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Previous issue date: 2014-03-12 / Melanoma is one of the most aggressive malignant tumors, and its incidence has been increasing steadily in recent years. Usually in the early stages, treatment for melanoma is local surgery with reasonable efficiency. However, treatments such as chemotherapies for advanced melanoma have limited benefits, prolonging the patient's life in a few months. Thus the search for more effective therapies for melanoma is necessary. More recent studies suggest that tumor immune response conducted by subtypes of CD4+ T helper cells subsets have an important role in cancer control. According to tumor infiltrating Th17 and Treg cellsand the cytokines they secrete the tumor microenvironment profile may be suggested anti or pro-tumor activities or exerted by these cells. In this study, we investigated the transcriptional markers of CD4+Foxp3+ T cells and CD4+ROR?t+ T cells in draining lymph nodes of animals throughout the melanoma tumor growth and evaluate whether the combined action of cisplatin (cis-diamino-dichloro-platin, CDDP) and TLR2 (peptidoglycan) or TLR3 (acid-Polyribosilic Polyribocytidilic) or TLR4 (lipopolysaccharide) agonists, can change these parameters. The animals were injected with melanoma cell line B16F10 and according tumor progression the tumor draining lymph node (TDLN) were excised for analysis of Treg and Th17 cells by flow cytometry. Furthermore, we analyzed the survival of animals treated with combined therapies. We found an increase in the percentage and absolute number of Th17 and Treg cells in TDLN according tumor progression, which was consistent with previous studies. Our results indicate that treatment with cisplatin promotes tumor growth by increasing Treg and Th17 cells. Treatment with CDDP plus TLR2 agonist significantly decreases the percentage of Th17 cells in TDLN. We demonstrated here, that combinated CDDP and TLR3 or TLR4 agonist therapy impairs tumor growth and modulate the frequency of these cells by decreasing the percentage of CD4+Foxp3+ T cells. In addition, this combination also showed a modest increase insurvivalof the melanoma bearing mice. These results showed that TLRs agonists may be used in combination with cisplatin as a potential adjuvant capable impair tumor growth in melanoma bearing mice. / Melanoma ? um dos tumores malignos mais agressivos, e sua incid?ncia vem aumentando continuamente nos ?ltimos anos. Geralmente em est?gios iniciais, o tratamento para melanoma ? local, por cirurgia, com razo?vel efic?cia. Contudo, os tratamentos para melanoma em est?gios avan?ados por quimioterapia t?m benef?cios limitados, prolongando a vida do paciente em poucos meses. Assim se faz necess?ria a busca por terapias mais efetivas para melanomas. Estudos mais recentes sugerem que a resposta imunol?gica tumoral realizada pelos subtipos de c?lulas T CD4+ auxiliares possuem papel importante no controle do c?ncer. Conforme o infiltrado tumoral de c?lulas Th17 e Treg e o perfil de citocinas que elas secretam no microambiente tumoral, pode-se sugerir atividades anti ou pr?-tumorais exercidas por essas c?lulas. Neste estudo, n?s investigamos os marcadores transcricionais de c?lulas T CD4+Foxp3+ e c?lulas T CD4+ROR?t+ em linfonodos drenantes de animais com melanoma ao longo do crescimento tumoral e avaliamos se a a??o combinada de cisplatina (cis-diamino-dichloro-platin, CDDP) com agonistas de TLR2 (Peptidoglicano) ou TLR3 (?cido Polyribosilic-Polyribocytidilic) ou TLR4 (Lipopolissacar?deo) podem alterar esses par?metros. Os animais foram injetados com c?lulas de melanoma linhagem B16F10 e conforme a progress?o tumoral os linfonodos drenantes tumorais (TDLN) foram excisados para an?lise de c?lulas Th17 e Treg por citometria de fluxo. Al?m disso, analisamos a sobrevida dos animais com a a??o combinadas das terapias. Encontramos um aumento na porcentagem e n?mero absoluto de c?lulas Th17 e Treg no TDLN conforme a progress?o tumoral o qual foi condizente com estudos anteriores. Nossos resultados indicam que o tratamento apenas com cisplatina, promove o crescimento tumoral atrav?s do aumento de c?lulas Th17 e Treg. O tratamento de cisplatina com agonista de TLR2 diminui consideravelmente a porcentagem de c?lulas Th17 no TDLN. Demonstramos aqui que a combina??o de terapias utilizando CDDP juntamente com agonistas de TLR3 ou TLR4, prejudica o crescimento tumoral e pode modular a frequ?ncia dessas c?lulas atrav?s da diminui??o na porcentagem de c?lulas TCD4+Foxp3+. Adicionalmente, essa combina??o tamb?m mostrou um modesto aumento na sobreviv?ncia dos animais. Esses resultados mostram que agonistas de TLRs podem ser utilizados em combina??o com cisplatina como potencial adjuvante capaz de induzir inibir o crescimento tumoral em modelo de melanoma murino.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/6153 |
| Date | 12 March 2014 |
| Creators | Salin, M?lvaro Maculan |
| Contributors | Bonorino, Cristina Beatriz C. |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Biologia Celular e Molecular, PUCRS, Brasil, Faculdade de Bioci?ncias |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 8198246930096637360, 600, 600, 600, 36528317262667714, -3439178843068202161 |
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