Identification and Characterization of Ovarian Cancer-Initiating Cells from Primary Human Tumors

Zhang, Shu; Balch, Curt; Chan, Michael W.Y.; Lai, Hung Cheng; Matei, Daniela; Schilder, Jeanne M.; Yan, Pearlly S.; Huang, Tim H.M.; Nephew, Kenneth P.

doi:10.1158/0008-5472.can-08-0364

Cited by 1,170 publications

(1,163 citation statements)

References 58 publications

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“…[5][6][7][8][9] As shown in Figure 1b, all cell lines generated tumorospheres, and flow cytometry analyses showed that CD44 þ CD24 À population was highly enriched in tumorospheres (Supplementary Figure S1A). We sorted CD44 þ CD24 À cells from spheres of prostate and breast cancer using fluorescence-activated cell sorting (FACS) and achieved a purity of 495% as judged by postsorting flow analysis (Figure 1c).…”

Section: Resultsmentioning

confidence: 90%

“…Collectively, our data suggest that both CSCs and spheres exhibited diverse stem cell-associated characteristics, consistent with previous reports. [5][6][7][8][9] CSCs overexpressed BAD with elevated phosphorylation. As CSCs are resistant to drugs 11 and phosphorylated BAD correlates with drug resistance in cancer patients, 25 we determined the level of BAD expression and phosphorylation in CSCs and tumorospheres.…”

Section: Resultsmentioning

confidence: 99%

“…1,2 Subsequently, CSCs have been identified in several cancers. [3][4][5][6][7][8][9][10] Accumulating evidence suggests that current cancer therapies can only shrink tumors as they target and kill the differentiated cancer (DC) cells, but are unable to target the rare CSC population. 11,12 Thus, despite a wealth of information on DC cells, the active survival and self-renewal pathways in CSCs have not been characterized thoroughly.…”

mentioning

confidence: 99%

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Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Sastry

Al-Muftah

et al. 2014

Cell Death Differ

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Emerging evidence suggests that the resistance of cancer stem cells (CSC) to many conventional therapies is one of the major limiting factors of cancer therapy efficacy. Identification of mechanisms responsible for survival and self-renewal of CSC will help design new therapeutic strategies that target and eliminate both differentiated cancer cells and CSC. Here we demonstrated the potential role of proapoptotic protein BAD in the biology of CSC in melanoma, prostate and breast cancers. We enriched CD44 þ /CD24 À cells (CSC) by tumorosphere formation and purified this population by FACS. Both spheres and CSC exhibited increased potential for proliferation, migration, invasion, sphere formation, anchorage-independent growth, as well as upregulation of several stem cell-associated markers. We showed that the phosphorylation of BAD is essential for the survival of CSC. Conversely, ectopic expression of a phosphorylation-deficient mutant BAD induced apoptosis in CSC. This effect was enhanced by treatment with a BH3-mimetic, ABT-737. Both pharmacological agents that inhibit survival kinases and growth factors that are involved in drug resistance delivered their respective cytotoxic and protective effects by modulating the BAD phosphorylation in CSC. Furthermore, the frequency and self-renewal capacity of CSC was significantly reduced by knocking down the BAD expression. Consistent with our in vitro results, significant phosphorylation of BAD was found in CD44 þ CSC of 83% breast tumor specimens. In addition, we also identified a positive correlation between BAD expression and disease stage in prostate cancer, suggesting a role of BAD in tumor advancement. Our studies unveil the role of BAD in the survival and self-renewal of CSC and propose BAD not only as an attractive target for cancer therapy but also as a marker of tumor progression.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Sastry

Al-Muftah

et al. 2014

Cell Death Differ

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“…To test whether induction of TG2 by TGF-b1 has a role, we measured the effects of TG2 knock-down on spheroid formation. Transduction of short hairpin Prior studies indicated that cancer cells with stem cell phenotype aggregate as spheroids when cultured under low adherence conditions in the absence of differentiating factors (Al-Hajj and Clarke, 2004;Zhang et al, 2008). Further, cancer cells cultured as spheroids are enriched in cells with stem phenotype (Dontu et al, 2003).…”

Section: Tgf-b-regulated Tg2 Expression Is Significant To Emt and Ocmentioning

confidence: 99%

“…OC cells transitioned to a mesenchymal phenotype form spheroids, which allow dissemination in the peritoneal cavity. Spheroids are enriched in CD44 þ /CD117 þ cells, phenotype recognized as a signature for OC initiating cells (OCIC) (Zhang et al, 2008). TG2 knock-down prevented TGF-b-induced EMT, decreased the number of CD44 þ /CD117 þ cells and blocked spheroid formation by OC cells.…”

Section: Introductionmentioning

confidence: 99%

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

et al. 2011

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Tissue transglutaminase (TG2), an enzyme involved in cell proliferation, differentiation and apoptosis is overexpressed in ovarian carcinomas, where it modulates epithelial-to-mesenchymal transition (EMT) and promotes metastasis. Its regulation in ovarian cancer (OC) remains unexplored. Here, we show that transforming growth factor (TGF)-b, a cytokine involved in tumor dissemination is abundantly secreted in the OC microenvironment and induces TG2 expression and enzymatic activity. This is mediated at transcriptional level by SMADs and by TGFb-activated kinase 1-mediated activation of the nuclear factor-jB complex. TGF-b-stimulated OC cells aggregate as spheroids, which enable peritoneal dissemination. We show that TGF-b-induced TG2 regulates EMT, formation of spheroids and OC metastasis. TG2 knock-down in OC cells decreases the number of cells harboring a cancer stem cell phenotype (CD44 þ /CD117 þ ). Furthermore, CD44 þ /CD117 þ cells isolated from human ovarian tumors express high levels of TG2. In summary, TGFb-induced TG2 enhances ovarian tumor metastasis by inducing EMT and a cancer stem cell phenotype.

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Isolation and Characterization of Potential Cancer Stem Cells from Solid Human Tumors—Potential Applications

Dobbin

Landen

2013

CP Pharmacology

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Cancer stem cells (CSCs) are a subpopulation of cells within a heterogeneous tumor that have enhanced biologic properties e.g., increased capacity for self-renewal, increased tumorigenicity, enhanced differentiation capacity, and resistance to chemo-and radiotherapies. This unit describes protocols to isolate and characterize potential cancer stem cells from a solid tumor. This involves creating a single-cell suspension from tumor tissue, tagging the cell subpopulation of interest, and sorting cells into different populations. Finally, the sorted subpopulations can be evaluated for their ability to meet the functional requirements of a CSC, which primarily include increased tumorigenicity in an in vivo xenograft assay. Mastering the protocols in this unit will allow the researcher to study populations of cells that may have properties of CSCs.

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Identification and Characterization of Ovarian Cancer-Initiating Cells from Primary Human Tumors

Abstract: The objective of this study was to identify and characterize a self-renewing subpopulation of human ovarian tumor cells (ovarian cancer-initiating cells, OCICs) fully capable of serial propagation of their original tumor phenotype in animals.

Cited by 1,170 publications

References 58 publications

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Tissue transglutaminase links TGF-β, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer

Isolation and Characterization of Potential Cancer Stem Cells from Solid Human Tumors—Potential Applications

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