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

Background: Despite recognition of the devastating malignant potential of p ancreatic cancer, the exact pathophysiological events contributing to tumor growth, vascular invasiveness, and hepatic metastasis remain to be elucida ted. Methods: Twelve human pancreatic adenocarcinomas were evaluated using immun ohistochemical and in situ hybridization techniques for the appearance of t he 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, tu mors were examined further for the immunoappearance of inducible nitric oxi de synthase (iNOS) and nitrotyrosine. Results: Compared with normal human pancreatic tissue, tumor specimens exhi bited varying levels of enhanced staining for FGF ligands and receptors. Th e increased appearance of FGF-1 and FGF-2 proteins was accompanied by incre ased detection of messenger RNA encoding each growth factor. In addition, t hese pancreatic tumors demonstrated the overexpression of iNOS and immunost aining of nitrotyrosine compared with normal pancreatic tissue. Conclusions: 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, n ot seen in normal pancreatic tissue. Furthermore, we provide the first indi cation of increased expression of iNOS and protein tyrosine nitration, ther eby predicting the potential involvement of oxidant stress during developme nt and progression of pancreatic adenocarcinoma.