Astroglial c-Myc Overexpression Predisposes Mice to Primary Malignant Gliomas

Jensen, Niels Rosendal; Pedersen, Karen M.; Lihme, Frederikke; Rask, Lene; Nielsen, Jan; Rasmussen, Thomas; Mitchelmore, Cathy

doi:10.1074/jbc.m211195200

Cited by 46 publications

(29 citation statements)

References 47 publications

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“…In line with its involvement in a wide range of malignancies (51), there is circumstantial evidence that suggests a role of MYC and deregulation of MYC pathways in gliomagenesis (11,52). Multiple epigenetic and genetic mechanisms underlie the frequent overexpression, overactivation, and accumulation of MYC in human gliomas, including increased upstream growth factor receptor tyrosine kinase signaling (53), amplification and rearrangement of the MYC locus at 8q24.21 (11), inactivation of MYC pathway antagonists (54), and prolongation of MYC half-life (55).…”

Section: Discussionmentioning

confidence: 99%

Functional Network Analysis Reveals Extended Gliomagenesis Pathway Maps and Three Novel MYC-Interacting Genes in Human Gliomas

et al. 2005

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Gene expression profiling has proven useful in subclassification and outcome prognostication for human glial brain tumors. The analysis of biological significance of the hundreds or thousands of alterations in gene expression found in genomic profiling remains a major challenge. Moreover, it is increasingly evident that genes do not act as individual units but collaborate in overlapping networks, the deregulation of which is a hallmark of cancer. Thus, we have here applied refined network knowledge to the analysis of key functions and pathways associated with gliomagenesis in a set of 50 human gliomas of various histogenesis, using cDNA microarrays, inferential and descriptive statistics, and dynamic mapping of gene expression data into a functional annotation database. Highest-significance networks were assembled around the myc oncogene in gliomagenesis and around the integrin signaling pathway in the glioblastoma subtype, which is paradigmatic for its strong migratory and invasive behavior. Three novel MYC-interacting genes (UBE2C, EMP1, and FBXW7) with cancer-related functions were identified as network constituents differentially expressed in gliomas, as was CD151 as a new component of a network that mediates glioblastoma cell invasion. Complementary, unsupervised relevance network analysis showed a conserved selforganization of modules of interconnected genes with functions in cell cycle regulation in human gliomas. This approach has extended existing knowledge about the organizational pattern of gene expression in human gliomas and identified potential novel targets for future therapeutic development.

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Section: Discussionmentioning

confidence: 99%

Functional Network Analysis Reveals Extended Gliomagenesis Pathway Maps and Three Novel MYC-Interacting Genes in Human Gliomas

et al. 2005

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“…Early study showed that c-Myc expression levels correlate with tumor grade in gliomas (Herms et al, 1999). Conditional overexpression of c-Myc in mouse astroglia leads to brain tumors that resemble human malignant gliomas (Jensen et al, 2003). In addition, c-Myc prevents cell differentiation and promotes self-renewal of tumor cells derived from the pten/p53 double null mouse model (Zheng et al, 2008a).…”

Section: Specific Transcription Factors and The Maintenance Of Glioblmentioning

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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“…When injected into the cerebellum, c-myc cooperates with sonic hedgehog (shh) overexpression to generate medulloblastomas (29). However, a transgenic mouse with c-myc overexpressed in GFAP+ (astroglial) cells results in malignant glial tumors (30). If one accepts the theory (to be discussed below) that most malignant brain tumors arise in altered stem cells or progenitors, these studies underscore the heterogeneity of stem cell populations in the mammalian brain, which may have clinical implications for the treatment of brain tumors.…”

Section: Neural Stem Cellcharacterizationmentioning

confidence: 99%

Targeting Stem Cells in Brain Tumors

Lasky

Liau

2006

Technol Cancer Res Treat

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Stem cells are commonly defined as undifferentiated cells capable of self-renewing and giving rise to a large number of differentiated progeny. It is becoming increasingly apparent that there exist cancer stem cells (CSCs) from which the cells of any given malignancy arise. whereby only a few cells out of a population of cancer cells are able to initiate tumor formation. These CSCs, like their normal counterparts, are characterized by self-renewal and the ability to "differentiate" into all of the cell types in the original tumor. Current chemotherapeutic strategies involve using non-specific cytotoxic agents that target rapidly cycling cells. Although this may reduce disease burden in many cases. these therapies may miss the rare. self-renewing population that truly gives rise to the malignancy (the CSC). This review will focus on the recent discovery of stem cell-like cells In human brain tumors, putative "brain cancer stem cells," which exhibit the properties of self-renewal and the ability to recapitulate the original tumor heterogeneity. Dissecting the molecular mechanisms that underlie the ability of these cells to self-renew and maintain quiescence may aliow the development of novel therapeutic strategies that will allow for more efficacious and less toxic therapies for these devastating malignancies.

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Astroglial c-Myc Overexpression Predisposes Mice to Primary Malignant Gliomas

Cited by 46 publications

References 47 publications

Functional Network Analysis Reveals Extended Gliomagenesis Pathway Maps and Three Novel MYC-Interacting Genes in Human Gliomas

Functional Network Analysis Reveals Extended Gliomagenesis Pathway Maps and Three Novel MYC-Interacting Genes in Human Gliomas

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

Targeting Stem Cells in Brain Tumors

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