Schwann Cells Promote Tumor Cell Invasion Through Regulation of the Laminin Receptor α6β1

Abstract

Neurotropic cancers including pancreatic and prostate cancer utilize nerves as a major route of metastasis in a process known as nerve invasion (NI). During NI, tumor cells invade the perineurium of nerves and into the endoneural space where tumor cells contact Schwann cells responsible for secretion of laminin extracellular matrix proteins and myelination of peripheral nerve axons. The laminin binding cell adhesion receptor α6β1 is expressed on tumor cells undergoing NI and cleavage of α6β1 by urokinase plasminogen activator to form the variant α6β1 promotes tumor cell invasion. Here, we demonstrate that conditioned media from immortalized S16 and S16Y Schwann cells, which are of the myelinating and non-myelinating morphology respectively, regulate α6pβ1 formation and tumor invasion of neurotropic tumor cell lines. The results demonstrate that S16Y conditioned medium inhibited invasion and ð€„®6 conversion to α6p in DU145, CFPAC1 and PC3 cancer cells while S16 conditioned medium increased α6p expression and tumor cell invasion. The increased invasion mediated by the S16 cells was dependent on α6pβ1 since a function-blocking antibody, targeting α6pβ1 formation inhibited invasion. Taken together these results suggest that myelinating Schwann cells in the nerve environment promote α6β1 receptor dependent tumor cell nerve invasion.