Macrófagos associados a tumores: um potencial alvo terapêutico em câncer de mama
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da UFMG |
Texto Completo: | http://hdl.handle.net/1843/35906 https://orcid.org/0000-0002-9676-7745 |
Resumo: | Tumor-associated macrophages (TAMs) representing most of the leukocyte population in the tumor microenvironment of breast cancer. TAMs can act on neoplastic development over different mechanisms depending on their activation status. Considering the evidence of the critical role of these cells in the tumor microenvironment, this work aimed to evaluate the role of TAMs on the metastatic progression of 4T1 mouse mammary carcinoma and spontaneous canine mammary carcinomas. Additionally, it was evaluated the immunomodulatory effects of thalidomide as a possible therapeutic target on TAMs polarization in mice inoculated with 4T1 mouse mammary carcinoma. The 4T1 cells were inoculated into female BALB/c mice to obtain the solid tumor and the animals were euthanized at different times of tumor progression (14th, 21st and 28th day of inoculation). Primary tumor and lung were collected for the evaluation of TAMs, versican expression, inflammatory mediators, tumor angiogenesis, and metastases. Forced spirometry technique was also performed to evaluate the mice’s pulmonary functions. Spontaneous canine mammary carcinomas samples were selected and evaluated for TAMs infiltration and versican expression. In a second experiment, 4T1 tumor-bearing mice received oral daily treatment of thalidomide at concentrations of 50 mg/kg, 100 mg/kg, and 150 mg/kg for 23 days. The results obtained demonstrate that TAMs infiltration and versican expression was associated to low-grade and advanced stages of canine mammary carcinomas. In mice, TAMs and versican shown higher in late stages of tumor progression and associated to increased inflammation and angiogenesis of the primary’s tumors, while in the lung TAMs infiltration was associated with pulmonary dysfunction due to the increased number of metastatic nodules, airways leukocytes influx, and high inflammatory mediators’ levels. In the lung, the administration of thalidomide at dose 150 mg/kg reduced the neoplastic proliferation and the numbers of metastatic nodules associated to an increase in inflammation with higher number of TAMs. In conclusion, TAMs appear to play a critical role in the metastatic progression of breast cancer, the immunomodulatory effect of thalidomide may be a therapeutic option for this disease. |
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Macrófagos associados a tumores: um potencial alvo terapêutico em câncer de mamaMacrófagosTalidomidaNeoplasias da mamaMetástase neoplásicaImunoterapiaVersicanasInflamaçãoMacrófagosTalidomidaNeoplasias da MamaMetástase NeoplásicaImunoterapiaVersicanasInflamaçãoDissertação AcadêmicaTumor-associated macrophages (TAMs) representing most of the leukocyte population in the tumor microenvironment of breast cancer. TAMs can act on neoplastic development over different mechanisms depending on their activation status. Considering the evidence of the critical role of these cells in the tumor microenvironment, this work aimed to evaluate the role of TAMs on the metastatic progression of 4T1 mouse mammary carcinoma and spontaneous canine mammary carcinomas. Additionally, it was evaluated the immunomodulatory effects of thalidomide as a possible therapeutic target on TAMs polarization in mice inoculated with 4T1 mouse mammary carcinoma. The 4T1 cells were inoculated into female BALB/c mice to obtain the solid tumor and the animals were euthanized at different times of tumor progression (14th, 21st and 28th day of inoculation). Primary tumor and lung were collected for the evaluation of TAMs, versican expression, inflammatory mediators, tumor angiogenesis, and metastases. Forced spirometry technique was also performed to evaluate the mice’s pulmonary functions. Spontaneous canine mammary carcinomas samples were selected and evaluated for TAMs infiltration and versican expression. In a second experiment, 4T1 tumor-bearing mice received oral daily treatment of thalidomide at concentrations of 50 mg/kg, 100 mg/kg, and 150 mg/kg for 23 days. The results obtained demonstrate that TAMs infiltration and versican expression was associated to low-grade and advanced stages of canine mammary carcinomas. In mice, TAMs and versican shown higher in late stages of tumor progression and associated to increased inflammation and angiogenesis of the primary’s tumors, while in the lung TAMs infiltration was associated with pulmonary dysfunction due to the increased number of metastatic nodules, airways leukocytes influx, and high inflammatory mediators’ levels. In the lung, the administration of thalidomide at dose 150 mg/kg reduced the neoplastic proliferation and the numbers of metastatic nodules associated to an increase in inflammation with higher number of TAMs. In conclusion, TAMs appear to play a critical role in the metastatic progression of breast cancer, the immunomodulatory effect of thalidomide may be a therapeutic option for this disease.Os macrófagos associados a tumores (TAMs) são os leucócitos mais abundantes no microambiente tumoral do câncer de mama. TAMs podem atuar no desenvolvimento neoplásico sobre diferentes mecanismos a depender do seu status de ativação. Diante das evidências do papel dessas células no microambiente tumoral, esse trabalho teve como objetivo avaliar a participação de TAMs na progressão metastática do carcinoma mamário murino 4T1 e de carcinomas mamárias espontâneas da cadela. Ademais, foi avaliado o efeito imunomodulador da talidomida como um possível alvo terapêutico na polarização de TAMs em camundongos inoculados com o carcinoma mamário murino 4T1. As células 4T1 foram inoculadas em camundongos BALB/c fêmeas para obtenção do tumor sólido e os animais foram eutanasiados em diferentes tempos de progressão tumoral (14º 21º e 28º dia de inoculação). As amostras de tumor primário e pulmão foram coletados para a avalição de TAMs, expressão de versican, mediadores inflamatórios, angiogênese e metástases. A espirometria forçada foi também realizada para avaliar as funções pulmonares desses animais. As amostras de carcinoma mamário espontâneo da cadela foram selecionadas e avaliadas quanto à infiltração de TAMs e expressão de versican. Em um segundo experimento, camundongos inoculados com células 4T1 receberam tratamento diário por via oral de talidomida nas doses de 50 mg/kg, 100 mg/kg e 150mg/kg durante 24 dias. Os resultados obtidos demonstram que a infiltração de TAMs e a expressão de versican estão associadas tumores mamários de baixo grau e em estádios mais avançados. Em camundongos, TAMs e versican mostraram-se aumentados em estágios tardios de progressão tumoral e associados com aumento da inflamação e angiogênese nos tumores primários, enquanto no pulmão à infiltração de TAMs esteve associada à disfunção pulmonar devido aumentado número de nódulos metastáticos, influxo de leucócitos para as vias aéreas e elevadas quantidade de mediadores inflamatórios. O tratamento com talidomida na dose de 150 mg/kg resultou em uma redução do crescimento tumoral, diminuição da proliferação celular no tumor primário e aumento da inflamação tecidual com reduzido número de TAMs. No pulmão, o tratamento com 150 mg/kg de talidomida diminui a proliferação celular e redução no número de nódulos metastáticos associados a um aumento da inflamação com elevado número de TAMs. Tais achados nos levam a concluir que os TAMs possuem um papel importante na progressão metastática do câncer de mama e o efeito imunomodulador da talidomida pode ser uma opção terapêutica para essa doença.CNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorUniversidade Federal de Minas GeraisBrasilPrograma de Pós-Graduação em PatologiaUFMGGeovanni Dantas Cassalihttp://lattes.cnpq.br/5921185698230768Enio FerreiraRemo de Castro RussoLucíola da Silva BarcelosAndré Luís Branco de BarrosRosy Iara Maciel de Azambuja RibeiroSilvía Ligório FialhoDiego Carlos dos Reis2021-05-06T20:54:46Z2021-05-06T20:54:46Z2018-12-10info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://hdl.handle.net/1843/35906https://orcid.org/0000-0002-9676-7745porinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFMGinstname:Universidade Federal de Minas Gerais (UFMG)instacron:UFMG2021-05-06T20:54:46Zoai:repositorio.ufmg.br:1843/35906Repositório InstitucionalPUBhttps://repositorio.ufmg.br/oairepositorio@ufmg.bropendoar:2021-05-06T20:54:46Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG)false |
dc.title.none.fl_str_mv |
Macrófagos associados a tumores: um potencial alvo terapêutico em câncer de mama |
title |
Macrófagos associados a tumores: um potencial alvo terapêutico em câncer de mama |
spellingShingle |
Macrófagos associados a tumores: um potencial alvo terapêutico em câncer de mama Diego Carlos dos Reis Macrófagos Talidomida Neoplasias da mama Metástase neoplásica Imunoterapia Versicanas Inflamação Macrófagos Talidomida Neoplasias da Mama Metástase Neoplásica Imunoterapia Versicanas Inflamação Dissertação Acadêmica |
title_short |
Macrófagos associados a tumores: um potencial alvo terapêutico em câncer de mama |
title_full |
Macrófagos associados a tumores: um potencial alvo terapêutico em câncer de mama |
title_fullStr |
Macrófagos associados a tumores: um potencial alvo terapêutico em câncer de mama |
title_full_unstemmed |
Macrófagos associados a tumores: um potencial alvo terapêutico em câncer de mama |
title_sort |
Macrófagos associados a tumores: um potencial alvo terapêutico em câncer de mama |
author |
Diego Carlos dos Reis |
author_facet |
Diego Carlos dos Reis |
author_role |
author |
dc.contributor.none.fl_str_mv |
Geovanni Dantas Cassali http://lattes.cnpq.br/5921185698230768 Enio Ferreira Remo de Castro Russo Lucíola da Silva Barcelos André Luís Branco de Barros Rosy Iara Maciel de Azambuja Ribeiro Silvía Ligório Fialho |
dc.contributor.author.fl_str_mv |
Diego Carlos dos Reis |
dc.subject.por.fl_str_mv |
Macrófagos Talidomida Neoplasias da mama Metástase neoplásica Imunoterapia Versicanas Inflamação Macrófagos Talidomida Neoplasias da Mama Metástase Neoplásica Imunoterapia Versicanas Inflamação Dissertação Acadêmica |
topic |
Macrófagos Talidomida Neoplasias da mama Metástase neoplásica Imunoterapia Versicanas Inflamação Macrófagos Talidomida Neoplasias da Mama Metástase Neoplásica Imunoterapia Versicanas Inflamação Dissertação Acadêmica |
description |
Tumor-associated macrophages (TAMs) representing most of the leukocyte population in the tumor microenvironment of breast cancer. TAMs can act on neoplastic development over different mechanisms depending on their activation status. Considering the evidence of the critical role of these cells in the tumor microenvironment, this work aimed to evaluate the role of TAMs on the metastatic progression of 4T1 mouse mammary carcinoma and spontaneous canine mammary carcinomas. Additionally, it was evaluated the immunomodulatory effects of thalidomide as a possible therapeutic target on TAMs polarization in mice inoculated with 4T1 mouse mammary carcinoma. The 4T1 cells were inoculated into female BALB/c mice to obtain the solid tumor and the animals were euthanized at different times of tumor progression (14th, 21st and 28th day of inoculation). Primary tumor and lung were collected for the evaluation of TAMs, versican expression, inflammatory mediators, tumor angiogenesis, and metastases. Forced spirometry technique was also performed to evaluate the mice’s pulmonary functions. Spontaneous canine mammary carcinomas samples were selected and evaluated for TAMs infiltration and versican expression. In a second experiment, 4T1 tumor-bearing mice received oral daily treatment of thalidomide at concentrations of 50 mg/kg, 100 mg/kg, and 150 mg/kg for 23 days. The results obtained demonstrate that TAMs infiltration and versican expression was associated to low-grade and advanced stages of canine mammary carcinomas. In mice, TAMs and versican shown higher in late stages of tumor progression and associated to increased inflammation and angiogenesis of the primary’s tumors, while in the lung TAMs infiltration was associated with pulmonary dysfunction due to the increased number of metastatic nodules, airways leukocytes influx, and high inflammatory mediators’ levels. In the lung, the administration of thalidomide at dose 150 mg/kg reduced the neoplastic proliferation and the numbers of metastatic nodules associated to an increase in inflammation with higher number of TAMs. In conclusion, TAMs appear to play a critical role in the metastatic progression of breast cancer, the immunomodulatory effect of thalidomide may be a therapeutic option for this disease. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-12-10 2021-05-06T20:54:46Z 2021-05-06T20:54:46Z |
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 |
http://hdl.handle.net/1843/35906 https://orcid.org/0000-0002-9676-7745 |
url |
http://hdl.handle.net/1843/35906 https://orcid.org/0000-0002-9676-7745 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais Brasil Programa de Pós-Graduação em Patologia UFMG |
publisher.none.fl_str_mv |
Universidade Federal de Minas Gerais Brasil Programa de Pós-Graduação em Patologia UFMG |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFMG instname:Universidade Federal de Minas Gerais (UFMG) instacron:UFMG |
instname_str |
Universidade Federal de Minas Gerais (UFMG) |
instacron_str |
UFMG |
institution |
UFMG |
reponame_str |
Repositório Institucional da UFMG |
collection |
Repositório Institucional da UFMG |
repository.name.fl_str_mv |
Repositório Institucional da UFMG - Universidade Federal de Minas Gerais (UFMG) |
repository.mail.fl_str_mv |
repositorio@ufmg.br |
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1816829672789377024 |