Our interest in the phagocyte- and tumor cell-derived protein MFG-E8 continues but our level of efforts has decreased. Currently, all of our effort in this area is via collaborative efforts that are led or co-led by extramural investigators. In the past, we 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 carefully localized MFG-E8 accumulation in vivo in tumors and in normal tissues. Utilizing highly specific affinity-purified polyclonal antibodies, we determined that MFG-E8 was 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 hypothesized that pericyte-derived MFG-E8 regulates endothelial cell function and tested 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 subsequently 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. Results of these experiments suggested that MFG-E8 potentiated PDGF signaling via a mechanism that is integrin-dependent and that may protect PDGF receptors from ubiquitin-dependent degradation. Our in vivio and in vitro findings are described in 2 manuscripts that have now been published in Arterisclerosis, Thrombosis and Vascular Biology in 2011. In collaboration with a former post-doctoral fellow, Dr. Sei-ichiuro Motegi, we have assessed the role of MFG-E8 in glomerular function since glomerular mesangial cells represent a subpopulation of pericytes, and PDGF-mediated signaling is critically important for glomerular development and function. We have localized MFG-E8 to murine mesangial cells and have determined that expression of MFG-E8 in kidney has functional consequences. Also, in collaboration with Dr. Motegi, we are studying the extent to which MFG-E8 regulates full-thickness wound healing. Manuscript describing these findings are binng prepared for publication. We have initiated a collaboration with Dr. Nick Marsh-Armstrong of Johns Hopkins University to assess the possible involvement of MFG-E8 in normal physiology and pathophysiology in the central nervous system. In a separate collaboration with Dr. George Hajishengallis at U Penn, we are exploring MFG-E8 function in a unique inflammation model. We are also collaborating with Dr. Harvey Florman at the University of Massachusetts to determine if MFG-E8 might have a role in female fertility.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010976-06
Application #
8763290
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$142,693
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Abe, Toshiharu; Shin, Jieun; Hosur, Kavita et al. (2014) Regulation of osteoclast homeostasis and inflammatory bone loss by MFG-E8. J Immunol 193:1383-91
Uchiyama, Akihiko; Yamada, Kazuya; Ogino, Sachiko et al. (2014) MFG-E8 regulates angiogenesis in cutaneous wound healing. Am J Pathol 184:1981-90