Targeting Stem Cells in Brain Tumors

Lasky, Joseph L.; Liau, Linda M.

doi:10.1177/153303460600500312

Cited by 9 publications

(5 citation statements)

References 97 publications

(90 reference statements)

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“…It has been reported that CD133 + GBMderived CSCs make up *0.1%-10% of the tumor, with the average level reported being < 1% [19][20][21][22]. Similar to reports on CSC subpopulations, our CD133 + population represented < 1% of the total tumor parent population [19][20][21][22].…”

Section: Cell Sorting Of Cd133supporting

confidence: 66%

Lectins Identify Glycan Biomarkers on Glioblastoma-Derived Cancer Stem Cells

Tucker-Burden

Chappa

Krishnamoorthy³

et al. 2012

Stem Cells and Development

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Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Despite aggressive therapy with surgery, radiotherapy, and chemotherapy, nearly all patients succumb to disease within 2 years. Several studies have supported the presence of stem-like cells in brain tumor cultures that are CD133-positive, are capable of self-renewal, and give rise to all cell types found within the tumor, potentially perpetuating growth. CD133 is a widely accepted marker for glioma-derived cancer stem cells; however, its reliability has been questioned, creating a need for other identifiers of this biologically important subpopulation. We used a panel of 20 lectins to identify differences in glycan expression found in the glycocalyx of undifferentiated gliomaderived stem cells and differentiated cells that arise from them. Fluorescently labeled lectins that specifically recognize a-N-acetylgalactosamine (GalNAc) and a-N-acetylglucosamine (GlcNAc) differentially bound to the cell surface based on the state of cellular differentiation. GalNAc and GlcNAc were highly expressed on the surface of undifferentiated cells and showed markedly reduced expression over a 12-day duration of differentiation. Additionally, the GalNAc-recognizing lectin Dolichos biflorus agglutinin was capable of specifically selecting and sorting glioma-derived stem cell populations from an unsorted tumor stock and this subpopulation had proliferative properties similar to CD133+ cells in vitro and also had tumor-forming capability in vivo. Our preliminary results on a single cerebellar GBM suggest that GalNAc and GlcNAc are novel biomarkers for identifying glioma-derived stem cells and can be used to isolate cancer stem cells from unsorted cell populations, thereby creating new cell lines for research or clinical testing.

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Section: Cell Sorting Of Cd133supporting

confidence: 66%

Lectins Identify Glycan Biomarkers on Glioblastoma-Derived Cancer Stem Cells

Tucker-Burden

Chappa

Krishnamoorthy³

et al. 2012

Stem Cells and Development

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“…Despite advances in surgery, radiation therapy and chemotherapy, the 1-year overall survival rate is less than 30%, and the median survival time of patients with high-grade glioma is approximately 15 months (1,2). To develop more optimized and effective treatment strategies for glioblastomas, it is critical to gain a deeper understanding of the molecular mechanisms underlying gliomagenesis and to identify targets for therapeutic intervention (3,4).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Src enhances the cytotoxic effect of temozolomide through AKT in glioma

Wang

Sun

et al. 2013

Oncology Reports

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Abstract. Src is an attractive target since it is overexpressed in a number of malignancies, including glioma. However, the mechanism of Src signaling as well as its silencing effect on temozolomide in glioma is not well known. We hypothesized that downregulation of Src may enhance the cytotoxic effect of temozolomide on glioma. As expected, Src was overexpressed in glioblastoma multiforme (GBM) compared with normal brain tissues. Src silencing suppressed tumor proliferation and induced apoptosis in glioma. In addition, Src silencing combined with temozolomide treatment resulted in significant inhibition of tumor growth. These effects may be mediated by AKT which is a downstream effector of Src, since downregulation of AKT exhibited a similar effect as Src siRNA when combined with temozolomide. Finally, we demonstrated that overexpression of AKT suppressed the enhanced cytotoxic effect of temozolomide mediated by Src silencing. Thus, the present study demonstrated that Src plays a biologically significant role in tumor proliferation and apoptosis and enhances the cytotoxic effect of temozolomide through AKT supression in glioma.

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“…Despite the advances in surgery, radiation therapy, and chemotherapy, the 1-year overall survival rate is less than 30%, and the median survival time of patients with high-grade glioma is only approximately 15 months (1,2). To develop more optimized and effective treatment strategies for glioblastomas, it is critical to gain deeper understanding of the molecular mechanisms underlying gliomagenesis and to identify targets for therapeutic intervention (3,4).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of miR-221/222 sensitizes glioma cells to temozolomide by regulating apoptosis independently of p53 status

Chen

Zhang²,

Han³

et al. 2011

Oncol Rep

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Abstract.A previous study showed that miR-221/222 can regulate cell apoptosis. p53 is a well known tumor suppressor which can influence the chemosensitivity of glioma cells. However, the effect of miR-221/222 in gliomas with different p53 status is unknown. Here, we demostrate that knockdown of miR-221/222 increases apoptosis in human gliomas of different p53 types (U251 cells, p53 mutant-type; LN308 cells, p53 null-type; and U87 cells, p53 wild-type). Furthermore, the effect of miR-221/22 caused no change of p53 expression in the glioma cells studied. In addition, when a specific siRNA against p53 was employed in U87 cells, no attenuation of apoptosis was found after knockdown of miR-221/222. Importantly, we found that As-miR-221/222-treated cells increased expression of Bax, cytochrome c, Apaf-1 and cleaved-caspase-3. Our results showed that low expression of miR-221/222 sensitized glioma cells to temozolomide (TMZ); in addition, ectopic expression of PUMA by pcDNA-PUMA had a similar effect. Taken together, our study indicates that downregulated miR-221/222 can sensitize glioma cells to TMZ by regulating apoptosis independently of p53 status. IntroductionGlioblastoma, the most aggressive type of tumor arising in the central nervous system (CNS), is considered to be one of the deadliest of human cancers. Despite the advances in surgery, radiation therapy, and chemotherapy, the 1-year overall survival rate is less than 30%, and the median survival time of patients with high-grade glioma is only approximately 15 months (1,2). To develop more optimized and effective treatment strategies for glioblastomas, it is critical to gain deeper understanding of the molecular mechanisms underlying gliomagenesis and to identify targets for therapeutic intervention (3,4).MicroRNAs are small regulatory RNA molecules that in recent years have been identified in the progression of various cancers and proposed as novel targets for anticancer therapies (5,6). By negatively regulating their mRNA targets to either degradation or translational repression, they can act as both tumor suppressors and oncogenes (7). Recent studies showed frequent deregulation of miR-221/222 in glioblastoma and astrocytoma cell lines (8). Overexpression of miR-221/222 increased glioma cell proliferation and invasion in vitro and induced glioma growth in a subcutaneous mouse model (9). In addition, blockade of miR-221/222 cluster suppressed human glioma cell growth, suggesting the cosuppression of miR-221/222 cluster might be a potential therapeutic strategy in glioma (10). Our previous study demostrated that miR-221/222 can directly target PUMA inducing apoptosis (11). p53, an upstream gene of PUMA, is a well known tumor-suppressor. However, the role of miR-221/222 in glioma of different p53 status is not well elucidated.In this study, we identified the involvement of miR-221/-222 in mediating apoptosis in glioma regardless of p53 status. Furthermore, we confirmed that low expression of miR-221/222 sensitizes glioma cells to the alkylating agent TMZ partly...

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Targeting Stem Cells in Brain Tumors

Cited by 9 publications

References 97 publications

Lectins Identify Glycan Biomarkers on Glioblastoma-Derived Cancer Stem Cells

Lectins Identify Glycan Biomarkers on Glioblastoma-Derived Cancer Stem Cells

Downregulation of Src enhances the cytotoxic effect of temozolomide through AKT in glioma

Downregulation of miR-221/222 sensitizes glioma cells to temozolomide by regulating apoptosis independently of p53 status

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