Genetic disruption of host interferon-gamma drastically enhances the metastasis of pancreatic adenocarcinoma through impaired expression of induciblenitric oxide synthase

Synergistic induction of the inducible nitric oxide synthase (NOS II) gene requires a combination of interferon-gamma (IFN-gamma) and lipopolysacchari de (LPS). In this study, we determined whether the induction of IFN-gamma w as required for NOS U-mediated antitumor activity in viro. Highly metastati c H7 murine pancreatic adenocarcinoma cells were implanted into the subcuti s, footpad, and pancreas of syngeneic IFN-gamma (+/+) and IFN-gamma (-/-) m ice. These cells grew and produced metastases and ascites in IFN-gamma (+/) mice. In sharp contrast, the same tumor cells grew much more aggressively , metastasized more extensively, and produced a larger amount of malignant ascites in IFN-gamma (-/-) mice. Also, induction of IFN-gamma correlated wi th NOS II gene expression and NO production in IFN-gamma (+/+) injected wit h the tumor cells but not in IFN-gamma (-/-) mice or IFN-gamma (+/+) mice w ithout tumor challenge. In vitro, only LPS plus IFN-gamma induced a high le vel of NO production and cytotoxicity against H7 cells. These data suggeste d that the tumor cells stimulated IFN-gamma secretion from host cells, whic h in turn stimulated NO production by host cells and suppressed tumor growt h and metastasis.