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

Rybak AP, Bristow RG, Kapoor A - Oncotarget (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: McMaster Institute of Urology, Division of Urology, Department of Surgery, McMaster University, ON, Canada.

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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Related in: MedlinePlus

Schematic representation of the cellular architecture of the prostate epitheliumThe 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.
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Figure 1: Schematic representation of the cellular architecture of the prostate epitheliumThe 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.

Mentions: The prostate contains epithelial cells of various lineage hierarchy that compose this glandular tissue. In adult males, the prostate gland contributes to the production of secretory proteins which are present within the seminal fluid [5]. Within the prostate epithelium, three epithelial cell types exist: luminal secretory cells, basal cells and intermediate cells. Luminal cells are a differentiated androgen-dependent cell type that produce and release prostatic secretory proteins into the lumen including PSA [9], a serine (Ser) protease responsible for preventing semen coagulation during ejaculation [10]. Luminal cells are characterized by the expression of androgen receptor (AR) [11], CD24 and CD26 cell surface proteins [12], as well as CK8 and CK18 [13]. Basal cells, which are located between luminal cells and the basement membrane, express CD44, p63 and CK5/14 proteins [13-15], display low AR protein levels [11] and lack PSA expression [9]. Intermediate cells are luminally-located cells in budding acini during prostate development that express cytokeratins found in basal and luminal cells [16], and are associated with luminal differentiation of basal cells [16-18]. Dispersed among basal and luminal cells are neuroendocrine cells, a rare AR-negative cell type in the prostate epithelium [19] (Figure 1).


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

Rybak AP, Bristow RG, Kapoor A - Oncotarget (2015)

Schematic representation of the cellular architecture of the prostate epitheliumThe 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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385825&req=5

Figure 1: Schematic representation of the cellular architecture of the prostate epitheliumThe 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.
Mentions: The prostate contains epithelial cells of various lineage hierarchy that compose this glandular tissue. In adult males, the prostate gland contributes to the production of secretory proteins which are present within the seminal fluid [5]. Within the prostate epithelium, three epithelial cell types exist: luminal secretory cells, basal cells and intermediate cells. Luminal cells are a differentiated androgen-dependent cell type that produce and release prostatic secretory proteins into the lumen including PSA [9], a serine (Ser) protease responsible for preventing semen coagulation during ejaculation [10]. Luminal cells are characterized by the expression of androgen receptor (AR) [11], CD24 and CD26 cell surface proteins [12], as well as CK8 and CK18 [13]. Basal cells, which are located between luminal cells and the basement membrane, express CD44, p63 and CK5/14 proteins [13-15], display low AR protein levels [11] and lack PSA expression [9]. Intermediate cells are luminally-located cells in budding acini during prostate development that express cytokeratins found in basal and luminal cells [16], and are associated with luminal differentiation of basal cells [16-18]. Dispersed among basal and luminal cells are neuroendocrine cells, a rare AR-negative cell type in the prostate epithelium [19] (Figure 1).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: McMaster Institute of Urology, Division of Urology, Department of Surgery, McMaster University, ON, Canada.

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.

Show MeSH
Related in: MedlinePlus