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 MGF-E8 acts are not fully understood. In this study, we investigated how this factor acts to promote the growth of melanomas which 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 (KO) into mice and monitored tumor growth. Tumor growth and M2 macrophages were each attenuated in subjects co-implanted with KO-MSC compared to 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 to 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.

Elevated serum MFG‐E8 level is possibly associated with the presence of high‐intensity cerebral lesions on magnetic resonance imaging in patients with systemic lupus erythematosus

“…28,29 In addition, we previously determined that hypoxia stimulation enhanced the synthesis of MFG-E8 in vascular endothelial cells and pericytes in vivo and in vitro, and that MFG-E8 expression in the skin of mice with ischemiareperfusion injury was enhanced in vivo. 12,13 Collectively, elevated serum MFG-E8 levels may play protective roles against cerebrovascular diseases, including ischemic cerebral infarction in patients with SLE.…”

“…[7][8][9] Furthermore, interactions of MFG-E8 with integrin aV have also been implicated in the regulation of various functions, such as angiogenesis and mammary gland branching. 5,6,[10][11][12][13][14] With respect to SLE and MFG-E8, it has been reported that serum MFG-E8 levels are higher in SLE patients compared with in healthy controls. [15][16][17] A positive correlation between serum MFG-E8 levels and immune complex level was reported.…”

Regulation of efferocytosis as a novel cancer therapy

“…Moreover, overexpression of MFG-E8 is negatively associated with prognosis in various cancers including breast, colorectal and esophageal cancers [83][84][85]. According to Yamada et al, MFG-E8 promotes angiogenesis by upregulating the expression of VEGF and endothelin (ET)-1 in bone marrow-derived mesenchymal stromal cells to trigger tumor progression in melanomas [86]. Besides, MFG-E8 enhances M2 polarization of macrophages [86,87], and blockade of MFG-E8 enhances antitumor effector T cells but inhibits Treg cells, leading to tumor destruction [17].…”

Macrophages in skin melanoma-the key element in melanomagenesis (Review)

“…In response to stimulation with these cytokines, melanoma cells produce angiogenic factors, including IL-8, VEGF, TIE2 and CD31, which results in neoangiogenesis (29,41). Furthermore, the proangiogenic factor released by pericytes-milk fat globule-epidermal growth factor 8 stimulates the polarization of M2 macrophages, suggesting that they also increase tumor angiogenesis (42).…”