title: MFG-E8 Drives Melanoma Growth by Stimulating Mesenchymal Stromal Cell-Induced Angiogenesis and M2 Polarization of Tumor-Associated Macrophages.
abstract: Secretion of the powerful angiogenic factor MFG-E8 by pericytes can bypass the therapeutic effects of anti-VEGF therapy, but the mechanisms by which MFG-E8 acts are not fully understood. In this study, we investigated how this factor acts to promote the growth of melanomas that express it. We found that mouse bone marrow-derived mesenchymal stromal cells (MSC) expressed a substantial amount of MFG-E8. To assess its expression from this cell type, we implanted melanoma cells and MSC derived from wild type (WT) or MFG-E8 deficient [knockout (KO)] into mice and monitored tumor growth. Tumor growth and M2 macrophages were each attenuated in subjects coimplanted with KO-MSC compared with WT-MSC. In both xenograft tumors and clinical specimens of melanoma, we found that MFG-E8 expression was heightened near blood vessels where MSC could be found. Through in vitro assays, we confirmed that WT-MSC-conditioned medium was more potent at inducing M2 macrophage polarization, compared with KO-MSC-conditioned medium. VEGF and ET-1 expression in KO-MSC was significantly lower than in WT-MSC, correlating in vivo with reduced tumor growth and numbers of pericytes and M2 macrophages within tumors. Overall, our results suggested that MFG-E8 acts at two levels, by increasing VEGF and ET-1 expression in MSC and by enhancing M2 polarization of macrophages, to increase tumor angiogenesis. Cancer Res; 76(14); 4283-92. ©2016 AACR.
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Uchiyama
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Uehara
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Buddhini
authors.initials: B
authors.lastname: Perera
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ogino
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yokoyama
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Takeuchi
authors.affiliation: Dermatology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Udey
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ishikawa
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan. smotegi@gunma-u.ac.jp.
authors.forename: Sei-Ichiro
authors.initials: S
authors.lastname: Motegi
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D016764:Cell Polarity; D019332:Endothelin-1 / Q000096:biosynthesis; D005260:Female; D008264:Macrophages / Q000502:physiology*; D008545:Melanoma / Q000098:blood supply / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins; D009389:Neovascularization, Pathologic / Q000209:etiology*; D020286:Pericytes / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D000954:Antigens, Surface; D019332:Endothelin-1; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A