Androgen-induced programs for prostate epithelial growth and invasion arise in embryogenesis and are reactivated in cancer

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Oncogene (Impact Factor: 8.56). 10/2008; 27(57):7180-91. DOI: 10.1038/onc.2008.327
Source: PubMed

ABSTRACT Cancer cells differentiate along specific lineages that largely determine their clinical and biologic behavior. Distinct cancer phenotypes from different cells and organs likely result from unique gene expression repertoires established in the embryo and maintained after malignant transformation. We used comprehensive gene expression analysis to examine this concept in the prostate, an organ with a tractable developmental program and a high propensity for cancer. We focused on gene expression in the murine prostate rudiment at three time points during the first 48 h of exposure to androgen, which initiates proliferation and invasion of prostate epithelial buds into surrounding urogenital sinus mesenchyme. Here, we show that androgen exposure regulates genes previously implicated in prostate carcinogenesis comprising pathways for the phosphatase and tensin homolog (PTEN), fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), and Wnt signaling along with cellular programs regulating such 'hallmarks' of cancer as angiogenesis, apoptosis, migration and proliferation. We found statistically significant evidence for novel androgen-induced gene regulation events that establish and/or maintain prostate cell fate. These include modulation of gene expression through microRNAs, expression of specific transcription factors, and regulation of their predicted targets. By querying public gene expression databases from other tissues, we found that rather than generally characterizing androgen exposure or epithelial budding, the early prostate development program more closely resembles the program for human prostate cancer. Most importantly, early androgen-regulated genes and functional themes associated with prostate development were highly enriched in contrasts between increasingly lethal forms of prostate cancer, confirming a 'reactivation' of embryonic pathways for proliferation and invasion in prostate cancer progression. Among the genes with the most significant links to the development and cancer, we highlight coordinate induction of the transcription factor Sox9 and suppression of the proapoptotic phospholipid-binding protein Annexin A1 that link early prostate development to early prostate carcinogenesis. These results credential early prostate development as a reliable and valid model system for the investigation of genes and pathways that drive prostate cancer.

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Available from: Giovanni Parmigiani, Jul 30, 2015
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    • "that we have identified as expressed in fetal prostate mesenchyme and CAFs have been described in cancer stroma of breast , prostate and other tumours . ASPN is a leucine rich proteoglycan family member that is expressed in breast cancer - associated stroma ( Ma et al . , 2009 ) , which appears to show some androgen dependence in prostate cancer ( Schaeffer et al . , 2008 ) and which binds to TGFb ( Kizawa et al . , 2005 ) . CAV1 is downregulated in breast and prostate CAFs and predicts early tumour recurrence and poor outcome ( Di Vizio et al . , 2009 ; Witkiewicz et al . , 2009 ) . S100A6 is an S100 calcium binding protein family member that is upregulated in many tumours ( Lesniak et al . , 2009 ) , b"
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    ABSTRACT: The stromal microenvironment has key roles in prostate development and cancer, and cancer-associated fibroblasts (CAFs) stimulate tumourigenesis via several mechanisms including the expression of pro-tumourigenic factors. Mesenchyme (embryonic stroma) controls prostate organogenesis, and in some circumstances can re-differentiate prostate tumours. We have applied next-generation Tag profiling to fetal human prostate, normal human prostate fibroblasts (NPFs) and CAFs to identify molecules expressed in prostatic stroma. Comparison of gene expression profiles of a patient-matched pair of NPFs vs CAFs identified 671 transcripts that were enriched in CAFs and 356 transcripts whose levels were decreased, relative to NPFs. Gene ontology analysis revealed that CAF-enriched transcripts were associated with prostate morphogenesis and CAF-depleted transcripts were associated with cell cycle. We selected mRNAs to follow-up by comparison of our data sets with published prostate cancer fibroblast microarray profiles as well as by focusing on transcripts encoding secreted and peripheral membrane proteins, as well as mesenchymal transcripts identified in a previous study from our group. We confirmed differential transcript expression between CAFs and NPFs using QrtPCR, and defined protein localization using immunohistochemistry in fetal prostate, adult prostate and prostate cancer. We demonstrated that ASPN, CAV1, CFH, CTSK, DCN, FBLN1, FHL1, FN, NKTR, OGN, PARVA, S100A6, SPARC, STC1 and ZEB1 proteins showed specific and varied expression patterns in fetal human prostate and in prostate cancer. Colocalization studies suggested that some stromally expressed molecules were also expressed in subsets of tumour epithelia, indicating that they may be novel markers of EMT. Additionally, two molecules (ASPN and STC1) marked overlapping and distinct subregions of stroma associated with tumour epithelia and may represent new CAF markers.
    Oncogene 08/2011; 31(9):1130-42. DOI:10.1038/onc.2011.312 · 8.56 Impact Factor
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    • "First, androgen can directly activate PI3K signaling in androgen-sensitive benign epithelial cells by interaction with the regulatory p85 subunit of PI3K (Baron et al., 2004). Second, gene expression studies have documented that androgen induces expression of a number of regulatory members of the PI3K and mTOR signaling pathways, including Pik3r3 and Rheb in embryonic prostate tissue (Schaeffer et al., 2008). Third, androgen indirectly activates PI3K signaling in the prostate via FGF signaling since PI3K signaling is also compromised in the prostates of mice with genetic inactivation of FGFR2 (Zhang et al., 2008). "
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    • "Genes expressed during prostate initiation include Sox9, Nkx3.1, FGFs and multiple Wnt factors(Schaeffer, Marchionni et al. 2008). Distinct developmental gene expression patterns were enriched at distinct phases of prostate cancer initiation and progression(Schaeffer, Marchionni et al. 2008). Together, this work emphasizes the highly conserved genetic program that is initially induced in development by androgens and subsequently reactivated in pathologic conditions. "
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    ABSTRACT: Prostatic development is a dynamic process in which basic mechanisms of epithelial outgrowth and epithelial-mesenchymal interaction are initiated by androgens and androgen receptor signaling. Even in adulthood, the prostate's function remains tightly regulated by androgens--without them, pathologic diseases, including hyperplastic and malignant growth that together plague nearly 50% of aging males, do not occur. Unraveling the etiology of these pathologic processes is a complex and important goal. In fact, many insights into these processes have come from an intimate understanding of the complex signaling networks that regulate physiologic prostatic growth in development. This review aims to highlight important key molecules such as Nkx3.1, sonic hedgehog, and Sry box 9, as well as key signaling pathways including the fibroblast growth factor and wingless pathways. These molecules and pathways are critical for prostate development with both known and postulated roles in prostatic pathology.
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