Targeting Stem Cells-Clinical Implications for Cancer Therapy

Tu, Lan Chun; Foltz, Greg; Lin, Edward H.; Hood, Leroy; Tian, Qiang

doi:10.2174/157488809788167373

Cited by 52 publications

(36 citation statements)

References 76 publications

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“…The hypothesis that cancer arises from a tumorigenic subpopulation denoted as "cancer stem cells" affords a unique developmental perspective to interrogate cancer cell heterogeneity for better understanding disease pathogenesis and for developing targeted therapy (25). Full realization of CSC clinical potential is dependent on the rigorous delineation of CSC identity in terms of cell-surface markers and the underlying molecular compositions.…”

Section: Discussionmentioning

confidence: 99%

A CD133-related gene expression signature identifies an aggressive glioblastoma subtype with excessive mutations

Yan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Cancer cells are heterogeneous and, it has been proposed, fall into at least two classes: the tumor-initiating cancer stem cells (CSC) and the more differentiated tumor cells. The transmembrane protein CD133 has been widely used to isolate putative CSC populations in several cancer types, but its validity as a CSC marker and hence its clinical ramifications remain controversial. Here, we conducted transcriptomic profiling of sorted CD133 + and CD133 − cells from human glioblastoma multiforme (GBM) and, by subtractive analysis, established a CD133 gene expression signature composed of 214 differentially expressed genes. Extensive computational comparisons with a compendium of published gene expression profiles reveal that the CD133 gene signature transcriptionally resembles human ES cells and in vitro cultured GBM stem cells, and this signature successfully distinguishes GBM from lower-grade gliomas. More importantly, the CD133 gene signature identifies an aggressive subtype of GBM seen in younger patients with shorter survival who bear excessive genomic mutations as surveyed through the Cancer Genome Atlas Network GBM mutation spectrum. Furthermore, the CD133 gene signature distinguishes higher-grade breast and bladder cancers from their lower-grade counterparts. Our systematic analysis provides molecular and genetic support for the stem cell-like nature of CD133 + cells and an objective means for evaluating cancer aggressiveness. molecular profiling | systems biology T he identification of tumor-initiating cancer stem cell (CSC) subpopulations in leukemia (1) and subsequently in breast cancer (2) has led to the hypothesis that tumor proliferation arises largely from these stem/progenitor-like cells and raises the possibility that a similar hypothesis can be applied to a number of solid tumor types (3) including glioblastoma multiforme (GBM) (4), the most deadly form of brain cancer with a diverse cellular phenotype and genetic heterogeneity (5-7). A CD133 + cell population has been isolated from brain as well as other cancers and has been shown to possess stem-cell properties (4, 8), to be more tumorigenic than the CD133 − cells in xenografted animal models (4,8,9), and to confer radiation resistance (10). Gene-expression signatures derived from both tumorigenic and normal stem cells have been correlated to expression profiles of patient samples in an attempt to stratify these patients according to their disease aggressiveness (presumably more CSCs indicate greater aggressiveness). For instance, an invasiveness gene signature derived from tumorigenic breast CSCs has been related to poor survival in breast cancer patients, suggesting that CSCs may contribute to tumor invasion and metastasis (11). A recent computational analysis linking an ES cell-like gene expression signature to the poorly differentiated states of aggressive human tumors, including breast cancer and GBM, further strengthens the putative stem-cell origins of cancer cell proliferation (12). However, this ES cell signature was unable to stratify t...

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Section: Discussionmentioning

confidence: 99%

A CD133-related gene expression signature identifies an aggressive glioblastoma subtype with excessive mutations

Yan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

120

105

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“…These cells use ATP-binding cassette membrane transporters (Goodell et al, 1996) or high expression of aldehyde dehydrogenase (Storms et al, 1999) to rapidly export or degrade xenobiotics. Targeting the subpopulation of cells with acquired stem-cell-like properties and development of treatment procedures to overcome their potential drug resistance seems vital for both tumor growth inhibition and prevention of tumor recurrence (Tu et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Targeted Inhibition of CD133⁺ Cells in Oral Cancer Cell Lines

Damek-Poprawa¹,

Volgina²,

Korostoff³

et al. 2011

J Dent Res

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Resistance to treatment and the appearance of secondary tumors in head and neck squamous cell carcinomas (HNSCC) have been attributed to the presence of cells with stem-cell-like properties in the basal layer of the epithelium at the site of the lesion. In this study, we tested the hypothesis that these putative cancer stem cells (CSC) in HNSCC could be specifically targeted and inhibited. We found that 9 of 10 head and neck tumor biopsies contained a subpopulation of cells that expressed CD133, an unusual surface-exposed membrane-spanning glycoprotein associated with CSC. A genetically modified cytolethal distending toxin (Cdt), from the periodontal pathogen Aggregatibacter actinomycetemcomitans, was conjugated to an anti-human CD133 monoclonal antibody (MAb). The Cdt-MAb complex preferentially inhibited the proliferation of CD133 + cells in cultures of established cell lines derived from HNSCC. Inhibition of the CD133 + cells was rate-and dosedependent. Saturation kinetics indicated that the response to the Cdt-MAb complex was specific. Healthy primary gingival epithelial cells that are native targets of the wild-type Cdt were not affected. Analysis of these data provides a foundation for the future development of new therapies to target CSC in the early treatment of HNSCC. Abbreviations: Cdt, cytolethal distending toxin; CSC, cancer stem cells; HNSCC, head and neck squamous cell carcinoma; MAb, monoclonal antibody.

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“…Thus, new generation cancer therapies are being developed to specifically target CSCs. Drug targets include surface molecules such as the drug transporters; specific oncoproteins; normal and neoplastic stem cell pathways including WNT, SHH, and NOTCH; survival factors; oxidative stress and related signal transduction pathways; and niche factors (Tu et al 2009). Several uncertainties, however, remain in understanding the biological and clinical consequences of CSCs.…”

Section: Future Perspectivesmentioning

confidence: 99%

Human ovarian cancer stem cells

Bapat¹

2010

Reproduction

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The isolation and identification of stem-like cells in solid tumors or cancer stem cells (CSCs) have been exciting developments of the last decade, although these rare populations had been earlier identified in leukemia. CSC biology necessitates a detailed delineation of normal stem cell functioning and maintenance of homeostasis within the organ. Ovarian CSC biology has unfortunately not benefited from a pre-established knowledge of stem cell lineage demarcation and functioning in the normal organ. In the absence of such information, some of the classical parameters such as long-term culture-initiating assays to isolate stem cell clones from tumors, screening and evaluation of other epithelial stem cell surface markers, dye efflux, and label retention have been applied toward the putative isolation of CSCs from ovarian tumors. The present review presents an outline of the various approaches developed so far and the various perspectives revealed that are now required to be dealt with toward better disease management.

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Targeting Stem Cells-Clinical Implications for Cancer Therapy

Cited by 52 publications

References 76 publications

A CD133-related gene expression signature identifies an aggressive glioblastoma subtype with excessive mutations

A CD133-related gene expression signature identifies an aggressive glioblastoma subtype with excessive mutations

Targeted Inhibition of CD133⁺ Cells in Oral Cancer Cell Lines

Human ovarian cancer stem cells

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Targeting Stem Cells-Clinical Implications for Cancer Therapy

Cited by 52 publications

References 76 publications

A CD133-related gene expression signature identifies an aggressive glioblastoma subtype with excessive mutations

A CD133-related gene expression signature identifies an aggressive glioblastoma subtype with excessive mutations

Targeted Inhibition of CD133+ Cells in Oral Cancer Cell Lines

Human ovarian cancer stem cells

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Targeted Inhibition of CD133⁺ Cells in Oral Cancer Cell Lines