Avaliação in vivo dos efeitos da lipoxina sobre o perfil de macrófagos associados ao tumor

Abstract

The relationship between the inflammatory response and cancer has been extensively studied. In the tumor microenvironment, the primarily pro-inflammatory (M1) macrophages acquire an anti-inflammatory and pro-tumor (M2) characteristics, and are now called TAM (tumor-associated macrophage). Recent studies show that these TAMs are derived from LY6Chigh inflammatory monocytes that accumulate in tumors and renew the population of TAMs. During the tumor development, the spleen acts as an extra-medullar reservoir of monocytes, which can migrate to the tumor and differentiate into TAM. Our group demonstrated that lipoxins (LXs), a lipid mediators with pro-resolving and anti-inflammatory activity, change the phenotype of TAMs in vitro, restoring their cytotoxic properties and leading the tumor cell to apoptosis. However, the in vivo effects of LX on TAM should be better elucidated. The aim of this study is to investigate the effects of 15-epi-lipoxin A4 (ATL-1), on the modulation of murine TAMs in vitro and in vivo. Our data show that the treatment of TAMs derived from mice bone marrow (BMDM-TAM) with LX decreases, in vitro, the expression of CD206, arginase-1 and IL-10, three classical M2/TAM markers. The results are similar to those obtained with human TAMs, showing that LX modify TAM phenotype. Corroborate those data, we demonstrate in a murine melanoma model with established tumors (14 days), that, 7 days post-treatment, LX decreased, in vivo, the expression of the M2 markers in TAMs, and diminished the LY6Chigh population of mononuclear cells in spleen, blood and bone marrow. Additionally, the treatment with ATL-1 reduced the tumor angiogenesis, and increased the caspase-3 activity in tumor cells that undergo apoptosis. Finally, confirming our reports, we observed that, 7 day after the treatment, ATL-1 significantly decreased the weight and in the internal volume of the tumors. Together, our data show that LX is able to change the TAM profile in vivo, leading to decrement of tumor progression. This study highlights the important role of LX in tumor progression, suggesting that this lipid mediator may become a new tool in cancer control.