GFR1, which is secreted by nerves, is a limiting factor for RET signaling, creating a perineural niche where RET signaling can occur. strong class=”kwd-title” Keywords: prostate cancer, signal transduction, RET, p70 S6 kinase INTRODUCTION Prostate cancer (PCa) is the second-leading cancer cause of cancer in American men, with 27,540 deaths expected to occur due to PCa in 2015 (1). by anti-GFR1 antibody. Perineural invasion in the dorsal root ganglion assay is inhibited by anti-GFR antibody and RET knockdown. In vivo, knockdown of RET inhibits tumor growth. RET signaling activates ERK or AKT signaling depending on context, but phosphorylation of p70S6 kinase is markedly increased in all cases. Knockdown of p70S6 kinase markedly decreases RET induced transformed phenotypes. YIL 781 Finally, RET is expressed in 18% of adenocarcinomas and all three small cell carcinomas examined. Conclusions RET promotes transformation associated phenotypes, including perineural invasion in prostate cancer via activation of p70S6 kinase. GFR1, which is secreted YIL 781 by nerves, is a limiting factor for RET signaling, creating a perineural niche where RET signaling can occur. strong class=”kwd-title” Keywords: prostate cancer, signal transduction, RET, p70 S6 kinase INTRODUCTION Prostate cancer (PCa) is the second-leading cancer cause of cancer in American men, with 27,540 deaths expected to YIL 781 occur due to PCa in 2015 (1). While the prognosis for early stage PCa is generally excellent, few effective therapeutic options exist for advanced PCa. It has been appreciated for many years that the tumor microenvironment plays an important role in the initiation and progression of prostate and other cancers. One important component of this microenvironment is nerves. It is well known that PCa has a propensity to grow in perineural locations, as do a number of other cancers such as pancreatic cancer. Perineural invasion (PNI) is defined as the presence of cancer infiltration in, around and/or through the nerves (2) and is the result of reciprocal interactions between cancer cells and adjacent nerves(3). PNI is an adverse prognostic factor for many cancers, including prostate, pancreatic, head and neck, colon, skin and salivary cancers (4C8). While PNI per se is not predictive of aggressive disease in PCa, large diameter perineural tumor is one of the most significant pathological predictors of poor outcome (9) following radical prostatectomy. Furthermore, PNI is associated with poor outcomes following radiation therapy(10,11), suggesting a pro-survival effect of PCa cell interactions with nerves. These clinical observations show that the interactions between nerves and PCa cells can have a YIL 781 significant impact on treatment outcomes in men with PCa which ultimately must be related to the underlying biology. Recent functional studies in vitro and correlative studies in vivo have shown significant interactions between nerves and adjacent cancer cells that promote cell survival, proliferation and migration of PCa cells (2,3,12). For example, PCa cells adjacent to nerves display increased proliferation and decreased apoptosis compared to cells away from nerves(12), indicating local microenvironmental influence on the cancer cells in this niche. Similar findings have been reported in other neurotrophic cancer such as pancreatic cancer(13). Studies in rats have shown that denervation of the YIL 781 prostate leads to almost complete loss of epithelium (14), indicating a strong trophic effect of nerves on normal prostate epithelium. Similarly, men with complete spinal cord injury had significantly smaller prostates than controls(15). Studies by Magnon et al(16) have shown that chemical or surgical ablation of nerves inhibits tumorigenesis and metastasis in both xenograft and transgenic mouse models of PCa, unequivocally establishing that nerve-PCa cell interactions play a significant role in PCa initiation and progression KCTD18 antibody but the molecular basis of these interactions is still unclear. We have carried out expression microarray analysis of laser captured PCa reactive stroma (17) and shown that among the upregulated genes is glial cell line-derived neurotrophic factor (GDNF). Interestingly, GDNF levels are increased during androgen induced regrowth of the prostate after castration(18). GDNF is present in the peripheral nerves of normal prostate and in reactive stroma in PCas where it can be secreted and potentially interact with PCa cells. Of course, GDNF is expressed in nerves in potential metastatic sites as well. Functional studies in pancreatic cancer implicate GDNF as a key factor promoting perineural migration in vitro in this disease.