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Melanoma Differentiation-associated Gene 7/Interleukin (IL)-24 Is a Novel Ligand That Regulates Angiogenesis via the IL-22 Receptor¹

Departments of Thoracic and Cardiovascular Surgery [R. R., F. T., Y. S., C. D. B., A. B.] and Bioimmunotherapy [J. B. M., E. A. G., S. C.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Introgen Therapeutics Inc., Houston, Texas 77030 [A. M. M., K. S., A. L. S., S. C.]; Department of Ludwig Institute for Cancer Research, Brussels, Belgium [L. D., J-C. R.]; and Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey, Newark, New Jersey [S. K.]

The melanoma differentiation-associated gene 7 (mda-7), also called interleukin (IL)-24, suppresses the growth of some cancers in vitro and in vivo as a result of the ectopic expression of its protein. However, the function of the secreted form of the protein in cancer has not been previously studied. The purpose of this study was to determine the antiangiogenic function of a secreted form of the MDA-7/IL-24 protein (sMDA-7/IL-24). In vitro, sMDA-7/IL-24 inhibited both endothelial cell differentiation and migration of endothelial cells induced by vascular endothelial growth factor and basic fibroblast growth factor. The sMDA-7/IL-24-mediated inhibitory effect was 10–50 times more potent than endostatin, IFN-, and IFN-inducible protein 10 in vitro. Furthermore, the inhibitory effect was not mediated by IFN or IFN-inducible protein 10. IL-22 receptor mediated the antiangiogenic activity of sMDA-7/IL-24. Administration of a blocking antibody to IL-22 receptor in conjunction with sMDA-7/IL-24 led to abrogation of inhibition of endothelial differentiation. sMDA-7/IL-24 inhibited vascular endothelial growth factor-induced angiogenesis as evidenced by reduced vascularization and hemoglobin content in in vivo Matrigel plug assays. In vivo, the growth of human lung tumor cells was significantly inhibited, and vascularization was reduced when the cells were mixed with 293 cells stably expressing sMDA-7/IL-24. Systemic administration of sMDA-7/IL-24 inhibited lung tumor growth in a mouse xenograft model. Associated with tumor growth inhibition was decreased tumor microvessel density and hemoglobin content, indicating the presence of antiangiogenic activity. These data demonstrate that sMDA-7/IL-24 is a novel and potent antiangiogenic effector and support the development of MDA-7/IL-24-based therapeutics.

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