Macrófagos associados a tumores: um potencial alvo terapêutico em câncer de mama

Detalhes bibliográficos
Autor(a) principal: Diego Carlos dos Reis
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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spelling 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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