IL-12 regulates VEGF and MMPs in a murine breast cancer model.
In a murine model of breast cancer, IL-12 therapy exerts potent anti-angiogenic effects which contribute to tumor regression. After 7 days of treatment, levels of tumor VEGF protein decline markedly and are undetectable at 14 days. This decline is accompanied by a fall in MMP-9 and, as the tumors regress, an increase in its natural inhibitor, TIMP-1. A cell line established from the primary tumor produced VEGF in vitro. IFN-gamma reduced tumor cell production of VEGF over a 24-hr period in vitro, suggesting that IL-12-induced IFN-gamma may be responsible for the decline in VEGF levels in vivo. There is also in vitro evidence that IL-12 regulates stromal cell interactions, leading to decreased MMP-9 and increased TIMP-1 production. Thus, we suggest that at least 2 mechanisms are involved in IL-12 regulation of angiogenesis, removing the pro-angiogenic stimulus and blocking the release and activity of MMPs.
Biological Therapies Laboratory, Imperial Cancer Research Fund, London, UK. diassjr@icrf.icnet.uk
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Dias
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Boyd
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Balkwill
D000818:Animals; D018920:Coculture Techniques; D017364:Collagenases / Q000096:biosynthesis*; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D005260:Female; D018664:Interleukin-12 / Q000494:pharmacology*; D008222:Lymphokines / Q000096:biosynthesis*; D008264:Macrophages / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D019715:Tissue Inhibitor of Metalloproteinase-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D018664:Interleukin-12; D017364:Collagenases; D020780:Matrix Metalloproteinase 9