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Tumour-initiating stem-like cells in human prostate cancer exhibit increased NF-κB signalling.

Rajasekhar VK, Studer L, Gerald W, Socci ND, Scher HI - Nat Commun (2011)

Bottom Line: These TICs possess stem cell characteristics and multipotency as demonstrated by in vitro sphere-formation and in vivo tumour-initiation, respectively.The cells represent an undifferentiated subtype of basal cells and can be purified from prostate tumours based on coexpression of the human pluripotent stem cell marker TRA-1-60 with CD151 and CD166.These TICs exhibit increased nuclear factor-κB activity.

View Article: PubMed Central - PubMed

Affiliation: 1] Stem Cell Center and Developmental Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. [2] Sidney Kimmel Center for Prostate and Urologic Cancers, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

ABSTRACT
Androgen depletion is a key strategy for treating human prostate cancer, but the presence of hormone-independent cells escaping treatment remains a major therapeutic challenge. Here, we identify a minor subset of stem-like human prostate tumour-initiating cells (TICs) that do not express prostate cancer markers, such as androgen receptor or prostate specific antigen. These TICs possess stem cell characteristics and multipotency as demonstrated by in vitro sphere-formation and in vivo tumour-initiation, respectively. The cells represent an undifferentiated subtype of basal cells and can be purified from prostate tumours based on coexpression of the human pluripotent stem cell marker TRA-1-60 with CD151 and CD166. Such triple-marker-positive TICs recapitulate the original parent tumour heterogeneity in serial xeno-transplantations indicating a tumour cell hierarchy in human prostate cancer development. These TICs exhibit increased nuclear factor-κB activity. These findings are important in understanding the molecular basis of human prostate cancer.

No MeSH data available.


Related in: MedlinePlus

Global mRNA expression in marker-positive human prostate tumour cells.(a) Venn-diagram of genes differentially expressed in prospectively isolated CWR22 OT-tumour cells with low (expressing EpCAM, CD44 or α2-integrin), moderate (expressing TRA-1-60, CD151 or CD166) and high (triple-marker-positives) sphere/tumour-forming efficiencies (S/TFE). Gene expression data in β4-integrin-positive (no sphere-forming) cells and the total tumour cells were used as baseline expression control. (b) Fold enrichment of gene ontology based functional categories in all the S/TFE data sets. (c–f) Catalogue of top differentially expressed genes: (c) shared among all the above three data sets, (d) shared between moderate and high S/TFE data sets, (e) expressed specifically in moderate S/TFE data set and (f) expressed specifically in high S/TFE data set.
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f5: Global mRNA expression in marker-positive human prostate tumour cells.(a) Venn-diagram of genes differentially expressed in prospectively isolated CWR22 OT-tumour cells with low (expressing EpCAM, CD44 or α2-integrin), moderate (expressing TRA-1-60, CD151 or CD166) and high (triple-marker-positives) sphere/tumour-forming efficiencies (S/TFE). Gene expression data in β4-integrin-positive (no sphere-forming) cells and the total tumour cells were used as baseline expression control. (b) Fold enrichment of gene ontology based functional categories in all the S/TFE data sets. (c–f) Catalogue of top differentially expressed genes: (c) shared among all the above three data sets, (d) shared between moderate and high S/TFE data sets, (e) expressed specifically in moderate S/TFE data set and (f) expressed specifically in high S/TFE data set.

Mentions: Expression of a set of mRNAs was shared in all the S/TFE data sets (Fig. 5a). In contrast, only a few shared miRNAs were observed among all three S/TFE data sets (Supplementary Fig. S6a). But a relatively large list of miRNAs was common between moderate and high S/TFE data sets. Gene expression data analysis using DAVID31 (http://david.abcc.ncifcrf.gov) and gene ontology revealed a striking enrichment in gene expression related to cell development, differentiation and cell death (Fig. 5b). Importantly, an involvement of protein kinase C (PKC)/NF-κB signalling axis was evident in all the mRNA data sets (as exemplified by NFKBIA, LGALS1, CRYAB (αB-crystallin), IFIH1, CGB5, CGB8, XM_938419, NRAP, PTPLAD2, TSHZ1; Fig. 5c–f) and the miRNA data sets (Supplementary Fig. S6b–e) in addition to those related to stem cell biology, embryonic development and oncogenesis.


Tumour-initiating stem-like cells in human prostate cancer exhibit increased NF-κB signalling.

Rajasekhar VK, Studer L, Gerald W, Socci ND, Scher HI - Nat Commun (2011)

Global mRNA expression in marker-positive human prostate tumour cells.(a) Venn-diagram of genes differentially expressed in prospectively isolated CWR22 OT-tumour cells with low (expressing EpCAM, CD44 or α2-integrin), moderate (expressing TRA-1-60, CD151 or CD166) and high (triple-marker-positives) sphere/tumour-forming efficiencies (S/TFE). Gene expression data in β4-integrin-positive (no sphere-forming) cells and the total tumour cells were used as baseline expression control. (b) Fold enrichment of gene ontology based functional categories in all the S/TFE data sets. (c–f) Catalogue of top differentially expressed genes: (c) shared among all the above three data sets, (d) shared between moderate and high S/TFE data sets, (e) expressed specifically in moderate S/TFE data set and (f) expressed specifically in high S/TFE data set.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105310&req=5

f5: Global mRNA expression in marker-positive human prostate tumour cells.(a) Venn-diagram of genes differentially expressed in prospectively isolated CWR22 OT-tumour cells with low (expressing EpCAM, CD44 or α2-integrin), moderate (expressing TRA-1-60, CD151 or CD166) and high (triple-marker-positives) sphere/tumour-forming efficiencies (S/TFE). Gene expression data in β4-integrin-positive (no sphere-forming) cells and the total tumour cells were used as baseline expression control. (b) Fold enrichment of gene ontology based functional categories in all the S/TFE data sets. (c–f) Catalogue of top differentially expressed genes: (c) shared among all the above three data sets, (d) shared between moderate and high S/TFE data sets, (e) expressed specifically in moderate S/TFE data set and (f) expressed specifically in high S/TFE data set.
Mentions: Expression of a set of mRNAs was shared in all the S/TFE data sets (Fig. 5a). In contrast, only a few shared miRNAs were observed among all three S/TFE data sets (Supplementary Fig. S6a). But a relatively large list of miRNAs was common between moderate and high S/TFE data sets. Gene expression data analysis using DAVID31 (http://david.abcc.ncifcrf.gov) and gene ontology revealed a striking enrichment in gene expression related to cell development, differentiation and cell death (Fig. 5b). Importantly, an involvement of protein kinase C (PKC)/NF-κB signalling axis was evident in all the mRNA data sets (as exemplified by NFKBIA, LGALS1, CRYAB (αB-crystallin), IFIH1, CGB5, CGB8, XM_938419, NRAP, PTPLAD2, TSHZ1; Fig. 5c–f) and the miRNA data sets (Supplementary Fig. S6b–e) in addition to those related to stem cell biology, embryonic development and oncogenesis.

Bottom Line: These TICs possess stem cell characteristics and multipotency as demonstrated by in vitro sphere-formation and in vivo tumour-initiation, respectively.The cells represent an undifferentiated subtype of basal cells and can be purified from prostate tumours based on coexpression of the human pluripotent stem cell marker TRA-1-60 with CD151 and CD166.These TICs exhibit increased nuclear factor-κB activity.

View Article: PubMed Central - PubMed

Affiliation: 1] Stem Cell Center and Developmental Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. [2] Sidney Kimmel Center for Prostate and Urologic Cancers, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

ABSTRACT
Androgen depletion is a key strategy for treating human prostate cancer, but the presence of hormone-independent cells escaping treatment remains a major therapeutic challenge. Here, we identify a minor subset of stem-like human prostate tumour-initiating cells (TICs) that do not express prostate cancer markers, such as androgen receptor or prostate specific antigen. These TICs possess stem cell characteristics and multipotency as demonstrated by in vitro sphere-formation and in vivo tumour-initiation, respectively. The cells represent an undifferentiated subtype of basal cells and can be purified from prostate tumours based on coexpression of the human pluripotent stem cell marker TRA-1-60 with CD151 and CD166. Such triple-marker-positive TICs recapitulate the original parent tumour heterogeneity in serial xeno-transplantations indicating a tumour cell hierarchy in human prostate cancer development. These TICs exhibit increased nuclear factor-κB activity. These findings are important in understanding the molecular basis of human prostate cancer.

No MeSH data available.


Related in: MedlinePlus