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WIREs Syst Biol Med
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Recent advances in prostate development and links to prostatic diseases

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Abstract The prostate is a branched ductal‐acinar gland that is part of the male reproductive tract. Prostate development depends upon the integration of steroid hormone signals, paracrine interactions between the stromal and epithelial tissue layers, and the actions of cell autonomous factors. Several genes and signaling pathways are known to be required for one or more steps of prostate development including epithelial budding, duct elongation, branching morphogenesis, and/or cellular differentiation. Recent progress in the field of prostate development has included the application of genome‐wide technologies including serial analysis of gene expression, expression profiling microarrays, and other large‐scale approaches to identify new genes and pathways that are essential for prostate development. The aggregation of experimental results into online databases by organized multilab projects including the Genitourinary Developmental Molecular Atlas Project has also accelerated the understanding of molecular pathways that function during prostate development and identified links between prostate anatomy and molecular signaling. Rapid progress has also recently been made in understanding the nature and role of candidate stem cells in the developing and adult prostate. This has included the identification of putative prostate stem cell markers, lineage tracing, and organ reconstitution studies. However, several issues regarding their origin, precise nature, and possible role(s) in disease remain unresolved. Nevertheless, several links between prostatic developmental mechanisms and the pathogenesis of prostatic diseases including benign prostatic hyperplasia and prostate cancer have led to recent progress on targeting developmental pathways as therapeutic strategies for these diseases. WIREs Syst Biol Med 2013, 5:243–256. doi: 10.1002/wsbm.1208 This article is categorized under: Developmental Biology > Developmental Processes in Health and Disease

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Recent advances in the anatomy of prostate development. (a) The mouse prostate is composed of three distinct lobes that have bilateral symmetry. The image shown is a photograph of an adult prostate. The four lobes of the prostate are labeled anterior, dorsal, lateral, and ventral. Each lobe of the mouse prostate exhibits unique branching patterns, which is highlighted in the work of Sugimura et al.1 Hematoxylin and eosin (H&E) staining of 12‐week prostate demonstrates the distinct histological appearance of the (b) anterior (AP), (c) dorsolateral (DLP), and (d) ventral (VP) mouse prostate lobes. The loose connective tissue (LCT) is labeled in the mouse prostate and insets highlight the muscular stroma (MS) and epithelial (E) cells of the mouse prostate. (e) H&E staining of adult human prostate from a biopsy specimen. In contrast to the mouse prostate there is more stroma (pink staining, S) and distinct organization of the epithelium (E). (f) In situ hybridization (ISH) for Wnt10b (purple) and immunofluorescence for cadherin 1 (red) and α‐smooth muscle actin 2 (αSMA2, green) in the UGS of an E18 mouse. Wnt10b is a newly identified marker for budding prostate epithelium. Epithelial and mesenchymal cells are represented by cadherin 1 and αSMA2, respectively. (g) ISH for Nkx3.1 expression that is a well‐characterized marker of prostate epithelial cells. Images in f and g are from the UGS of male mice at Theiler stage 26 (18 dpc) from the GUDMAP database (images #14307 and #14311 from the laboratory of Dr. Chad Vezina). (h) Traditionally, the developing prostate is divided into the UGM and UGE, but new studies have identified markers that further divide the developing prostate into distinct compartments at 17 dpc. Epithelium is represented by cadherin 1 expression (pink) and mesenchyme is based upon expression of αSMA2 (green). Wnt 10b (red) and Nkx3.1 (violet) depict the budding prostate epithelium. Mesenchymal compartments in addition to general mesenchyme include Acta2‐positive muscularis mucosa (dark green) and Snai1‐positive lamina propria (tan). Expression data from GUDMAP ISH files deposited by Dr. Chad Vezina's laboratory were used to determine expression pattern and demonstrate that the mesenchyme and epithelium contain distinct compartments even at the initial stages of prostate development.

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Advances in signaling pathways involved prostate development and disease. Prostate development progresses from the undifferentiated UGS epithelium and stromal cells to the invasion of the mesenchyme by the developing epithelium. The budding and branching of the epithelium form the ductal structures observed in the mature prostate. Although the prostate can remain healthy, over the lifetime of a man there is 1:6 chance of developing prostate cancer. Interestingly, pathways that are essential for prostate development are often re‐expressed in prostatic diseases. Although many different signaling pathways have been implicated in disease and development, here we highlight those pathways where recent progress has been made in links to prostate cancer, particularly those that are target of novel therapeutics that are in clinical trials. The pathways that increase in prostate cancer are in black and those that are repressed or have a loss of expression are shown in gray. Nkx3.1 and Pten, markers of early epithelium and differentiation, are completely absent or have reduced expression in prostate cancer.3,52,53 In addition TGFβRII is frequently downregulated in cancer.54 Pathways such as AR, Shh, PI3K, and Wnt signaling are upregulated in prostate cancer and promote the proliferation and tumor formation.28,55,56 AR, Shh, and PI3K pathways are the targets for several drugs that are in clinical trials for prostate cancer.57–61 In addition to signaling pathways, prostate cancer also displays a gene expression profile that is more similar to the developing prostate than the healthy adult prostate.13 The return to a less differentiated state is a hallmark in many cancers, and the current studies in prostate cancer support the re‐expression of many pathways that are important in development.

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Recent advances in understanding prostate stem cells. The prostate stem cells identified in mouse and human prostate have distinct markers. The illustration depicts recently identified cellular markers for prostate stem cells. Several studies have identified distinct markers for prostate stem cells including human basal‐like stem cells with, CD44+CD49f+Ck5+p63+Ck8‐AR‐PSA‐47 (shown in pink). Several populations of murine stem cells with distinct makers form prostate tissue containing all three types of differentiated prostate epithelial cells when combined with UGM and implanted in the kidney capsule of a nude mouse. These putative murine stem cells can be categorized as luminal epithelial‐like (depicted in blue Nkx3.1+AR+CK18+p63‐CK14‐ and CK5‐Sca1+CD44+CD117+ CD133+48), uncommitted (shown in green LIN‐ cells46 and Sca148+ CD49f+CD45‐CD31‐Ter119‐ cells45), and multilineage (shown in orange, Sca1+CD49f+p63+Ck5+Ck14+AR+Ck8+Ck18+49). Recent studies have demonstrated that the stem cell niche, particularly the stromal cells, is critical for maintaining the undifferentiated state of the prostate stem cells. Signaling pathways in the niche that have differential expression in the UGM29 are thought to contribute to the maintenance of the stem cells and are depicted. Receptors with increased expression include components of the Wnt (Lrp 8, Lrp11, and Fzd4), Notch (Notch4), TGFβ (TGFβ RII), FGF (FGFR1), Shh (Ptch1 and Ptch2), and Bmp (Bmp4, Bmp5, and Bmp6) signaling pathways. In the majority of these pathways, the corresponding receptors or ligands are upregulated in the UGE. This suggests that reciprocal interactions between the stromal cells and epithelial cells are critical for maintaining the stem cell niche.

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Recent advances in paracrine signaling pathways in prostate development. Communication between the prostate mesenchymal (orange) and epithelial cells (green) is essential for normal prostate development. Here, recent progress in paracrine signaling involved in prostate development is highlighted. Arrows indicate the directionality of the communication between the mesenchyme and epithelium. Pathways including the Wnt, sonic hedgehog (Shh), androgen receptor (AR) ,28 and fibroblast growth factor (FGF) pathways are critical for the normal growth, differentiation, and development of the prostate. Receptor and ligand locations in the mesenchyme and epithelium are depicted in the model. FGF 7, 13, and 14 are secreted by the mesenchyme and bind to epithelial FGFR1 and FGFR2.29 The FGF pathway also works in the opposite direction where the UGM expresses FGFR1 and the UGE secretes FGF1. Studies using TGFβRII knockout in the epithelium or mesenchyme demonstrated that TGFβRII receptor on the UGM was important for androgen response.30 SFRP1 and SFRP2 are expressed in the developing UGM and activate noncanonical Wnt signaling pathways by binding to Wnt receptors such as Wnt4 that activates epithelial proliferation.10,12 Shh secretion by the UGE to activate stromal smoothened (Smo) and patched (Ptch) is critical for normal prostate development, but this same pathway can also activate inhibitors of prostate development such as Bmp7.25 Notch expression in the epithelium is required for budding of the prostate epithelium, but is restricted to specific locations by mesenchymal Bmp7.19 This complex network of signaling between the UGM and UGE is critical for normal prostate development.

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