Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 140, Issue 2, Pages 346-357Publisher
WILEY
DOI: 10.1002/ijc.30424
Keywords
tumor; inflammation; lipoxin; macrophage
Categories
Funding
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro [E-26/103.174/2011]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [302238/2009-3]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior [23038.38.006279/2011]
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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(4), could modulate TAM activity profile. We show that human macrophages (M Phi) 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(4) and the aspirin induced 15-epi-LXA(4) (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.
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