Abstract B22: The role of phosphodiesterase 4D and the microenvironment in prostate cancer

Abstract

Abstract Phosphodiesterase 4D (PDE4D) was implicated as a candidate gene in prostate cancer through a transposon-mutagenesis screen in mice. Functionally, PDE4D regulates cellular levels of cAMP, which is critical for multiple signaling pathways including protein kinase A and mTor. PDE4D expression was localized to the prostate epithelial cells and increased in the earliest stages of human prostate cancer (prostate intraepithelial neoplasia) through aggressive metastatic prostate cancer. Based on its function, PDE4D may also function to regulate signaling between epithelial and stromal cells. The purpose of this study was to examine the role of PDE4D signaling in prostate cancer and how it is influenced by the microenvironment. The role of PDE4D in prostate cancer was assessed both in vivo, using genetically modified mouse and xenograft models, and in vitro, using prostate cancer cell lines and novel microchannel cultures. Castration resistant C4 prostate cancer cells grown as xenografts under the kidney capsules of nude mice and were treated with control or PDE4D inhibitors cilomilast and NVP-ABE171. Treatment with cilomilast or NVP-ABE171 decreased the overall size of the C4 xenografts and increased apoptotic cells. For in vitro studies a novel microchannel culture system was used to examine to examine the effect of the microenvironment on PDE4D signaling. In microchannels distinct cell types can be cultured in small volumes (2-4 microliters), which concentrates secreted factors and allows for either culture with direct contact between the cells or separation between multiple cell types but permits the diffusion of soluble signaling factors. The effect of co-culturing prostate stromal and epithelial cells on growth, PDE4D signaling, growth factor secretion, and gene expression was examined. In this model prostate epithelial cells were co-cultured with prostate stromal cells. Proliferation of the epithelial cells increased when they were co-cultured with stromal cells. This proliferation occurred when the cells are cultured in chambers separated by diffusion ports that allow exchange of soluble factors. Preliminary studies showed differential secretion of growth factors and cytokines, including transforming growth factor beta (TGFβ) and vascular endothelial growth factor (VEGF), between cells in monoculture and co-culture. Initial studies also suggested that PDE4D inhibition might have differential effects on the prostate epithelial and stromal cells in monoculture and co-culture. The in vitro data demonstrated that co-culture of prostate epithelial and stromal cells can lead to increased proliferation, differential expression of secreted factors and genes, as well as response to PDE4D inhibitor treatment. Results from the in vivo studies suggested that PDE4D inhibitors may be a useful strategy for prostate cancer treatment as they decreases the growth and increased apoptosis of prostate cancer xenografts in vivo. Overall the results of these studies indicated that PDE4D might have a role in signaling between prostate epithelial and stromal cells and that some of the anti-tumor effects of PDE4D inhibitors are due to their impact on paracrine signaling. Citation Format: Ginny L. Powers, Kimberly DP Hammer, Xiaojing Su, Maribella Domenech, David J. Beebe, Paul C. Marker. The role of phosphodiesterase 4D and the microenvironment in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B22.