Abstract 1407: Sonic hedgehog signaling and Androgens are linked in tumor-stromal interaction through Epithelial-Mesenchymal transition (EMT) in prostate cancer progression

Abstract

Abstract Backgrounds: Sonic hedgehog (Shh) signaling is known to relate to cancer progression but the detail about how to correlate and link with another signaling is debating. The purpose of this study is to investigate the link between Shh signaling, androgens and epithelial-mesenchymal transition (EMT) in prostate tumor-stroma interaction during prostate cancer (PCa) progression. Materials and Methods: We investigated cell proliferation in LNCaP PCa cells, Normal Prostate Fibroblasts (NPF), and Cancer-associated Prostate Fibroblasts (CPF) in the presence of representative androgen, dihydrotestosterone (DHT) and/or Shh signaling inhibitor, cyclopamine (Cyc). With these stimulators or inhibitors, real time RT-PCR was performed to investigate downstream transcriptional factors of Shh signaling, Gli-1, EMT markers (E-cadherin, N-cadherin, and Vimentin), and Osteonectin (ON), a possible Shh target gene shown in our previous work. Expression levels of AR, Gli-1, Ki-67, Shh, and ON in specimens from PCa patients were measured by immunohistochemical (IHC) staining and correlated with clinical data. Results: While significant cell proliferation was induced by DHT in LNCaP, NPF, and CPF, Cyc inhibited these enhanced growths. CPF tended to react to DHT more but less to Cyc than LNCaP or NPF. RT-PCR results showed Shh induced EMT and DHT induced the expression of Gli-1, ON and EMT, and those inductions were blocked by Cyc. IHC staining showed that Stromal ON (ONstr) had significant correlation with serum PSA (p=0.031), high Gleason Scores had significant correlation with Ki-67, and PSA recurrence was related significantly to Gli-1 expression and lower expression of ONstr, suggesting PCa recurrence had a significant correlation with Shh-Gli-1 signaling. Conclusions: Shh signaling is involved in tumor-stromal interaction through a link with Androgens and EMT, and thus plays a pivotal role in PCa progression. Cyclopamine may therefore be a possible therapeutic agent for blocking PCa progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1407. doi:1538-7445.AM2012-1407