Identification of A2b5+cd133− Tumor-Initiating Cells in Adult Human Gliomas

Ogden, Alfred T.; Waziri, Allen; Lochhead, Richard A.; Fusco, David J.; Lopez, Kim A.; Ellis, Jason A.; Kang, Joann J.; Assanah, Marcela C.; McKhann, Guy M.; Sisti, Michael B.; McCormick, Paul C.; Canoll, Peter; Bruce, Jeffrey N.

doi:10.1227/01.neu.0000316019.28421.95

Cited by 367 publications

(291 citation statements)

References 25 publications

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“…It is intriguing that hypoxia might expand cells with enhanced infiltrative property. A2B5, a cell surface ganglioside glial progenitor marker, is a putative CSC marker also associated with tumor recapitulation in xenografts (Ogden et al, 2008). Finally, high levels of CD24 expression have been used to identify transit-amplifying cells as well as differentiated neurons, and CD24 is required for the terminal differentiation of neuronal progenitors (Nieoullon et al, 2005;Panchision et al, 2007).…”

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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“…Several molecules, including CD133 (Singh et al, 2003(Singh et al, , 2004, CD15 (Read et al, 2009;Son et al, 2009;Ward et al, 2009), A2B5 (Ogden et al, 2008;Tchoghandjian et al, 2010) and L1CAM (Bao et al, 2008), have been identified on cell surface of GSCs (Fig. 1B, 3A).…”

Section: Specific Cell Surface Molecules In Glioblastoma Stem Cellsmentioning

confidence: 99%

“…But whether CD15 can be used as a target for GSCs is not clear because the function of CD15 in normal stem cells and cancer stem cells remains poorly understood, and CD15 is a carbohydrate antigen expressed by normal neural and progenitor cells (Capela and Temple, 2002) rather than a distinct protein target. Other surface markers such as A2B5 have been used for the enrichment of GSC population (Ogden et al, 2008;Tchoghandjian et al, 2009), but further investigations are needed to determine whether this surface marker can be used for targeting GSCs in GBMs.…”

Section: Specific Cell Surface Molecules In Glioblastoma Stem Cellsmentioning

confidence: 99%

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

et al. 2010

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Glioblastomas (GBMs) are highly lethal primary brain tumors. Despite current therapeutic advances in other solid cancers, the treatment of these malignant gliomas remains essentially palliative. GBMs are extremely resistant to conventional radiation and chemotherapies. We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells (GSCs) promotes therapeutic resistance. We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth, which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs. Furthermore, stem cell-like cancer cells (cancer stem cells) have been shown to promote metastasis. Although GBMs rarely metastasize beyond the central nervous system, these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection, and GSCs display an aggressive invasive phenotype. These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment. Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells, but also display critical distinctions that provide important clues into useful therapeutic targets. In this review, we summarize the current understanding and advances in glioma stem cell research, and discuss potential targeting strategies for future development of anti-GSC therapies.

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“…Recent work on GBM has focused highly on the small fraction of tumor cells with stem cell characteristics that are thought to initiate and maintain tumor growth (Hemmati et al 2003;Singh et al 2003;Galli et al 2004;Singh et al 2004). Several markers identifying a glioma stem cell population have been proposed, including CD133, Nestin (Singh et al 2003), and A2B5 (Ogden et al 2008). HIF-2α was recently shown to be expressed at high levels in CD133 + glioma stem cells grown in vitro (McCord et al 2009), and to co-localize with stem cell markers in tumor specimens ), suggesting that HIF-2α is an independent marker for glioma stem cells.…”

Section: Non-small Cell Lung Carcinoma Hif Protein Expression Is Virmentioning

confidence: 99%

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

Pietras

Johnsson

Påhlman

2010

Current Topics in Microbiology and Immunology

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Identification of A2b5+cd133− Tumor-Initiating Cells in Adult Human Gliomas

Abstract: Together, these results demonstrate that human gliomas contain multiple populations of cells with the capacity to form tumors and specifically identify a population of tumorigenic A2B5+ cells that are phenotypically distinct from CD133+ cells.

Cited by 367 publications

References 25 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

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

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