Role of MFG-E8 in Tumor Biology and Immunophysiology

Division Of Basic Sciences - Nci

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Abstract

Our interest in the phagocyte- and tumor cell-derived protein MFG-E8 continues. We have generated several MFG-E8 mouse mutants to determine if MFG-E8 has a role tumor biology and immunophysiology in vivo. Results, to date, indicate that tumor cells produce MFG-E8 and that MFG-E8 promotes tumorigenesis in both orthotopic and transgenic models of cancer in mice (melanoma, non-melanoma skin cancer, colon cancer and pancreatic beta-cell cancer). In addition, ongoing experiments suggest that MFG-E8 may be a relevant therapeutic target in cancer. To gain additional understanding of the roles that MFG-E8 plays in tumor formation and immunophysiology, we are carefully localizing MFG-E8 accumulation in vivo in tumors and in normal tissues. Utilizing highly specific affinity-purified polyclonal antibodies, we have determined that MFG-E8 is found focally in vascular or perivascular locations and in other specific locations as well. We have documented that, in tumors, pericytes produce more MFG-E8, on a per cell basis, than leukocytes, endothelial cells and tumor cells. We hypothesize that pericyte-derived MFG-E8 regulates endothelial cell function and are testing this hypothesis in several in vitro and in vivo models. We also hypothesized that pericyte-derived MFG-E8 might influence pericyte function, and we have demonstrated that MFG-E8 enhances perciyte migration in vitro. In the course of these studies, we determined that some of the anti-MFG-E8 antibodies that we have developed have function neutralizing activity in vitro. This led us assess the role of MFG-E8 in pathologic angiogenesis in the well characterized mouse oxygen-induced retinopathy model. In these studies, angiogenesis was attenuated in MFG-E8 knockout mice and in mice treated with some anti-MFG-E8 antibodies. Thus, MFG-E8 may represent a valid therapeutic target in diseases in which unwanted angiogenesis is a critical factor. we are actively engaged in a series of in vitro experiments designed to provide insights into the mechanism(s) by which MFG-E8 enhances pericyte function and angiogenesis. Finally, we are assessing the role of MFG-E8 in glomerular function since glomerular mesangial cells represent a subpopulation of pericytes. We have localized MFG-E8 to murine mesangial cells and are in the process of determining the significance of this observation.