Abstract B03: Developmental paracrine signaling pathways promote prostate cancer progression

Classic experiments in prostate embryology showed more than 30 years ago that reciprocal paracrine signals between the developing prostatic epithelium and mesenchyme were an essential feature of prostatic branching morphogenesis. Parallel research on the role of epithelial-stromal interactions during the progression of prostate cancer also showed that one or more stromal-to-epithelial paracrine signaling pathways play key roles in promoting disease progression in prostatic adenocarcinomas. Modeling these paracrine interactions involving multiple cell types for mechanistic studies in vitro can be difficult using traditional co-culture and transwell approaches. The current study utilized a novel microfluidics-based culture system to examine paracrine interactions among multiple prostate cell types. The microfluidics culture system allowed culture of cells in a single chamber that are in direct contact or in separated chambers that prevented direct cell-cell contact but permited exchange of soluble factors. Two immortalized prostate stromal cell lines that are wild type (BHPrS-1) or have dominant negative TGFβ receptor II (BHPrS-DN) were previously demonstrated to have the properties cancer associated fibroblast (CAFs) when co-cultured were utilized in these studies. Co-culture of prostate epithelial cells with CAF-like stromal cells increased epithelial cell proliferation compared to monoculture, and they promoted other cancer-related epithelial phenotypes including invasive growth and loss of E-cadherin. These effects of the stromal cells were mediated by paracrine signaling because epithelial proliferation, invasive growth, and loss of E-cadherin occurred when there was no direct contact between the epithelial and stromal cells. The effects of co-culture on relevant prostate cancer associated pathways, such as the androgen receptor pathway, were examined by qRT-PCR. In addition, soluble factors from conditioned media from mono and co-cultured epithelial and stromal cells were assessed to identify paracrine factors that were differentially expressed in co-culture. Several candidate mediators of altered stromal-epithelial interactions were identified. In particular the hedgehog signaling pathway was implicated as a known prostate developmental paracrine signaling pathway that also drives abnormal stromal-epithelial interactions in cancer progression. The requirement for hedgehog signaling in the response of prostate epithelial to abnormal stroma was confirmed using hedgehog pathway inhibitors. These data support the concept that prostate developmental signaling pathways become reactivated in the cancer microenvironment as an important feature of prostate cancer progression and that therapies targeting these paracrine signaling may be potential anti-cancer strategies. Citation Format: Ginny Powers, Xiaojing Su, David Beebe, Paul Marker. Developmental paracrine signaling pathways promote prostate cancer progression. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B03.