Papel da hidr?lise extracelular de ATP na imunossupress?o, resist?ncia ? quimioterapia e invasividade dos gliomas
| Autor: | Scheffel, Thamiris Becker |
|---|---|
| Přispěvatelé: | Morrone, Fernanda Bueno |
| Jazyk: | portugalština |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Biblioteca Digital de Teses e Dissertações da PUC_RS Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS) instacron:PUC_RS |
| Popis: | Os gliomas s?o tumores cerebrais extremamente agressivos. A malignidade tumoral tem sido atribu?da aos diversos mecanismos de resist?ncia ? terapia que compreendem a intensa capacidade imunomodulat?ria e a invas?o do tecido subjacente. Sugere-se que purinas e pirimidinas possam atuar como mol?culas sinalizadoras, influenciando tais caracter?sticas. A hidr?lise de ATP pelas ectonucleos?deo trifosfato difosfoidrolases (ENTPDases) e a consequente forma??o de adenosina est?o relacionadas ? regula??o positiva de vias de prolifera??o, migra??o, sobreviv?ncia celular e de checkpoints imunol?gicos inibit?rios como a via PD-1/PD-L1. Deste modo, a hip?tese deste trabalho ? que a inibi??o da atividade ATP?sica resultaria na redu??o da imunossupress?o, da resist?ncia ? quimioterapia e da invasividade tumoral, de forma direta ou indiretamente atrav?s da a??o no microambiente tumoral. A atua??o sin?rgica da via da adenosina e do eixo PD-1/PD-L1 na manuten??o da imunossupress?o em gliomas foi descrita neste trabalho. ? not?rio o envolvimento destas vias na progress?o dos gliomas. Neste contexto, a inibi??o da forma??o de adenosina juntamente com o favorecimento de altas concentra??es de ATP extracelular poderiam aumentar a carga inflamat?ria antitumoral no microambiente tumoral e minimizar os mecanismos tumorais de resist?ncia ? terapia. O uso do inibidor de E-NTPDases polioxometalato-1 (POM-1) mostrou estar relacionado com a potencializa??o do efeito da temozolomida, atrav?s da redu??o da viabilidade celular e indu??o de apoptose em c?lulas de glioblastoma (GBM). Al?m disso, a an?lise do potencial invasivo-migrat?rio das c?lulas de GBM foi avaliado em modelo de cultura tridimensional atrav?s do m?todo migratory fitness, desenvolvido ao longo deste trabalho. A inibi??o da hidr?lise extracelular de ATP favoreceu a ocorr?ncia de um fen?tipo celular menos invasivo, reduzindo a massa de c?lulas migrat?rias. Com base nos achados in vitro, o efeito do POM-1 foi avaliado em um estudo piloto de GBM em modelo murino que envolveu a administra??o intranasal do inibidor e demonstrou uma forte tend?ncia ao aumento da inflama??o no local do tumor e redu??o da infiltra??o de linf?citos Tregulat?rios, que caracteriza redu??o da imunossupress?o. De modo geral, este trabalho demonstra estrat?gias de modula??o do microambiente tumoral que enfraquecem mecanismos de resist?ncia ? temozolomida e minimizam a invasividade de tumores extremamente malignos. Gliomas are extremely aggressive. Tumor malignancy has been attributed to several mechanisms of resistance to therapy that include the intense immunomodulatory capacity and the invasion of the underlying tissue. It is suggested that purines and pyrimidines may act as signaling molecules, influencing such characteristics. ATP hydrolysis by ectonucleoside triphosphate diphosphohydrolases (E-NTPDases) and the consequent formation of adenosine are related to the positive regulation of proliferation, migration, cell survival and inhibitory immunological checkpoints such as the PD-1/PD-L1 pathway. Thus, the hypothesis of this study is that the inhibition of ATPase activity would result in the reduction of immunosuppression, resistance to chemotherapy and tumor invasiveness, directly or indirectly through action on the tumor microenvironment. The synergistic action of the adenosine pathway and the PD-1/PD-L1 axis maintaining immunosuppression in gliomas was described in this study. The involvement of these pathways in the progression of gliomas is well known. In this context, the inhibition of adenosine formation together with the favoring of high concentrations of extracellular ATP could increase the antitumor landscape in the tumor microenvironment and minimize the tumor mechanisms of resistance to therapy. The use of the E-NTPDase inhibitor polyoxometalate-1 (POM-1) was shown to be related to the potentiation of the effect of temozolomide, through the reduction of cell viability and induction of apoptosis in glioblastoma cells (GBM). Furthermore, the analysis of the invasive-migratory potential of GBM cells was evaluated in a 3D culture model using the migratory fitness method, developed throughout this work. Inhibition of extracellular ATP hydrolysis favored the occurrence of a less invasive cellular phenotype, reducing the mass of migrating cells. Based on in vitro findings, the effect of POM-1 was evaluated in a pilot study of GBM murine model that involved intranasal administration of the inhibitor and demonstrated a strong tendency to increase inflammation at the tumor site and reduce lymphocyte infiltration of regulatory T cells, which characterizes reduced immunosuppression. Overall, this work demonstrates tumor microenvironment modulation strategies that weaken temozolomide resistance mechanisms and minimize the invasiveness of extremely malignant tumors. Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES |
| Databáze: | OpenAIRE |
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