Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma

Prince, Mark E.; Sivanandan, Ranjiv; Kaczorowski, Adam; Wolf, Gregory T.; Kaplan, Michael; Dalerba, Piero; Weissman, Irving L.; Clarke, Michael F.; Ailles, Laurie

doi:10.1073/pnas.0610117104

Cited by 1,923 publications

(1,694 citation statements)

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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.…”

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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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“…Moreover, a link between poor prognosis and increased ALDH1 activity was found in breast tumors [33]. Since the above discoveries, as well as additional CSCs markers, CSCs have been prospectively isolated from a variety of malignancies, thus far including pancreas, skin, head and neck, and prostate cancers, and the list is ever growing [26][27][28][36][37][38]. The identification of CSCs was facilitated by significant progress achieved over the last several years in this field.…”

Section: Cancer Stem Cells-past and Currentmentioning

confidence: 99%

Targeted therapy aimed at cancer stem cells: Wilms’ tumor as an example

2013

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Wilms' tumor (WT), a common renal pediatric solid tumor, serves as a model for a malignancy formed by renal precursor cells that have failed to differentiate properly. Here we review recent evidence showing that the tumors' heterogeneous cell population contains a small fraction of cancer stem cells (CSC) identified by two markers: Neural Cell Adhesion Molecule 1 (NCAM1) expression and Aldehyde dehydrogenase 1 (ALDH1) enzymatic activity. In vivo studies show these CSCs to both self-renew and differentiate to give rise to all tumor components. Similar to other malignancies, the identification of a specific CSC fraction has allowed the examination of a novel targeted therapy, aimed at eradicating the CSC population. The loss of CSCs abolishes the tumor's ability to sustain and propagate, hence, causing tumor degradation with minimal damage to normal tissue.

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“…Many malignant diseases are understood to have an underlying stem cell population [7][8][9] which this technology is capable of probing. For myeloproliferative neoplasms (MPN) and leukaemias, this stem cell population has been associated with deregulated protein tyrosine kinase (PTK) activity (for review see Mitelman 10 ), including FMS-like tyrosine kinase 3 (FLT3) in acute myeloid leukaemia (AML) 11 , Janus kinase 2 (JAK2) in erythroid neoplasia 12 and BCR-ABL in chronic myeloid leukaemia (CML) 13,14 .…”

Section: Introductionmentioning

confidence: 99%

Antibody-based detection of protein phosphorylation status to track the efficacy of novel therapies using nanogram protein quantities from stem cells and cell lines

et al. 2014

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This protocol describes a highly reproducible antibody-based method providing protein level and phosphorylation status information from nanogram quantities of protein cell lysate. Nanocapillary isoelectric focusing (cIEF) combines with UV activated linking chemistry to detect changes in phosphorylation status. We describe how to detect changes in response to tyrosine kinase inhibitors (TKIs) in the phosphorylation status of the adapter protein CrkL a major substrate of the oncogenic tyrosine kinase BCR/ABL in chronic myeloid leukaemia (CML), using highly enriched CML stem cells and mature cell populations in vitro. This protocol provides a 2.5pg/nL limit of protein detection (<0.2% of a stem cell sample containing <10 4 cells). Additional assays are described for pTyr207-CrkL and PTPRC/CD45, developed using this protocol and applied to CML patient samples. This method is high throughput and can act as a screen for in vitro cancer stem cell response to drugs and novel agents. SummaryThis protocol uses a highly sensitive and reproducible antibody-based capillary isoelectric focusing approach to establish protein phosphorylation status from nanogram quantities of protein cell lysate from cell line or primary stem cell material. Is-protocol-to

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Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma

Cited by 1,923 publications

References 29 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

Targeted therapy aimed at cancer stem cells: Wilms’ tumor as an example

Antibody-based detection of protein phosphorylation status to track the efficacy of novel therapies using nanogram protein quantities from stem cells and cell lines

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