Neuralized1 causes apoptosis and downregulates Notch target genes in medulloblastoma (original) (raw)
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Notch1-Induced Brain Tumor Models the Sonic Hedgehog Subgroup of Human Medulloblastoma
Cancer Research, 2013
While activation of the Notch pathway is observed in many human cancers, it is unknown whether elevated Notch1 expression is sufficient to initiate tumorigenesis in most tissues. To test the oncogenic potential of Notch1 in solid tumors, we expressed an activated form of Notch1 (N1ICD) in the developing mouse brain. N1ICD;hGFAP-cre mice were viable but developed severe ataxia and seizures, and died by weaning age. Analysis of transgenic embryo brains revealed that N1ICD expression induced p53-dependent apoptosis. When apoptosis was blocked by genetic deletion of p53, 30% to 40% of N1ICD;GFAP-cre;p53 þ/À and N1ICD; GFAP-cre;p53 À/À mice developed spontaneous medulloblastomas. Interestingly, N1ICD-induced medulloblastomas most closely resembled the sonic hedgehog subgroup of human medulloblastoma at the molecular level. Surprisingly, N1ICD-induced tumors do not maintain high levels of the Notch pathway gene expression, except for Notch2, showing that initiating oncogenic events may not be decipherable by analyzing growing tumors in some cases. In summary, this study shows that Notch1 has an oncogenic potential in the brain when combined with other oncogenic hits, such as p53 loss, and provides a novel mouse model of medulloblastoma. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):
NOTCH ligands JAG1 and JAG2 as critical pro-survival factors in childhood medulloblastoma
Acta neuropathologica communications, 2014
Medulloblastoma (MB), the most common pediatric malignant brain cancer, typically arises as pathological result of deregulated developmental pathways, including the NOTCH signaling cascade. Unlike the evidence supporting a role for NOTCH receptors in MB development, the pathological functions of NOTCH ligands remain largely unexplored. By examining the expression in large cohorts of MB primary tumors, and in established in vitro MB models, this research study demonstrates that MB cells bear abnormal levels of distinct NOTCH ligands. We explored the potential association between NOTCH ligands and the clinical outcome of MB patients, and investigated the rational of inhibiting NOTCH signaling by targeting specific ligands to ultimately provide therapeutic benefits in MB. The research revealed a significant over-expression of ligand JAG1 in the vast majority of MBs, and proved that JAG1 mediates pro-proliferative signals via activation of NOTCH2 receptor and induction of HES1 expressio...
2010
Purpose: Notch signaling has been implicated to play a critical role in the tumorigenesis of neuroblastoma (NB) and can modulate calreticulin (CRT) expression that strongly correlates with tumor differentiation and favorable prognosis of NB. We thus sought to determine how Notch regulates CRT expression and affects NB tumor behavior. Experimental Design: The Notch-dependent regulation of CRT expression in cultured NB cells was analyzed by confocal microscopy and Western blotting. Notch1 protein expression in 85 NB tumors was examined by immunohistochemistry and correlated with the clinicopathologic/biological characters of NB patients. The progression of NB tumors in response to attenuated Notch signaling was examined by using a xenograft mouse model. Results: We showed that CRT is essential for the neuronal differentiation of NB cells elicited by inhibition of Notch signaling. This effect was mediated by a c-Jun-NH 2-kinase-dependent pathway. Furthermore, NB tumors with elevated Notch1 protein expression were strongly correlated with advanced tumor stages, MYCN amplification, an undifferentiated histology, as well as a low CRT expression level. Most importantly, the opposing effect between Notch1 and CRT could reciprocally affect the survival of NB patients. The administration of a γ-secretase inhibitor into a xenograft mouse model of NB significantly suppressed the tumor progression. Conclusions: Our findings provide the first evidence that a c-Jun-NH 2-kinase-CRT-dependent pathway is essential for the neuronal differentiation elicited by Notch signaling blockade and that Notch1 and CRT can synergistically predict the clinical outcomes of NB patients. The present data suggest that Notch signaling could be a therapeutic target for NB. Clin Cancer Res; 16(17); 4411-20. ©2010 AACR. Neuroblastoma (NB) is a childhood tumor derived from sympathoadrenal lineage of the neural crest progenitor cells. It is one of the most common pediatric cancers; more than 90% of NB patients are diagnosed as having the disease before the age of 10 years (1). Most children who are older than 1 year at the time of diagnosis exhibit advanced or metastatic disease, and their overall prognosis remains poor (2). The disease is remarkable for its broad spectrum of clinical manifestations. The clinical behaviors of NB can be categorized into three distinct patterns: (a) life-threatening progression, (b) maturation to ganglioneuroblastoma (GNB) or ganglioneuroma, and (c) spontaneous regression (3). The heterogeneity of NB tumors is largely due to the diverse biological characteristics that link to the
Child's Nervous System, 2014
Purpose Infant medulloblastoma (MB) is a malignant neuroepithelial embryonal tumor of the cerebellum, believed to derive from precursor granule cells with stem or progenitor cells appearance, and caused by a change in expression profile of genes related to the development. This work aims to study the expression profile of these genes in MB tumors, correlating with clinicopathological characteristics. Methods We quantified, by qPCR in 40 MB tumor samples, the expression of genes in HH (PTCH1, PTCH2, and GLI1), WNT (APC, CTNNB1, WIF1, and DKK2), and NOTCH pathways (NOTCH2 and HES1), which have a crucial role in development, and genes as MYCC, MYCN, and TERT, correlating this findings to patient's clinicopathological characteristics.
Notch Pathway Inhibition Depletes Stem-like Cells and Blocks Engraftment in Embryonal Brain Tumors
Cancer Research, 2006
The Notch signaling pathway is required in both nonneoplastic neural stem cells and embryonal brain tumors, such as medulloblastoma, which are derived from such cells. We investigated the effects of Notch pathway inhibition on medulloblastoma growth using pharmacologic inhibitors of γ-secretase. Notch blockade suppressed expression of the pathway target Hes1 and caused cell cycle exit, apoptosis, and differentiation in medulloblastoma cell lines. Interestingly, viable populations of better-differentiated cells continued to grow when Notch activation was inhibited but were unable to efficiently form soft-agar colonies or tumor xenografts, suggesting that a cell fraction required for tumor propagation had been depleted. It has recently been hypothesized that a small population of stem-like cells within brain tumors is required for the long-term propagation of neoplastic growth and that CD133 expression and Hoechst dye exclusion (side population) can be used to prospectively identify s...
Targeting Notch pathway induces growth inhibition and differentiation of neuroblastoma cells
Neuro-oncology, 2010
High-risk neuroblastoma is a severe pediatric tumor characterized by poor prognosis. Understanding the molecular mechanisms involved in tumor development and progression is strategic for the improvement of pharmacological therapies. Notch was recently proposed as a pharmacological target for the therapy of several cancers and is emerging as a new neuroblastoma-related molecular pathway. However, the precise role played by Notch in this cancer remains to be studied extensively. Here, we show that Notch activation by the Jagged1 ligand enhances the proliferation of neuroblastoma cells, and we propose the possible use of Notch-blocking γ-secretase inhibitors (GSIs) in neuroblastoma therapy. Two different GSIs, Compound E and DAPT, were tested alone or in combination with 13-cis retinoic acid (RA) on neuroblastoma cell lines. SH-SY5Y and IMR-32 cells were chosen as paradigms of lower and higher malignancy, respectively. Used alone, GSIs induced complete cell growth arrest, promoted neur...
A Tumor Suppressor Function for Notch Signaling in Forebrain Tumor Subtypes
Cancer Cell, 2015
Highlights d Notch signaling and p53 cooperate to reduce initiation of forebrain tumor subtypes d Anti-tumorigenic effects of Notch are linked to regulation of quiescence d Inhibiting Notch promotes a primitive neuroectodermal-like tumor fate d Low Notch activity correlates with poor prognosis for patients with glioma subtypes
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 2011
Medulloblastomas (MB) are highly aggressive primitive neuroectodermal tumors (PNET) usually located in the posterior fossa. Current treatment for MBs, which includes a combination of surgery, chemotherapy and radiation, remain challenging especially in younger patients. However, advances in the understanding of regulatory pathways in cerebellar development have elucidated possible areas of dysfunction involved in tumorigenesis. Multiple studies have demonstrated the importance of the sonic hedgehog, Wnt, and Notch pathways in MB pathogenesis at the molecular level. While staging and prognosis are often based on the Chang classification system, future algorithms will involve identifying molecular markers in order to allow for more specific risk stratifications of various MB subtypes and provide improved correlation with staging and prognosis. Future development of novel therapies that target the heterogeneity of MB and are tailored to the tumor's unique molecular profile may yie...
STEM CELLS, 2010
Medulloblastoma (MDB) is the most common brain malignancyof childhood. It is currently thought that MDB arises from aberrantly functioning stem cells in the cerebellum that fail to maintain proper control of self-renewal. Additionally, it has been reported that MDB cells display higher endogenous Notch signaling activation, known to promote the survival and proliferation of neoplastic neural stem cells and to inhibit their differentiation. While interaction between Hypoxia Inducible Factor-1α (HIF-1α) and Notch signalling is required to maintain normal neural precursors in an undifferentiated state, an interaction has not been identified in MDB. Here we investigate whether hypoxia, through HIF-1α stabilization, modulates Notch1 signaling in primary MDB-derived cells. Our results indicate that MDB-derived precursor cells require hypoxic conditions for in vitro expansion, whereas acute exposure to 20% oxygen induces tumor cell differentiation and death through inhibition of Notch signaling. Importantly, stimulating Notch1 activation with its ligand Dll4 under hypoxic conditions leads to expansion of MDB-derived CD133 + and nestin + precursors, suggesting a regulatory effect on stem cells. In contrast, MDB cells undergo neuronal differentiation when treated with γ-secretase inhibitor, which prevents Notch activation. These results suggest that hypoxia, by maintaining Notch1 in its active form, preserves MDB stem cell viability and expansion.
Inhibition of notch signaling blocks growth of glioblastoma cell lines and tumor neurospheres
Genes & cancer, 2010
Glioblastoma (GBM) is the most common malignant brain tumor that is characterized by high proliferative rate and invasiveness. Since dysregulation of Notch signaling is implicated in the pathogenesis of many human cancers, here we investigated the role of Notch signaling in GBM. We found that there is aberrant activation of Notch signaling in GBM cell lines and human GBM-derived neurospheres. Inhibition of Notch signaling via the expression of a dominant negative form of the Notch coactivator, mastermind-like 1 (DN-MAML1), or the treatment of a γ-secretase inhibitor, (GSI) MRK-003, resulted in a significant reduction in GBM cell growth in vitro and in vivo. Knockdown of individual Notch receptors revealed that Notch1 and Notch2 receptors differentially contributed to GBM cell growth, with Notch2 having a predominant role. Furthermore, blockade of Notch signaling inhibited the proliferation of human GBM-derived neurospheres in vitro and in vivo. Our overall data indicate that Notch s...