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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.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.

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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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 signalingAbnormalities 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.
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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 signalingAbnormalities 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.

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)

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 signalingAbnormalities 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.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

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 signalingAbnormalities 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.
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.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.

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