Soki Fabiana N, Koh Amy J, Jones Jacqueline D, Kim Yeo Won, Dai Jinlu, Keller Evan T, Pienta Kenneth J, Atabai Kamran, Roca Hernan, McCauley Laurie K
From the Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109.
the Department of Urology, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109.
J Biol Chem. 2014 Aug 29;289(35):24560-72. doi: 10.1074/jbc.M114.571620. Epub 2014 Jul 8.
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.
肿瘤细胞分泌可调节巨噬细胞激活并使其极化为M2型肿瘤相关巨噬细胞的因子，这些巨噬细胞会促进肿瘤生长、进展和转移。介导这种极化的机制尚不清楚。巨噬细胞是参与凋亡细胞清除的吞噬细胞，这一过程称为胞葬作用。乳脂肪球表皮生长因子8（MFG-E8）是一种促进胞葬作用并与抑制促炎反应相关的桥连蛋白。本研究调查了MFG-E8介导的胞葬作用促进M2极化这一假说。与对照组相比，前列腺癌患者的组织和血清外泌体呈现出更高水平的MFG-E8，这是人类前列腺癌中的一项新发现。巨噬细胞与凋亡癌细胞共培养可增加胞葬作用，提高MFG-E8蛋白表达水平，并诱导巨噬细胞极化为交替激活的M2表型。给予抗MFG-E8抗体可显著减弱M2极化的增加。使用抑制剂Stattic抑制STAT3磷酸化可在体外降低胞葬作用和M2巨噬细胞极化，同时伴随SOCS3蛋白表达增加。此外，用野生型或MFG-E8缺陷型巨噬细胞培养MFG-E8基因敲低的肿瘤细胞会导致SOCS3表达增加，STAT3激活减少。这表明当受到MFG-E8和胞葬作用刺激时，SOCS3和磷酸化STAT3以反向依赖的方式发挥作用。这些结果揭示了通过MFG-E8进行胞葬作用作为巨噬细胞极化为促肿瘤M2细胞的一种机制所具有的独特作用。
