Abstract
Macrophages are potent immune cells with well-established roles in the response to stress, injury, infection and inflammation. The classically activated macrophages (M1) are induced by lipopolysaccharide (LPS) and express a wide range of pro-inflammatory genes. M2 macrophages are induced by T helper type 2 cytokines such as interleukin-4 (IL4) and express high levels of anti-inflammatory and tissue repair genes. The strong association between macrophages and tumour cells as well as the high incidences of leukocyte infiltration in solid tumours have contributed to the discovery that tumour-associated macrophages (TAMs) are key to tumour progression. Here, we investigated the role of Annexin A1 (ANXA1), a well characterized immunomodulatory protein on macrophage polarization and the interaction between macrophages and breast cancer cells. Our results demonstrate that ANXA1 regulates macrophage polarization and activation. ANXA1 can act dually as an endogenous signalling molecule or as a secreted mediator which acts via its receptor, FPR2, to promote macrophage polarization. Furthermore, ANXA1 deficient mice exhibit reduced tumour growth and enhanced survival in vivo, possibly due to increased M1 macrophages within the tumor microenvironment. These results provide new insights into the molecular mechanisms of macrophage polarization with therapeutic potential to suppress breast cancer growth and metastasis.
Highlights
Macrophages are heterogeneous cells that are released from the bone marrow as immature monocyte and after circulating in the blood vessels, migrate into target tissues to undergo final differentiation into mature macrophages[1,2]
67NR breast cancer cell lines were derived from a single mammary tumour that develop spontaneously in a BALB/c mouse. 4T1 cells are highly invasive leading to metastases, whereas 67NR cells were derived from primary tumours, but do not metastasize or invade[29,30]
Given the ability of tumour-associated macrophages (TAMs) to be recruited to tumours by a range of growth factors and chemokines, which are often produced by the tumour cells themselves, we sought to determine the effect of 4T1 and 67NR-conditioned media (CM) on macrophage polarization
Summary
Macrophages are heterogeneous cells that are released from the bone marrow as immature monocyte and after circulating in the blood vessels, migrate into target tissues to undergo final differentiation into mature macrophages[1,2]. The complex interplay between cancer cells and the host immune response has been well established, supporting the concept that disruption of endogenous mechanisms that promotes resolution of inflammation, could result in tumour progression[4,5,6]. ANXA1 is highly expressed in metastatic and triple negative (estrogen, progesterone and HER2 receptor) breast cancer and it has been reported to promote tumour development and progression[23]. We show an underlying mechanism that demonstrates that macrophage ANXA1 is required for and plays an important role in the tumour microenvironment, and is important in the induction of expression of M2 macrophage subset markers
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