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  • 101.
    Roche, Francis P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ohlin, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Histidine-Rich Glycoprotein (HRG): A Novel Gene-Therapy Effector for the Treatment of Cancer2013In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 21, p. S241-S241Article in journal (Other academic)
  • 102.
    Roche, Francis P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ohlin, Elisabet K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Histidine-Rich Glycoprotein (HRG): A Novel Gene-Therapy Effector for the Treatment of Cancer2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S243-S244Article in journal (Other academic)
  • 103.
    Savary, Katia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Caglayan, Demet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Caja, Laia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tzavlaki, Kalliopi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bin Nayeem, Sarmah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jiang, Yiwen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Forsberg-Nillson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ferletta, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Snail depletes the tumorigenic potential of glioblastoma2013In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 47, p. 5409-5420Article in journal (Refereed)
    Abstract [en]

    Glioblastoma multiforme (GBM) is an aggressive brain malignancy characterized by high heterogeneity and invasiveness. It is increasingly accepted that the refractory feature of GBM to current therapies stems from the existence of few tumorigenic cells that sustain tumor growth and spreading, the so-called glioma-initiating cells (GICs). Previous studies showed that cytokines of the bone morphogenetic protein (BMP) family induce differentiation of the GICs, and thus act as tumor suppressors. Molecular pathways that explain this behavior of BMP cytokines remain largely elusive. Here, we show that BMP signaling induces Smad-dependent expression of the transcriptional regulator Snail in a rapid and sustained manner. Consistent with its already established promigratory function in other cell types, we report that Snail silencing decreases GBM cell migration. Consequently, overexpression of Snail increases GBM invasiveness in a mouse xenograft model. Surprisingly, we found that Snail depletes the GBM capacity to form gliomaspheres in vitro and to grow tumors in vivo, both of which are important features shared by GICs. Thus Snail, acting downstream of BMP signaling, dissociates the invasive capacity of GBM cells from their tumorigenic potential.

  • 104. 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.

  • 105.
    Singh, Umashankar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Maturi, Varun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Evidence for multiple forms and modifications of human POT12013In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 12, no 11, p. 876-877Article in journal (Refereed)
    Abstract [en]

    Human POT1, a widely studied telomere protector protein is perceived to be expressed as a single 70 kDa form. A survey of the literature as well as different commercially available antibodies against POT1 suggests occurrence of multiple forms of POT1. Knowledge about possible various forms of an important protein like POT1 is necessary for our understanding about its function. We have discovered that POT1 exists in at least three consistently occurring forms; 90,70 and 45 kDa. The unexpected molecular weights of POT1 seem to be associated with SUMO1 and ubiquitin conjugation; the latter occurring at a double lysine residue at 289-KK-290. We also present evidence that the relative abundance of the different POT1 forms can be altered by experimental modulation of POT1 nuclear localization. We thus present strong evidence that there are post-translational modifications of POT1 that can affect its molecular weight as well as intracellular localization and function.

  • 106.
    Smits, Anja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Elsir, Tamador
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Pedder, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nistér, Monica
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Aronica, Eleonora
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GABA-A Channel Subunit Expression in Human Glioma Correlates with Tumor Histology and Clinical Outcome2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e37041-Article in journal (Refereed)
    Abstract [en]

    GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter in the CNS and is present in high concentrations in presynaptic terminals of neuronal cells. More recently, GABA has been ascribed a more widespread role in the control of cell proliferation during development where low concentrations of extrasynaptic GABA induce a tonic activation of GABA receptors. The GABA-A receptor consists of a ligand-gated chloride channel, formed by five subunits that are selected from 19 different subunit isoforms. The functional and pharmacological properties of the GABA-A channels are dictated by their subunit composition. Here we used qRT-PCR to compare mRNA levels of all 19 GABA-A channel subunits in samples of human glioma (n = 29) and peri-tumoral tissue (n = 5). All subunits except the ρ1 and ρ3 subunit were consistently detected. Lowest mRNA levels were found in glioblastoma compared to gliomas of lower malignancy, except for the θ subunit. The expression and cellular distribution of the α1, γ1, ρ2 and θ subunit proteins was investigated by immunohistochemistry on tissue microarrays containing 87 gliomas grade II. We found a strong co-expression of ρ2 and θ subunits in both astrocytomas (r = 0.86, p<0.0001) and oligodendroglial tumors (r = 0.66, p<0.0001). Kaplan-Meier analysis and Cox proportional hazards modeling to estimate the impact of GABA-A channel subunit expression on survival identified the ρ2 subunit (p = 0.043) but not the θ subunit (p = 0.64) as an independent predictor of improved survival in astrocytomas, together with established prognostic factors. Our data give support for the presence of distinct GABA-A channel subtypes in gliomas and provide the first link between specific composition of the A-channel and patient survival.

  • 107.
    Sooman, Linda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Freyhult, Eva
    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.
    Jaiswal, Archita
    Navani, Sanjay
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Elsir, Tamador
    Cancer Center Karolinska, Karolinska University Hospital Solna, Stockholm, Sweden.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    FGF2 as a potential prognostic biomarker for proneural glioma patients2015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 3, p. 385-394Article in journal (Refereed)
    Abstract [en]

    Background. The survival of high-grade glioma patients is poor and the treatment of these patients can cause severe side effects. This fosters the necessity to identify prognostic biomarkers, in order to optimize treatment and diminish unnecessary suffering of patients. The aim of this study was to identify prognostic biomarkers for high-grade glioma patients.

    Methods. Eleven proteins were selected for analysis due to their suggested importance for survival of patients with other types of cancers and due to a high variation in protein levels between glioma patients (according to the Human Protein Atlas, www.proteinatlas.org). Protein expression patterns of these 11 proteins were analyzed by immunohistochemistry in tumor samples from 97 high-grade glioma patients. The prognostic values of the proteins were analyzed with univariate and multivariate Cox regression analyses for the high-grade glioma patients, including subgroup analyses of histological subtypes and immunohistochemically defined molecular subtypes.

    Results. The proteins with the most significant (univariate and multivariate p < 0.05) correlations were analyzed further with cross-validated Kaplan-Meier analyses for the possibility of predicting survival based on the protein expression pattern of the corresponding candidate. Random Forest classification with variable subset selection was used to analyze if a protein signature consisting of any combination of the 11 proteins could predict survival for the high-grade glioma patients and the subgroup with glioblastoma patients. The proteins which correlated most significantly (univariate and multivariate p < 0.05) to survival in the Cox regression analyses were Myc for all high-grade gliomas and FGF2, CA9 and CD44 for the subgroup of proneural gliomas, with FGF2 having a strong negative predictive value for survival. No prognostic signature of the proteins could be found.

    Conclusion. FGF2 is a potential prognostic biomarker for proneural glioma patients, and warrants further investigation.

  • 108. Studham, Matthew E.
    et al.
    Tjarnberg, Andreas
    Nordling, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Sonnhammer, Erik L. L.
    Functional association networks as priors for gene regulatory network inference2014In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 30, no 12, p. 130-138Article in journal (Refereed)
    Abstract [en]

    Motivation: Gene regulatory network (GRN) inference reveals the influences genes have on one another in cellular regulatory systems. If the experimental data are inadequate for reliable inference of the network, informative priors have been shown to improve the accuracy of inferences. Results: This study explores the potential of undirected, confidence-weighted networks, such as those in functional association databases, as a prior source for GRN inference. Such networks often erroneously indicate symmetric interaction between genes and may contain mostly correlation-based interaction information. Despite these drawbacks, our testing on synthetic datasets indicates that even noisy priors reflect some causal information that can improve GRN inference accuracy. Our analysis on yeast data indicates that using the functional association databases FunCoup and STRING as priors can give a small improvement in GRN inference accuracy with biological data.

  • 109. Sun, Zuyue
    et al.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Massena, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Kutschera, Simone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Padhan, Narendra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Gualandi, Laura
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Sundvold-Gjerstad, Vibeke
    Gustafsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Choy, Wing Wen
    Zang, Guangxiang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Quach, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Abid, Md Ruhul
    Spurkland, Anne
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    VEGFR2 induces c-Src signaling and vascular permeability in vivo via the adaptor protein TSAd2012In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 209, no 7, p. 1363-1377Article in journal (Refereed)
    Abstract [en]

    Regulation of vascular endothelial (VE) growth factor (VEGF)-induced permeability is critical in physiological and pathological processes. We show that tyrosine phosphorylation of VEGF receptor 2 (VEGFR2) at Y951 facilitates binding of VEGFR2 to the Rous sarcoma (Src) homology 2-domain of T cell-specific adaptor (TSAd), which in turn regulates VEGF-induced activation of the c-Src tyrosine kinase and vascular permeability. c-Src was activated in vivo and in vitro in a VEGF/TSAd-dependent manner, and was regulated via increased phosphorylation at pY418 and reduced phosphorylation at pY527. Tsad silencing blocked VEGF-induced c-Src activation, but did not affect pathways involving phospholipase C gamma, extracellular regulated kinase, and endothelial nitric oxide. VEGF-induced rearrangement of VE-cadherin-positive junctions in endothelial cells isolated from mouse lungs, or in mouse cremaster vessels, was dependent on TSAd expression, and TSAd formed a complex with VE-cadherin, VEGFR2, and c-Src at endothelial junctions. Vessels in tsad(-/-) mice showed undisturbed flow and pressure, but impaired VEGF-induced permeability, as measured by extravasation of Evans blue, dextran, and microspheres in the skin and the trachea. Histamine-induced extravasation was not affected by TSAd deficiency. We conclude that TSAd is required for VEGF-induced, c-Src-mediated regulation of endothelial cell junctions and for vascular permeability.

  • 110.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Myc proteins in brain tumor development and maintenance2012In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 117, no 2, p. 122-131Article, review/survey (Refereed)
    Abstract [en]

    Myc proteins are often deregulated in human brain tumors, especially in embryonal tumors that affect children. Many observations have shown how alterations of these pleiotropic Myc transcription factors provide initiation, maintenance, or progression of tumors. This review will focus on the role of Myc family members (particularly c-myc and Mycn) in tumors like medulloblastoma and glioma and will further discuss how to target stabilization of these proteins for future brain tumor therapies.

  • 111.
    Swartling, Fredrik J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Bolin, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Phillips, Joanna J
    Dept. of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
    Persson, Anders I.
    Department of Neurology, Sandler Neurosciences Center, University of California, San Francisco.
    Signals that regulate the oncogenic fate of neural stem cells and progenitors2014In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 260, p. 56-68Article, review/survey (Refereed)
    Abstract [en]

    Brain tumors have frequently been associated with a neural stem cell (NSC) origin and contain stem-like tumor cells, so-called brain tumor stem cells (BTSCs) that share many features with normal NSCs. A stem cell state of BTSCs confers resistance to radiotherapy and treatment with alkylating agents. It is also a hallmark of aggressive brain tumors and is maintained by transcriptional networks that are also active in embryonic stem cells. Advances in reprogramming of somatic cells into induced pluripotent stem (iPS) cells have further identified genes that drive stemness. In this review, we will highlight the possible drivers of stemness in medulloblastoma and glioma, the most frequent types of primary malignant brain cancer in children and adults, respectively. Signals that drive expansion of developmentally defined neural precursor cells are also active in corresponding brain tumors. Transcriptomal subgroups of human medulloblastoma and glioma match features of NSCs but also more restricted progenitors. Lessons from genetically-engineered mouse (GEM) models show that temporally and regionally defined NSCs can give rise to distinct subgroups of medulloblastoma and glioma. We will further discuss how acquisition of stem cell features may drive brain tumorigenesis from a non-NSC origin. Genetic alterations, signaling pathways, and therapy-induced changes in the tumor microenvironment can drive reprogramming networks and induce stemness in brain tumors. Finally, we propose a model where dysregulation of microRNAs (miRNAs) that normally provide barriers against reprogramming plays an integral role in promoting stemness in brain tumors.

  • 112.
    Swartling, Fredrik J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Hede, Sanna-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Weiss, William A.
    Dept. of Neurology, University of California, San Francisco.
    What underlies the diversity of brain tumors?2013In: Cancer Metastasis Review, ISSN 0167-7659, E-ISSN 1573-7233, Vol. 32, no 1-2 (SI), p. 5-24Article, review/survey (Refereed)
    Abstract [en]

    Glioma and medulloblastoma represent the most commonly occurring malignant brain tumors in adults and in children, respectively. Recent genomic and transcriptional approaches present a complex group of diseases and delineate a number of molecular subgroups within tumors that share a common histopathology. Differences in cells of origin, regional niches, developmental timing, and genetic events all contribute to this heterogeneity. In an attempt to recapitulate the diversity of brain tumors, an increasing array of genetically engineered mouse models (GEMMs) has been developed. These models often utilize promoters and genetic drivers from normal brain development and can provide insight into specific cells from which these tumors originate. GEMMs show promise in both developmental biology and developmental therapeutics. This review describes numerous murine brain tumor models in the context of normal brain development and the potential for these animals to impact brain tumor research.

  • 113.
    Swartling, Fredrik J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Persson, Anders I.
    Chen, Justin
    Hackett, Christopher S.
    Northcott, Paul A.
    Grimmer, Matthew R.
    Lau, Jasmine
    Chesler, Louis
    Perry, Arie
    Phillips, Joanna J.
    Taylor, Michael D.
    Weiss, William A.
    Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC2012In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 21, no 5, p. 601-613Article in journal (Refereed)
    Abstract [en]

    The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally stabilized murine N-myc(T58A) into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem, and forebrain. Transplantation of N-myc(WT) NSCs was insufficient for tumor formation. N-myc(T58A) cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating Sonic Hedgehog (SHH) dependence and SHH independence, respectively. These differences were regulated in part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal.

  • 114.
    Swartling, Fredrik Johansson
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Grimmer, Matthew R
    Hackett, Christopher S
    Northcott, Paul A
    Fan, Qi-Wen
    Goldenberg, David D
    Lau, Jasmine
    Masic, Selma
    Nguyen, Kim
    Yakovenko, Slava
    Zhe, Xiao-Ning
    Gilmer, Heather C Flynn
    Collins, Rodney
    Nagaoka, Mai
    Phillips, Joanna J
    Jenkins, Robert B
    Tihan, Tarik
    Vandenberg, Scott R
    James, C David
    Tanaka, Kohichi
    Taylor, Michael D
    Weiss, William A
    Chesler, Louis
    Pleiotropic role for MYCN in medulloblastoma2010In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 24, no 10, p. 1059-1072Article in journal (Refereed)
    Abstract [en]

    Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Sonic Hedgehog (SHH) signaling drives a minority of MB, correlating with desmoplastic pathology and favorable outcome. The majority, however, arises independently of SHH and displays classic or large cell anaplastic (LCA) pathology and poor prognosis. To identify common signaling abnormalities, we profiled mRNA, demonstrating misexpression of MYCN in the majority of human MB and negligible expression in normal cerebella. We clarified a role in pathogenesis by targeting MYCN (and luciferase) to cerebella of transgenic mice. MYCN-driven MB showed either classic or LCA pathologies, with Shh signaling activated in approximately 5% of tumors, demonstrating that MYCN can drive MB independently of Shh. MB arose at high penetrance, consistent with a role for MYCN in initiation. Tumor burden correlated with bioluminescence, with rare metastatic spread to the leptomeninges, suggesting roles for MYCN in both progression and metastasis. Transient pharmacological down-regulation of MYCN led to both clearance and senescence of tumor cells, and improved survival. Targeted expression of MYCN thus contributes to initiation, progression, and maintenance of MB, suggesting a central role for MYCN in pathogenesis.

  • 115. Tatin, Florence
    et al.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Lymphatic vascular morphogenesis2014In: Molecular Mechanisms of Angiogenesis: From Ontogenesis to Oncogenesis, Springer Publishing Company, 2014, p. 25-44Chapter in book (Refereed)
    Abstract [en]

    Lymphatic vessels participate in tissue homeostasis and immune surveillance by draining excess fluid and immune cells from tissues to blood circulation. Impaired lymphatic function can lead to tissue swelling, or lymphoedema, and associated complications, such as chronic inflammation and fat accumulation. The critical role of lymphatic vessels in a number of pathological conditions, including tumour metastasis, has led to an interest in identifying signalling pathways regulating lymphatic vessel development and growth. Here, we review the current knowledge on the molecular mechanisms of lymphatic development and how lymphatic vasculature contributes to diseases.

  • 116. Thomson, Benjamin R
    et al.
    Heinen, Stefan
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ghosh, Asish K
    Fatima, Anees
    Sung, Hoon-Ki
    Onay, Tuncer
    Chen, Hui
    Yamaguchi, Shinji
    Economides, Aris N
    Flenniken, Ann
    Gale, Nicholas W
    Hong, Young-Kwon
    Fawzi, Amani
    Liu, Xiaorong
    Kume, Tsutomu
    Quaggin, Susan E
    A lymphatic defect causes ocular hypertension and glaucoma in mice2014In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, no 10, p. 4320-4324Article in journal (Refereed)
    Abstract [en]

    Glaucoma is a leading cause of blindness, afflicting more than 60 million people worldwide. Increased intraocular pressure (IOP) due to impaired aqueous humor drainage is a major risk factor for the development of glaucoma. Here, we demonstrated that genetic disruption of the angiopoietin/TIE2 (ANGPT/TIE2) signaling pathway results in high IOP, buphthalmos, and classic features of glaucoma, including retinal ganglion degeneration and vision loss. Eyes from mice with induced deletion of Angpt1 and Angpt2 (A1A2FloxWB mice) lacked drainage pathways in the corneal limbus, including Schlemm’s canal and lymphatic capillaries, which share expression of the PROX1, VEGFR3, and FOXC family of transcription factors. VEGFR3 and FOXCs have been linked to lymphatic disorders in patients, and FOXC1 has been linked to glaucoma. In contrast to blood endothelium, in which ANGPT2 is an antagonist of ANGPT1, we have shown that both ligands cooperate to regulate TIE2 in the lymphatic network of the eye. While A1A2FloxWB mice developed high IOP and glaucoma, expression of ANGPT1 or ANGPT2 alone was sufficient for ocular drainage. Furthermore, we demonstrated that loss of FOXC2 from lymphatics results in TIE2 downregulation, suggesting a mechanism for ocular defects in patients with FOXC mutations. These data reveal a pathogenetic and molecular basis for glaucoma and demonstrate the importance of angiopoietin ligand cooperation in the lymphatic endothelium.

  • 117. Tjarnberg, Andreas
    et al.
    Nordling, Torbjörn E. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Studham, Matthew
    Nelander, Sven
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Sonnhammer, Erik L. L.
    Avoiding pitfalls in L-1-regularised inference of gene networks2015In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 11, no 1, p. 287-296Article in journal (Refereed)
    Abstract [en]

    Statistical regularisation methods such as LASSO and related L-1 regularised regression methods are commonly used to construct models of gene regulatory networks. Although they can theoretically infer the correct network structure, they have been shown in practice to make errors, i.e. leave out existing links and include non-existing links. We show that L-1 regularisation methods typically produce a poor network model when the analysed data are ill-conditioned, i.e. the gene expression data matrix has a high condition number, even if it contains enough information for correct network inference. However, the correct structure of network models can be obtained for informative data, data with such a signal to noise ratio that existing links can be proven to exist, when these methods fail, by using least-squares regression and setting small parameters to zero, or by using robust network inference, a recent method taking the intersection of all non-rejectable models. Since available experimental data sets are generally ill-conditioned, we recommend to check the condition number of the data matrix to avoid this pitfall of L-1 regularised inference, and to also consider alternative methods.

  • 118.
    Tugues, Sonia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Honjo, Satoshi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    König, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Padhan, Narendra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Kroon, Jeffrey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gualandi, Laura
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Barkefors, Irmeli
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Thijssen, Victor L.
    Griffioen, Arjan W.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Tetraspanin CD63 Promotes Vascular Endothelial Growth Factor Receptor 2-beta 1 Integrin Complex Formation, Thereby Regulating Activation and Downstream Signaling in Endothelial Cells in Vitro and in Vivo2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 26, p. 19060-19071Article in journal (Refereed)
    Abstract [en]

    CD63 is a member of the transmembrane-4 glycoprotein superfamily (tetraspanins) implicated in the regulation of membrane protein trafficking, leukocyte recruitment, and adhesion processes. We have investigated the involvement of CD63 in endothelial cell (EC) signaling downstream of beta 1 integrin and VEGF. We report that silencing of CD63 in primary ECs arrested capillary sprouting and tube formation in vitro because of impaired adhesion and migration of ECs. Mechanistically, CD63 associated with both beta 1 integrin and the main VEGF receptor on ECs, VEGFR2. Our data suggest that CD63 serves to bridge between beta 1 integrin and VEGFR2 because CD63 silencing disrupted VEGFR2-beta 1 integrin complex formation identified using proximity ligation assays. Signaling downstream of beta 1 integrin and VEGFR2 was attenuated in CD63-silenced cells, although their cell surface expression levels remained unaffected. CD63 was furthermore required for efficient internalization of VEGFR2 in response to VEGF. Importantly, systemic delivery of VEGF failed to potently induce VEGFR2 phosphorylation and downstream signaling in CD63-deficient mouse lungs. Taken together, our findings demonstrate a previously unrecognized role for CD63 in coordinated integrin and receptor tyrosine kinase signaling in vitro and in vivo.

  • 119.
    Tugues, Sònia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Honjo, Satoshi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    König, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Noguer, Oriol
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Hedlund, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Deschoemaeker, Sofie
    Wenes, Mathias
    Rolny, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Jahnen-Dechent, Wilhelm
    Mazzone, Massimiliano
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Genetic deficiency in plasma protein HRG enhances tumor growth and metastasis by exacerbating immune escape and vessel abnormalization2012In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445Article in journal (Refereed)
    Abstract [en]

    Histidine-rich glycoprotein (HRG) is a 75 kDa heparin-binding plasma protein implicated in the regulation of tumor growth and vascularization. In this study, we show that hrg-/- mice challenged with fibrosarcoma or pancreatic carcinomas grow larger tumors with increased metastatic properties. Compared with wild type mice, fibrosarcomas in hrg-/- mice were more hypoxic, necrotic and less perfused, indicating enhanced vessel abnormalization. HRG-deficiency was associated with a suppressed anti-tumor immune response, with both increased infiltration of M2-marker-expressing macrophages and decreased infiltration of dendritic cells and cytotoxic T cells. Analysis of transcript expression in tumor-associated as well as peritoneal macrophages from hrg-/- mice revealed an increased expression of genes associated with a pro-angiogenic and immunoinhibitory phenotype. In accordance, expression arrays performed on HRG-treated peritoneal macrophages showed induction of genes involved in extracellular matrix biology and immune responsiveness. In conclusion, our findings demonstrate that macrophages are a direct target of HRG. HRG loss influences macrophage gene regulation, leading to excess stimulation of tumor angiogenesis, suppression of tumor immune response, and increased tumor growth and metastatic spread.

  • 120. Van Steenkiste, Christophe
    et al.
    Ribera, Jordi
    Geerts, Anja
    Pauta, Montse
    Tugues, Sonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Casteleyn, Christophe
    Libbrecht, Louis
    Olievier, Kim
    Schroyen, Ben
    Reynaert, Hendrik
    van Grunsven, Leo A.
    Blomme, Bram
    Coulon, Stephanie
    Heindryckx, Femke
    De Vos, Martine
    Stassen, Jean Marie
    Vinckier, Stefan
    Altamirano, Jose
    Bataller, Ramon
    Carmeliet, Peter
    Van Vlierberghe, Hans
    Colle, Isabelle
    Morales-Ruiz, Manuel
    Inhibition of Placental Growth Factor Activity Reduces the Severity of Fibrosis, Inflammation, and Portal Hypertension in Cirrhotic Mice2011In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 53, no 5, p. 1629-1640Article in journal (Refereed)
    Abstract [en]

    Placental growth factor (PlGF) is associated selectively with pathological angiogenesis, and PlGF blockade does not affect the healthy vasculature. Anti-PlGF is therefore currently being clinically evaluated for the treatment of cancer patients. In cirrhosis, hepatic fibrogenesis is accompanied by extensive angiogenesis. In this paper, we evaluated the pathophysiological role of PlGF and the therapeutic potential of anti-PlGF in liver cirrhosis. PlGF was significantly up-regulated in the CCl4-induced rodent model of liver cirrhosis as well as in cirrhotic patients. Compared with wild-type animals, cirrhotic PlGF(-/-) mice showed a significant reduction in angiogenesis, arteriogenesis, inflammation, fibrosis, and portal hypertension. Importantly, pharmacological inhibition with anti-PlGF antibodies yielded similar results as genetic loss of PlGF. Notably, PlGF treatment of activated hepatic stellate cells induced sustained extracellular signal-regulated kinase 1/2 phosphorylation, as well as chemotaxis and proliferation, indicating a previously unrecognized profibrogenic role of PlGF. Conclusion: PlGF is a disease-candidate gene in liver cirrhosis, and inhibition of PlGF offers a therapeutic alternative with an attractive safety profile.

  • 121.
    Wallenquist, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Holmqvist, Karin
    Hånell, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ibuprofen attenuates the inflammatory response and allows formation of migratory neuroblasts from grafted stem cells after traumatic brain injury2012In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 30, no 1, p. 9-19Article in journal (Refereed)
    Abstract [en]

    Purpose: There is hope for neural stem and progenitor cells (NSPC) to enhance regeneration when transplanted to the injured brain after traumatic brain injury (TBI). So far, the therapeutic effects of NSPC transplantation have been hampered mainly by the notable death of the transplanted cells. Neuroinflammation may lead to additional cell death after TBI and we hypothesized that survival of grafted NSPC could be enhanced by anti-inflammatory treatment.

    Methods: Mice that were subjected to controlled cortical impact TBI and grafted with NSPC, were treated with the non-steroidal anti-inflammatory drug ibuprofen.

    Results: Ibuprofen was found to down-regulate the TBI-induced inflammatory response. In addition, migrating neuroblasts from transplanted cells were observed near the contusion and in the ipsilateral hippocampus in ibuprofen-treated animals only, suggesting that the anti-inflammatory treatment had beneficial effects on graft survival and/or differentiation. However, Morris Water Maze performance or TBI-induced tissue loss was not influenced by ibuprofen treatment.

    Conclusions: Our data suggests that anti-inflammatory strategies may be a complement to enhance the outcome for the cell transplants following TBI.

  • 122.
    Wallgard, Elisabet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Nitzsche, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Guo, Xiaoyuan
    Dieterich, Lothar C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pontén, Fredrik C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Maekinen, Taija
    Kalen, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Paladin (X99384) is expressed in the vasculature and shifts from endothelial to vascular smooth muscle cells during mouse development2012In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 241, no 4, p. 770-786Article in journal (Refereed)
    Abstract [en]

    Background: Angiogenesis is implicated in many pathological conditions. The role of the proteins involved remains largely unknown, and few vascular-specific drug targets have been discovered. Previously, in a screen for angiogenesis regulators, we identified Paladin (mouse: X99384, human: KIAA1274), a protein containing predicted S/T/Y phosphatase domains.

    Results: We present a mouse knockout allele for Paladin with a beta-galactosidase reporter, which in combination with Paladin antibodies demonstrate that Paladin is expressed in the vasculature. During mouse embryogenesis, Paladin is primarily expressed in capillary and venous endothelial cells. In adult mice Paladin is predominantly expressed in arterial pericytes and vascular smooth muscle cells. Paladin also displays vascular-restricted expression in human brain, astrocytomas, and glioblastomas.

    Conclusions: Paladin, a novel putative phosphatase, displays a dynamic expression pattern in the vasculature. During embryonic stages it is broadly expressed in endothelial cells, while in the adult it is selectively expressed in arterial smooth muscle cells.

  • 123.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Glioblastoma: a moving target2012In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 117, no 2, p. 251-256Article, review/survey (Refereed)
    Abstract [en]

    The slow development of effective treatment of glioblastoma is contrasted by the rapidly advancing research on the molecular mechanisms underlying the disease. Amplification and overexpression of receptor tyrosine kinases, particularly EGFR and PDGFRA, are complemented by mutations in the PI3K, RB1, and p53 signaling pathways. In addition to finding effective means to target these pathways, we may take advantage of the recent understanding of the hierarchical structure of tumor cell populations, where the progressive expansion of the tumor relies on a minor subpopulation of glioma stem cells, or gliomainitiating cells. Finding ways to reprogram these cells and block their self-renewal is one of the most important topics for future research.

  • 124.
    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.

  • 125.
    Wicher, Grzegorz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Holmqvist, Karin
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Common Denominators of Self-renewal and Malignancy in Neural Stem Cells and Glioma2012In: Stem Cells and Human Disease / [ed] Rakesh Srivastava & Sharmila Shankar, Dordrecht: Springer Netherlands, 2012, p. 387-418Chapter in book (Other academic)
  • 126.
    Wicher, Grzegorz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Husic, Ena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Gunnar
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Developmental expression of IL-33 in the mouse brain2013In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 555, p. 171-176Article in journal (Refereed)
    Abstract [en]

    IL-33 has important functions in inflammatory and autoimmune diseases. In the brain, models of experimental encephalomyelitis are accompanied by up-regulation of IL-33 expression, and the cytokine is seen as an amplifier of the innate immune response. Little is known, however, about IL-33 the normal brain in adult life, or during development. We have analyzed the expression of IL-33 in the mouse brain during embryonic and postnatal development. Here we report that IL-33 expression was first detected in the CNS during late embryogenesis. From postnatal day 2 (P2) until P9 the expression increased and was strongest in the cerebellum, pons and thalamus, as well as in olfactory bulbs. Expression of IL-33 then became weaker and declined until P23, and it was not present in the adult brain. Both astrocytes and oligodendrocyte precursors expressed IL-33. The vast majority of IL-33 positive cells in the brain displayed nuclear staining, and this was found to be the case also in vitro, using mixed glial cultures. Our data suggest that IL-33 expression is under tight regulation in the normal brain. Its detection during the first three weeks of postnatal life coincides with important parts of the CNS developmental programs, such as general growth and myelination. This opens the possibility that IL-33 plays a role also in the absence of an inflammatory response.

  • 127.
    Wicher, Grzegorz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallenquist, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Enoksson, M.
    Fuchs, B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Husic, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Nilsson, G.
    Forsberg Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Interleukin-33 in brain development and traumatic brain injury2013In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 61, no S1, p. S185-S185Article in journal (Other academic)
  • 128. Xiao, Zhijie
    et al.
    Rodriguez, Patricia Q.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Tryggvason, Karl
    Patrakka, Jaakko
    Wtip- and Gadd45a-Interacting Protein Dendrin Is Not Crucial for the Development or Maintenance of the Glomerular Filtration Barrier2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e83133-Article in journal (Refereed)
    Abstract [en]

    Glomerular podocyte cells are critical for the function of the renal ultrafiltration barrier. Especially, the highly specialized cell cell junction of podocytes, the slit diaphragm, has a central role in the filtration barrier. This is highlighted by the fact that mutations in molecular components of the slit diaphragm, inclucling nephrin and Cd2-associated protein (Cd2ap), result in proteinuric diseases in man. Dendrin is a poorly characterized cytosalic component of the slit diaphragm in where it interact h nephrin and Cd2ap. Dendrin is highly specific for the podocyte slit diaphragm, suggesting that it has a dedicated role in glomerular filtration barrier. In this study, we have generated a dendrin knockout mouse line and explored the molecular interactions of dendrin. Dendrin-deficient mice were viable, fertile, and had a normal life span. Morphologically, the glomerulogenesis proceeded normally and adult dendrin-deficient mice showed normal glomerular histology. No significant protainuria was observed. Fallowing glomerular injury, lack of dendrin did not affect the severity of the damage or h recovery process. Yeast two-hybrid screen and co-immunoprecipitation experiments showed that dendrin binds to interacting protein (Wtip) and growth arrest and DNA-damage-inducible 45 alpha (Gadd45a). Wtip and Gadd45a mediate gene transcription in the nucleus, suggesting that dendrin may have similar functions in podacytes In line with this, we observed he relocation of dendrin to nucleus in adriamycin nephropathy model. Our results indicate that dendrin is dispensable forth unction of the normal glomerular filtration barrier and that dendrin interacts with Wtip and Gadd45a.

  • 129.
    Xie, Yuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Bergström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Jiang, Yiwen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Lindberg, Nanna
    Marinescu, Voichita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Segerman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Wicher, Grzegorz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Niklasson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Sreedharan, Smitha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Hermansson, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Holland, Eric
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Forsberg-Nilsson, Karin
    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.
    Modeling Human Glioblastoma Subtypes in vitro using Stem Cell Culture ConditionsManuscript (preprint) (Other academic)
  • 130. Yao, Li-Chin
    et al.
    Testini, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Tvorogov, Denis
    Anisimov, Andrey
    Vargas, Sara O.
    Baluk, Peter
    Pytowski, Bronislaw
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Alitalo, Kari
    McDonald, Donald M.
    Pulmonary Lymphangiectasia Resulting From Vascular Endothelial Growth Factor-C Overexpression During a Critical Period2014In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 114, no 5, p. 806-822Article in journal (Refereed)
    Abstract [en]

    Rationale: Lymphatic vessels in the respiratory tract normally mature into a functional network during the neonatal period, but under some pathological conditions they can grow as enlarged, dilated sacs that result in the potentially lethal condition of pulmonary lymphangiectasia. Objective: We sought to determine whether overexpression of the lymphangiogenic growth factor (vascular endothelial growth factor-C [VEGF-C]) can promote lymphatic growth and maturation in the respiratory tract. Unexpectedly, perinatal overexpression of VEGF-C in the respiratory epithelium led to a condition resembling human pulmonary lymphangiectasia, a life-threatening disorder of the newborn characterized by respiratory distress and the presence of widely dilated lymphatics. Methods and Results: Administration of doxycycline to Clara cell secretory protein-reverse tetracycline-controlled transactivator/tetracycline operator-VEGF-C double-transgenic mice during a critical period from embryonic day 15.5 to postnatal day 14 was accompanied by respiratory distress, chylothorax, pulmonary lymphangiectasia, and high mortality. Enlarged sac-like lymphatics were abundant near major airways, pulmonary vessels, and visceral pleura. Side-by-side comparison revealed morphological features similar to pulmonary lymphangiectasia in humans. The condition was milder in mice given doxycycline after age postnatal day 14 and did not develop after postnatal day 35. Mechanistic studies revealed that VEGF recptor (VEGFR)-3 alone drove lymphatic growth in adult mice, but both VEGFR-2 and VEGFR-3 were required for the development of lymphangiectasia in neonates. VEGFR-2/VEGFR-3 heterodimers were more abundant in the dilated lymphatics, consistent with the involvement of both receptors. Despite the dependence of lymphangiectasia on VEGFR-2 and VEGFR-3, the condition was not reversed by blocking both receptors together or by withdrawing VEGF-C. Conclusions: The findings indicate that VEGF-C overexpression can induce pulmonary lymphangiectasia during a critical period in perinatal development.

  • 131.
    Yu, Di
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jin, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ramachandran, Mohanraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Xu, Jing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Berith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Le Blanc, Katarina
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Adamson, Rachel
    Maitland, Norman
    Fan, Xiaolong
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Adenovirus Serotype 5 Vectors with Tat-PTD Modified Hexon and Serotype 35 Fiber Show Greatly Enhanced Transduction Capacity of Primary Cell Cultures2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e54952-Article in journal (Refereed)
    Abstract [en]

    Recombinant adenovirus serotype 5 (Ad5) vectors represent one of the most efficient gene delivery vectors in life sciences. However, Ad5 is dependent on expression of the coxsackievirus-adenovirus- receptor (CAR) on the surface of target cell for efficient transduction, which limits it's utility for certain cell types. Herein we present a new vector, Ad5PTDf35, which is an Ad5 vector having serotype 35 fiber-specificity and Tat-PTD hexon-modification. This vector shows dramatically increased transduction capacity of primary human cell cultures including T cells, monocytes, macrophages, dendritic cells, pancreatic islets and exocrine cells, mesenchymal stem cells and tumor initiating cells. Biodistribution in mice following systemic administration (tail-vein injection) show significantly reduced uptake in the liver and spleen of Ad5PTDf35 compared to unmodified Ad5. Therefore, replication-competent viruses with these modifications may be further developed as oncolytic agents for cancer therapy. User-friendly backbone plasmids containing these modifications were developed for compatibility to the AdEasy-system to facilitate the development of surface-modified adenoviruses for gene delivery to difficult-to-transduce cells in basic, pre-clinical and clinical research.

  • 132.
    Çağlayan, Demet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Molecular and Cellular Complexity of Glioma: Highlights on the Double-Edged-Sword of Infiltration Versus Proliferation and the Involvement of T Cells2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glioblastoma multiforme (GBM), the most common and malignant brain tumor, is characterized by high molecular and cellular heterogeneity within and among tumors. Parameters such as invasive growth, infiltration of immune cells and endothelial proliferation contribute in a systemic manner to maintain the malignancy.

    Studies in this thesis show that the expression of Sox2 is correlated with Sox21 in human gliomas. We demonstrate that an upregulation of Sox21 induces loss of proliferation, apoptosis and differentiation in glioma cells in vitro and in vivo and seems to correlate with decreased Sox2 expression. Induced expression of Sox21 in vivo significantly reduces the tumor size and increase the survival extensively, suggesting that Sox21 can act as a tumor suppressor Our studies indicate that the balance of Sox21-Sox2 in glioma cells is decisive of either a proliferative or a non-proliferative state.

    Several TGFß family members have an important role in glioma development. TGFß promotes proliferation and tumorigenicity whereas BMPs mostly inhibit proliferation. We demonstrate that BMP7 can induce the transcription factor Snail in glioma cells and that this reduces the tumorigenicity with a concomitant increase in invasiveness. Thus, we have identified a mechanism to the double-edged sword of proliferation versus invasiveness in GBM, the latter contributing to relapse in patients.

    Experimental gliomas were induced with the Sleeping Beauty (SB) model in mice with different immunological status of their T cells. The tumors that developed were either GBMs or highly diffuse in their growth, reminiscent of gliomatosis cerebri (GC). GC is a highly uncommon form of glioma characterized by extensive infiltrative growth in large parts of the brain. It is an orphan disease and today there is practically a total lack of relevant experimental models. The SB system would constitute a novel experimental model to study the mechanisms behind the development of diffusely growing tumors like GC. The presence or absence of T cells did not affect tumor development.

    The work in this thesis demonstrates that the proliferative and the invasive capacities of glioma cells can be dissociated and that the SB model constitutes an excellent model to study the highly proliferative cells in GBMs versus the highly invasive cells in diffuse tumors like .GC.

    List of papers
    1. Forced expression of Sox21 inhibits Sox2 and induces apoptosis in human glioma cells
    Open this publication in new window or tab >>Forced expression of Sox21 inhibits Sox2 and induces apoptosis in human glioma cells
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    2011 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 129, no 1, p. 45-60Article in journal (Refereed) Published
    Abstract [en]

    Numerous studies support a role for Sox2 to keep stem cells and progenitor cells in an immature and proliferative state. Coexpression of Sox2 and GFAP has been found in regions of the adult brain where neural stem cells are present and in human glioma cells. In our study, we have investigated the roles of Sox2 and its counteracting partner Sox21 in human glioma cells. We show for the first time that Sox21 is expressed in both primary glioblastoma and in human glioma cell lines. We found that coexpression of Sox2, GFAP and Sox21 was mutually exclusive with expression of fibronectin. Our result suggests that glioma consists of at least two different cell populations: Sox2+/GFAP+/Sox21+/FN- and Sox2-/GFAP-/Sox21-/FN1+. Reduction of Sox2 expression by using siRNA against Sox2 or by overexpressing Sox21 using a tetracyclineregulated expression system (Tet-on) caused decreased GFAP expression and a reduction in cell number due to induction of apoptosis. We suggest that Sox21 can negatively regulate Sox2 in glioma. Our findings imply that Sox2 and Sox21 may be interesting targets for the development of novel glioma therapy.

    Keywords
    Glioma, brain tumor, Sox2, Sox21, GFAP
    National Category
    Cell and Molecular Biology
    Research subject
    Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-151784 (URN)10.1002/ijc.25647 (DOI)000289987300005 ()20824710 (PubMedID)
    Available from: 2011-04-18 Created: 2011-04-18 Last updated: 2018-01-12Bibliographically approved
    2. Sox21 inhibits glioma progression in vivo by reducing Sox2 and stimulating aberrant differentiation
    Open this publication in new window or tab >>Sox21 inhibits glioma progression in vivo by reducing Sox2 and stimulating aberrant differentiation
    Show others...
    2013 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 6, p. 1345-1356Article in journal (Refereed) Published
    Abstract [en]

    Sox2 is a transcription factor in neural stem cells and keeps the cells immature and proliferative. Sox2 is expressed in primary human glioma such as glioblastoma multiforme (GBM), primary glioma cells and glioma cell lines and is implicated in signaling pathways in glioma connected to malignancy. Sox21, the counteracting partner of Sox2, has the same expression pattern as Sox2 in glioma but in general induces opposite effects. In this study, Sox21 was overexpressed by using a tetracycline-regulated expression system (tet-on) in glioma cells. The glioma cells were injected subcutaneously into immunodeficient mice. The control tumors were highly proliferative, contained microvascular proliferation and large necrotic areas typical of human GBM. Induction of Sox21 in the tumor cells resulted in a significant smaller tumor size, and the effect correlated with the onset of treatment, where earlier treatment gave smaller tumors. Mice injected with glioma cells orthotopically into the brain survived significantly longer when Sox21 expression was induced. Tumors originating from glioma cells with an induced expression of Sox21 exhibited an increased formation of Sox2:Sox21 complexes and an upregulation of S100β, CNPase and Tuj1. Sox21 appears to decrease the stem-like cell properties of the tumor cells and initiate aberrant differentiation of glioma cells in vivo. Taken together our results indicate that Sox21 can function as a tumor suppressor during gliomagenesis mediated by a shift in the balance between Sox2 and Sox21. The wide distribution of Sox2 and Sox21 in GBM makes the Sox2/Sox21 axis a very interesting target for novel therapy of gliomas.

    Keywords
    brain tumors, glioma, Sox2, Sox21, S100
    National Category
    Medical and Health Sciences Cell and Molecular Biology
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-182943 (URN)10.1002/ijc.28147 (DOI)
    Available from: 2012-10-19 Created: 2012-10-19 Last updated: 2018-01-12Bibliographically approved
    3. Snail depletes the tumorigenic potential of glioblastoma
    Open this publication in new window or tab >>Snail depletes the tumorigenic potential of glioblastoma
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    2013 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 32, no 47, p. 5409-5420Article in journal (Refereed) Published
    Abstract [en]

    Glioblastoma multiforme (GBM) is an aggressive brain malignancy characterized by high heterogeneity and invasiveness. It is increasingly accepted that the refractory feature of GBM to current therapies stems from the existence of few tumorigenic cells that sustain tumor growth and spreading, the so-called glioma-initiating cells (GICs). Previous studies showed that cytokines of the bone morphogenetic protein (BMP) family induce differentiation of the GICs, and thus act as tumor suppressors. Molecular pathways that explain this behavior of BMP cytokines remain largely elusive. Here, we show that BMP signaling induces Smad-dependent expression of the transcriptional regulator Snail in a rapid and sustained manner. Consistent with its already established promigratory function in other cell types, we report that Snail silencing decreases GBM cell migration. Consequently, overexpression of Snail increases GBM invasiveness in a mouse xenograft model. Surprisingly, we found that Snail depletes the GBM capacity to form gliomaspheres in vitro and to grow tumors in vivo, both of which are important features shared by GICs. Thus Snail, acting downstream of BMP signaling, dissociates the invasive capacity of GBM cells from their tumorigenic potential.

    Keywords
    BMP, glioblastoma multiforme, glioma initiating cells, invasiveness, Snail
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-182944 (URN)10.1038/onc.2013.67 (DOI)000327177600004 ()23524585 (PubMedID)
    Available from: 2012-10-19 Created: 2012-10-19 Last updated: 2018-12-03Bibliographically approved
    4. Induction of Glioblastoma Multiforme and Gliomatosis Cerebri with a Sleeping Beauty gene transfer system, implications for T regulatory cell involvement during glioma formation.
    Open this publication in new window or tab >>Induction of Glioblastoma Multiforme and Gliomatosis Cerebri with a Sleeping Beauty gene transfer system, implications for T regulatory cell involvement during glioma formation.
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Glioblastoma Multiforme (GBM), the most malignant and common  neoplasm of the central nervous system (CNS), has been classified into subgroups with gene-expression profile as the basis for categorization. Among these the mesenchymal subgroup is most greatly associated with inflammatory infiltrates and increased expression of inflammatory associated genes. GBMs exhibit T cell infiltration to a varying degree and today the degree of infiltration is not used in prognostics. The Sleeping Beauty (SB) system was used to introduce AKT, a mutant variant of NRAS and a shp53 coupled to green fluorescent protein (GFP) into mice that are fully immunocomptetent, lack mature T cells or have reduced regulatory T (Treg) cell function respectively. We report, for the first time, the induction of Gliomatosis Cerebri with the SB system. Tumors that originated were either GBM or Gliomatosis Cerebri with a similar incidence. There was no difference in survival, grade or incidence of induced tumors in wild type mice and mice that lack mature T cells.

    Keywords
    : brain tumors, Sleeping Beauty, T cells, AKT, NRAS, shp53
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-183668 (URN)
    Available from: 2012-10-31 Created: 2012-10-31 Last updated: 2013-02-11
123 101 - 132 of 132
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