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  • 1. Bandopadhayay, Pratiti
    et al.
    Bergthold, Guillaume
    Nguyen, Brian
    Schubert, Simone
    Gholamin, Sharareh
    Tang, Yujie
    Bolin, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Schumacher, Steven
    Zeid, Rhamy
    Masoud, Sabran
    Yu, Furong
    Vue, Nujsaubnusi
    Gibson, William
    Paolella, Brenton
    Mitra, Siddhartha
    Cheshier, Samuel
    Qi, Jun
    Liu, Kun-Wei
    Wechsler-Reya, Robert
    Weiss, William
    Swartling, Fredrik Johansson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Kieran, Mark W.
    Bradner, James E.
    Beroukhim, Rameen
    Cho, Yoon-Jae
    Medulloblastoma models which harbor amplifications of myc family members are sensitive to BET-Bromodomain inhibition2014In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, p. 90-90Article in journal (Other academic)
  • 2.
    Baskaran, Sathishkumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Göransson Kultima, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bergström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Isaksson, Anders
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 8, p. 1080-1091Article in journal (Refereed)
    Abstract [en]

    Background: Primary glioblastoma cell (GC) cultures have emerged as a key model in brain tumor research, with the potential to uncover patient-specific differences in therapy response. However, there is limited quantitative information about the stability of such cells during the initial 20-30 passages of culture.

    Methods: We interrogated 3 patient-derived GC cultures at dense time intervals during the first 30 passages of culture. Combining state-of-the-art signal processing methods with a mathematical model of growth, we estimated clonal composition, rates of change, affected pathways, and correlations between altered gene dosage and transcription.

    Results: We demonstrate that GC cultures undergo sequential clonal takeovers, observed through variable proportions of specific subchromosomal lesions, variations in aneuploid cell content, and variations in subpopulation cell cycling times. The GC cultures also show significant transcriptional drift in several metabolic and signaling pathways, including ribosomal synthesis, telomere packaging and signaling via the mammalian target of rapamycin, Wnt, and interferon pathways, to a high degree explained by changes in gene dosage. In addition to these adaptations, the cultured GCs showed signs of shifting transcriptional subtype. Compared with chromosomal aberrations and gene expression, DNA methylations remained comparatively stable during passaging, and may be favorable as a biomarker.

    Conclusion: Taken together, GC cultures undergo significant genomic and transcriptional changes that need to be considered in functional experiments and biomarker studies that involve primary glioblastoma cells.

  • 3.
    Berntsson, Shala
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Savitcheva, I.
    Larsson, E.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    11c-methionine PET combined with advanced MRI for the preoperative evaluation of suspected diffuse low-grade gliomas2012In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, no suppl 3, p. iii11-iii12Article in journal (Other academic)
    Abstract [en]

    PURPOSE: To evaluate positron emission tomography (PET) with the tracer 11C-methionine (MET) combined with perfusion- and diffusion MRI (pMRI and dMRI) for the preoperative evaluation of patients with suspected diffuse low-grade gliomas (DLGG).

    MATERIALS AND METHODS: In this prospective study with institutional review board approval, 25 patients with suspected DLGG in cortical structures (n=24) were examined with 11C-methionine PET (MET PET), pMRI and dMRI. The hot spot (HS) in the tumor, i.e. the area with highest MET uptake, was used as a reference region for evaluating maximum relative cerebral blood volume (rCBVmax) and minimum apparent diffusion coefficient values (ADCmin) by MRI. The concordance between MET PET, pMRI and dMRI, as single parameters and combined, was assessed with respect to histological tumor diagnosis, which was available for 18 patients.

    RESULTS: In all but one patient tumor diagnosis was confirmed. The region showing highest rCBVmax corresponded with the HS region identified by MET PET in all cases, and a positive correlation between MET uptake and rCBVmax was found (Spearman: r=0.67, P < 0.0001). The concordance between MET uptake and rCBVmax in predicting malignancy grade of gliomas was 67%. MET uptake in the HS was inversely correlated with ADCmin values measured in this region (Spearman: r=-0.54, p < 0.005).

    CONCLUSION: MET PET combined with advanced MRI facilitates the identification of specific regions of interest for histological tumor diagnosis and thereby provides a powerful tool in the preoperative evaluation of DLGG.

  • 4.
    Ehrstedt, Christoffer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Laurencikas, Evaldas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Björklund, Ann-Christin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Strömberg, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hedborg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Pfeifer, Susan
    Weekly vinblastine is a therapeutic option in recurrent/refractory pediatric low-grade gliomas2012In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, no suppl 1, p. i70-i70Article in journal (Other academic)
    Abstract [en]

    BACKGROUND: In a majority of cases efficient treatment of low-grade gliomas in the pediatric population is achieved by surgery, sometimes accompanied by chemotherapy according to the LGG SIOP 2003 protocol. However, some cases of LGG is refractory, treatment options in these cases often consists of LGG SIOP 2003 relapse protocol or radiotherapy. Vinblastine can be used as a secondline chemotherapy.

    METHODS: Four patients with refractory low grade gliomas were given vinblastine intravenously. These patients had previously failed chemotherapy and/or radiation for unresectable low-grade glioma. Tumor location has differed, 1 brainstem, 1 optic pathway, 1 thalamus, 1 cerebellar. Three of the patients were given vinblastine at a dose of 6mg/m2 weekly, the fourth patient received a 50% dose reduction because of intolerable side-effects. The treatment was given for at least 12 months in three of the cases.

    RESULTS: There have been significant reduction of tumor size in the 3 patients who have received vinblastine for at least 12 months. Response to treatment has been followed at three months interval with MRI. None of the patients have been forced to discontinue the treatment because of intolerable side-effects. The fourth patient has been treated for three months and follow-up with MRI indicates a slight reduction of tumor size.

    CONCLUSION: Vinblastine should be considered as a secondline chemotherapy in refractory low grade gliomas. Extended administration (>12 months) seems to be tolerated well. If untolerable side effects dose reduction should be tried.

  • 5.
    Ehrstedt, Christoffer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Rydell, Ann-Margret
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Hallsten, Marina Gabert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Strömberg, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Ahlsten, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Cognition, Health-Related Quality Of Life and Mood in Children and Young Adults Diagnosed with a Glioneuronal Tumor in Childhood2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, p. 161-161Article in journal (Other academic)
  • 6. Elsir, T.
    et al.
    Qu, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Berntsson, Shala
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Orrego, A.
    Olofsson, T.
    Lindström, M.
    Nister, M.
    Ribom, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    PROX1 IS A PREDICTOR OF SURVIVAL FOR ASTROCYTIC GLIOMAS BUT NOT FOR OLIGODENDROGLIOMAS GRADE II2010In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 12, p. 51-51Article in journal (Other academic)
  • 7.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    De Luca, Francesca
    Univ G dAnnunzio, Fac Med & Surg, Sch Med & Hlth Sci, Chieti, Italy.
    van Westen, Danielle
    Skane Univ Hosp, Image & Funct, Lund, Sweden;Lund Univ, Inst Clin Sci Lund, Diagnost Radiol, Lund, Sweden.
    Delgado, Anna Falk
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Arterial spin labeling MR imaging for differentiation between high- and low-grade glioma: a meta-analysis2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 11, p. 1450-1461Article in journal (Refereed)
    Abstract [en]

    Background. Arterial spin labeling is an MR imaging technique that measures cerebral blood flow (CBF) noninvasively. The aim of the study is to assess the diagnostic performance of arterial spin labeling (ASL) MR imaging for differentiation between high-grade glioma and low-grade glioma.

    Methods. Cochrane Library, Embase, Medline, and Web of Science Core Collection were searched. Study selection ended November 2017. This study was prospectively registered in PROSPERO (CRD42017080885). Two authors screened all titles and abstracts for possible inclusion. Data were extracted independently by 2 authors. Bivariate random effects meta-analysis was used to describe summary receiver operating characteristics. Trial sequential analysis (TSA) was performed.

    Results. In total, 15 studies with 505 patients were included. The diagnostic performance of ASL CBF for glioma grading was 0.90 with summary sensitivity 0.89 (0.79-0.90) and specificity 0.80 (0.72-0.89). The diagnostic performance was similar between pulsed ASL (AUC 0.90) with a sensitivity 0.85 (0.71-0.91) and specificity 0.83 (0.690.92) and pseudocontinuous ASL (AUC 0.88) with a sensitivity 0.86 (0.79-0.91) and specificity 0.80 (0.65-0.87). In astrocytomas, the diagnostic performance was 0.89 with sensitivity 0.86 (0.79 to 0.91) and specificity 0.79 (0.63 to 0.89). Sensitivity analysis confirmed the robustness of the findings. TSA revealed that the meta-analysis was adequately powered.

    Conclusion. Arterial spin labeling MR imaging had an excellent diagnostic accuracy for differentiation between high-grade and low-grade glioma. Given its low cost, non-invasiveness, and efficacy, ASL MR imaging should be considered for implementation in the routine workup of patients with glioma.

  • 8. Fedele, V.
    et al.
    Dai, F.
    Marinescu, Voichita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kim, H.
    Weyerbrock, A.
    Prinz, M.
    Bredel, M.
    Carro, M.
    ZBTB18 Methylation Promotes Mesenchymal Transformation in Glioblastoma2014In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16Article in journal (Other academic)
  • 9.
    Ferrucci, Veronica
    et al.
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;European Sch Mol Med SEMM, Milan, Italy.
    de Antonellis, Pasqualino
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy.
    Pennino, Francesco Paolo
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy.
    Asadzadeh, Fatemeh
    CEINGE Biotecnol Avanzate, Naples, Italy.
    Siciliano, Roberto
    CEINGE Biotecnol Avanzate, Naples, Italy.
    Virgilio, Antonella
    Univ Napoli Federico II, Dipartimento Farm, Naples, Italy.
    Galeone, Aldo
    Univ Napoli Federico II, Dipartimento Farm, Naples, Italy.
    De Martino, Lucia
    Osped Santobono Pausilipon, Paediat Neurosurg, Naples, Italy.
    Quaglietta, Lucia
    Osped Santobono Pausilipon, Paediat Neurosurg, Naples, Italy.
    Errico, Maria Elena
    Osped Santobono Pausilipon, Surg Pathol, Naples, Italy.
    Donofrio, Vittoria
    Osped Santobono Pausilipon, Surg Pathol, Naples, Italy.
    Picard, Daniel
    Univ Hosp Dusseldorf, German Canc Consortium DKTK, Dept Paediat Oncol Haematol & Clin Immunol, Dusseldorf, Germany.
    Remke, Marc
    Univ Hosp Dusseldorf, German Canc Consortium DKTK, Dept Paediat Oncol Haematol & Clin Immunol, Dusseldorf, Germany.
    Chesler, Louis
    Inst Canc Res, Div Clin Studies, London, England.
    Johansson, Fredrik K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Weiss, William
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA.
    Taylor, Michael
    Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada;Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada.
    Cinalli, Giuseppe
    Osped Santobono Pausilipon, Paediat Neurosurg, Naples, Italy.
    Zollo, Massimo
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy.
    Targeting PRUNE-1 in a GEMM of Metastatic Medulloblastoma: A Potential Route of Inhibition for New Future Therapies2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, p. 139-139Article in journal (Other academic)
  • 10. Hagerstrand, Daniel
    et al.
    He, Xiaobing
    Lindh, Maja Bradic
    Hoefs, Saskia
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Ostman, Arne
    Nister, Monica
    Identification of a SOX2-dependent subset of tumor- and sphere-forming glioblastoma cells with a distinct tyrosine kinase inhibitor sensitivity profile2011In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 13, no 11, p. 1178-1191Article in journal (Refereed)
    Abstract [en]

    Putative cancer stem cells have been identified in glioblastomas and are associated with radio- and chemoresistance. Further knowledge about these cells is thus highly warranted for the development of better glioblastoma therapies. Gene expression analyses of 11 high-grade glioma cultures identified 2 subsets, designated type A and type B cultures. The type A cultures displayed high expression of CXCR4, SOX2, EAAT1, and GFAP and low expression of CNP, PDGFRB, CXCL12, and extracellular matrix proteins. Clinical significance of the 2 types was indicated by the expression of type A-and type B-defining genes in different clinical glioblastoma samples. Classification of glioblastomas with type A- and type B-defining genes generated 2 groups of tumors composed predominantly of the classical, neural, and/or proneural subsets and the mesenchymal subset, respectively. Furthermore, tumors with EGFR mutations were enriched in the group of type A samples. Type A cultures possessed a higher capacity to form xenograft tumors and neurospheres and displayed low or no sensitivity to monotreatment with PDGF-and IGF-1-receptor inhibitors but were efficiently growth inhibited by combination treatment with low doses of these 2 inhibitors. Furthermore, siRNA-induced downregulation of SOX2 reduced sphere formation of type A cultures, decreased expression of type A-defining genes, and conferred sensitivity to monotreatment with PDGF-and IGF-1receptor inhibitors. The present study thus describes a tumor-and neurosphere-forming SOX2-dependent subset of glioblastoma cultures characterized by a gene expression signature similar to that of the recently described classical, proneural, and/or neural subsets of glioblastoma. The findings that resistance to PDGF-and IGF-1-receptor inhibitors is related to SOX2 expression and can be overcome by combination treatment should be considered in ongoing efforts to develop novel stem cell-targeting therapies.

  • 11. Hasselblatt, Martin
    et al.
    Jeibmann, Astrid
    Eikmeier, Kristin
    Linge, Anna
    Johann, Pascal
    Koos, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Bartelheim, Kerstin
    Kool, Marcel
    Pfister, Stefan M.
    Fruehwald, Michael C.
    Paulus, Werner
    Hippo Signaling is Essential for the Phenotype Associated with Snr1 Loss in Drosophila Melanogastera and Involved in the Biology of Smarcb1-Deficient Atypical Teratoid/Rhabdoid Tumors2014In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, p. 3-4Article in journal (Other academic)
  • 12. Hill, Rebecca
    et al.
    Kuijper, Sanne
    Lindsey, Janet
    Schwalbe, Ed
    Barker, Karen
    Boult, Jessica
    Williamson, Daniel
    Ahmad, Zai
    Hallsworth, Albert
    Ryan, Sarra
    Poon, Evon
    Robinson, Simon
    Ruddle, Ruth
    Raynaud, Florence
    Howell, Louise
    Kwok, Colin
    Joshi, Abhijit
    Nicholson, Sarah Leigh
    Crosier, Stephen
    Wharton, Stephen
    Robson, Keith
    Michalski, Antony
    Hargrave, Darren
    Jacques, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pizer, Barry
    Bailey, Simon
    Swartling, Fredrik
    Petrie, Kevin
    Weiss, William
    Chesler, Louis
    Clifford, Steven
    Myc and Tp53 Defects Emerge and Interact at Medulloblastoma Relapse, Define Rapidly Progressive Disease and Can be Targeted Therapeutically2014In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, p. 74-74Article in journal (Other academic)
  • 13. Huang, Miller
    et al.
    Persson, Anders
    Swartling, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Moriarity, Branden
    Kreitzer, Faith
    Largaespada, David
    Conklin, Bruce
    Taylor, Michael
    Weiss, William
    Humanized Mouse Models for Medulloblastoma2013In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 15, no S1, p. 30-30Article in journal (Other academic)
  • 14. Hägerstrand, Daniel
    et al.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Eriksson, Anna
    Sigurdardottir, Sunna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hartman, Magdalena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nistér, Monica
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Östman, Arne
    Gene expression analyses of grade II gliomas and identification of rPTPbeta/ as a candidate oligodendroglioma marker2008In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 10, no 1, p. 2-9Article in journal (Refereed)
    Abstract [en]

    Grade 11 gliomas are morphologically and clinically heterogeneous tumors for which histopathological typing remains the major tool for clinical classification. To what extent the major histological subtypes-astrocytomas, oligodendrogliomas, and oligoastrocytomas-constitute true biological entities is largely unresolved. Furthermore, morphological classification is often ambiguous and would be facilitated by specific subtype markers. In this study, 23 grade II gliomas were expression-profiled and subjected to hierarchical clustering. All six oligodendrogliomas were grouped together in one of two major clusters; a significant correlation was thus observed between gene expression and histopathological subtype. Supervised analyses were performed to identify genes differentiating oligodendrogliomas from other grade II tumors. In a leave-one-out test using 10 features for classification, 20 out of 23 tumors were correctly classified. Among the most differentially expressed genes was rPT beta/zeta. The expression of the rPTP beta/zeta protein in oligodendrogliomas and astrocytomas was further validated by immunohistochemistry in an independent set of tumors. All 11 oligodendrogliomas of this set displayed strong staining. In contrast, neoplastic astrocytes were mostly negative for rPTP beta/zeta staining. In summary, this study demonstrates a correlation between gene expression pattern and histological subtype in grade 11 gliomas. Furthermore, the results from the immunohistochemical analyses of rPTP beta/zeta expression should prompt further evaluation of this protein as a novel oligodendroglioma marker.

  • 15. Hörnquist, Lina
    et al.
    Rickardsson, Jenny
    Lannering, Birgitta
    Gustafsson, Göran
    Boman, Krister K
    Altered self-perception in adult survivors treated for a CNS tumor in childhood or adolescence: population-based outcomes compared with the general population2015In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 17, no 5, p. 733-40Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Survivors of pediatric CNS tumors are at risk for persistent tumor/treatment-related morbidity, physical disability and social consequences that may alter self-perception, vital for self-identity, mental health and quality of survival. We studied the long-term impact of childhood CNS tumors and their treatment on the self-perception of adult survivors and compared outcomes with those of the general population.

    METHODS: The cohort included 697 Swedish survivors diagnosed with a primary CNS tumor during 1982-2001. Comparison data were randomly collected from a stratified general population sample. Survivors and general population individuals were compared as regards self-perception in 5 domains: body image, sports/physical activities, peers, work, and family, and with a global self-esteem index. Within the survivor group, determinants of impact on self-perception were identified.

    RESULTS: The final analyzed sample included 528 survivors, 75.8% of the entire national cohort. The control sample consisted of 995, 41% of 2500 addressed. Survivors had significantly poorer self-perception outcomes in domains of peers, work, body image, and sports/physical activities, and in the global self-perception measure, compared with those of the general population (all P < .001). Within the survivor group, female gender and persistent visible physical sequelae predicted poorer outcomes in several of the studied domains. Tumor type and a history of cranial radiation therapy were associated with outcomes.

    CONCLUSION: An altered self-perception is a potential late effect in adult survivors of pediatric CNS tumors. Self-perception and self-esteem are significant elements of identity, mental health and quality of survival. Therefore, care and psychosocial follow-up of survivors should include measures for identifying disturbances and for assessing the need for psychosocial intervention.

  • 16.
    Malmström, A.
    et al.
    Dept Adv Home Care, Linköping, Sweden.;Dept Clin & Expt Med IKE, Div Cell Biol CELLB, Linköping, Sweden..
    Asklund, T.
    Umeå Univ, Dept Radiat Sci & Oncol, Umeå, Sweden..
    Kinhult, S.
    Skåne Univ Hosp, Dept Oncol, Lund, Sweden..
    Sjögren, M.
    Sahlgrens Univ Hosp, Dept Oncol, Gothenburg, Sweden..
    Hylin, S.
    Karolinska Univ Hosp, Dept Neurol, Stockholm, Sweden..
    Rosenlund, L.
    Reg Canc Ctr Stockholm Gotland, Stockholm, Sweden..
    Bergqvist, M.
    Umeå Univ, Dept Radiat Sci & Oncol, Umeå, Sweden.;Gävle Cent Hosp, Dept Oncol, Gävle, Sweden..
    Milos, P.
    Linköping Univ, Dept Neurosurg, Linköping, Sweden.;Linköping Univ, Dept Clin & Expt Med, Linköping, Sweden..
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Henriksson, R.
    Umeå Univ, Dept Radiat Sci & Oncol, Umeå, Sweden.;Reg Canc Ctr Stockholm Gotland, Stockholm, Sweden..
    A Complete Nation-Based Registration Ensures Equal And Optimal Management Of Primary Brain Tumors Patients2016In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 18, p. 21-22Article in journal (Other academic)
  • 17. Meyerowitz, Justin G.
    et al.
    Gustafson, W. Clay
    Nekritz, Erin A.
    Swartling, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Shokat, Kevan M.
    Ruggero, Davide
    Weiss, William A.
    Targeting the Translational Apparatus in Mycn-Driven Medulloblastoma2013In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 15, no S1, p. 16-16Article in journal (Other academic)
  • 18.
    Nord, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hartmann, Christian
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pfeifer, Susan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Piotrowski, Arkadiusz
    Bogdan, Adam
    Kloc, Wojciech
    Sandgren, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Blomquist, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    von Deimling, Andreas
    Bruder, Carl E. G.
    Southern Research Institute, Birmingham, AL, USA.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    de Ståhl, Teresita Díaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array2009In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 11, no 6, p. 803-818Article in journal (Refereed)
    Abstract [en]

    Glioblastomas (GBs) are malignant CNS tumors often associated with devastating symptoms. Patients with GB have a very poor prognosis, and despite treatment, most of them die within 12 months from diagnosis. Several pathways, such as the RAS, tumor protein 53 (TP53), and phosphoinositide kinase 3 (PIK3) pathways, as well as the cell cycle control pathway, have been identified to be disrupted in this tumor. However, emerging data suggest that these aberrations represent only a fraction of the genetic changes involved in gliomagenesis. In this study, we have applied a 32K clone-based genomic array, covering 99% of the current assembly of the human genome, to the detailed genetic profiling of a set of 78 GBs. Complex patterns of aberrations, including high and narrow copy number amplicons, as well as a number of homozygously deleted loci, were identified. Amplicons that varied both in number (three on average) and in size (1.4 Mb on average) were frequently detected (81% of the samples). The loci encompassed not only previously reported oncogenes (EGFR, PDGFRA, MDM2, and CDK4) but also numerous novel oncogenes as GRB10, MKLN1, PPARGC1A, HGF, NAV3, CNTN1, SYT1, and ADAMTSL3. BNC2, PTPLAD2, and PTPRE, on the other hand, represent novel candidate tumor suppressor genes encompassed within homozygously deleted loci. Many of these genes are already linked to several forms of cancer; others represent new candidate genes that may serve as prognostic markers or even as therapeutic targets in the future. The large individual variation observed between the samples demonstrates the underlying complexity of the disease and strengthens the demand for an individualized therapy based on the genetic profile of the patient.

  • 19. Olsson, Maja
    et al.
    Kling, Teresia
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Meta-Analysis of Neural Childhood Cancer Networks2014In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, p. 140-140Article in journal (Other academic)
  • 20.
    Pfeifer, Susan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nister, Monica
    de Stahl, Teresita Diaz
    Basmaci, Elisa
    Swedish Biobank for Childhood Tumors2014In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, p. 141-141Article in journal (Other academic)
  • 21. Sandgren, Johanna
    et al.
    Pfeifer, Susan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Popova, Svetlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    de Stahl, Teresita Diaz
    Bi-Allelic Mismatch Repair Msh6 Gene Mutations in a Patient Surviving a Childhood Malignant Brain Tumor2014In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, p. 53-53Article in journal (Other academic)
  • 22. Schmidt, Linnea
    et al.
    Kling, Teresia
    Monsefi, Naser
    Olsson, Maja
    Hansson, Caroline
    Baskaran, Sathishkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Lundgren, Bo
    Martens, Ulf
    Haggblad, Maria
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Nilsson, Karin Forsberg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Karlsson-Lindahl, Linda
    Gerlee, Philip
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Comparative drug pair screening across multiple glioblastoma cell lines reveals novel drug-drug interactions2013In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 15, no 11, p. 1469-1478Article in journal (Refereed)
    Abstract [en]

    Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults, and despite state-of-the-art treatment, survival remains poor and novel therapeutics are sorely needed. The aim of the present study was to identify new synergistic drug pairs for GBM. In addition, we aimed to explore differences in drug-drug interactions across multiple GBM-derived cell cultures and predict such differences by use of transcriptional biomarkers. We performed a screen in which we quantified drug-drug interactions for 465 drug pairs in each of the 5 GBM cell lines U87MG, U343MG, U373MG, A172, and T98G. Selected interactions were further tested using isobole-based analysis and validated in 5 glioma-initiating cell cultures. Furthermore, drug interactions were predicted using microarray-based transcriptional profiling in combination with statistical modeling. Of the 5 465 drug pairs, we could define a subset of drug pairs with strong interaction in both standard cell lines and glioma-initiating cell cultures. In particular, a subset of pairs involving the pharmaceutical compounds rimcazole, sertraline, pterostilbene, and gefitinib showed a strong interaction in a majority of the cell cultures tested. Statistical modeling of microarray and interaction data using sparse canonical correlation analysis revealed several predictive biomarkers, which we propose could be of importance in regulating drug pair responses. We identify novel candidate drug pairs for GBM and suggest possibilities to prospectively use transcriptional biomarkers to predict drug interactions in individual cases.

  • 23.
    Sooman, Linda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ekman, S.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Bergstrom, S.
    Johansson, M.
    Wu, Xuping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Blomquist, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    SHP1 expression is epigenetically regulated and influences the sensitivity to chemotherapeutic agents in glioblastoma cells2012In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, no suppl 3, p. iii18-iii18Article in journal (Other academic)
    Abstract [en]

    INTRODUCTION: Glioblastoma is characterized by chemoresistance. One factor than can contribute to chemoresistance is aberrant DNA methylation of specific genes relevant for drug response, e.g. tumor suppressor genes. AIM: The aim of this study was to investigate whether the tumor suppressor gene SHP1 is epigenetically regulated and if its overexpression affects the sensitivity to chemotherapeutic drugs with different mechanisms of action in glioblastoma cell lines.

    METHODS: Differences in methylation levels in the SHP1 promoter and SHP1 protein expressions between untreated cells and cells treated with the demethylating agent decitabine were analyzed with bisulfite Pyrosequencing and Western blotting. Differences in drug sensitivity to a panel of chemotherapeutic drugs with different mechanisms of action between SHP1 overexpressing clones and control clones were analyzed with the fluorometric microculture cytotoxicity assay.

    RESULTS: We demonstrated that SHP1 promoter methylation was correlated to SHP1 expression and that the expression was increased upon demethylation. Overexpression of SHP1 resulted in lower (p < 0.05) sensitivity to the proteasome inhibitor bortezomib and the alkylating agents cisplatin and melphalan.

    CONCLUSION: SHP1 expression may be epigenetically regulated and its overexpression influences the sensitivity to chemotherapeutic drugs in glioblastoma derived cells.

  • 24.
    Swartling, Fredrik J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Cancer, Matko
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Bolin, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fotaki, Grammatiki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Dubuc, Adrian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Remke, Marc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ramaswamy, Vijay
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Weishaupt, Holger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Taylor, Michael D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Metastasis and Tumor Recurrence from Rare SOX9-Positive Cells in MYCN-Driven Medulloblastoma2014In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16Article in journal (Other academic)
  • 25.
    Weishaupt, Holger
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Mainwaring, Oliver
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hutter, Sonja
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jernberg Wiklund, Helena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Rosén, Gabriela
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Johansson, Fredrik K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    GMYC: A Novel Inducible Transgenic Model of Group 3 Medulloblastoma2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, p. 137-137Article in journal (Other academic)
  • 26.
    Westermark, Ulrica K
    et al.
    Karolinska Institutet, Institutionen för onkologi-patologi.
    Lindberg, Nanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Roswall, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Bråsäter, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Helgadottir, Hildur R
    Memorial Sloan-Kettering Cancer Center, New York.
    Hede, Sanna
    Karolinska Institutet, Institutionen för onkologi-patologi.
    Zetterberg, Anders
    Karolinska Institutet, Institutionen för onkologi-patologi.
    Jasin, Maria
    Memorial Sloan-Kettering Cancer Center, New York.
    Nistér, Monica
    Karolinska Institutet, Institutionen för onkologi-patologi.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    RAD51 can inhibit PDGFB-induced gliomagenesis and genomic instability2011In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 13, no 12, p. 1277-1287Article in journal (Refereed)
    Abstract [en]

    Faithful replication and DNA repair are vital for maintenance of genome integrity. RAD51 is a central protein in homologous recombination repair and during replication, when it protects and restarts stalled replication forks. Aberrant RAD51 expression occurs in glioma, and high expression has been shown to correlate with prolonged survival. Furthermore, genes involved in DNA damage response (DDR) are mutated or deleted in human glioblastomas, corroborating the importance of proper DNA repair to suppress gliomagenesis. We have analyzed DDR and genomic instability in PDGF-B-induced gliomas and investigated the role of RAD51 in glioma development. We show that PDGF-B-induced gliomas display genomic instability and that co-expression of RAD51 can suppress PDGF-B-induced tumorigenesis and prolong survival. Expression of RAD51 inhibited proliferation and genomic instability of tumor cells independent of Arf status. Our results demonstrate that the RAD51 pathway can prevent glioma initiation and maintain genome integrity of induced tumors, suggesting reactivation of the RAD51 pathway as a potential therapeutic avenue.

  • 27.
    Zhang, Lei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Shaanxi Normal Univ, Natl Engn Lab Resource Developing Endangered Chin, Coll Life Sci, Key Lab, Minist Educ Med Plant Resource & Nat Phar, Xian, Shaanxi, Peoples R China.
    He, Liqun
    Tianjin Med Univ Gen Hosp, Key Lab Postneuroinjury Neurorepair & Regenerat C, Tianjin Neurol Inst, Dept Neurosurg, Minist Educ & Tianjin City, Tianjin, Peoples R China.
    Lugano, Roberta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Roodakker, Kenney Roy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Umeå Univ Hosp, Dept Radiat Sci & Oncol, Umeå, Sweden.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 11, p. 1505-1516Article in journal (Refereed)
    Abstract [en]

    Background: Vascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades II–III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH) mutation status affects vascular phenotype.

    Methods: Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the database of The Cancer Genome Atlas. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grades II–IV gliomas and nonmalignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro.

    Results: Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of laminin subunit alpha 4 (LAMA4) and angiopoietin 2 (ANGPT2) in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including upregulation of ANGPT2 and serpin family H (SERPINH1), connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased transforming growth factor beta (TGFβ) and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was upregulated by stimulation of endothelial cells with TGFβ2, vascular endothelial growth factor, or cobalt chloride in vitro.

    Conclusion: IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGFβ and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.

1 - 27 of 27
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