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- Jeibmann, Astrid, et al.
(författare)
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Identification of genes involved in the biology of atypical teratoid/rhabdoid tumours using Drosophila melanogaster
- 2014
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5, s. 4005-
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Tidskriftsartikel (refereegranskat)abstract
- Atypical teratoid/rhabdoid tumours (AT/RT) are malignant brain tumours. Unlike most other human brain tumours, AT/RT are characterized by inactivation of one single gene, SMARCB1. SMARCB1 is a member of the evolutionarily conserved SWI/SNF chromatin remodelling complex, which has an important role in the control of cell differentiation and proliferation. Little is known, however, about the pathways involved in the oncogenic effects of SMARCB1 inactivation, which might also represent targets for treatment. Here we report a comprehensive genetic screen in the fruit fly that revealed several genes not yet associated with loss of snr1, the Drosophila homologue of SMARCB1. We confirm the functional role of identified genes (including merlin, kibra and expanded, known to regulate hippo signalling pathway activity) in human rhabdoid tumour cell lines and AT/RT tumour samples. These results demonstrate that fly models can be employed for the identification of clinically relevant pathways in human cancer.
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- Koechling, Michaela, et al.
(författare)
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hTERT promoter methylation in pituitary adenomas
- 2016
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Ingår i: BRAIN TUMOR PATHOLOGY. - : Springer Science and Business Media LLC. - 1433-7398 .- 1861-387X. ; 33:1, s. 27-34
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Tidskriftsartikel (refereegranskat)abstract
- Telomerase reverse transcriptase (TERT) expression is a hallmark in tumorigenesis and upregulated due to mutations and methylation of the human (h)TERT promoter. As mutations are rare but methylation is common in pituitary adenomas (PA), we determined promoter methylation and its clinical impact in 85 primary and 15 recurrent PA by methylation-specific PCR. 40 females (47 %) and 45 males (53 %) with a median age of 53 years harboring micro-, macro-, and giant adenomas in 12, 82, and 6 % were included (prolactinomas, corticotroph, somatotroph, gonadotroph, thyreotroph, plurihormonal, and null cell adenomas in 11, 18, 10, 29, 1, 10, and 21 %, respectively). In primary diagnosed tumors, methylation rate was 27 % and higher in males than in females (40 vs. 13 %, p = 0.001) after uni- and multivariate analyses. Methylation differed among PA subtypes (0-42 %, p = n.s.) and was not significantly correlated with tumor size, cavernous sinus invasion, or serum hormone levels. Ki67 labeling index and recurrence (N = 16, 19 %) were independent of methylation. In recurrent tumors, methylation was similar to primary PA (N = 5/15, 33 %) and remained unchanged along follow-up. Thus, while being commonly observed in PA, hTERT promoter methylation is stable along follow-up and independent of most clinical variables, PA subtype, proliferation, and without prognostic value.
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- Koos, Björn, et al.
(författare)
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Platelet-derived growth factor receptor expression and activation in choroid plexus tumors
- 2009
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 175:4, s. 1631-1637
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Tidskriftsartikel (refereegranskat)abstract
- Choroid plexus tumors are intraventricular neoplasms predominantly affecting young children. In contrast to choroid plexus papillomas, choroid plexus carcinomas progress frequently, necessitating the development of adjuvant treatment concepts. Platelet derived growth factor (PDGF) signaling has been shown to support growth in a variety of tumors. The finding of PDGF receptor expression in choroid plexus tumors prompted us to elucidate PDGF receptor activation state using a novel method, in situ proximity ligation assay, on formalin-fixed, paraffin-embedded, archival samples of 19 choroid plexus tumors. As assessed by in situ proximity ligation assay, the proportion of phosphorylated PDGF receptor alpha was low in choroid plexus papillomas and choroid plexus carcinomas, whereas phosphorylated PDGF receptor beta was found to be significantly higher in choroid plexus carcinomas. In the immortalized choroid plexus epithelial cell line Z310 expressing PDGF receptor beta, PDGF-BB exhibited a time- and dose-dependent proliferative response, which was significantly attenuated by imatinib (gleevec). In conclusion, our findings suggest that PDGF receptor beta is functionally involved in the biology of choroid plexus tumors and may represent a molecular target for therapy. In addition, this study demonstrates the feasibility and usefulness of in situ proximity ligation assay for monitoring receptor tyrosine kinase activation in formalin-fixed, paraffin-embedded, archival tissues.
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- Paulsson, Janna, et al.
(författare)
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Prognostic but not predictive role of platelet-derived growth factor receptors in patients with recurrent glioblastoma
- 2011
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 128:8, s. 1981-1988
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor receptor (PDGFR) signaling has been implicated in the pathogenesis of glioblastomas and represents a target for the tyrosine kinase inhibitor imatinib. To examine the prognostic or predictive role of PDGFRs in recurrent glioblastomas, expression was examined in tumor samples of 101 patients of CSTI571BDE40, a randomized trial comparing hydroxyurea monotherapy and a combination of hydroxyurea and imatinib. Furthermore, PDGFRa phosphorylation was investigated using in situ proximity ligation assay. PDGFRa protein was expressed in 33% of tumors and was associated with male sex, young age, presence of R132H mutated isocitrate dehydrogenase 1 protein and short median survival (142 vs. 187 days, p = 0.028). Tumor PDGFRa phosphorylation was also associated with short survival (p = 0.030). The subset of patients with PDGFRa positive glioblastoma did not have longer survival on treatment with hydroxyurea and imatinib compared with hydroxyurea monotherapy. In conclusion, both PDGFRa protein expression and phosphorylation status had a prognostic role in recurrent glioblastomas but did not define a group that showed benefit from the combination therapy consisting of hydroxyurea and imatinib.
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