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An Essential Role for Macrophage Migration Inhibitory Factor (MIF) in Angiogenesis and the Growth of a Murine Lymphoma

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Abstract

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.

Materials and 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.

Conclusion

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.

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Acknowledgments

This work was supported by grants from the NIH (AI42310-01A1) and the Arthritis Foundation.

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Authors and Affiliations

  1. Laboratory of Medical Biochemistry, The Picower Institute for Medical Research, 350 Community Drive, Manhasset, New York, 11030, USA

    Jason Chesney, Christine Metz, Michael Bacher, Tina Peng &  Richard Bucala

  2. Department of Anatomy and Cell Biology, Philipps University, Marburg, Germany

    Andreas Meinhardt

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  1. Jason Chesney
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  2. Christine Metz
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  3. Michael Bacher
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  4. Tina Peng
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  5. Andreas Meinhardt
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  6. Richard Bucala
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Correspondence to Richard Bucala.

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Communicated by R. Bucala.

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Chesney, J., Metz, C., Bacher, M. et al. An Essential Role for Macrophage Migration Inhibitory Factor (MIF) in Angiogenesis and the Growth of a Murine Lymphoma. Mol Med 5, 181–191 (1999). https://doi.org/10.1007/BF03402061

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