Milk fat globule epithelial growth factor VIII (MFG-E8) sustains survival of cancer cells by prompting tumor angiogenesis and suppressing host immunities ⁎

Abstract

Abstract Milk fat globule epithelial growth factor VIII (MFG-E8) is a novel adhesion protein mainly produced by macrophages and dendritic cells; it is expressed in most of the human tissues and functions to prompt cancer progression and survival. MFG-E8 contains a signal sequence for secretion, two epidermal growth factor (EGF)-like domains at the NH2 terminus and two discoidin domains with blood-clotting factor V/factor VIII (C1 and C2) at the COOH terminus. The second EGF domain contains an arginine-glycine-aspartic (RGD) integrin-binding motif that engages αvβ5 integrins to facilitate cell adhesion and induce integrinmediated signal transduction. Integrin αvβ3 associates with VEGF receptor 2, engagement of integrins can promote angiogenesis, which plays key roles in growth, proliferation, and survival of cancer cells. VEGF stimulates the expression of αvβ3 and αvβ5 integrins on angiogenic vasculature, thereby potentiating effects of VEGF receptor engagement. Mice expressing a mutant form of αvβ3 integrin are unable to undergo tyrosine phosphorylation, confirming the important role that this integrin plays in pathological angiogenesis and providing important mechanistic insights. The C-terminus discoidin-like domains promote binding to membrane phospholipids, functioning close to VEGF like angiogenesis. MFG-E8 is an opsonin for apoptotic cells, and it acts as a bridging protein between apoptotic cells and phagocytes. It also influences cell immunities by altering CD4+ and/or CD8+ cells. Antibody or small peptide works with MFG-E8 at different functional sites or interacts with EGF-like domains and/or discoidin-like domains may play an important role in anti-angiogenesis or immune restoration. Altering the structures and/or functions of MFG-E8 and/or its domains is promising for development of novel anti-cancer strategies. List of abbreviations: milk fat globule epithelial growth factor VIII (MFG-E8); vascular endothelial growth factors (VEGFs); fibroblast growth factor (FGF); tripeptide Arg-Gly-Asp (RGD); granulocyte/monocyte colony-stimulating factor (GM-CSF); cyclin-dependent kinase inhibitor 1 (P21WAF1/CIP1); B-cell lymphoma 2/Bcl-2 associated X protein (Bcl-2/Bax); platelet-derived growth factor receptor β (PDGFRβ); tumor cells proliferation rate index (Ki-67); toll-like receptor (TLR)