| 1. |
- Haag, Daniel, et al.
(author)
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Nos2 inactivation promotes the development of medulloblastoma in Ptch1(+/-) mice by deregulation of Gap43-dependent granule cell precursor migration.
- 2012
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In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:3
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Journal article (peer-reviewed)abstract
- Medulloblastoma is the most common malignant brain tumor in children. A subset of medulloblastoma originates from granule cell precursors (GCPs) of the developing cerebellum and demonstrates aberrant hedgehog signaling, typically due to inactivating mutations in the receptor PTCH1, a pathomechanism recapitulated in Ptch1(+/-) mice. As nitric oxide may regulate GCP proliferation and differentiation, we crossed Ptch1(+/-) mice with mice lacking inducible nitric oxide synthase (Nos2) to investigate a possible influence on tumorigenesis. We observed a two-fold higher medulloblastoma rate in Ptch1(+/-) Nos2(-/-) mice compared to Ptch1(+/-) Nos2(+/+) mice. To identify the molecular mechanisms underlying this finding, we performed gene expression profiling of medulloblastomas from both genotypes, as well as normal cerebellar tissue samples of different developmental stages and genotypes. Downregulation of hedgehog target genes was observed in postnatal cerebellum from Ptch1(+/+) Nos2(-/-) mice but not from Ptch1(+/-) Nos2(-/-) mice. The most consistent effect of Nos2 deficiency was downregulation of growth-associated protein 43 (Gap43). Functional studies in neuronal progenitor cells demonstrated nitric oxide dependence of Gap43 expression and impaired migration upon Gap43 knock-down. Both effects were confirmed in situ by immunofluorescence analyses on tissue sections of the developing cerebellum. Finally, the number of proliferating GCPs at the cerebellar periphery was decreased in Ptch1(+/+) Nos2(-/-) mice but increased in Ptch1(+/-) Nos2(-/) (-) mice relative to Ptch1(+/-) Nos2(+/+) mice. Taken together, these results indicate that Nos2 deficiency promotes medulloblastoma development in Ptch1(+/-) mice through retention of proliferating GCPs in the external granular layer due to reduced Gap43 expression. This study illustrates a new role of nitric oxide signaling in cerebellar development and demonstrates that the localization of pre-neoplastic cells during morphogenesis is crucial for their malignant progression.
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| 2. |
- Barbus, Sebastian, et al.
(author)
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Differential retinoic acid signaling in tumors of long- and short-term glioblastoma survivors.
- 2011
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 103:7
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Journal article (peer-reviewed)abstract
- Although the prognosis of most glioblastoma patients is poor, 3%-5% patients show long-term survival of 36 months or longer after diagnosis. To study the differences in activation of biochemical pathways, we performed mRNA and protein expression analyses of primary glioblastoma tissues from 11 long-term survivors (LTS; overall survival ≥ 36 months) and 12 short-term survivors (STS; overall survival ≤ 6 months). The mRNA expression ratio of the retinoic acid transporters fatty acid-binding protein 5 (FABP5) and cellular retinoic acid-binding protein 2 (CRABP2), which regulate the differential delivery of retinoic acid to either antioncogenic retinoic acid receptors or prooncogenic nuclear receptor peroxisome proliferator-activated receptor delta, was statistically significantly higher in the tumor tissues of STS than those of LTS (median ratio in STS tumors = 3.64, 10th-90th percentile = 1.43-4.54 vs median ratio in LTS tumors = 1.42, 10th-90th percentile = -0.98 to 2.59; P < .001). High FABP5 protein expression in STS tumors was associated with highly proliferating tumor cells and activation of 3-phosphoinositide-dependent protein kinase-1 and v-akt murine thymoma viral oncogene homolog. The data suggest that retinoic acid signaling activates different targets in glioblastomas from LTS and STS. All statistical tests were two-sided.
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| 3. |
- Hudson, Thomas J., et al.
(author)
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International network of cancer genome projects
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Journal article (peer-reviewed)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 4. |
- Kiesel, Barbara, et al.
(author)
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PERIOPERATIVE IMAGING OF BRAIN METASTASES : A EUROPEAN ASSOCIATION OF NEURO-ONCOLOGY (EANO) YOUNGSTERS SURVEY
- 2018
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In: Neuro-Oncology. - : OXFORD UNIV PRESS INC. - 1522-8517 .- 1523-5866. ; 20, s. 59-59
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Journal article (other academic/artistic)abstract
- BACKGROUNDNeurosurgical resection is an important treatment option in the multimodal therapy of brain metastases (BM). Perioperative imaging is established in primary brain tumors to assess the extent of resection. However, structured guidelines on the use of perioperative imaging for BM patients are so far missing.METHODSThe European Association of Neuro-Oncology (EANO) Youngsters committee designed a comprehensive questionnaire on the use of perioperative imaging. The survey was distributed to physicians with neuro-oncologic focus via the EANO and the European Association of Neurosurgical Societies (EANS) network.RESULTS120 physicians from non-European countries and European countries responded to the survey. 76/120 neurosurgeons, 18/120 radiation oncologists and 17/120 neurologists participated. 89/120 participants worked at academic hospitals and 39/40 participants worked in high patient volume centers as defined by >50 BM cases per year. Local standard operating procedures for perioperative imaging were applied by 94/120 physicians. The preferred preoperative imaging method represented MRI for 112/120 (93.3%) participants. Postsurgical imaging was routinely performed by 106/120 physicians. 77/120 participants indicated MRI as the preferred postoperative imaging method, however, only 71/120 performed postoperative MRI imaging within 72 hours after resection. No correlation of postsurgical MRI and localization at an academic hospital (58/79 [73.4%] vs. 19/27 [70.4%], p>0.05) or patient volume (49/71 [69%] vs 25/40 [62.5%], p>0.05) was evident. The most frequently indicated reason for postsurgical imaging was the assessment of extent of resection as participants indicated to adjust the radiotherapy plan or even considered re-surgery to achieve complete resection. CONCLUSIONS: This EANO survey indicates that preoperative MRI is the preferred imaging technique for the majority of physicians, whereas a high variability of postoperative neuroimaging routines including CT and MRI was observed. International guidelines for perioperative imaging with special focus on postoperative MRI are warranted in order to optimize perioperative treatment modalities for BM patients.
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| 5. |
- Northcott, Paul A, et al.
(author)
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Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
- 2014
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 511:7510, s. 428-428
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Journal article (peer-reviewed)abstract
- Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
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| 6. |
- Reifenberger, Guido
(author)
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Molecular genetic studies on gliomas and capillary hemangioblastomas of the central nervous system
- 1996
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Doctoral thesis (other academic/artistic)abstract
- The molecular genetic alterations associated with the initiation and progression of central nervous system tumors are complex and poorly understood at present. This thesis aims at the further elucidation of the molecular genetics of two important types of central nervous system tumors: gliomas and capillary hemangioblastomas. Gliomas are the most common primary central nervous system tumors and comprise astrocytic tumors (including the glioblastoma), oligodendroglial tumors, mixed gliomas, and ependymomas. The vast majority of gliomas cannot be cured by the presently available therapeutic options. Thus the prognosis for most glioma patients is still poor. In contrast, capillary hemangioblastomas are generally benign tumors of uncertain histogenesis. They occur either in patients with von Hippel-Lindau syndrome or, more frequently, as solitary sporadic lesions without any hereditary predisposition. In spite of their biologically benign nature, both sporadic and hereditary capillary hemangioblastomas are associated with a significant mortality rate. The first part of the molecular studies on gliomas consists of the analysis of 157 primary brain tumors (150 gliomas and 7 primitive neuroectodermal tumors) for amplification and expression of the MDM2 (murine double minute 2) gene. MDM2 codes for a protein that can complex the p53 tumor suppressor gene product and inhibit its function. We found MDM2 amplification and overexpression in 8 - 10% of glioblastomas and anaplastic astrocytomas. Sequencing of the p53 transcripts from exon 2 to 10 in the cases with MDM2 amplification revealed no mutations and restriction fragment length polymorphism analysis showed, with one exception, no losses of alleles on chromosome 17. Thus, MDM2 amplification appears to be an alternative mechanism to p53 mutation by which a subset of human malignant gliomas escapes from p53-regulated growth control. We then analyzed an extended series of 234 brain tumors, including 218 gliomas, for amplification and overexpression of 9 different gene loci located close to MDM2 at 12ql3-ql5. Amplification of one or more of these loci was found in about 15% of anaplastic astrocytomas and glioblastomas. Detailed mapping of the individual amplicons combined with mRNA expression analysis of the amplified genes showed that CDK4 (cyclin dependent kinase 4) and SAS (sarcoma amplified sequence) were the most frequently amplified genes (18/19 cases). MDM2 was co-amplified in 11 tumors and was the only amplified gene in one glioblastoma. Our data implicate CDK4, SAS and MDM2 as the targets for the amplification events at 12ql3-ql5 in malignant gliomas. In a further study, 136 gliomas were analyzed for loss of heterozygosity at 16 polymorphic loci from both arms of chromosome 12. Allelic loss on 12 was found in only 16% of the tumors. However, a significant association between amplification of genes from 12ql3-ql5 and loss of alleles from 12q was found. This finding supports a model considering chromosome breakage and deletion as important events in the development of gene amplification. In order to characterize the genetic alterations in oligodendroglial tumors and mixed gliomas, a comprehensive allelotyping and amplification screening was performed on a series of 37 cases (21oligodendroglial tumors and 16 mixed gliomas). All chromosomal arms were examined for allelic loss by restriction fragment length polymorphism analysis and/or densitometric evaluation of l 85loci. These studies showed that initial alterations in oligodendroglial tumors differ from astrocytomas and typically consist of loss of genetic information from l9q and lp. Anaplastic oligodendrogliomas showed an increased incidence of additional allelic losses, most frequently including loci on 9p and 10, and in individual cases amplification of proto-oncogenes. A further abnormality frequently found in both low-grade and anaplastic oligodendroglial tumors was overexpression of the epidermal growth factor receptor (EGFR) in the absence of EGFR gene amplification. Molecular analysis of capillary hemangioblastomas revealed mutations of the von Hippel-Lindau tumor suppressor gene (VHL) in 10 of 20 tumors. In addition, we found a consistent co-expression of transforming growth factor alpha and epidermal growth factor receptor in capillary hemangioblastomas. Thus, our data implicate mutational inactivation of VHL as well as autocrine and/or juxtacrine growth stimulation via the epidermal growth factor receptor as molecular mechanisms involved in the growth of capillary hemangioblastomas.
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| 7. |
- Seidel, Sascha, et al.
(author)
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A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha
- 2010
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 133, s. 983-995
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Journal article (peer-reviewed)abstract
- Glioma growth and progression depend on a specialized subpopulation of tumour cells, termed tumour stem cells. Thus, tumour stem cells represent a critical therapeutic target, but the molecular mechanisms that regulate them are poorly understood. Hypoxia plays a key role in tumour progression and in this study we provide evidence that the hypoxic tumour microenvironment also controls tumour stem cells. We define a detailed molecular signature of tumour stem cell genes, which are overexpressed by tumour cells in vascular and perinecrotic/hypoxic niches. Mechanistically, we show that hypoxia plays a key role in the regulation of the tumour stem cell phenotype through hypoxia-inducible factor 2 alpha and subsequent induction of specific tumour stem cell signature genes, including mastermind-like protein 3 (Notch pathway), nuclear factor of activated T cells 2 (calcineurin pathway) and aspartate beta-hydroxylase domain-containing protein 2. Notably, a number of these genes belong to pathways regulating the stem cell phenotype. Consistently, tumour stem cell signature genes are overexpressed in newly formed gliomas and are associated with worse clinical prognosis. We propose that tumour stem cells are maintained within a hypoxic niche, providing a functional link between the well-established role of hypoxia in stem cell and tumour biology. The identification of molecular regulators of tumour stem cells in the hypoxic niche points to specific signalling mechanisms that may be used to target the glioblastoma stem cell population.
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| 8. |
- Toepoel, Mascha, et al.
(author)
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Haplotype-specific expression of the human PDGFRA gene correlates with the risk of glioblastomas
- 2008
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 123:2, s. 322-329
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Journal article (peer-reviewed)abstract
- Aberrant expression of the platelet-derived growth factor a-receptor (PDGFRA) gene has been associated with various diseases, including neural tube defects and gliomas. We have previously identified 5 distinct haplotypes for the PDGFRA promoter region, designated H1, H2 alpha, H2 beta, H2 gamma and H2 delta. Of these haplotypes H1 and H2 alpha: are the most common, whereby H1 drives low and H2 alpha high transcriptional activity in transient transfection assays. Here we have investigated the role of these PDGFRA promoter haplotypes in gliomagenesis at both the genetic and cellular level. In a case-control study on 71 glioblastoma patients, we observed a clear underrepresentation of H1 alleles, with pH1 = 0.141 in patients and pH1 = 0.211 in a combined Western European control group (n = 998, p < ; 0.05). Furthermore, in 3 out of 4 available H1/H2 alpha heterozygous human glioblastoma cell lines, H1-derived mRNA levels were more than 10-fold lower than from H2 alpha, resulting at least in part from haplotype-specific epigenetic differences such as DNA methylation and histone acetylation. Together, these results indicate that PDGFRA promoter haplotypes may predispose to gliomas. We propose a model in which PDGFRA is upregulated in a haplotype-specific manner during neural stem cell differentiation, which affects the pool size of cells that can later undergo gliomagenesis.
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| 9. |
- Weller, Michael, et al.
(author)
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EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma
- 2014
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In: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 15:9, s. E395-E403
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Research review (peer-reviewed)abstract
- This guideline provides recommendations for diagnostic and therapeutic procedures for patients with malignant gliomas. We differentiate evidence-based standards from reasonable options or non-evidence-based measures that should no longer be considered. The recommendations herein should provide a framework and assurance for the choice of diagnostic procedures and therapeutic measures and aim to reduce complications from unnecessary treatment and cost. The guideline contributes to a critical appreciation of concurrent drugs with a focus on the controlled use of anticonvulsants and steroids. It should serve as a guideline for all professionals involved in the diagnostics and care of glioma patients and also as a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in Europe. Implementation of the recommendations summarised here will need interdisciplinary structures of care for patients with brain tumours and structured processes of diagnostic and therapeutic procedures.
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| 10. |
- Weller, Michael, et al.
(author)
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EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood.
- 2021
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In: Nature reviews. Clinical oncology. - : Springer Science and Business Media LLC. - 1759-4782 .- 1759-4774. ; 18, s. 170-186
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Research review (peer-reviewed)abstract
- In response to major changes in diagnostic algorithms and the publication of mature results from various large clinical trials, the European Association of Neuro-Oncology (EANO) recognized the need to provide updated guidelines for the diagnosis and management of adult patients with diffuse gliomas. Through these evidence-based guidelines, a task force of EANO provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. The diagnostic component is based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy - Not Officially WHO (cIMPACT-NOW). With regard to therapy, we formulated recommendations based on the results from the latest practice-changing clinical trials and also provide guidance for neuropathological and neuroradiological assessment. In these guidelines, we define the role of the major treatment modalities of surgery, radiotherapy and systemic pharmacotherapy, covering current advances and cognizant that unnecessary interventions and expenses should be avoided. This document is intended to be a source of reference for professionals involved in the management of adult patients with diffuse gliomas, for patients and caregivers, and for health-care providers.
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