Abstract B152: Modulating the activity of nerve growth factor (NGF) and its receptors tropomyosin-related kinase A (TRKA) and p75 neurotrophin receptor (p75NTR) in perineural invasion (PNI) in pancreatic cancer.

Abstract Pancreatic cancer is the fourth leading cause of cancer-related death in the US with a 5-year survival rate of less than 5%. Even after surgery and chemotherapy, prognosis is dismal due to tumor re-occurrence. Perineural Invasion (PNI) is a process where surrounding pancreatic nerves are invaded by pancreatic cancer cells. This invasive and proliferative ability of pancreatic cancer cells is indicative of their aggressiveness and is shown to be associated with poor prognosis and pain in pancreatic cancer patients. The nerve growth factor (NGF) signaling pathway is implicated in PNI and NGF binds to a high-affinity receptor, tropomyosin kinase A (TRKA), which is differentially expressed in pancreatic tumor tissues and a low-affinity receptor, p75 neurotrophin receptor (p75NTR), whose role in PNI in pancreatic cancer is unclear. In this study, we seek to understand the molecular mechanisms of NGF regulation of PNI in pancreatic cancer. Whether NGF regulates PNI via an autocrine or paracrine manner is not well understood. Signaling via NGF-TRKA pathway induces neurites in the PC-12 neurite extension assay and conditioned media (CM) from several pancreatic cancer cell lines including BxPC3 induced neurites in this assay. Addition of an antibody to neutralize NGF in the CM or an azaoxindole inhibitor (GW441756) of TRKA resulted approximately in a 50% and 40% decrease in neurites respectively in the PC-12 assay. These results could indicate a paracrine action of NGF in promoting neurite extension in the PC-12 assay and perhaps nerve growth as related to PNI. Furthermore, knocking down the expression of NGF, p75NTR, TRKA using siRNA or inhibitor GW441756 of TRKA decreased migration of BxPC3 pancreatic cancer cells in the Boyden chamber assay by 45 − 60%. A similar inhibitory effect was observed in the movement of pancreatic cancer cells towards dorsal root ganglia (DRG) in a DRG-pancreatic cancer cell co-culture assay. Thus, NGF may function in an autocrine manner to increase proliferation and invasiveness of pancreatic cancer cells in PNI. Currently, we are working to further optimize our assays to delineate the interplay between NGF and TrkA (autocrine or paracrine) in PNI and understand the involvement of p75NTR (low-affinity NGF receptor) in NGF signaling and consequently in PNI. Understanding the molecular mechanisms involved in PNI will aid in designing novel therapeutics that prevent PNI and alleviate pain associated with PNI in patients with pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B152.