Association of increased immunostaining for inducible nitric oxide synthase and nitrotyrosine with fibroblast growth factor transformation in pancreatic cancer.

Abstract

Despite recognition of the devastating malignant potential of pancreatic cancer, the exact pathophysiological events contributing to tumor growth, vascular invasiveness, and hepatic metastasis remain to be elucidated. Twelve human pancreatic adenocarcinomas were evaluated using immunohistochemical and in situ hybridization techniques for the appearance of the angiogenic and neurogenic growth factors, acidic fibroblast (FGF-1) and basic fibroblast growth factor (FGF-2), and their high-affinity receptors. Since FGF biological processes appear to be regulated by oxidant stress, tumors were examined further for the immunoappearance of inducible nitric oxide synthase (iNOS) and nitrotyrosine. Compared with normal human pancreatic tissue, tumor specimens exhibited varying levels of enhanced staining for FGF ligands and receptors. The increased appearance of FGF-1 and FGF-2 proteins was accompanied by increased detection of messenger RNA encoding each growth factor. In addition, these pancreatic tumors demonstrated the overexpression of iNOS and immunostaining of nitrotyrosine compared with normal pancreatic tissue. The enhanced expression of FGF and FGF receptors suggests that these polypeptide mitogens may serve as important mediators of growth and of angiogenic and metastatic responses associated with pancreatic tumors, not seen in normal pancreatic tissue. Furthermore, we provide the first indication of increased expression of iNOS and protein tyrosine nitration, thereby predicting the potential involvement of oxidant stress during development and progression of pancreatic adenocarcinoma.