Mesenchymal stem cells and the embryonic reawakening theory of BPH

Brennen, W. Nathaniel; Isaacs, John T.

doi:10.1038/s41585-018-0087-9

Cited by 35 publications

(36 citation statements)

References 138 publications

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“…Prostate embryonic development, subsequent pubertal and adult growth, homeostatic maintenance, and regenerative capability require androgen-mediated paracrine interactions between stromal and epithelial cell compartments [1,2] [6]. The expression of AR occurs in urogenital mesenchyme before and during prostate morphogenesis, and then extends to urogenital epithelia after prostatic budding and the beginning of branching morphogenesis [24,25].…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we also observed aberrant alterations of other signaling pathways related to prostate development, stem cells, and organ morphogenesis in AR deficient Gli1-expressing cells. It has been shown that a variety of andromedins are produced in mesenchymal AR expressing cells and play significant and different roles in inducing both epithelial and stromal early development and morphogenesis [6,29]. Therefore, further in-depth mechanistic analyses using the current mouse models are extremely important for determining the signaling pathways and master regulators in facilitating the biological roles of AR in stromal Gli1-expressing cells in prostate development, morphogenesis, and regeneration.…”

Section: Discussionmentioning

confidence: 99%

“…Early tissue recombination studies that were done over 30 years ago showed that AR-deficient UGM combined with wild type UGE failed to develop into a prostate [3][4][5], implicating a decisive role of mesenchymal AR signaling in inducing development of the prostatic epithelium through paracrine regulation. Androgen signaling still remains essential in the postnatal prostate, controlling maturation, growth, and regeneration through mesenchymal-epithelial interactions [6]. However, the precise mechanisms for the regulation are still unclear.…”

Section: Introductionmentioning

confidence: 99%

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Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration

Aldahl

et al. 2020

PLoS Genet

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Prostate embryonic development, pubertal and adult growth, maintenance, and regeneration are regulated through androgen signaling-mediated mesenchymal-epithelial interactions. Specifically, the essential role of mesenchymal androgen signaling in the development of prostate epithelium has been observed for over 30 years. However, the identity of the mesenchymal cells responsible for this paracrine regulation and related mechanisms are still unknown. Here, we provide the first demonstration of an indispensable role of the androgen receptor (AR) in sonic hedgehog (SHH) responsive Gli1-expressing cells, in regulating prostate development, growth, and regeneration. Selective deletion of AR expression in Gli1-expressing cells during embryogenesis disrupts prostatic budding and impairs prostate development and formation. Tissue recombination assays showed that urogenital mesenchyme (UGM) containing AR-deficient mesenchymal Gli1-expressing cells combined with wildtype urogenital epithelium (UGE) failed to develop normal prostate tissue in the presence of androgens, revealing the decisive role of AR in mesenchymal SHH responsive cells in prostate development. Prepubescent deletion of AR expression in Gli1expressing cells resulted in severe impairment of androgen-induced prostate growth and regeneration. RNA-sequencing analysis showed significant alterations in signaling pathways related to prostate development, stem cells, and organ morphogenesis in AR-deficient Gli1-expressing cells. Among these altered pathways, the transforming growth factor β1 (TGFβ1) pathway was up-regulated in AR-deficient Gli1-expressing cells. We further demonstrated the activation of TGFβ1 signaling in AR-deleted prostatic Gli1-expressing cells, which inhibits prostate epithelium growth through paracrine regulation. These data demonstrate a novel role of the AR in the Gli1-expressing cellular niche for regulating prostatic cell fate, morphogenesis, and renewal, and elucidate the mechanism by which mesenchymal

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration

Aldahl

et al. 2020

PLoS Genet

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“…According to these observations, it was recently proposed a hypothesis to explain the development of BPH in ageing men in which various episodic occurrences of prostatic inflammation trigger the recruitment of mesenchymal stem cells to the transition periurethral zone under the effect of chemokines exerting an attractive effect on the migration of these cells from the bone marrow [513]. Recruited MSCs in the prostate tissue displace the periurethral smooth muscle sphincter and stimulate the benign prostatic neoplastic expansion of epithelial stem cells, allowing the formation of BPH nodules [513]. This hypothesis is supported by observations made at the level of BPH tissues.…”

Section: Stem Cells In Benign Prostatic Hyperplasia (Bph)mentioning

confidence: 99%

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

2019

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Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with low tendency to progression. Three stages of development of human prostate tumors have been identified: intraepithelial neoplasia, adenocarcinoma androgen-dependent, and adenocarcinoma androgen-independent or castration-resistant. Advances in molecular technologies have provided a very rapid progress in our understanding of the genomic events responsible for the initial development and progression of prostate cancer. These studies have shown that prostate cancer genome displays a relatively low mutation rate compared with other cancers and few chromosomal loss or gains. The ensemble of these molecular studies has led to suggest the existence of two main molecular groups of prostate cancers: one characterized by the presence of ERG rearrangements (~50% of prostate cancers harbor recurrent gene fusions involving ETS transcription factors, fusing the 5′ untranslated region of the androgen-regulated gene TMPRSS2 to nearly the coding sequence of the ETS family transcription factor ERG) and features of chemoplexy (complex gene rearrangements developing from a coordinated and simultaneous molecular event), and a second one characterized by the absence of ERG rearrangements and by the frequent mutations in the E3 ubiquitin ligase adapter SPOP and/or deletion of CDH1, a chromatin remodeling factor, and interchromosomal rearrangements and SPOP mutations are early events during prostate cancer development. During disease progression, genomic and epigenomic abnormalities accrued and converged on prostate cancer pathways, leading to a highly heterogeneous transcriptomic landscape, characterized by a hyperactive androgen receptor signaling axis.

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“…In this process, adhesion between epithelial cells and basement membrane gradually disappears; instead, changes in the cytoskeleton and shape are observed. In addition, an increase in podoplanin and motor abilities, and enhanced migratory and invasive abilities have been identified (14,15). In the process of embryonic development and the formation of organs, cells may diffuse from the primary tissue through EMT, and migrate to secondary tissue sites to continue to grow and differentiate (16,17).…”

Section: Introductionmentioning

confidence: 99%

URG11 promotes proliferation and induced apoptosis of LNCaP cells

et al. 2019

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von Willebrand factor C and EGF domain-containing protein (URG11), a cell growth regulator, is involved in the progression of a variety of types of cancer, including prostate cancer (Pca). However, the functions of the URG11 gene in Pca cells require in-depth investigation. The mRNA and protein levels of URG11 were measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. Cell Counting kit-8 (CCK-8), wound-healing and Transwell assays were used to detect cell viability, migration and invasion, respectively. Apoptosis and cell cycle analyses were performed using flow cytometry. The mRNA and protein expression levels of epithelial (E)-cadherin, vimentin, α-smooth muscle actin (α-SMA), cyclin D1 and MYC proto-oncogene protein (c-Myc) were analyzed by RT-qPCR and western blot analysis. In the present study, the mRNA and protein levels of URG11 were markedly upregulated in Pca cell lines compared with those in the normal prostate epithelial cell line. With functional experiments, the cell viability, migration and invasion of Pca cells were markedly promoted by URG11 overexpression. The cell cycle was effectively induced by URG11 and apoptosis was inhibited by the overexpression of URG11. Concomitantly, the epithelial marker E-cadherin was downregulated, and the mesenchymal markers vimentin and α-SMA were upregulated following URG11 overexpression. By contrast, genetic knockout of URG11 elicited the opposite effects. The present study also identified that the downstream effector genes of the Wnt/β-catenin signal pathway, cyclin D1 and c-Myc, were increased following the overexpression of endogenous URG11, which are known to regulate cell proliferation. In addition, the Wnt/β-catenin inhibitor FH535 ameliorated the promotive effects of URG11 on LNCaP cells viability, migration and invasion, and the Wnt/β-catenin agonist LiCl reversed the inhibitory effects of siURG11 in LNCaP cells on cell viability, migration and invasion. The present study demonstrated that URG11 served an oncogenic role in the development of Pca cells and provided evidence that URG11 has potential as a novel therapeutic target in Pca.

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Mesenchymal stem cells and the embryonic reawakening theory of BPH

Cited by 35 publications

References 138 publications

Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration

Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

URG11 promotes proliferation and induced apoptosis of LNCaP cells

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