Molecular analysis of ex-vivo CD133+ GBM cells revealed a common invasive and angiogenic profile but different proliferative signatures among high grade gliomas

Hernández, Juan Luis García; Pérez-Caro, María; Gómez-Moreta, J.A.; González, Francisco; Ortiz, J.; Blanco, Óscar; Sancho, M.; Hernández-Rivas, Jesús María; González‐Sarmiento, Rogelio; Sánchez-Martı́n, Manuel

doi:10.1186/1471-2407-10-454

Cited by 26 publications

(24 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As shown in Figure A, CSCs expressed LGR5 mRNA up to 10‐fold higher when compared with cultured normal astrocytes and total normal brain extract, suggesting a stem‐like cell‐specific high‐level expression. Moreover, LGR5 mRNA expression in glioblastoma cells sorted for their CD133 content was determined by in silico analysis of publicly available microarray data , using R2 analysis software. LGR5 expression was found to correlate with CD133 content ( r = 0.582, P = 0.02, Figure B).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

LGR5 is a Marker of Poor Prognosis in Glioblastoma and is Required for Survival of Brain Cancer Stem‐Like Cells

et al. 2012

View full text Add to dashboard Cite

In various types of cancers including glioblastoma, accumulating evidence show the existence of cancer stem-like cells (CSCs), characterized by stem cell marker expression, capability of differentiation and self-renewal, and high potential for tumor propagation in vivo. LGR5, whose expression is positively regulated by the Wnt signaling pathway, is a stem cell marker in intestinal mucosa and hair follicle in the skin. As Wnt signaling is also involved in brain development, the function of LGR5 in the maintenance of brain CSCs is to be assessed. Our study showed that the LGR5 transcript level was increased in CSCs. Co-immunofluorescence staining demonstrated the co-localization of CD133- and LGR5-positive cells in glioblastoma tissue sections. Functionally, silencing of LGR5 by lentiviral shRNA-mediated knockdown induced apoptosis in brain CSCs. Moreover, LGR5 depletion led to a downregulation of L1 cell adhesion molecule expression. In line with an important function in glioma tumorigenesis, LGR5 expression increased with glioma progression and correlated with an adverse outcome. Our findings suggest that LGR5 plays a role in maintenance and/or survival of brain CSCs.

show abstract

Section: Resultsmentioning

confidence: 99%

“…R2, a microarray analysis and visualization platform, provided by the Department of Human Genetics of the Academic Medical Centre (Amsterdam, the Netherlands; http://r2.amc.nl), was used to study LGR5 mRNA expression in CD133 sorted glioblastoma cells [ ; n = 8]. Expression data was MAS5.0 normalized prior to analysis.…”

Section: Methodsmentioning

confidence: 99%

LGR5 is a Marker of Poor Prognosis in Glioblastoma and is Required for Survival of Brain Cancer Stem‐Like Cells

et al. 2012

View full text Add to dashboard Cite

show abstract

“…The fact that we observed a CD133 + cell population in fewer GBM patients and at a smaller fraction among total tumor cells than observed in other reports suggests a more stringent cell-sorting scheme and possibly reflects a higher cell purity in our study. More recently, additional gene expression profiling data comparing CD133 + vs. CD133 − GBM cells have become available, including molecular signatures containing 41 genes and 24 genes, respectively (27,28). A direct comparison with our GBM CD133 gene signature revealed no overlapping genes at all, further demonstrating the heterogeneous nature of the disease and the need for continued intensive study of increasing numbers of samples.…”

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.

120

105

View full text Add to dashboard Cite

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...

show abstract

“…GSCs are responsible for tumor propagation (24-28), therapeutic resistance (29;30), and have a higher invasive capacity (31;32). Here we report that EphA2 signaling axis is required for intracranial invasion of GSCs.…”

Section: Introductionmentioning

confidence: 99%

EphA2 promotes infiltrative invasion of glioma stem cells in vivo through cross-talk with Akt and regulates stem cell properties

et al. 2014

View full text Add to dashboard Cite

Diffuse infiltrative invasion is a major cause for the dismal prognosis of glioblastoma (GBM), but the underlying mechanisms remain incompletely understood. Using human glioblastoma stem cells (GSCs) that recapitulate the invasive propensity of primary GBM, we find that EphA2 critically regulates GBM invasion in vivo. EphA2 was expressed in all seven GSC lines examined, and overexpression of EphA2 enhanced intracranial invasion. The effects required Akt-mediated phosphorylation of EphA2 on serine 897. In vitro the Akt-EphA2 signaling axis is maintained in the absence of ephrin-A ligands and is disrupted upon ligand stimulation. To test whether ephrinAs in tumor microenvironment can regulate GSC invasion, the newly established Efna1;Efna3;Efna4 triple knockout mice (TKO) were used in an ex vivo brain slice invasion assay. We observed significantly increased GSC invasion through the brain slices of TKO mice relative to wild type littermates. Mechanistically EphA2 knockdown suppressed stem properties of GSCs, causing diminished self-renewal, reduced stem marker expression and decreased tumorigenicity. In a subset of GSCs, the reduced stem properties were associated with lower Sox2 expression. Overexpression of EphA2 promoted stem properties in a kinase-independent manner and Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms HHS Public Access

show abstract

Molecular analysis of ex-vivo CD133+ GBM cells revealed a common invasive and angiogenic profile but different proliferative signatures among high grade gliomas

Cited by 26 publications

References 63 publications

LGR5 is a Marker of Poor Prognosis in Glioblastoma and is Required for Survival of Brain Cancer Stem‐Like Cells

LGR5 is a Marker of Poor Prognosis in Glioblastoma and is Required for Survival of Brain Cancer Stem‐Like Cells

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

EphA2 promotes infiltrative invasion of glioma stem cells in vivo through cross-talk with Akt and regulates stem cell properties

Contact Info

Product

Resources

About