Intact nitric oxide synthase II gene is required for interferon-beta-mediated suppression of growth and metastasis of pancreatic adenocarcinoma.
Previous studies have shown that enforced expression of IFN-beta suppressed tumor growth and metastasis. In this report, we determined whether the induction of nitric oxide synthase II (NOS II) gene is required for IFN-beta-mediated antitumor activity using syngeneic mice with intact (NOS II+/+) or genetically disrupted (NOS II-/-) NOS II gene. PANC02-H7 highly metastatic murine pancreatic adenocarcinoma cells were transfected with an IFN-beta expression vector or a control pcDNA3 vector. The parental PANC02-H7, control vector-transfected, and IFN-beta-transfected cells were orthotopically implanted into the pancreas of syngeneic NOS II+/+ and NOS II-/- C57BL/6J mice. In NOS II+/+ C57BL/ 6J, both parental and control vector-transfected cells grew progressively in pancreas and produced numerous liver metastases and a large amount of malignant ascites, whereas IFN-beta-secreting cells did not. In NOS II-/- C57BL/6J mice, however, IFN-beta-secreting cells grew much more aggressively. Higher NO induction was detected in NOS II+/+ mice that received injections with IFN-beta-secreting cells than with the control cells, but it was not detected in NOS II-/- mice. These data suggested that IFN-beta secreted from tumor cells stimulates NO production by host cells and suppresses tumor growth and metastasis.
Wang
B
B
Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Xiong
Q
Q
Shi
Q
Q
Le
X
X
Abbruzzese
J L
JL
Xie
K
K
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000818:Animals; D002455:Cell Division / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000556:secondary; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D011994:Recombinant Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured
D006131:Growth Inhibitors; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D009569:Nitric Oxide; D016899:Interferon-beta; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II