An essential role for macrophage migration inhibitory factor (MIF) in angiogenesis and the growth of a murine lymphoma

Background: Macrophage migration inhibitory factor (MIF) has been shown to counterregulate glucocorticoid action and to play an essential role in the activation of macrophages and T cells in vivo. MIF also may function as an autocrine growth factor in certain cell systems. We have explored the role of MTF in the growth of the 38Cl3 B cell lymphoma in C3H/HeN mice, a well-c haracterized syngeneic model for the study of solid tumor biology. Materials and Methods: Tumor-bearing mice were treated with a neutralizing anti-MIF monoclonal antibody and the tumor response assessed grossly and hi stologically. Tumor capillaries were enumerated by immunohistochemistry and analyzed for MIF expression. The effect of MIF on endothelial cell prolife ration was studied in vitro, utilizing both specific antibody and antisense oligonucleotide constructs. The role of MIF in angiogenesis also was exami ned in a standard Matrigel model of new blood vessel formation in vivo. Results: The administration of anti-MIF monoclonal antibodies to mice was f ound to reduce significantly the growth and the vascularization of the 38C1 3 B cell lymphoma. By immunohistochemistry, MIF was expressed predominantly within the tumor-associated neovasculature. Cultured microvascular endothe lial cells, bur not 38C13 B cells, produced MIF protein and required its ac tivity for proliferation in vitro. Anti-MIF monoclonal antibody also was fo und to markedly inhibit the neovascularization response elicited by Matrige l implantation. Conclusion: These data significantly expand the role of MIF in host respons es, and suggest a new target for the development of anti-neoplastic agents that inhibit tumor neovascularization.