O papel do microambiente tumoral na modulação de monócitos e dos macrófagos associados ao tumor

Abstract

The concept that the tumor microenvironment plays an important role in the regulation of cell behavior has become increasingly accepted in the study of cancer biology. Monocytes and macrophages play important roles in the immune and inflammation response by modulating different stages of tumor development. For a long time, monocytes were considered as a homogeneous population, but now its phenotypic heterogeneity is well described. Currently, monocytes are divided into three subsets and can be classified as classical monocytes characterized by high expression of CCR2 and low levels of CX3CR1, intermediate monocytes characterized by CX3CR1 expression, and non-classical monocytes (CD14+ CD16++ or CD14dimCD16+) characterizing by low levels of CCR2 and high levels of CX3CR1. Monocyte-derived macrophages are the major non-tumor cells present in the microenvironment, and could be characterized by two profiles of activation: M1 macrophages, with pro-inflammatory and antitumoral activity; and M2 macrophage, with anti-inflammatory and pro-tumor properties. In the tumor microenvironment, macrophages are denominated tumor associated macrophage (TAM), sharing similar characteristics to M2 profile. In this scenario, extracellular matrix plays an important role in regulating various cell functions such as adhesion, migration, proliferation, polarity, differentiation and apoptosis. In pathological conditions like cancer, there is a change in the composition of the extracellular matrix, due to increased synthesis of certain components of the extracellular matrix and / or increased degradation as a result of the generation of ECM cleavage products, resulting in a tumor phenotype very more aggressive that contributes to tumor growth and progression. Lipoxins (LX) are metabolites of arachidonic acid, produced in vitro and in vivo by the sequential action of different lipoxygenase, with important anti-inflammatory role and during the resolution of inflammation. This work investigates the role of components of the tumor microenvironment, conditioned medium and extracellular matrix produced by the tumor cells, in the modulation of monocytes and macrophages, as well the lipoxin effects in these cells stimulated by tumor microenvironment factors. In this work, the components of the tumor microenvironment change the functional profile of blood monocytes decreasing the expression of CX3CR1 and CD16, mainly by the decrease of intermediate monocytes population. Here, we demonstrated that these components regulate functional effects of tumor progression, increasing iNOS/ arginase ratio, migration and cellular adhesion. In macrophages ECM induces M2 polarization, increasing the expression of CD206 and CD163, key markers M2 profile. Lipoxin shift the monocytes and macrophage profile induced by tumor components, and reverts pro-tumoral functions triggered by the tumor microenvironment factors. Togheter, these results highlights the important role of lipoxin in tumor control, contributing to the study and possible development of new tools to be used in the treatment of this disease