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-a ngiogenic effects which contribute to tumor regression. After 7 days o f treatment, levels of tumor VEGF protein decline markedly and are und etectable at 14 days. This decline is accompanied by a fall in MMP-9 a nd, as the tumors regress, an increase in its natural inhibitor, TIMP- 1. A cell line established from the primary tumor produced VEGF in vit ro. IFN-gamma reduced tumor cell production of VEGF over a 24-hr perio d 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 eviden ce that IL-12 regulates stromal cell interactions, leading to decrease d MMP-9 and increased TIMP-1 production. Thus, we suggest that at leas t 2 mechanisms are involved in IL-12 regulation of angiogenesis, remov ing the pro-angiogenic stimulus and blocking the release and activity of MMPs. Int. J. Cancer 78:361-365, 1998. (C) 1998 Wiley-Liss, Inc.