Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma:Expression patterns and effects on in vitro invasive behavior

The aggressive and highly metastatic behavior observed in pancreatic ductal adenocarcinoma (PDAC) may be due to autocrine and/or paracrine interaction s (tumor/stromal) involving altered expression of peptide growth factors an d their corresponding receptors, The neurotrophin (NT) growth factor family and their cognate receptors have been demonstrated to play a role in the i nvasiveness, chemotactic behavior and tumor cell survival of both neuronal and non-neuronal cancers, We hypothesized that aberrant expression of the N Ts and/or the Trk receptors may contribute to the malignant phenotype of PD AC, specifically tumor cell invasiveness, through autocrine and/or paracrin e interactions. In this study, we examined the expression of NTs, Trks and p75(NGFR) by immunohistochemical and in situ hybridization analyses in both normal (n = 14) and neoplastic pancreas (n = 47) and PDAC-derived cell lin es (n = 6), Further, we evaluated the effects of various NTs on the in vitr o invasive and chemotactic behavior on 6 human PDAC-derived cell lines in a modified Boyden chamber assay, Brain-derived nerve growth factor (BDNF), N T-3, NT-4/5 and Trks A, B and C exhibited diffuse cytoplasmic and membranou s immunostaining patterns in both the ducts and the acini of the exocrine p ancreas and the islets of the endocrine pancreas of both normal and PDAC sp ecimens, NT expression was primarily within the stromal compartment of the tumor, while Trk expression was weak or absent. We observed a 68%, 64% and 66% increase in the expression of Trks A, B and C, respectively, in the duc tal elements of the PDAC samples examined compared with the normal adjacent tissue. Invasiveness of 4 of 6 PDAC cell lines was significantly inhibited (p < 0.05) when the cells were incubated with inn ng/ml NT, However, when select cell lines were incubated with lower concentrations of NT-3 and BDNF (0, 1, 5, 25 and 50 ng/ml), invasiveness was significantly stimulated (p < 0.05) through the Matrigel matrix. Collectively, our data suggest the poss ibility that paracrine and/or autocrine NT-Trk interactions may influence t he phenotype (possibly the invasive behavior) of PDAC. (C) 1999 Wiley-Liss, Inc.