Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves

Abstract

BackgroundThe ability of cancer to infiltrate along nerves is a common clinical observation in pancreas, head and neck, prostate, breast, and gastrointestinal carcinomas. For these tumors, nerves may provide a conduit for local cancer progression into the central nervous system. Although neural invasion is associated with poor outcome, the mechanism that triggers it is unknown.MethodsWe used an in vitro Matrigel dorsal root ganglion and pancreatic cancer cell coculture model to assess the dynamic interactions between nerves and cancer cell migration and the role of glial cell-derived neurotrophic factor (GDNF). An in vivo murine sciatic nerve model was used to study how nerve invasion affects sciatic nerve function.ResultsNerves induced a polarized neurotrophic migration of cancer cells (PNMCs) along their axons, which was more efficient than in the absence of nerves (migration distance: mean=187.1 μm, 95% confidence interval [CI]=148 to 226 μm vs 14.4 μm, 95% CI = 9.58 to 19.22 μm, difference = 143 μm; P