Genetic disruption of host interferon-γ drastically enhances the metastasis of pancreatic adenocarcinoma through impaired expression of inducible nitric oxide synthase

Abstract

Synergistic induction of the inducible nitric oxide synthase (NOS II) gene requires a combination of interferon-γ (IFN-γ) and lipopolysaccharide (LPS). In this study, we determined whether the induction of IFN-γ was required for NOS II-mediated antitumor activity in vivo. Highly metastatic H7 murine pancreatic adenocarcinoma cells were implanted into the subcutis, footpad, and pancreas of syngeneic IFN-γ^+/+ and IFN-γ^−/− mice. These cells grew and produced metastases and ascites in IFN-γ^+/+ 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-γ^−/− mice. Also, induction of IFN-γ correlated with NOS II gene expression and NO production in IFN-γ^+/+ injected with the tumor cells but not in IFN-γ^−/− mice or IFN-γ^+/+ mice without tumor challenge. In vitro, only LPS plus IFN-γ induced a high level of NO production and cytotoxicity against H7 cells. These data suggested that the tumor cells stimulated IFN-γ secretion from host cells, which in turn stimulated NO production by host cells and suppressed tumor growth and metastasis.