Research

Most males will require clinical intervention for a prostate-related disease at some point in their lifetime. Men are faced with a 30 percent lifetime risk of developing symptomatic prostatitis. More than half of men older than age 60 suffer from symptomatic benign prostatic hyperplasia and incidence of this disease increases proportionally with age. American men have a 17 percent lifetime risk of being diagnosed with prostate cancer and a 3 percent chance of dying from it. Clearly, there is a need to improve our understanding of prostate growth mechanisms and identify new therapeutic targets for treating prostate disease. We are using the developing prostate as a model system to elucidate these growth signals.

Overview of Prostate Development

Figure 1. Diagram of mouse urogenital sinus (UGS). Shown is a sagittal UGS section from a mouse fetus, approximately 17.5 days post-coitus. UGS epithelium is comprised of urothelial cells (white), prostate stem/ progenitor cells (black), transit amplifying cells (pink), and UGS basal epithelial cells (tan/gray). UGS mesenchyme is comprised of fibroblasts and myofibroblasts and other poorly characterized cells. Peri-prostatic UGM cells (light blue) are important for fetal prostate development because androgen receptors (ARs) in this multi-cell layer are required for prostatic bud formation.

The prostate derives from the fetal urogenital sinus (UGS), a stratified epithelial tube that is ensheathed in mesenchyme and comprised of at least four different cell types (Fig. 1). Prostate development begins with the binding of circulating testosterone or its more potent metabolite, 5?-dihydrotestosterone, to androgen receptors in UGS mesenchyme. Androgen receptor activation releases inductive signals from UGS mesenchyme that act on UGS epithelium to stimulate cell proliferation, form prostate ductal progenitors (prostatic buds), and regulate cell adhesion dynamics to permit prostatic bud outgrowth (Fig. 2). These epithelial-mesenchymal interactions are required for prostate development and are critically important in prostate disease etiology.

There are three phases of prostatic budding: (1) Specification, when instructive developmental cues define where buds will form in the UGS, (2) Initiation, when prostatic buds begin to form, and (3) Elongation, when proliferation, cell adhesion, and cell migration coordinate outgrowth of prostatic buds into surrounding mesenchyme. These phases of prostatic bud formation are mechanistically related to the three phases of prostate carcinogenesis (initiation, promotion, and metastasis). In fact, inappropriate reawakening of developmental signaling molecules likely drives prostate cancer progression.

Prostate ductal complexity is conferred post-natally during branching morphogenesis. Solid cords of prostate epithelium formed in utero elongate post-natally and their tips bifurcate giving rise to primary, secondary, and tertiary branches in a unique pattern for each prostate lobe, providing each lobe with distinct glandular architecture. Concurrent with branching morphogenesis, the solid cords of epithelium differentiate into glandular acini comprised of two cell layers: a layer of secretory columnar luminal epithelium and a layer of basal epithelium containing neuroendocrine cells, transit amplifying cells, and stem/progenitor cells. Basic prostatic architecture is established by puberty and acquires secretory function thereafter. The developing human prostate undergoes a similar series of morphogenetic events especially during prostatic bud formation, but gives rise to a mature glandular prostate that is morphologically unique from the rodent in that instead of containing individual capsulated prostate lobes, human prostate features peripheral, central, and transitional zones.

Our research Goals.

Figure 2. Morphogenetic processes in prostatic bud initiation. Prior to budding, urogenital sinus epithelium (UGE) is arranged in a stratified epithelial sheet that is anchored by intracellular adherens junctions (shown in red) and other adhesion complexes. Testicular androgens bind to androgen receptors in urogenital sinus mesenchyme (UGM) which (1) specifies where prostatic buds will form in neighboring UGE cells (yellow), (2) promotes proliferation of specified cells (curved arrows), and (3) modifies adhesion dynamics to permit migration of specified cells out of the plane of the epithelial sheet and into surrounding mesenchyme. Our research is focused on identifying genes and signaling pathways involved in these processes, as these are likely reactivated inappropriately in prostate disease.

We are investigating several aspects of prostate development in mice. Our overarching goals are to:

1. Identify androgen-responsive signals that guide epithelial cell proliferation and prostatic bud specification and initiation in male fetal mice.

2. Characterize cell adhesion regulators during invasive penetration of prostatic buds into surrounding mesenchyme.

3. Test, using a prostate disease model, whether regulators of cell growth and adhesion in the developing prostate also regulate cell growth and adhesion in the diseased prostate.

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