MFG-E8 Drives Melanoma Growth by Stimulating Mesenchymal Stromal Cell–Induced Angiogenesis and M2 Polarization of Tumor-Associated Macrophages

• Published in: Cancer research (Chicago, Ill.) Vol. 76; no. 14; pp. 4283 - 4292
• Main Authors: Yamada, Kazuya, Uchiyama, Akihiko, Uehara, Akihito, Perera, Buddhini, Ogino, Sachiko, Yokoyama, Yoko, Takeuchi, Yuko, Udey, Mark C., Ishikawa, Osamu, Motegi, Sei-ichiro
• Format: Journal Article
• Language: English
• Published: United States 15.07.2016
• Subjects: Animals; Antigens, Surface - physiology; Cell Polarity; Endothelin-1 - biosynthesis; Female; Macrophages - physiology; Melanoma - blood supply; Melanoma - pathology; Mesenchymal Stem Cells - physiology; Mice; Mice, Inbred C57BL; Milk Proteins; Neovascularization, Pathologic - etiology; Pericytes - pathology; Platelet Endothelial Cell Adhesion Molecule-1 - analysis; Vascular Endothelial Growth Factor A - biosynthesis
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-15-2812

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.