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notch signaling in glioma

Yi-Hong Zhou, Yuanjie Hu, Liping Yu, Chao Ke, Christopher Vo, Hao Hsu, Zhenzhi Li, Anne T Di Donato, Abhishek Chaturbedi, Ji Won Hwang, Eric R Siegel, Mark E Linskey
De-regulated EFEMP1 gene expression in solid tumors has been widely reported with conflicting roles. We dissected EFEMP1 to identify domains responsible for its cell context-dependent dual functions, with the goal being to construct an EFEMP1-derived tumor-suppressor protein (ETSP) that lacked tumor-promoting function. Exon/intron boundaries of EFEMP1 were used as boundaries of functional modules in constructing EFEMP1 variants, with removal of various module(s), and/or mutating an amino acid residue to convert a weak integrin binding-site into a strong one...
2016: Oncoscience
Sanaz Yahyanejad, Henry King, Venus Sosa Iglesias, Patrick V Granton, Lydie M O Barbeau, Stefan J van Hoof, Arjan J Groot, Roger Habets, Jos Prickaerts, Anthony J Chalmers, Daniëlle B P Eekers, Jan Theys, Susan C Short, Frank Verhaegen, Marc Vooijs
Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. The current standard of care includes surgery followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). Treatment often fails due to the radiation resistance and intrinsic or acquired TMZ resistance of a small percentage of cells with stem cell-like behavior (CSC). The NOTCH signaling pathway is expressed and active in human glioblastoma and NOTCH inhibitors attenuate tumor growth in vivo in xenograft models. Here we show using an image guided micro-CT and precision radiotherapy platform that a combination of the clinically approved NOTCH/γ-secretase inhibitor (GSI) RO4929097 with standard of care (TMZ + RT) reduces tumor growth and prolongs survival compared to dual combinations...
May 10, 2016: Oncotarget
Ran Xu, Fumiko Shimizu, Koos Hovinga, Kathryn Beal, Sasan Karimi, Leif A Droms, Kyung K Peck, Philip Gutin, J Bryan Iorgulescu, Thomas J Kaley, Lisa M DeAngelis, Elena Pentsova, Craig Nolan, Christian Grommes, Timothy A Chan, Dylan Bobrow, Adilia Hormigo, Justin R Cross, Nian Wu, Naoko Takebe, Katherine Panageas, S Percy Ivy, Jeffrey G Supko, Viviane Tabar, Antonio M P Omuro
BACKGROUND: High grade gliomas are associated with a dismal prognosis. Notch inhibition via the gamma-secretase inhibitor RO2929097 has emerged as a potential therapeutic option based on modulation of the cancer-initiating cell (CIS) population and a presumed anti-angiogenic role. METHODS: In this phase 0/I trial, 21 patients with newly-diagnosed glioblastoma or anaplastic astrocytoma received RO4929097 combined with temozolomide and radiotherapy. In addition to establishing the maximum tolerated dose, the study design enabled exploratory studies evaluating tumor and brain drug penetration and neuro-imaging parameters...
May 6, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Elena Codrici, Ana-Maria Enciu, Ionela-Daniela Popescu, Simona Mihai, Cristiana Tanase
Malignant gliomas are aggressive brain tumors with limited therapeutic options, possibly because of highly tumorigenic subpopulations of glioma stem cells. These cells require specific microenvironments to maintain their "stemness," described as perivascular and hypoxic niches. Each of those niches induces particular signatures in glioma stem cells (e.g., activation of Notch signaling, secretion of VEGF, bFGF, SDF1 for the vascular niche, activation of HIF2α, and metabolic reprogramming for hypoxic niche)...
2016: Stem Cells International
Wen Cheng, Chuanbao Zhang, Xiufang Ren, Yang Jiang, Sheng Han, Yang Liu, Jinquan Cai, Mingyang Li, Kuanyu Wang, Yanwei Liu, Huimin Hu, Qingbin Li, Pei Yang, Zhaoshi Bao, Anhua Wu
OBJECTIVE Glioblastoma (GBM) is the most common and lethal type of malignant glioma. The Cancer Genome Atlas divides the gene expression-based classification of GBM into classical, mesenchymal, neural, and proneural subtypes, which is important for understanding GBM etiology and for designing effective personalized therapy. Signal transducer and activator of transcription 3 (STAT3), a critical transcriptional activator in tumorigenesis, is persistently phosphorylated and associated with an unfavorable prognosis in GBM...
March 11, 2016: Journal of Neurosurgery
László Hackler, Béla Ózsvári, Márió Gyuris, Péter Sipos, Gabriella Fábián, Eszter Molnár, Annamária Marton, Nóra Faragó, József Mihály, Lajos István Nagy, Tibor Szénási, Andrea Diron, Árpád Párducz, Iván Kanizsai, László G Puskás
C-150 a Mannich-type curcumin derivative, exhibited pronounced cytotoxic effects against eight glioma cell lines at micromolar concentrations. Inhibition of cell proliferation by C-150 was mediated by affecting multiple targets as confirmed at transcription and protein level. C-150 effectively reduced the transcription activation of NFkB, inhibited PKC-alpha which are constitutively over-expressed in glioblastoma. The effects of C-150 on the Akt/ Notch signaling were also demonstrated in a Drosophila tumorigenesis model...
2016: PloS One
Subhas Mukherjee, Carol Tucker-Burden, Changming Zhang, Kenneth Moberg, Renee Read, Costas Hadjipanayis, Daniel J Brat
Cancer stem cells exert enormous influence on neoplastic behavior, in part by governing asymmetric cell division and the balance between self-renewal and multipotent differentiation. Growth is favored by deregulated stem cell division, which enhances the self-renewing population and diminishes the differentiation program. Mutation of a single gene in Drosophila, Brain Tumor (Brat), leads to disrupted asymmetric cell division resulting in dramatic neoplastic proliferation of neuroblasts and massive larval brain overgrowth...
April 15, 2016: Cancer Research
Shang-Hang Shen, Ning Yu, Xi-Yao Liu, Guo-Wei Tan, Zhan-Xiang Wang
Glioma as an aggressive type tumor is rapidly growing and has become one of the leading cause of cancer-related death worldwide. γ-Glutamylcyclotransferase (GGCT) has been shown as a diagnostic marker in various cancers. To reveal whether there is a correlation between GGCT and human glioma, GGCT expression in human glioma tissues and cell lines was first determined. We found that GGCT expression was up-regulated in human glioma tissues and cell lines. Further, we demonstrate that GGCT knockdown inhibits glioma cell T98G and U251 proliferation and colony formation, whereas GGCT overexpression leads to oppose effects...
March 18, 2016: Biochemical and Biophysical Research Communications
Jianpeng Wang, Zhiyong Yan, Xia Liu, Shusheng Che, Chao Wang, Weicheng Yao
Glioma is among the most common human malignancies with poor prognosis. Glioma stem cells (GSCs) are the culprit of glioma, suggesting that GSCs are potential therapeutic targets. Notch signaling pathway plays a pivotal role for the function of GSCs, implying that suppression of Notch pathway may be an effective strategy for GSC-targeting therapy. In this study, we found that alpinetin, a natural compound, can suppress the proliferation and invasiveness of GSCs and induce apoptosis in GSCs. Immunoblot analysis and luciferase assay revealed that Notch signaling was suppressed by alpinetin...
July 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
(no author information available yet)
Loss of Notch signaling enhances the growth of PDGF-driven Trp53-null forebrain tumors.
February 2016: Cancer Discovery
Yawei Wang, Hongwei Hou, Ming Li, Yang Yang, Lan Sun
Eupatilin, one of the major flavonoids in Artemisia asiatica Nakai (Asteraceae), has been reported to possess antitumor properties. However, thus far there have been no reports regarding the effects of eupatilin on glioma. Therefore, in the current study the effects of eupatilin on glioma and the underlying molecular mechanism were explored. The effect of eupatilin on cell viability was detected by the MTT assay. Cell invasion and migration were performed with Transwell assays and cell apoptosis was determined by flow cytometric analysis...
February 2016: Molecular Medicine Reports
Claudio Giachino, Jean-Louis Boulay, Robert Ivanek, Alvaro Alvarado, Cristobal Tostado, Sebastian Lugert, Jan Tchorz, Mustafa Coban, Luigi Mariani, Bernhard Bettler, Justin Lathia, Stephan Frank, Stefan Pfister, Marcel Kool, Verdon Taylor
In the brain, Notch signaling maintains normal neural stem cells, but also brain cancer stem cells, indicating an oncogenic role. Here, we identify an unexpected tumor suppressor function for Notch in forebrain tumor subtypes. Genetic inactivation of RBP-Jκ, a key Notch mediator, or Notch1 and Notch2 receptors accelerates PDGF-driven glioma growth in mice. Conversely, genetic activation of the Notch pathway reduces glioma growth and increases survival. In humans, high Notch activity strongly correlates with distinct glioma subtypes, increased patient survival, and lower tumor grade...
December 14, 2015: Cancer Cell
Rajeswari Narayanappa, Pritilata Rout, Madhuri G S Aithal, Ashis Kumar Chand
Glioblastoma is the most common malignant brain tumor accounting for more than 54 % of all gliomas. Despite aggressive treatments, median survival remains less than 1 year. This might be due to the unavailability of effective molecular diagnostic markers and targeted therapy. Thus, it is essential to discover molecular mechanisms underlying disease by identifying dysregulated pathways involved in tumorigenesis. Notch signaling is one such pathway which plays an important role in determining cell fates. Since it is found to play a critical role in many cancers, we investigated the role of Notch genes in glioblastoma with an aim to identify biomarkers that can improve diagnosis...
May 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Manabu Natsumeda, Kosuke Maitani, Yang Liu, Hiroaki Miyahara, Harpreet Kaur, Qian Chu, Hongyan Zhang, Ulf Kahlert, Charles G Eberhart
Glioblastomas are highly aggressive tumors that contain treatment resistant stem-like cells. Therapies targeting developmental pathways such as Notch eliminate many neoplastic glioma cells, including those with stem cell features, but their efficacy can be limited by various mechanisms. One potential avenue for chemotherapeutic resistance is the induction of autophagy, but little is known how it might modulate the response to Notch inhibitors. We used the γ-secretase inhibitor (GSI) MRK003 to block Notch pathway activity in glioblastoma neurospheres and assessed effects on autophagy...
November 27, 2015: Brain Pathology
C Zhou, W J Teng, J Zhuang, H L Liu, S F Tang, X J Cao, B N Qin, C C Wang, C G Sun
Glioma is the most aggressive type of brain tumor. Great progress has been achieved in glioma treatment, but the protein-protein interaction networks underlining glioma are poorly understood. We identified the protein-protein interaction network for glioma based on gene expression and predicted biological pathways underlying the molecular complexes in the network. Genes involved in glioma were selected from the Online Mendelian Inheritance in Man (OMIM) database. A literature search was performed using the Agilent Literature Search plugin, and Cytoscape was used to establish a protein-protein interaction network...
2015: Genetics and Molecular Research: GMR
Yuntian Shen, Hua Chen, Jinshi Zhang, Yanming Chen, Mengyao Wang, Jiawei Ma, Lei Hong, Ning Liu, Qiuhong Fan, Xueguan Lu, Ye Tian, Aidong Wang, Jun Dong, Qing Lan, Qiang Huang
BACKGROUND: Host malignant stromal cells induced by glioma stem/progenitor cells were revealed to be more radiation-resistant than the glioma stem/progenitor cells themselves after malignant transformation in nude mice. However, the mechanism underlying this phenomenon remains unclear. METHODS: Malignant stromal cells induced by glioma stem/progenitor cell 2 (GSC-induced host brain tumor cells, ihBTC2) were isolated and identified from the double color-coded orthotopic glioma nude mouse model...
2015: PloS One
Ulf D Kahlert, Menglin Cheng, Katharina Koch, Luigi Marchionni, Xing Fan, Eric H Raabe, Jarek Maciaczyk, Kristine Glunde, Charles G Eberhart
Notch signaling can promote tumorigenesis in the nervous system and plays important roles in stem-like cancer cells. However, little is known about how Notch inhibition might alter tumor metabolism, particularly in lesions arising in the brain. The gamma-secretase inhibitor MRK003 was used to treat glioblastoma neurospheres, and they were subdivided into sensitive and insensitive groups in terms of canonical Notch target response. Global metabolomes were then examined using proton magnetic resonance spectroscopy, and changes in intracellular concentration of various metabolites identified which correlate with Notch inhibition...
March 1, 2016: International Journal of Cancer. Journal International du Cancer
Weijie Min, Yanan Li, Yihui Zhang, Dongwei Dai, Yiqun Cao, Zhijian Yue, Jianmin Liu
OBJECTIVE: To investigate the drug targets related to Notch signaling pathway for glioma treatment. METHODS: Gene expression profiles GSE44561, GSE48079 and GSE22772GSE48079GSE22772 of glioma cells samples with activated Notch signaling pathway and control samples were downloaded from Gene Expression Omnibus database to screen the differentially expressed genes (DEGs) using limma package. GO (Gene Oncology) function and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analyses were conducted using DAVID tools to predict the underlying function of these DEGs...
November 15, 2015: Gene
Baohui Liu, Xi Lin, Xiangsheng Yang, Huimin Dong, Xiaojing Yue, Kelsey C Andrade, Zhentao Guo, Jian Yang, Liquan Wu, Xiaonan Zhu, Shenqi Zhang, Daofeng Tian, Junmin Wang, Qiang Cai, Qizuan Chen, Shanping Mao, Qianxue Chen, Jiang Chang
Activation of Notch signaling contributes to glioblastoma multiform (GBM) tumorigenesis. However, the molecular mechanism that promotes the Notch signaling augmentation during GBM genesis remains largely unknown. Identification of new factors that regulate Notch signaling is critical for tumor treatment. The expression levels of RND3 and its clinical implication were analyzed in GBM patients. Identification of RND3 as a novel factor in GBM genesis was demonstrated in vitro by cell experiments and in vivo by a GBM xenograft model...
September 2015: Cancer Medicine
Junchao Yao, Kebin Zheng, Chunhui Li, Haipeng Liu, Xiaosong Shan
Glioma is the most common malignant tumors in adult brains, and Notch signaling pathway plays an important role in cell differentiation. The aim of the present study is to investigate the role of Notch1 in the progression of glioma cancers and clarify the mechanism of Notch1 silencing on inhibiting the proliferation of glioma cancer cells. First, endogenous Notch1 expression was interfered with a lentiviral vector of Notch1 shRNA. RT-PCR and western blotting were used for detecting the expression of Notch1 mRNA and protein, respectively...
June 2015: Medical Oncology
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