Abstract 1543: Potential role of Schwann cells and laminin adhesion in prostate cancer perineural invasion

Prostate tumor cell migration and invasion of prostatic nerves, a process known as perineural invasion (PNI), is a major route for extracapsular extension during prostate cancer metastasis. The clinical significance of perineural invasion as a predictor for poor patient outcome has been extensively documented. The laminin family of extracellular matrix glycoproteins lines the neural route and plays a prominent role in the development and maintenance of the peripheral nervous system. Evidence has shown that the laminin receptor integrin α6β1 promotes prostate tumor cell migration and invasion in aggressive disease. We hypothesize that α6β1 regulates prostate cancer perineural invasion by regulating laminin dependent adhesion and migration on nerves. In this study we demonstrate remarkable integrin α6 expression in prostate tumors undergoing active perineural invasion using immunohistochemical analysis of human prostate tumors. The expression of integrin α6 correlates with expression of the laminin subunits α5 and γ1 which comprise laminin-511, the major ligand for integrin α6β1. The laminin extracellular matrix on the peripheral nerves of the prostate is derived from Schwann cells during the myelination process. We demonstrate here that Schwann cells are highly expressed in prostatic nerves using immunohistochemical analysis of the Schwann cell specific marker S-100, suggesting that tumor cells invade myelinated nerves. We also demonstrate two specific patterns of prostate tumor nerve invasion along prostatic nerves. Invasion along the external surface of the nerve sheath or in the perineural space maintains nerve structure while invasion of the endoneural space disrupts nerve structure and displaces Schwann cells. This suggests that tumor interactions with nerves and Schwann cells may illicit nerve damage during the PNI process. Using a DU-145 prostate tumor and neuron/glial cell in vitro co-culture model we demonstrate that DU-145 cells (cytokeratin positive) migrate towards glial cells (GFAP positive) and neurons (Beta-III tubulin positive) isolated from dorsal root ganglia of male SCID mice. Mature cultures of the prostate tumor cells and neuron/glial cells demonstrate distinct islands of growth. The patterns of colony formation were non-random and interspersed colonies of tumor and nerve cells were not observed. Taken together, our immunohistochemical results suggest that perineural invasion of laminin coated nerves is regulated by the laminin adhesion receptor α6β1. Our in vitro model system demonstrates that tumor cells migrate to neuron/glial cells and dominate the co-culture, correlating with our immunohistochemical data. We expect that blocking α6β1 function in this system will impede prostate tumor cell migration and invasion in the nerve environment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1543. doi:10.1158/1538-7445.AM2011-1543