Identification of molecular subtypes of glioblastoma by gene expression profiling

Mischel, Paul S.; Shai, Ruty Mehrian; Shi, Tao; Horvath, Steve; Lu, Kan V.; Choe, Gheeyoung; Seligson, David B.; Kremen, Thomas J.; Palotie, Aarno; Liau, Linda M.; Cloughesy, Timothy F.; Nelson, Stanley F.

doi:10.1038/sj.onc.1206344

Cited by 237 publications

(138 citation statements)

References 59 publications

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“…Our data suggest that these tumors are somewhat similar to NSCs but more strongly suggest that pediatric astrocytomas and high-grade gliomas are derived from either NSCs or progenitor cells. Previous studies have demonstrated that adult high-grade gliomas can form multiple differentiated cell types (42), and that some cells can form neurospheres with multiple differentiated cell types (40). It is unknown whether the originating cells of PNETs, medulloblastomas and gliomas, may be the same type of cell, such as a NSC, but resulting from different transformation events, or whether the glial tumors arise from a cell at a later stage of differentiation.…”

Section: Discussionmentioning

confidence: 98%

Cancerous stem cells can arise from pediatric brain tumors

Hemmati

Nakano

Lazareff

et al. 2003

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

1,650

1,350

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Section: Discussionmentioning

confidence: 98%

Cancerous stem cells can arise from pediatric brain tumors

Hemmati

Nakano

Lazareff

et al. 2003

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

1,650

1,350

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“…Several works (Sallinen et al, 2000;Khan et al, 2001;Ramaswamy et al, 2001;Rickman et al, 2001;Agrawal et al, 2002;Kim et al, 2002;Veer et al, 2002;Vijver et al, 2002;Boom et al, 2003;Godard et al, 2003;Hunter et al, 2003;Mischel et al, 2003;Nutt et al, 2003;Shai et al, 2003;Sorlie et al, 2003;Freije et al, 2004;Mischel et al, 2004;Hoelzinger et al, 2005;Liang et al, 2005;Nigro et al, 2005;Rich et al, 2005;Somasundaram et al, 2005;Wong et al, 2005) showed the usefulness of utilizing methods of analysis of multiple forms of data including both clinical and multiple genes, to achieve a more precise discrimination of outcomes for individual patients. The same logical use of multiple forms of data and methods of analysis has been applied in the present study to accurately achieve better classification and prediction of glioma patients.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, developed microarray technology has permitted development of multi-organ cancer classification including gliomas (Ramaswamy et al, 2001;Rickman et al, 2001;Kim et al, 2002;Hunter et al, 2003;Mischel et al, 2004), identification of tumor subclasses (Khan et al, 2001;Mischel et al, 2003;Shai et al, 2003;Sorlie et al, 2003;Liang et al, 2005;Nigro et al, 2005;Wong et al, 2005), discovery of progression markers (Sallinen et al, 2000;Agrawal et al, 2002;van de Boom et al, 2003;Godard et al, 2003;Hoelzinger et al, 2005;Rich et al, 2005;Somasundaram et al, 2005) and prediction of disease outcomes (van't Veer et al, 2002;van de Vijver et al, 2002;Nutt et al, 2003;Freije et al, 2004). Unlike clinicopathological staging, molecular staging can predict long-term outcomes of any individual based on gene expression profile of the tumor at diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Identification of expressed genes characterizing long-term survival in malignant glioma patients

Arao²,

et al. 2006

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Better understanding of the underlying biology of malignant gliomas is critical for the development of early detection strategies and new therapeutics. This study aimed to define genes associated with survival. We investigated whether genes coupled with a class prediction model could be used to define subgroups of high-grade gliomas in a more objective manner than standard pathology. RNAs from 29 malignant gliomas were analysed using Agilent microarrays. We identified 21 genes whose expression was most strongly and consistently related to patient survival based on univariate proportional hazards models. In six out of 10 genes, changes in gene expression were validated by quantitative real-time PCR. After adjusting for clinical covariates based on a multivariate analysis, we finally obtained a statistical significance level for DDR1 (discoidin domain receptor family, member 1), DYRK3 (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 3) and KSP37 (Ksp37 protein). In independent samples, it was confirmed that DDR1 protein expression was also correlated to the prognosis of glioma patients detected by immunohistochemical staining. Furthermore, we analysed the efficacy of the short interfering RNA (siRNA)-mediated inhibition of DDR1 mRNA synthesis in glioma cell lines. Cell proliferation and invasion were significantly suppressed by siRNA against DDR1. Thus, DDR1 can be a novel molecular target of therapy as well as an important predictive marker for survival in patients with glioma. Our method was effective at classifying highgrade gliomas objectively, and provided a more accurate predictor of prognosis than histological grading.

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“…23 As these genetic lesions regulate biological and clinical behaviors of tumor cells, the resultant disrupted signaling pathways represent attractive targets for therapy. 24 The aim of this study was to elucidate whether PTEN status could alter cellular responses to IR using five different glioma cell lines. We found that PTEN-deficient U87, U373, and U252 glioma cells, which have an active AKT signaling pathway because of the absence of PTEN, entered senescence following IR exposure.…”

Section: Discussionmentioning

confidence: 99%

PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation

et al. 2010

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Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) has frequently been observed in human gliomas, conferring AKT activation and resistance to ionizing radiation (IR) and drug treatments. Recent reports have shown that PTEN loss or AKT activation induces premature senescence, but many details regarding this effect remain obscure. In this study, we tested whether the status of PTEN determined fate of the cell by examining PTEN-deficient U87, U251, and U373, and PTEN-proficient LN18 and LN428 glioma cells after exposure to IR. These cells exhibited different cellular responses, senescence or apoptosis, depending on the PTEN status. We further observed that PTEN-deficient U87 cells with high levels of both AKT activation and intracellular reactive oxygen species (ROS) underwent senescence, whereas PTEN-proficient LN18 cells entered apoptosis. ROS were indispensable for inducing senescence in PTEN-deficient cells, but not for apoptosis in PTENproficient cells. Furthermore, transfection with wild-type (wt) PTEN or AKT small interfering RNA induced a change from premature senescence to apoptosis and depletion of p53 or p21 prevented IR-induced premature senescence in U87 cells. Our data indicate that PTEN acts as a pivotal determinant of cell fate, regarding senescence and apoptosis in IR-exposed glioma cells. We conclude that premature senescence could have a compensatory role for apoptosis in the absence of the tumor suppressor PTEN through the AKT/ROS/p53/p21 signaling pathway.

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Identification of molecular subtypes of glioblastoma by gene expression profiling

Cited by 237 publications

References 59 publications

Cancerous stem cells can arise from pediatric brain tumors

Cancerous stem cells can arise from pediatric brain tumors

Identification of expressed genes characterizing long-term survival in malignant glioma patients

PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation

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