Genetic profile, PTEN mutation and therapeutic role of PTEN in glioblastomas

Fan, Xing; Aalto, Yan; Sanko, Stephen; Knuutila, Sakari; Klatzmann, David; Castresana, Javier S.

doi:10.3892/ijo.21.5.1141

Cited by 29 publications

(34 citation statements)

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“…Loss of chromosome 13q has been reported to occur frequently in GBMs (12,25,26). Homozygous deletions, LOH, and mutations in RB1 gene, which is located at chromosome 13q14.2, 23 Mb centromeric to DACH1, are found in human cancers including GBMs (13,26).…”

Section: Discussionmentioning

confidence: 99%

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Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells

Watanabe

Ogiwara

Ehata³

et al. 2011

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

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Loss or reduction in function of tumor suppressor genes contributes to tumorigenesis. Here, by allelic DNA copy number analysis using single-nucleotide polymorphism genotyping array and mass spectrometry, we report homozygous deletion in glioblastoma multiformes at chromosome 13q21, where DACH1 gene is located. We found decreased cell proliferation of a series of glioma cell lines by forced expression of DACH1. We then generated U87TR-Da glioma cells, where DACH1 expression could be activated by exposure of the cells to doxycycline. Both ex vivo cellular proliferation and in vivo growth of s.c. transplanted tumors in mice are reduced in U87TR-Da cells with DACH1 expression (U87-DACH1-high), compared with DACH1-nonexpressing U87TR-Da cells (U87-DACH1-low). U87-DACH1-low cells form spheroids with CD133 and Nestin expression in serum-free medium but U87-DACH1-high cells do not. Compared with spheroid-forming U87-DACH1-low cells, adherent U87-DACH1-high cells display lower tumorigenicity, indicating DACH1 decreases the number of tumor-initiating cells. Gene expression analysis and chromatin immunoprecipitation assay reveal that fibroblast growth factor 2 (FGF2/bFGF) is transcriptionally repressed by DACH1, especially in cells cultured in serum-free medium. Exogenous bFGF rescues spheroid-forming activity and tumorigenicity of the U87-DACH1-high cells, suggesting that loss of DACH1 increases the number of tumor-initiating cells through transcriptional activation of bFGF. These results illustrate that DACH1 is a distinctive tumor suppressor, which does not only suppress growth of tumor cells but also regulates bFGF-mediated tumor-initiating activity of glioma cells.neural differentiation | gliomagenesis

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Section: Discussionmentioning

confidence: 99%

“…The chromosomal losses were found at least in 11 samples (GBM case 1,3,4,5,18,19,24,25,26,27, and 28; 39.3%), and three of them (GBM case 4, 5, and 27; 10.7% of GBMs) displayed homozygous deletion (Fig. 1B and Fig.…”

Section: Dach1 Gene On Chromosome 13q21 Is Homozygously Deleted Inmentioning

confidence: 99%

Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells

Watanabe

Ogiwara

Ehata³

et al. 2011

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

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“…NF-B is constitutively activated in glioma and many other cancer cells, in which it promotes survival and metastatic potential of these cells as well as tumorigenesis (28,52). One of the key pathways that controls NF-B activity in gliomas is the phosphatidylinositol 3-kinase (PI3K) pathway (16,39), which is a converging point of EGFR-and PTEN-dependent signal transduction. Activation of receptor tyrosine kinase EGFR leads to recruitment and activation of PI-3 kinase, which phosphorylates phosphoinositol lipids to generate phosphatidylinositol-3-phosphates.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

Mei

Bachoo²,

Zhang³

2011

Molecular and Cellular Biology

159

131

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Dysregulated epidermal growth factor receptor (EGFR) signaling through either genomic amplification or dominant-active mutation (EGFR vIII ), in combination with the dual inactivation of INK4A/ARF and PTEN, is a leading cause of gliomagenesis. Our global expression analysis for microRNAs revealed that EGFR activation induces miR-146a expression, which is further potentiated by inactivation of PTEN. Unexpectedly, overexpression of miR-146a attenuates the proliferation, migration, and tumorigenic potential of Ink4a/Arf ؊/؊ Pten ؊/؊ Egfr vIII murine astrocytes. Its ectopic expression also inhibits the glioma development of a human glioblastoma cell line in an orthotopic xenograft model. Such an inhibitory function of miR-146a on gliomas is largely through downregulation of Notch1, which plays a key role in neural stem cell maintenance and is a direct target of miR-146a. Accordingly, miR-146a modulates neural stem cell proliferation and differentiation and reduces the formation and migration of glioma stem-like cells. Conversely, knockdown of miR-146a by microRNA sponge upregulates Notch1 and promotes tumorigenesis of malignant astrocytes. These findings indicate that, in response to oncogenic cues, miR-146a is induced as a negative-feedback mechanism to restrict tumor growth by repressing Notch1. Our results provide novel insights into the signaling pathways that link neural stem cells to gliomagenesis and may lead to new strategies for treating brain tumors.Gliomas are the most frequently observed brain tumors, with glioblastoma multiforme (GBM) being the most common and aggressive form in adults (35). Despite major therapeutic improvements made by combining neurosurgery, chemotherapy, and radiotherapy, the prognosis and survival rate for patients with GBM is still extremely poor (7). The deadly nature of GBM originates from explosive growth and invasive behavior, which are fueled by dysregulation of multiple signaling pathways. Epidermal growth factor receptor (EGFR) activation, in cooperation with loss of tumor suppressor functions, such as mutations in Ink4a/Arf and Pten genes, constitutes a lesion signature for GBM (4). Such dysregulated genetic pathways are sufficient to transform neural stem cells (NSCs) or astrocytes into cancer stem-like cells. This gives rise to highgrade malignant gliomas with a pathological phenotype resembling human GBM (5, 59). However, the downstream events underlying these genetic dysregulations in gliomagenic cells have not been fully elucidated.MicroRNAs are 20-to 22-nucleotide noncoding RNA molecules that have emerged as key players in controlling NSC self-renewal and differentiation (11,57). Aberrant expression of miRNAs, such as miR-21, miR-124, and miR-137, is linked to glioma formation (49). miR-199b-5p and miR-34a impair cancer stem-like cells through the negative regulation of several components of the Notch pathway in brain tumors (18,21). The Notch pathway is an evolutionarily conserved signaling pathway that plays an important role in neurogenesis (3, 10, 23). Upon bindi...

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“…Recent studies demonstrated that inactivation of PTEN (a well-known tumor suppressor) promotes undifferentiated state of GSCs (Zheng et al, 2008a, b), suggesting PTEN may promote GSC differentiation. PTEN is a phosphatase with dual-specificity for both protein and lipid and is often mutated in GBMs (Fan et al, 2002;Zheng et al, 2008a). It has been well known that PTEN deletion or functional loss is linked to progression and/or immunoresistance of malignant gliomas (Parsa et al, 2007).…”

Section: Differentiation Of 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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Genetic profile, PTEN mutation and therapeutic role of PTEN in glioblastomas

Cited by 29 publications

References 0 publications

Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells

Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells

MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

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