title: Polarization of prostate cancer-associated macrophages is induced by milk fat globule-EGF factor 8 (MFG-E8)-mediated efferocytosis.
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.
authors.affiliation: From the Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109.
authors.forename: Fabiana N
authors.initials: FN
authors.lastname: Soki
authors.affiliation: From the Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Koh
authors.affiliation: From the Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109.
authors.forename: Jacqueline D
authors.initials: JD
authors.lastname: Jones
authors.affiliation: From the Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109.
authors.forename: Yeo Won
authors.initials: YW
authors.lastname: Kim
authors.affiliation: the Department of Urology, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Jinlu
authors.initials: J
authors.lastname: Dai
authors.affiliation: the Department of Urology, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
authors.affiliation: the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, and.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.affiliation: the Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, California 94158.
authors.forename: Kamran
authors.initials: K
authors.lastname: Atabai
authors.affiliation: From the Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109.
authors.forename: Hernan
authors.initials: H
authors.lastname: Roca
authors.affiliation: From the Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, mccauley@umich.edu.
authors.forename: Laurie K
authors.initials: LK
authors.lastname: McCauley
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000954:Antigens, Surface; C098942:MFGE8 protein, human; D008894:Milk Proteins
keywords: Alternative Activation; Bone; Bone Marrow; Efferocytosis; MFG-E8; Macrophage; Phagocytosis; Prostate Cancer; Skeletal Metastasis; Tumor-associated Macrophages