Simões R L, De-Brito N M, Cunha-Costa H, Morandi V, Fierro I M, Roitt I M, Barja-Fidalgo C
Laboratório de Farmacologia Celular e Molecular, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Departamento de Biologia Celular, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Int J Cancer. 2017 Jan 15;140(2):346-357. doi: 10.1002/ijc.30424. Epub 2016 Oct 31.
In tumor microenvironments, the macrophage population is heterogeneous, but some macrophages can acquire tumor-promoting characteristics. These tumor-associated macrophages (TAM) exhibit an M2-like profile, with deficient production of NO and ROS, characteristics of pro-inflammatory M1 cytotoxic macrophages. Lipoxins (LX) and 15-epi-lipoxins are lipid mediators which can induce certain features of M2 macrophages in mononuclear cells, but their effects on TAM remain to be elucidated. This study tested the hypothesis that ATL-1, a synthetic analogue of 15-epi-lipoxin A , could modulate TAM activity profile. We show that human macrophages (MΦ) differentiated into TAM-like cells after incubation with conditioned medium from MV3, a human melanoma lineage cell. Contrasting with the effects observed in other M2 subsets and M1 profile macrophages, ATL-1 selectively decreased M2 surface markers in TAM, suggesting unique behavior of this particular M2 subset. Importantly, these results were replicated by the natural lipoxins LXA and the aspirin induced 15-epi-LXA (ATL). In parallel, ATL-1 stimulated TAM to produce NO by increasing the iNOS/arginase ratio and activated NADPH oxidase, triggering ROS production. These alterations in TAM profile induced by ATL-1 led to loss of the anti-apoptotic effects of TAM on melanoma cells and increased their cytotoxic properties. Finally, ATL-1 was found to inhibit tumor progression in a murine model in vivo, which was accompanied by alterations in TAM profile and diminished angiogenesis. Together, the results show an unexpected effect of lipoxin, which induces in TAM a change from an M2- to an M1-like profile, thereby triggering tumor cell apoptosis and down-modulating the tumor progression.
在肿瘤微环境中，巨噬细胞群体具有异质性，但一些巨噬细胞可获得促进肿瘤的特性。这些肿瘤相关巨噬细胞（TAM）呈现出类似M2的表型，一氧化氮（NO）和活性氧（ROS）生成不足，而促炎M1细胞毒性巨噬细胞则具有这些特征。脂氧素（LX）和15-表-脂氧素是脂质介质，可诱导单核细胞中M2巨噬细胞的某些特征，但它们对TAM的影响仍有待阐明。本研究检验了一种假说，即15-表-脂氧素A4的合成类似物ATL-1可调节TAM的活性谱。我们发现，人巨噬细胞（MΦ）与人类黑色素瘤系细胞MV3的条件培养基孵育后可分化为TAM样细胞。与在其他M2亚群和M1表型巨噬细胞中观察到的效应不同，ATL-1选择性降低了TAM中的M2表面标志物，表明该特定M2亚群具有独特行为。重要的是，天然脂氧素LXA4和阿司匹林诱导的15-表-LXA4（ATL）也得到了相同结果。同时，ATL-1通过提高诱导型一氧化氮合酶（iNOS）/精氨酸酶比值刺激TAM产生NO，并激活NADPH氧化酶，触发ROS生成。ATL-1诱导的TAM谱改变导致TAM对黑色素瘤细胞的抗凋亡作用丧失，并增强了其细胞毒性。最后，发现ATL-1在体内小鼠模型中可抑制肿瘤进展，这伴随着TAM谱的改变和血管生成减少。总之，这些结果显示了脂氧素的意外作用，它可诱导TAM从M2样表型转变为M1样表型，从而触发肿瘤细胞凋亡并下调肿瘤进展。
