Abstract
During tumor development, the spleen acts as an extra-medullar reservoir of LY6Chi inflammatory monocytes, which can migrate toward tumor to differentiate into tumor-associated macrophage (TAMs), renewing the TAM population. In the tumor microenvironment, pro-inflammatory macrophages (M1) acquire anti-inflammatory and pro-tumor (M2) characteristics favoring tumor development. We previously demonstrated that lipoxins, a family of pro-resolving lipid mediators, restored in vitro the cytotoxic M1-like properties of TAMs.Objective: In this study, we have investigated in vivo the cellular mechanisms underlying the anti-tumor property of lipoxins.Methods: Fourteen days after inducing B16-F10 melanoma tumors, mice received one single dose of ATL-1 (1 μg/i.v.), a lipoxin A4 analog. After further 7 days, blood and bone-marrow were collected, tumors and spleens were removed, and TAMs and blood monocytes were isolated.Results: While the population of LY6Chi monocytes was increased in non-treated tumor-bearing mice, the treatment with ATL-1 diminished the population of LY6Chi monocytes in spleen, blood and bone marrow, decreasing macrophage infiltration into the tumor and reducing the M2 markers expression on TAMs. Importantly, those effects were accompanied by an impairment of tumor growth and improved survival of tumor-bearing mice. The data evidence the anti-tumor mechanism of ATL-1, by decreasing the availability of TAM-precursor monocytes and changing TAMs profile in vivo, impairing tumor progression. ATL-1 may become a new tool in cancer control.
Highlights
Tumor progression shares basic mechanisms with inflammatory process [1], such as the presence of inflammatory cells and mediators released by both tumor cells and infiltrated leukocytes [2]
While the population of LY6Chi monocytes was increased in non-treated tumor-bearing mice, the treatment with stable analog of aspirin-triggered lipoxin – 15-epi-LXA4 (ATL-1) diminished the population of LY6Chi monocytes in spleen, blood and bone marrow, decreasing macrophage infiltration into the tumor and reducing the M2 markers expression on Tumor-associated macrophage (TAM)
ATL-1 Treatment Decreases CD115+ LY6Chi Cell Population in Bone Marrow, Spleen, and Blood of Tumor-Bearing Mice We analyzed the effect of lipoxin treatment on the profile of mononuclear cells derived from the bone marrow of tumorbearing mice
Summary
Tumor progression shares basic mechanisms with inflammatory process [1], such as the presence of inflammatory cells and mediators released by both tumor cells and infiltrated leukocytes [2]. The classical M1 activation is characterized by the efficient production of reactive oxygen and nitrogen species, as well as the production of proinflammatory cytokines (IL-1β, TNF-α, and IL-6), effectively participating as inducers and effectors of the response Th1. M2 or alternatively activated macrophages produce higher amounts of antiinflammatory cytokines and participate in type 2 (Th2) reactions, inducing remodeling and tissue repair [3, 4]. TAMs are among the most versatile tumor-infiltrating inflammatory cells and may represent around 50% of the noncancer cells of the tumor mass. They participate in all hallmarks of cancer by generating numerous growth factors, cytokines and extracellular matrix (ECM)-remodeling molecules, that regulate tumor growth, migration and angiogenesis [7,8,9]. Evidence have shown that an increased number of M2-like TAMs correlates with poor prognosis in different cancers types both in murine models and human patients [10, 11]
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