ABSTRACT
Perineural invasion (PNI) is thought to be one of the factors responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Signaling via the nerve growth factor (NGF) pathway between pancreatic cancer cells and the surrounding nerves has been implicated in PNI, and increased levels of these proteins have been correlated to poor prognosis. In this study, we examine the molecular mechanism of the NGF signaling pathway in PNI in pancreatic cancer. We show that knocking down NGF or its receptors, TRKA and p75NTR, or treatment with GW441756, a TRKA kinase inhibitor, reduces the proliferation and migration of pancreatic cancer cells in vitro. Furthermore, pancreatic cancer cells migrate towards dorsal root ganglia (DRG) in a co-culture assay, indicating a paracrine NGF signaling between the DRGs and pancreatic cancer cells. Knocking down the expression of NGF pathway proteins or inhibiting the activity of TRKA by GW441756 reduced the migratory ability of Mia PaCa2 towards the DRGs. Finally, blocking NGF signaling by NGF neutralizing antibodies or GW441756 inhibited the neurite formation in PC-12 cells in response to conditioned media from pancreatic cancer cells, indicating a reciprocal signaling pathway between the pancreatic cancer cells and nerves. Our results indicate that NGF signaling pathway provides a potential target for developing molecularly targeted therapies to decrease PNI and reduce pain generation. Since there are several TRKA antagonists currently in early clinical trials they could now be tested in the clinical situation of pancreatic cancer induced pain.
Subject(s)
Nerve Growth Factor/metabolism , Nervous System/pathology , Pancreatic Neoplasms/pathology , Signal Transduction/drug effects , Signal Transduction/genetics , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/genetics , Cell Proliferation/drug effects , Cell Proliferation/genetics , Cell Survival/drug effects , Cell Survival/genetics , Ganglia, Spinal/pathology , Gene Knockout Techniques , Humans , Indoles/pharmacology , Neoplasm Invasiveness , Nerve Growth Factor/deficiency , Nerve Growth Factor/genetics , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Nervous System/drug effects , Neurites/drug effects , Neurites/metabolism , Receptor, trkA/antagonists & inhibitors , Receptor, trkA/deficiency , Receptor, trkA/genetics , Receptors, Nerve Growth Factor/deficiency , Receptors, Nerve Growth Factor/geneticsSubject(s)
Adrenal Cortex Neoplasms , Adrenocortical Carcinoma , Mitotane/administration & dosage , Adrenal Cortex Neoplasms/drug therapy , Adrenal Cortex Neoplasms/pathology , Adrenocortical Carcinoma/drug therapy , Adrenocortical Carcinoma/pathology , Biomarkers, Pharmacological , Clinical Trials as Topic , Drug Resistance, Neoplasm , HumansABSTRACT
Perineural invasion (PNI) is a prominent characteristic of pancreatic cancer. PNI is a process whereby cancer cells invade the surrounding nerves, thus providing an alternative route for metastatic spread and pain generation. PNI is thought to be an indicator of aggressive tumour behaviour and has been shown to correlate with poor prognosis of patients with pancreatic cancer. Recent studies demonstrated that some signalling molecules and pathways that are involved in PNI are also involved in pain generation. Targeting these signalling pathways has shown some promise in alleviating pain and reducing PNI, which could potentially improve treatment outcomes for patients with pancreatic cancer.
