A role for the transcription factor HEY1 in glioblastoma

Hulleman, Esther; Quarto, Micaela; Vernell, Richard; Masserdotti, Giacomo; Colli, Elena; Kros, Johan M.; Levi, Daniel S.; Gaetani, Paolo; Tunici, Patrizia; Finocchiaro, Gaetano; Baena, Riccardo Rodriguez y; Capra, Maria; Helin, Kristian

doi:10.1111/j.1582-4934.2008.00307.x

Cited by 72 publications

(65 citation statements)

References 56 publications

(37 reference statements)

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“…BMP4 also induced the expression of Tnc, Sparc and Hey1 (Fig. 3D-F), genes known to be highly expressed in human gliomas (Hirata et al, 2009;Hulleman et al, 2009;Rempel et al, 1998). Interestingly, Tnc, which is known to strongly promote glioma invasion (Hirata et al, 2009), was upregulated over 100-fold after 18 to 72 h of BMP4 exposure in NSCs.…”

Section: Resultsmentioning

confidence: 99%

“…Increasing evidence supports the hypothesis that gliomas derive from a cancer stem cell (Das et al, 2008). Genes encoding the following proteins are expressed in gliomas: Tenascin C (Hirata et al, 2009;Mariani et al, 2001), Hey1 (Hulleman et al, 2009), SPARC (Rempel et al, 1998), Snail1 and Snail2 (Han et al, 2011;Yang et al, 2010), FGFR1 (Morrison et al, 1994), BMPR1a (Yamada et al, 1996), EGFR (Hegi et al, 2012), PDGFRa (Andrae et al, 2008;Nazarenko et al, 2012), Sox2 (Annovazzi et al, 2011), Podoplanin (Mishima et al, 2006), Gli3 (Shahi et al, 2008) and p75NGFR (Johnston et al, 2007). All these glioma-related genes were also expressed in normal NSCs during their transformation into invasive stem cells in the present study, including the constitutively expressed Fgfr1 and Bmpr1a genes (Panchision et al, 2001;Vescovi et al, 1993).…”

Section: Neural Stem Cell Invasion As a Model For Glioma Invasionmentioning

confidence: 99%

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Non-invasive neural stem cells become invasive in vitro by combinatorial FGF2 and BMP4 signaling

Sailer

Gerber²,

Tostado³

et al. 2013

Journal of Cell Science

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SummaryNeural stem cells (NSCs) typically show efficient self-renewal and selective differentiation. Their invasion potential, however, is not well studied. In this study, Sox2-positive NSCs from the E14.5 rat cortex were found to be non-invasive and showed only limited migration in vitro. By contrast, FGF2-expanded NSCs showed a strong migratory and invasive phenotype in response to the combination of FGF2 and BMP4. Invasive NSCs expressed Podoplanin (PDPN) and p75NGFR (Ngfr) at the plasma membrane after exposure to FGF2 and BMP4. FGF2 and BMP4 together upregulated the expression of Msx1, Snail1, Snail2, Ngfr, which are all found in neural crest (NC) cells during or after epithelial-mesenchymal transition (EMT), but not in forebrain stem cells. Invasive cells downregulated the expression of Olig2, Sox10, Egfr, Pdgfra, Gsh1/Gsx1 and Gsh2/Gsx2. Migrating and invasive NSCs had elevated expression of mRNA encoding Pax6, Tenascin C (TNC), PDPN, Hey1, SPARC, p75NGFR and Gli3. On the basis of the strongest upregulation in invasioninduced NSCs, we defined a group of five key invasion-related genes: Ngfr, Sparc, Snail1, Pdpn and Tnc. These genes were coexpressed and upregulated in seven samples of glioblastoma multiforme (GBM) compared with normal human brain controls. Induction of invasion and migration led to low expression of differentiation markers and repressed proliferation in NSCs. Our results indicate that normal forebrain stem cells have the inherent ability to adopt a glioma-like invasiveness. The results provide a novel in vitro system to study stem cell invasion and a novel glioma invasion model: tumoral abuse of the developmental dorsoventral identity regulation.

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Section: Resultsmentioning

confidence: 99%

Section: Neural Stem Cell Invasion As a Model For Glioma Invasionmentioning

confidence: 99%

Non-invasive neural stem cells become invasive in vitro by combinatorial FGF2 and BMP4 signaling

Sailer

Gerber²,

Tostado³

et al. 2013

Journal of Cell Science

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“…Notch signaling is a critical developmental pathway that controls neural stem cell fate and suppresses radial glia differentiation (Ehebauer et al, 2006). The notch signaling pathway is constitutively active in many high-grade gliomas and has been associated with progression of gliomas (Hulleman et al, 2009;Jeon et al, 2008;Shih and Holland, 2006;Zhang et al, 2008). Notch signaling from endothelial cells to hematopoetic stem cells (HSC) via expression of Notch ligands has been shown to drive the self-renewal characteristics and in vivo repopulation of long-term HSCs that lie adjacent to the vasculature (Butler et al, 2010).…”

Section: Brain Tumor-cell Endothelial-cell Signalingmentioning

confidence: 99%

The brain tumor microenvironment

Charles

Holland

Gilbertson

et al. 2011

Glia

693

327

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High-grade brain tumors are heterogeneous with respect to the composition of bona fide tumor cells and with respect to a range of intermingling parenchymal cells. Glioblastomas harbor multiple cell types, some with increased tumorigenicity and stem cell-like capacity. The stem-like cells may be the cells of origin for tumor relapse. However, the tumor-associated parenchymal cells such as vascular cells, microglia, peripheral immune cells, and neural precursor cells also play a vital role in controlling the course of pathology. In this review, we describe the multiple interactions of bulk glioma cells and glioma stem cells with parenchymal cell populations and highlight the pathological impact as well as signaling pathways known for these types of cell-cell communication. The tumor-vasculature not only nourishes glioblastomas, but also provides a specialized niche for these stem-like cells. In addition, microglial cells, which can contribute up to 30% of a brain tumor mass, play a role in glioblastoma cell invasion. Moreover, non-neoplastic astrocytes can be converted into a reactive phenotype by the glioma microenvironment and can then secrete a number of factors which influences tumor biology. The young brain may have the capacity to inhibit gliomagenesis by the endogenous neural precursor cells, which secrete tumor suppressive factors. The factors, pathways, and interactions described in this review provide a new prospective on the cell biology of primary brain tumors, which may ultimately generate new treatment modalities. However, our picture of the multiple interactions between parenchymal and tumor cells is still incomplete. V

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“…Increased activation of the NOTCH signaling has been reported in several tumor types (18). Recent studies showed that this pathway induces the survival and/or proliferation in GBM and glioma cells (19)(20)(21)(22), and the expression of stem cell markers in glioma cells (21,22). According to these findings, the inhibition of this pathway leads to depletion of stem-like cells and to the block of the engraftment in embryonal brain tumors (23).…”

Section: Introductionmentioning

confidence: 96%

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Monticone

Biollo

Fabiano

et al. 2009

Molecular Cancer Research

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γ-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. Here, we investigated two of such inhibitors, the Benzyloxicarbonyl-Leu-Leu-Nle-CHO (LLNle) and the N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to assess whether they were effective in killing human glioblastoma tumor-initiating cells (GBM TIC) in vitro. We found that only LLNle was able at the micromolar range to induce the death of GBM TICs by apoptosis. To determine the cellular processes that were activated in GBM TICs by treatment with LLNle, we analyzed the amount of the NOTCH intracellular domain and the gene expression profiles following treatment with LLNle, DAPT, and DMSO (vehicle). We found that LLNIe, beside inhibiting the generation of the NOTCH intracellular domain, also induces proteasome inhibition, proteolytic stress, and mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activating genes acting as mitotic inhibitors. DNA content flow cytometry clearly showed that cells treated with LLNle undergo arrest in the G 2 -M phases of the cell cycle. We also found that DAPT and L-685,458, another selective Notch inhibitor, were unable to kill GBM TICs, whereas lactacystin, a pure proteasome inhibitor, was effective although at a much less extent than LLNle. These data show that LLNle kills GBM TIC cells by inhibiting the proteasome activity. We suggest that LLNle, being able to target two relevant pathways for GBM TIC survival, may have a potential therapeutic value that deserves further investigation in animal models.

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A role for the transcription factor HEY1 in glioblastoma

Cited by 72 publications

References 56 publications

Non-invasive neural stem cells become invasive in vitro by combinatorial FGF2 and BMP4 signaling

Non-invasive neural stem cells become invasive in vitro by combinatorial FGF2 and BMP4 signaling

The brain tumor microenvironment

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

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