Brain Tumor Stem Cells From an Adenoid Glioblastoma Multiforme

Oka, Naoki; Soeda, Akio; Noda, Shinichi; Iwama, Toru

doi:10.2176/nmc.49.146

Cited by 12 publications

(5 citation statements)

References 15 publications

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“…Although many tumor cells respond to this metabolic stress through induction of the apoptotic mechanism, some cells may be able to cope with this stress through alterations in cellular metabolism (Li et al, 2004). These cells may subsequently stimulate neovascularization and contribute to further growth of the tumor (Zagzag et al, 2000;Bao et al, 2006b;Oka et al, 2009). Hypoxia also contributes to tumor growth by changing the metabolic state of the cells, resulting in the production of macromolecules needed for cellular proliferation (DeBerardinis et al, 2008).…”

Section: Growth Of Cscs In Hypoxiamentioning

confidence: 99%

Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α

et al. 2009

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Hypoxia contributes to the progression of a variety of cancers by activating adaptive transcriptional programs that promote cell survival, motility and tumor angiogenesis. Although the importance of hypoxia and subsequent hypoxia-inducible factor-1a (HIF-1a) activation in tumor angiogenesis is well known, their role in the regulation of glioma-derived stem cells is unclear. In this study, we show that hypoxia (1% oxygen) promotes the self-renewal capacity of CD133-positive human glioma-derived cancer stem cells (CSCs). Propagation of the glioma-derived CSCs in a hypoxic environment also led to the expansion of cells bearing CXCR4 (CD184), CD44 low and A2B5 surface markers. The enhanced self-renewal activity of the CD133-positive CSCs in hypoxia was preceded by upregulation of HIF-1a. Knockdown of HIF-1a abrogated the hypoxia-mediated CD133-positive CSC expansion. Inhibition of the phosphatidylinositol 3-kinase (PI3K)-Akt or ERK1/2 pathway reduced the hypoxiadriven CD133 expansion, suggesting that these signaling cascades may modulate the hypoxic response. Finally, CSCs propagated at hypoxia robustly retained the undifferentiated phenotype, whereas CSCs cultured at normoxia did not. These results suggest that response to hypoxia by CSCs involves the activation of HIF-1a to enhance the self-renewal activity of CD133-positive cells and to inhibit the induction of CSC differentiation. This study illustrates the importance of the tumor microenvironment in determining cellular behavior.

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Section: Growth Of Cscs In Hypoxiamentioning

confidence: 99%

Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α

et al. 2009

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“…CD133 + cell markers are positive in 60—70% of glioma tissue. Oka et al (29) reported that the percentage of tumor CSCs varied from 1.02% to 2.32% based on flow cytometric analysis. Singh et al (36) reported less than 20% of CD133 + in total tumor mass, but wide ranging variations in the CD133 + cell ratio (0.1—50% in GBM) were reported.…”

Section: The Component Amount Of Cscs In Gliomasmentioning

confidence: 99%

“…These stem cells may be the source of tumor recurrence after radiation (25). Oka et al (29) reported that CD133 + CSCs were identified in the peripheral brain regions adjacent to the tumor. They were frequently localized around vascular structures (the vascular niche).…”

Section: Introductionmentioning

confidence: 99%

The Role of Cancer Stem Cells (CD133⁺) in Malignant Gliomas

et al. 2011

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Malignant gliomas, particularly glioblastoma multiforme (GBM) tumors, are very difficult to treat by conventional approaches. Although most of the tumor mass can be removed by surgical resection, radiotherapy, and chemotherapy, it eventually recurs. There is growing evidence that cancer stem cells (CSCs) play an important role in tumor recurrence. These stem cells are radioresistant and chemoresistant. The most commonly used tumor marker for CSCs is CD133. The amount of CSC component is closely correlated with tumor malignancy grading. Isolating, identifying, and treating CSCs as the target is crucial for treating malignant gliomas. CSC-associated vascular endothelial growth factor (VEGF) promotes tumor angiogenesis, tumor hemorrhage, and tumor infiltration. Micro-RNA (miRNA) plays a role in CSC gene expression, which may regulate oncogenesis or suppression to influence tumor development or progression. The antigenesis of CSCs and normal stem cells may be different. The CSCs may escape the T-cell immune response. Identifying a new specific antigen from CSCs for vaccine treatment is a key point for immunotherapy. On the other hand, augmented treatment with radiosensitizer or chemosensitizer may lead to reduction of CSCs and lead to CSCs being vulnerable to radiotherapy and chemotherapy. The control of signaling pathway and cell differentiation to CSC growth is another new hope for treatment of malignant gliomas. Although the many physiological behavioral differences between CSCs and normal stem cells are unclear, the more we know about these differences the better we will be able to treat CSCs effectively.

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“…In comparison to CD133 - cells, CD133 + cells have 32- to 56-fold more activity of MGMT. Ji et al (36) showed that CD133 + CSCs express high levels of the drug transporter gene BCRP, combined with upregulation of DNA repair protein, MGMT mRNA, and mRNAs of other genes that inhibit apoptosis including FAS-associating death domain (FADD)-like antiapoptotic molecule (FLIP), B-cell CLL/lymphoma 2 (Bcl-2), Bcl-X, and some inhibitor of apoptosis (IAP) family members (55,57,61). Nakai et al (53) showed CSCs possess stronger drug resistance to conventional anticancer drugs such as doxorubicin, etoposide (VP-16), carboplatin, and bis -chloroethylnitrosourea (BCNU) than non-stem cells of malignant gliomas.…”

Section: Introductionmentioning

confidence: 99%

Targeting Cancer Stem Cells for Treatment of Glioblastoma Multiforme

et al. 2013

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Cancer stem cells (CSCs) in glioblastoma multiforme (GBM) are radioresistant and chemoresistant, which eventually results in tumor recurrence. Targeting CSCs for treatment is the most crucial issue. There are five methods for targeting the CSCs of GBM. One is to develop a new chemotherapeutic agent specific to CSCs. A second is to use a radiosensitizer to enhance the radiotherapy effect on CSCs. A third is to use immune cells to attack the CSCs. In a fourth method, an agent is used to promote CSCs to differentiate into normal cells. Finally, ongoing gene therapy may be helpful. New therapeutic agents for targeting a signal pathway, such as epidermal growth factor (EGF) and vascular epidermal growth factor (VEGF) or protein kinase inhibitors, have been used for GBM but for CSCs the effects still require further evaluation. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as cyclooxygenase-2 (Cox-2) inhibitors have proven to be effective for increasing radiation sensitivity of CSCs in culture. Autologous dendritic cells (DCs) are one of the promising immunotherapeutic agents in clinical trials and may provide another innovative method for eradication of CSCs. Bone-morphogenetic protein 4 (BMP4) is an agent used to induce CSCs to differentiate into normal glial cells. Research on gene therapy by viral vector is also being carried out in clinical trials. Targeting CSCs by eliminating the GBM tumor may provide an innovative way to reduce tumor recurrence by providing a synergistic effect with conventional treatment. The combination of conventional surgery, chemotherapy, and radiotherapy with stem cell-orientated therapy may provide a new promising treatment for reducing GBM recurrence and improving the survival rate.

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Brain Tumor Stem Cells From an Adenoid Glioblastoma Multiforme

Cited by 12 publications

References 15 publications

Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α

Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α

The Role of Cancer Stem Cells (CD133⁺) in Malignant Gliomas

Targeting Cancer Stem Cells for Treatment of Glioblastoma Multiforme

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Brain Tumor Stem Cells From an Adenoid Glioblastoma Multiforme

Cited by 12 publications

References 15 publications

Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α

Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α

The Role of Cancer Stem Cells (CD133+) in Malignant Gliomas

Targeting Cancer Stem Cells for Treatment of Glioblastoma Multiforme

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Product

Resources

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The Role of Cancer Stem Cells (CD133⁺) in Malignant Gliomas