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Review
. 2015 Feb 10;6(4):1900-19.
doi: 10.18632/oncotarget.2953.

Prostate cancer stem cells: deciphering the origins and pathways involved in prostate tumorigenesis and aggression

Adrian P Rybak  1   2 , Robert G Bristow  3   4 , Anil Kapoor  1   2
Affiliations
Review

Prostate cancer stem cells: deciphering the origins and pathways involved in prostate tumorigenesis and aggression

Adrian P Rybak et al. Oncotarget. .

Abstract

The cells of the prostate gland are dependent on cell signaling pathways to regulate their growth, maintenance and function. However, perturbations in key signaling pathways, resulting in neoplastic transformation of cells in the prostate epithelium, are likely to generate subtypes of prostate cancer which may subsequently require different treatment regimes. Accumulating evidence supports multiple sources of stem cells in the prostate epithelium with distinct cellular origins for prostate tumorigenesis documented in animal models, while human prostate cancer stem-like cells (PCSCs) are typically enriched by cell culture, surface marker expression and functional activity assays. As future therapies will require a deeper understanding of its cellular origins as well as the pathways that drive PCSC maintenance and tumorigenesis, we review the molecular and functional evidence supporting dysregulation of PI3K/AKT, RAS/MAPK and STAT3 signaling in PCSCs, the development of castration resistance, and as a novel treatment approach for individual men with prostate cancer.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Schematic representation of the cellular architecture of the prostate epithelium
The prostate epithelium consists of an inner layer of secretory luminal cells. Basal cells form a continuous layer of cells around the luminal cells and in contact with the basement membrane, which serves as a barrier between the epithelium and stromal compartment. Intermediate cells display both basal and luminal markers, while rare neuroendocrine cells are scattered throughout the epithelium. Markers used to distinguish each cell type are indicated in brackets, along with the surface markers used to identify human and murine prostate stem cells (PSCs). ChrA Chromogranin A; ND not determined.
Figure 2
Figure 2. PI3K/AKT, RAS/MAPK and STAT3 signaling pathways converge to regulate PCSC maintenance and promote tumorigenesis
Activation of PI3K/AKT (green), RAS/MAPK (blue) and STAT3 (red) signaling pathways, mediated by the activation of growth factor-driven receptor tyrosine kinase (RTK) (e.g. Epidermal growth factor receptor (EGFR)) or cytokine (e.g. IL-6) signaling, promote PCSC self-renewal activity and the various hallmarks of PCa development. These signaling pathways act directly, or through cross-talk activation, to mediate prostate tumorigenesis. P denotes phosphorylation of protein at specific residue(s), which is required for its activation (yellow). Red asterisk (*) marks key proteins within these signaling pathways that have been implicated in PCSC activity.
Figure 3
Figure 3. Prostate cancer initiation, progression and advancement are associated with proto-oncogene activation and inhibition of tumor suppressor genes involved in PI3K/AKT, RAS/MAPK and STAT3 signaling
Abnormalities in the prostate epithelium result in pre-neoplastic lesions called prostatic intraepithelial neoplasia (PIN), which feature luminal epithelial hyperplasia and a reduction in the number of basal cells. PIN lesions progress to invasive adenocarcinoma (luminal phenotype) with loss of the basal cell layer and basement membrane resulting in various tumor grades, beginning with indolent to more aggressive forms of PCa, and subsequent development of metastasis and castration resistance. Studies involving murine PCa models provide support for the role of proteins involved in PI3K/AKT, RAS/MAPK and STAT3 signaling at various stages of PCa development. Murine PCa models discussed in the text are illustrated, with specific promoter-driven gene knockout or transgene overexpression indicated in brackets. Figure is adapted from ref. [5]. BM bone marrow; c-Akt constitutive-active Akt; CR castration-resistant; Cre Cre-recombinase; CreER/CreERT2 TAM-inducible Cre; LN lymph node; OT orthotopic; PB probasin promoter; TAM tamoxifen.
Figure 4
Figure 4. Reduced dependence on AR signaling promotes activation and subsequent cross-talk between PI3K/AKT, RAS/MAPK and STAT3 pathways to regulate PCSC maintenance and tumorigenesis
Low-risk (indolent) PCa progresses during active surveillance to a heterogeneous tumor that is multifocal in nature. Conventional androgen-deprivation therapy (ADT) causes tumor regression by targeting androgen-responsive PCa cells. Inhibition of androgen receptor (AR) signaling promotes activation of cell survival pathways like PI3K/AKT, RAS/MAPK and STAT3, either directly or through cross-talk, in surviving androgen-independent PCSCs. Surviving PCSCs drive tumor regrowth and the development of castration-resistant prostate cancer (CRPC), with cell signal activation being sustained in castration-resistant disease.
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References

    1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for clinicians. 2014;64:9–29. - PubMed
    1. Fraser M, Berlin A, Bristow RG, van der Kwast T. Genomic, pathological, and clinical heterogeneity as drivers of personalized medicine in prostate cancer. Urologic oncology. 2014 - PubMed
    1. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005;23(32):8253–8261. - PubMed
    1. McNeal JE, Bostwick DG. Intraductal dysplasia: a premalignant lesion of the prostate. Hum Pathol. 1986;17:64–71. - PubMed
    1. Shen MM, Abate-Shen C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev. 2010;24:1967–2000. - PMC - PubMed

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