Melanoma differentiation-associated gene 7/interleukin (IL)-24 is a novel ligand that regulates angiogenesis via the IL-22 receptor.
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-gamma, 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.
Ramesh
Rajagopal
R
Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. rramesh@mdanderson.org
Mhashilkar
Abner M
AM
Tanaka
Fumihiro
F
Saito
Yuji
Y
Branch
Cynthia D
CD
Sieger
Kerry
K
Mumm
John B
JB
Stewart
Alexis L
AL
Boquoi
Amelie
A
Dumoutier
Laure
L
Grimm
Elizabeth A
EA
Renauld
Jean-Christophe
JC
Kotenko
Sergei
S
Chada
Sunil
S
Boquio
Amelia
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000502:physiology; D003094:Collagen / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D007378:Interleukins / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010446:Peptide Fragments / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000502:physiology*; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000099180:Interleukin-24
D020533:Angiogenesis Inhibitors; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D003094:Collagen; D004268:DNA-Binding Proteins; D043169:Endostatins; D007371:Interferon-gamma; D007378:Interleukins; D010446:Peptide Fragments; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000099180:Interleukin-24; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C415369:interleukin-22 receptor