Prostate gland development is dependent on stromal-epithelial interactions. Stromal cells induce and direct epithelial proliferation leading to ductal branching and differentiation to mature secretory acini. Mechanisms are unknown. Stromal-epithelial interactions are also involved in mechanisms of prostate cancer progression. Stromal factors involved in epithelial growth and differentiation control affect local proliferation and invasion of carcinoma cells. The previous project period has focused on a fetal urogenital sinus (prostate anlagen) mesenchyme-derived factor, UGIF(ps20), which is growth inhibitory to prostatic epithelial cells, induces synthesis of secretory proteins, and alters phenotypic morphology. In the last project period, the ps20 protein was purified to homogeneity, its biological activity characterized, antibody probes made, the full length rat and human cDNA cloned, recombinant proteins expressed, and stable transfectant cell lines generated. Sequence analysis indicates that ps20 is a novel member of the """"""""WAP-type four-disulfide core domain"""""""" family which share a common 8 cysteine motif. WAP protein family members function as protease inhibitors and are involved in developmental tissue remodeling, protease-induced growth factor bioavail-ability, matrix remodeling, and cell differentiation. Reduced expression is associated with cancer progression. Immuno-localization of ps20 is specific to smooth muscle in rat and human normal and diseased tissues. Heterogeneous loss of ps20 was observed in the stroma of human prostate cancer. It is hypothesized that ps20 functions as a protease inhibitor and a negative regulator of cell proliferation and invasion. To proceed in defining the mechanisms of ps20 action three Specific Aims are proposed. These include: 1.) to define the specific protease inhibitory activity and key interacting proteins; 2.) To assess ps20-induced alterations in cell proliferation, adhesion and matrix invasion; 3.) To assess alterations in ps20 expression and localization in human prostate cancer progression, and; 4.) To test ps20 as a tumor-suppressor with mouse xenograft human-tumor models and a ps20 transgenic mouse-prostate cancer model.
The Aims of this proposal are a natural extension of the previous progress period and are designed to answer specific fundamental questions about ps20 mechanisms of action. These studies will build a foundation from which to base long range studies, to specifically define the role of ps20 in prostate development, prostatic cancer progression, stromal-epithelial interactions and smooth muscle biology.
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