IL-12 regulates VEGF and MMPs in a murine breast cancer model

Abstract

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‐γ reduced tumor cell production of VEGF over a 24‐hr period in vitro, suggesting that IL‐12‐induced IFN‐γ 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. Int. J. Cancer 78:361–365, 1998.