Abstract
Tumor cells secrete factors that modulate macrophage activation and polarization into M2 type tumor-associated macrophages, which promote tumor growth, progression, and metastasis. The mechanisms that mediate this polarization are not clear. Macrophages are phagocytic cells that participate in the clearance of apoptotic cells, a process known as efferocytosis. Milk fat globule- EGF factor 8 (MFG-E8) is a bridge protein that facilitates efferocytosis and is associated with suppression of proinflammatory responses. This study investigated the hypothesis that MFG-E8-mediated efferocytosis promotes M2 polarization. Tissue and serum exosomes from prostate cancer patients presented higher levels of MFG-E8 compared with controls, a novel finding in human prostate cancer. Coculture of macrophages with apoptotic cancer cells increased efferocytosis, elevated MFG-E8 protein expression levels, and induced macrophage polarization into an alternatively activated M2 phenotype. Administration of antibody against MFG-E8 significantly attenuated the increase in M2 polarization. Inhibition of STAT3 phosphorylation using the inhibitor Stattic decreased efferocytosis and M2 macrophage polarization in vitro, with a correlating increase in SOCS3 protein expression. Moreover, MFG-E8 knockdown tumor cells cultured with wild-type or MFG-E8-deficient macrophages resulted in increased SOCS3 expression with decreased STAT3 activation. This suggests that SOCS3 and phospho-STAT3 act in an inversely dependent manner when stimulated by MFG-E8 and efferocytosis. These results uncover a unique role of efferocytosis via MFG-E8 as a mechanism for macrophage polarization into tumor-promoting M2 cells.
Highlights
The growing body of data on tumor-associated macrophages largely neglects phagocytosis of apoptotic cells
Given that prostate cancer has a high propensity to metastasize to the bone, which is rich in macrophages and anti-inflammatory factors that contribute to tumor growth, we hypothesized that Milk fat globule- EGF factor 8 (MFG-E8)-mediated efferocytosis modulates the bone marrow-derived macrophage suppressor of cytokine signaling 3 (SOCS3)/STAT3 pathway, inducing an M2 switch and promoting tumor growth
MFG-E8 Is Highly Expressed in Prostate Cancer—MFG-E8 has been correlated with tumor growth and progression of different types of cancers, such as melanoma and breast cancer, but its expression in prostate cancer is still unclear
Summary
The growing body of data on tumor-associated macrophages largely neglects phagocytosis of apoptotic cells. Coculture of macrophages with apoptotic cancer cells increased efferocytosis, elevated MFG-E8 protein expression levels, and induced macrophage polarization into an alternatively activated M2 phenotype. MFG-E8 knockdown tumor cells cultured with wild-type or MFG-E8-deficient macrophages resulted in increased SOCS3 expression with decreased STAT3 activation. SOCS3 proteins are known to inhibit the JAK/STAT signaling pathway, creating a negative feedback loop to prevent excessive activation of the pathway [23] This modulatory role has been suggested as a mechanism for macrophage polarization. Given that prostate cancer has a high propensity to metastasize to the bone, which is rich in macrophages and anti-inflammatory factors that contribute to tumor growth, we hypothesized that MFG-E8-mediated efferocytosis modulates the bone marrow-derived macrophage SOCS3/STAT3 pathway, inducing an M2 switch and promoting tumor growth. The impact of efferocytosis mediated by MFG-E8 on macrophage polarization into M2 TAMs was investigated, and the underlying mechanisms that could be developed as potential therapeutic targets were delineated
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