospectively selected 88 patients with NIMBC treated by endoscopic resection and adjuvant BCG who had or did not have disease recurrence during the postoperative follow-up at Hospital Brigadeiro between 2012 and 2017. We also evaluated the expression of these markers in a series of 77 patients with CBMI treated by radical cystectomy at the same time and location. Protein expression was evaluated semiquantitatively by immunohistochemistry in Tissue Micro Array containing three samples per case. We correlated the expression of these proteins with tumor grade, pathological stage, recurrence, smoking, treatment and disease progression. Results: Of the 162 patients who offered viable samples, 129 were men (79.6%) and 33 were women (20.4%). Most were elderly (70.4%>65 years old) and smokers (79.5%). As for the histological grade, 74% of the patients were of high grade and 26% of low grade. The high expression of IDO1 correlated with an early stage (NMIBC x MIBC) and with patients undergoing TUR (RTU x CR) (p<0.001). The high expression of CD39 was associated with NMIBC (p<0.001), the lower grade stage (Ta, T1 x T2, T3 and T4) and the RTU treatment (RTU x CR) (p<0.001). Regarding CD73, no clinical-pathological characteristics were associated. However, when combined with CD39 expression, low expression of CD39 and CD73 was associated with advanced BC. Regarding the treatment, the high expression of both was present in patients submitted to TUR in contrast to the low expression of both in the CR (p<0.001). Finally, the analysis of the correlation between the association of IDO, CD39 and CD73 expression proved to be significant (p<0.002). Conclusion: We propose that the analysis of IDO, CD39 and CD73 enzymes may be complementary biomarkers in the prognosis of BC. |
publishDate |
2021 |
dc.date.issued.fl_str_mv |
2021-03-24 |
dc.date.accessioned.fl_str_mv |
2022-07-21T14:19:13Z |
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.citation.fl_str_mv |
Ferreira, Janaina Mendes. Potencial prognóstico da expressão das proteínas imunomoduladoras IDO, CD39 e CD73 na progressão do câncer de bexiga. 2021. 81 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/2986 |
identifier_str_mv |
Ferreira, Janaina Mendes. Potencial prognóstico da expressão das proteínas imunomoduladoras IDO, CD39 e CD73 na progressão do câncer de bexiga. 2021. 81 f. Tese( Programa de Mestrado em Medicina) - Universidade Nove de Julho, São Paulo. |
url |
http://bibliotecatede.uninove.br/handle/tede/2986 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
8765449414823306929 |
dc.relation.confidence.fl_str_mv |
600 |
dc.rights.driver.fl_str_mv |
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eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Nove de Julho |
dc.publisher.program.fl_str_mv |
Programa de Mestrado em Medicina |
dc.publisher.initials.fl_str_mv |
UNINOVE |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Saúde |
publisher.none.fl_str_mv |
Universidade Nove de Julho |
dc.source.none.fl_str_mv |
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Universidade Nove de Julho (UNINOVE) |
instacron_str |
UNINOVE |
institution |
UNINOVE |
reponame_str |
Biblioteca Digital de Teses e Dissertações da Uninove |
collection |
Biblioteca Digital de Teses e Dissertações da Uninove |
bitstream.url.fl_str_mv |
http://localhost:8080/tede/bitstream/tede/2986/2/Janaina+Mendes+Ferreira.pdf http://localhost:8080/tede/bitstream/tede/2986/1/license.txt |
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MD5 MD5 |
repository.name.fl_str_mv |
Biblioteca Digital de Teses e Dissertações da Uninove - Universidade Nove de Julho (UNINOVE) |
repository.mail.fl_str_mv |
bibliotecatede@uninove.br||bibliotecatede@uninove.br |
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1800312366812889088 |