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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

PI3K/AKT, RAS/MAPK and STAT3 signaling pathways converge to regulate PCSC maintenance and promote tumorigenesisActivation 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.
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Figure 2: PI3K/AKT, RAS/MAPK and STAT3 signaling pathways converge to regulate PCSC maintenance and promote tumorigenesisActivation 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.

Mentions: A number of cell signaling pathways have been implicated in PCa progression towards an androgen-resistant state including receptor tyrosine kinases, like epidermal growth factor receptor (EGFR) [92-94], and developmental pathways including Wnt, Notch and Hedgehog signaling [95-97]. These developmental pathways have also been implicated in PCSC maintenance [98-100]. Human PSCs and PCSCs display low levels or lack AR expression [45, 64, 66, 72], with evidence to suggest that murine PSCs and PCSCs are capable of surviving in an androgen-independent state [26, 32, 101]. While not to undermine the importance of these developmental pathways and AR signaling in PCa, we will focus on the involvement of intracellular PI3K/AKT, RAS/MAPK and STAT3 pathways in maintaining PCSCs. Given that details of these signaling pathways and their ability to regulate various hallmarks of PCa have been reviewed thoroughly elsewhere [102-104], we highlight key proteins within these pathways that regulate PCSC activity (Figure 2), and the animal models that support their role in PCa development (Figure 3).


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

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

PI3K/AKT, RAS/MAPK and STAT3 signaling pathways converge to regulate PCSC maintenance and promote tumorigenesisActivation 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.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: PI3K/AKT, RAS/MAPK and STAT3 signaling pathways converge to regulate PCSC maintenance and promote tumorigenesisActivation 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.
Mentions: A number of cell signaling pathways have been implicated in PCa progression towards an androgen-resistant state including receptor tyrosine kinases, like epidermal growth factor receptor (EGFR) [92-94], and developmental pathways including Wnt, Notch and Hedgehog signaling [95-97]. These developmental pathways have also been implicated in PCSC maintenance [98-100]. Human PSCs and PCSCs display low levels or lack AR expression [45, 64, 66, 72], with evidence to suggest that murine PSCs and PCSCs are capable of surviving in an androgen-independent state [26, 32, 101]. While not to undermine the importance of these developmental pathways and AR signaling in PCa, we will focus on the involvement of intracellular PI3K/AKT, RAS/MAPK and STAT3 pathways in maintaining PCSCs. Given that details of these signaling pathways and their ability to regulate various hallmarks of PCa have been reviewed thoroughly elsewhere [102-104], we highlight key proteins within these pathways that regulate PCSC activity (Figure 2), and the animal models that support their role in PCa development (Figure 3).

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