Análise do perfil metabólico de macrófagos associados ao tumor: efeito das lipoxinas

• Autor(a) principal: Brito, Natália Mesquita de
• Data de Publicação: 2019
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UERJ
• Texto Completo: http://www.bdtd.uerj.br/handle/1/16122
• topic: Cancer; Tumor-associated macrophages; Inflammation; Metabolism; Lipoxin; Câncer; Macrófagos associados ao tumor; Inflamação; Metabolismo; Lipoxina; Lipoxinas; Macrófagos; Inflamação; Tumores; Neoplasias; CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA

In the tumor microenvironment, the infiltration of cells of the immune system, such as macrophages, may promote or inhibit the development of cancer. Differential activation of macrophages is critically supported by intracellular metabolic changes. M1 proinflammatory macrophages are highly glycolytic and present flux through the phosphate pentose pathway (PPP), which support their proliferative and cytotoxic functions. On the other hand, anti-inflammatory M2 macrophages depend on oxidative metabolism. TAMs (tumor-associated macrophages) play a dominant role as orchestrators of cancer-related inflammation, but little is known about their metabolism. In previous studies, our group observed that lipoxins, pro-resolutive mediators, induce a change in the M2-like profile of TAMs to a M1-like profile, increasing ROS and NO production and impairing tumor progression. Therefore, the purpose of this study was to elucidate the profile and metabolic requirements of TAMs and analyze the effects of lipoxin on its metabolic pathways. To obtain TAMs, human monocytes-derived macrophages were stimulated with MV3 (human melanoma cell line) conditioned medium. These TAMs, unlike the classic M2 macrophages (IL-4 stimulation), presented high glycolytic activity, consuming and secreting high levels of glucose and lactate, respectively. In addition, these cells exhibited high activity of the mTOR / Akt pathway and increased expression of GLUT-1 and the hexokinase-2 enzyme, in addition to high mitochondrial respiration and low absorption of exogenous fatty acids. We also observed that inhibition of the glycolytic pathway, but not the inhibition of oxidative phosphorylation or PPP, led to a decrease in the percentage of cells positive for M2 markers in TAMs. On the other hand, when PPP was inhibited, lipoxin was unable to restore the cytotoxic properties of TAMs on tumor cells, such as ROS and NO production. Taken together, our data suggest that TAMs, although generally considered M2-like macrophages, differently from these, rely on glycolytic metabolism to maintain their phenotype and functions. We also show that the effect of lipoxin, modifying the functional and phenotypic profile of TAMs, seems to involve a redirection of the metabolism of these cells, diverting the flow to the PPP pathway and thus increasing its anti-tumor activity.