Molecular Signatures of Prostate Stem Cells Reveal Novel Signaling Pathways and Provide Insights into Prostate Cancer

Abstract

BackgroundThe 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 FindingsA 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-β 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/SignificanceOur 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.

Targeting the Y/CCAAT box in cancer: YB-1 (YBX1) or NF-Y?

“…20,21 Y/CCAAT is Enriched in Promoters of 'Cancer' Genes Analysis of transcriptome profiles during cellular transformation identified the Y/CCAAT box as over-represented in promoters of genes overexpressed in diverse types of cancers, breast, colon, thyroid, prostate and leukemias. [22][23][24][25][26][27][28][29] Treating cells with cytotoxic drugs, or overexpressing growth suppressors, led to the downregulation of genes with CCAAT in their promoters. 30,31 However, it is important to remark that these exercises were performed with matrices included in TRANSFAC and JASPAR; hence, they could be highly biased, as the lists of transcription factor-binding sites (TFBS) present in databases certainly do not recapitulate all possible TF-binding sequences.…”

Monensin Induced Oxidative Stress Reduces Prostate Cancer Cell Migration and Cancer Stem Cell Population

“…Here, we showed that although monensin reduced the activities of several pathways known to play a role in tumourigenesis, the strongest reduction was seen in NF κB signalling. NF-κB activity promotes cell viability, tumorigenesis and metastasis as well as correlates with poor prognosis in prostate cancer patients (Blum et al 2009, Sarkar et al 2008. Importantly, NF-κB regulates the expression of genes responsible for antioxidant defence capacity and its inhibition induces oxidative stress as well as reduces tumourigenesis, metastasis and cancer stem cell potential (Gloire, Legrand-Poels & Piette 2006, Sarkar et al 2008, Gluschnaider et al 2010.…”

“…Steroidogenic enzymes as well as stem cell markers are induced in castration-resistant prostate cancer both in vitro and in vivo (Blum et al 2009, Pfeiffer et al 2011. Several studies have shown that steroidogenesis is inhibited by ROS (Tsai et al 2003, Stocco, Wells & Clark 1993, Kodaman, Aten & Behrman 1994, Lee et al 2009, Abidi et al 2008).…”

“…Interestingly, 7-ketocholesterol is a ligand for aryl hydrocarbon receptor (AhR) and acts as AhR antagonist (Savouret et al 2001). AhR expression is elevated in malignant prostate cells and its signalling is activated in prostate cancer stem cells (Blum et al 2009, Gluschnaider et al 2010. AhR pathway increases the expression of ALDH proteins and protects cells against oxidative stress and foreign chemicals (Lindros et al 1998, Vrzal, Ulrichova & Dvorak 2004, Nebert et al 2000, Kohle, Bock 2007.…”

Hepatocytic precursor (stem-like) WB-F344 cells reduce tumorigenicity of hepatoma CBRH-7919 cells via TGF-β/Smad pathway

“…We believe that, as a result of the different stages of stem cells, the cell signal transduction pathways that control cell growth, differentiation, and apoptosis are different; if the same pathway is involved, the mechanism involved may also be different (45). Studies of the molecular signatures of prostate stem cells also revealed that TGF-ß has a prominent role in adult stem cells (46), and the Wnt signaling pathway plays a critical role in the regulation of proliferation and in the migration/invasion capacity of hMSCs (47).…”