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Molecular signatures of prostate stem cells reveal novel signaling pathways and provide insights into prostate cancer.

ABSTRACT: BACKGROUND:The global gene expression profiles of adult and fetal murine prostate stem cells were determined to define common and unique regulators whose misexpression might play a role in the development of prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS:A distinctive core of transcriptional regulators common to both fetal and adult primitive prostate cells was identified as well as molecules that are exclusive to each population. Elements common to fetal and adult prostate stem cells include expression profiles of Wnt, Shh and other pathways identified in stem cells of other organs, signatures of the aryl-hydrocarbon receptor, and up-regulation of components of the aldehyde dehydrogenase/retinoic acid receptor axis. There is also a significant lipid metabolism signature, marked by overexpression of lipid metabolizing enzymes and the presence of the binding motif for Srebp1. The fetal stem cell population, characterized by more rapid proliferation and self-renewal, expresses regulators of the cell cycle, such as E2f, Nfy, Tead2 and Ap2, at elevated levels, while adult stem cells show a signature in which TGF-beta has a prominent role. Finally, comparison of the signatures of primitive prostate cells with previously described profiles of human prostate tumors identified stem cell molecules and pathways with deregulated expression in prostate tumors including chromatin modifiers and the oncogene, Erg. CONCLUSIONS/SIGNIFICANCE:Our data indicate that adult prostate stem or progenitor cells may acquire characteristics of self-renewing primitive fetal prostate cells during oncogenesis and suggest that aberrant activation of components of prostate stem cell pathways may contribute to the development of prostate tumors.

SUBMITTER: Blum R

PROVIDER: S-EPMC2684642 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Molecular signatures of prostate stem cells reveal novel signaling pathways and provide insights into prostate cancer.

Blum Roy R Gupta Rashmi R Burger Patricia E PE Ontiveros Christopher S CS Salm Sarah N SN Xiong Xiaozhong X Kamb Alexander A Wesche Holger H Marshall Lisa L Cutler Gene G Wang Xiangyun X Zavadil Jiri J Moscatelli David D Wilson E Lynette EL

PloS one 20090529 5

<h4>Background</h4>The global gene expression profiles of adult and fetal murine prostate stem cells were determined to define common and unique regulators whose misexpression might play a role in the development of prostate cancer.<h4>Methodology/principal findings</h4>A distinctive core of transcriptional regulators common to both fetal and adult primitive prostate cells was identified as well as molecules that are exclusive to each population. Elements common to fetal and adult prostate stem ...[more]

PMID: 19478945

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Project description:Signals between stem cells and stroma are important in establishing the stem cell niche. However, very little is known about the regulation of any mammalian stem cell niche as pure isolates of stem cells and their adjacent mesenchyme are not readily available. The prostate offers a unique model to study signals between stem cells and their adjacent stroma as in the embryonic prostate stem cell niche, the urogenital sinus mesenchyme is easily separated from the epithelial stem cells. Here we investigate the distinctive molecular signals of these two stem cell compartments in a mammalian system.We isolated fetal murine urogenital sinus epithelium and urogenital sinus mesenchyme and determined their differentially expressed genes. To distinguish transcripts that are shared by other developing epithelial/mesenchymal compartments from those that pertain to the prostate stem cell niche, we also determined the global gene expression of epidermis and dermis of the same embryos. Our analysis indicates that several of the key transcriptional components that are predicted to be active in the embryonic prostate stem cell niche regulate processes such as self-renewal (e.g., E2f and Ap2), lipid metabolism (e.g., Srebp1) and cell migration (e.g., Areb6 and Rreb1). Several of the enriched promoter binding motifs are shared between the prostate epithelial/mesenchymal compartments and their epidermis/dermis counterparts, indicating their likely relevance in epithelial/mesenchymal signaling in primitive cellular compartments. Based on differential gene expression we also defined ligand-receptor interactions that may be part of the molecular interplay of the embryonic prostate stem cell niche.We provide a comprehensive description of the transcriptional program of the major regulators that are likely to control the cellular interactions in the embryonic prostatic stem cell niche, many of which may be common to mammalian niches in general. This study provides a comprehensive source for further studies of mesenchymal/epithelial interactions in the prostate stem cell niche. The elucidation of pathways in the normal primitive niche may provide greater insight into mechanisms subverted during abnormal proliferative and oncogenic processes. Understanding these events may result in the development of specific targeted therapies for prostatic diseases such as benign prostatic hypertrophy and carcinomas.

Project description:Prostate adenocarcinoma accounts for more than 20% of deaths among males due to cancer. It is the fifth-leading cancer diagnosed in males across the globe. The mortality rate is quite high due to prostate cancer. Despite the fact that advancements in diagnostics and therapeutics have been made, there is a lack of effective drugs. Metabolic pathways are altered due to the triggering of androgen receptor (AR) signaling pathways, and elevated levels of dihydrotestosterone are produced due to defects in AR signaling that accelerate the growth of prostate cancer cells. Further, PI3K/AKT/mTOR pathways interact with AR signaling pathway and act as precursors to promote prostate cancer. Prostate cancer therapy has been classified into luminal A, luminal B, and basal subtypes. Therapeutic drugs inhibiting dihydrotestosterone and PI3K have shown to give promising results to combat prostate cancer. Many second-generation Androgen receptor signaling antagonists are given either as single agent or with the combination of other drugs. In order to develop a cure for metastasized prostate cancer cells, Androgen deprivation therapy (ADT) is applied by using surgical or chemical methods. In many cases, Prostatectomy or local radiotherapy are used to control metastasized prostate cancer. However, it has been observed that after 1.5 years to 2 years of Prostatectomy or castration, there is reoccurrence of prostate cancer and high incidence of castration resistant prostate cancer is seen in population undergone ADT. It has been observed that Androgen derivation therapy combined with drugs like abiraterone acetate or docetaxel improve overall survival rate in metastatic hormone sensitive prostate cancer (mHSPC) patients. Scientific investigations have revealed that drugs inhibiting poly ADP Ribose polymerase (PARP) are showing promising results in clinical trials in the prostate cancer population with mCRPC and DNA repair abnormalities. Recently, RISUG adv (reversible inhibition of sperm under guidance) has shown significant results against prostate cancer cell lines and MTT assay has validated substantial effects of this drug against PC3 cell lines. Current review paper highlights the advancements in prostate cancer therapeutics and new drug molecules against prostate cancer. It will provide detailed insights on the signaling pathways which need to be targeted to combat metastasized prostate cancer and castration resistant prostate cancer.

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Molecular signatures of prostate stem cells reveal novel signaling pathways and provide insights into prostate cancer.

Publications

Molecular signatures of prostate stem cells reveal novel signaling pathways and provide insights into prostate cancer.

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