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 MIF in the growth of the 38C13 B cell lymphoma in C3H/HeN mice, a well-characterized syngeneic model for the study of solid tumor biology.


METHODS
Tumor-bearing mice were treated with a neutralizing anti-MIF monoclonal antibody and the tumor response assessed grossly and histologically. Tumor capillaries were enumerated by immunohistochemistry and analyzed for MIF expression. The effect of MIF on endothelial cell proliferation was studied in vitro, utilizing both specific antibody and antisense oligonucleotide constructs. The role of MIF in angiogenesis also was examined in a standard Matrigel model of new blood vessel formation in vivo.


RESULTS
The administration of anti-MIF monoclonal antibodies to mice was found to reduce significantly the growth and the vascularization of the 38C13 B cell lymphoma. By immunohistochemistry, MIF was expressed predominantly within the tumor-associated neovasculature. Cultured microvascular endothelial cells, but not 38C13 B cells, produced MIF protein and required its activity for proliferation in vitro. Anti-MIF monoclonal antibody also was found to markedly inhibit the neovascularization response elicited by Matrigel implantation.


CONCLUSIONS
These data significantly expand the role of MIF in host responses, and suggest a new target for the development of anti-neoplastic agents that inhibit tumor neovascularization.
Laboratory of Medical Biochemistry, Picower Institute for Medical Research, Manhasset, New York 11030, USA.
J
J
Chesney
C
C
Metz
M
M
Bacher
T
T
Peng
A
A
Meinhardt
R
R
Bucala
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002455:Cell Division; D003094:Collagen; D004195:Disease Models, Animal; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011509:Proteoglycans; D014407:Tumor Cells, Cultured
D000906:Antibodies; D004338:Drug Combinations; D007797:Laminin; D008263:Macrophage Migration-Inhibitory Factors; D016376:Oligonucleotides, Antisense; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen