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  • 1.
    Adler, Jeremy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Parmryd, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Colocalization Analysis in Fluorescence Microscopy2012In: Cell Imaging Techniques: Methods and Protocols / [ed] Taatjes, Douglas J. & Roth, Jürgen, New York: Humana Press, 2012, p. 97-109Chapter in book (Refereed)
    Abstract [en]

    The measurement of colocalization requires images of two fluorophores that are aligned, with no cross talk, and that the intensities remain within the response range of the microscope. Quantitation depends upon differentiating between the presence and absence of fluorescence, and measurements should be made within biologically relevant regions of interest. Co-occurrence can be measured simply by area or with the M1 and M2 coefficients, and should be compared to random distributions. Correlation analysis should use the Pearson and Spearman coefficients, which need to be measured by replicate based noise corrected correlation to eliminate errors arising from differences in image quality. Ideally, both co-occurrence and correlation should be reported.

  • 2.
    Adler, Jeremy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Parmryd, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Quantification of Colocalisation; Co-Occurrence, Correlation, Empty Voxels, Regions of Interest and Thresholding2014In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 602A-602AArticle in journal (Other academic)
    Abstract [en]

    Measuring colocalisation is not straightforward with a plethora of coefficients that encapsulate different definitions. Measurements may also be implemented differently. Not only do measurements differ; interconversion is impossible making comparisons challenging. There is a need to cull coefficients and for clear definitions of what precisely is meant by colocalisation in individual studies. Colocalisation can be considered to have two components; co-occurrence which reports whether the fluorophores are found together and correlation which reports on the similarity in their patterns of intensity.

  • 3.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Teichmann, Martin
    Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux 2, rue , Robert Escarpit, 33607 Pessac, France..
    Jernberg Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Smit, Arian
    Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Singh, Umashankar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs2016In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 15, no 12, p. 1558-1571Article in journal (Refereed)
    Abstract [en]

    CGGBP1 (CGG triplet repeat-binding protein 1) regulates cell proliferation, stress response,cytokinesis, telomeric integrity and transcription. It could affect these processes by modulatingtarget gene expression under different conditions. Identification of CGGBP1-target genes andtheir regulation could reveal how a transcription regulator affects such diverse cellular processes.Here we describe the mechanisms of differential gene expression regulation by CGGBP1 inquiescent or growing cells. By studying global gene expression patterns and genome-wide DNAbindingpatterns of CGGBP1, we show that a possible mechanism through which it affects theexpression of RNA Pol II-transcribed genes in trans depends on Alu RNA. We also show that itregulates Alu transcription in cis by binding to Alu promoter. Our results also indicate thatpotential phosphorylation of CGGBP1 upon growth stimulation facilitates its nuclear retention,Alu-binding and dislodging of RNA Pol III therefrom. These findings provide insights into howAlu transcription is regulated in response to growth signals.

  • 4.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ehrencrona, Hans
    Gallini, Radiosa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Lal, Mark
    Ding, Hao
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Analysis of Mice Lacking the Heparin-Binding Splice Isoform of Platelet-Derived Growth Factor A2013In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 33, no 20, p. 4030-4040Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor A-chain (PDGF-A) exists in two evolutionarily conserved isoforms, PDGF-Along and PDGF-Ashort, generated by alternative RNA splicing. They differ by the presence (in PDGF-Along) or absence (in PDGF-Ashort) of a carboxyterminal heparin/heparan sulfate proteoglycan-binding motif. In mice, similar motifs present in other members of the PDGF and vascular endothelial growth factor (VEGF) families have been functionally analyzed in vivo, but the specific physiological importance of PDGF-A(long) has not been explored previously. Here, we analyzed the absolute and relative expression of the two PDGF-A splice isoforms during early postnatal organ development in the mouse and report on the generation of a Pdgfa allele (Pdgfa(Delta ex6) incapable of producing PDGF-A(long) due to a deletion of the exon 6 splice acceptor site. In situations of limiting PDGF-A signaling through PDGF receptor alpha (PDGFR alpha), or in mice lacking PDGF-C, homozygous carriers of Pdgfa(Delta ex6) showed abnormal development of the lung, intestine, and vertebral column, pinpointing developmental processes where PDGF-A(long) may play a physiological role.

  • 5.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Gouveia, Maria Leonor Seguardo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    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
    Characterization of Platelet-Derived Growth Factor-A Expression in Mouse Tissues Using a lacZ Knock-In Approach2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e105477-Article in journal (Refereed)
    Abstract [en]

    Expression of the platelet-derived growth factor A-chain gene (Pdgfa) occurs widely in the developing mouse, where it is mainly localized to various epithelial and neuronal structures. Until now, in situ mRNA hybridization (ISH) has been the only reliable method to identify Pdgfa expression in tissue sections or whole mount preparations. Validated protocols for in situ detection of PDGF-A protein by immunohistochemistry is lacking. In particular, this has hampered understanding of Pdgfa expression pattern in adult tissues, where ISH is technically challenging. Here, we report a gene targeted mouse Pdgfa allele, Pdgfa(ex4COIN), which is a combined conditional knockout and reporter allele. Cre-mediated inversion of the COIN cassette inactivates Pdgfa coding while simultaneously activating a beta-galactosidase (lacZ) reporter under endogenous Pdgfa transcription control. The generated Pdgfa(ex4COIN-INV-lacZ) allele can next be used to identify cells carrying a Pdgfa null allele, as well as to map endogenous Pdgfa expression. We evaluated the Pdgfa(ex4COIN-INV-lacZ) allele as a reporter for endogenous Pdgfa expression patterns in mouse embryos and adults. We conclude that the expression pattern of Pdgfa(ex4COIN-INV-lacZ) recapitulates known expression patterns of Pdgfa. We also report on novel embryonic and adult Pdgfa expression patterns in the mouse and discuss their implications for Pdgfa physiology.

  • 6. Arthur-Farraj, Peter J.
    et al.
    Latouche, Morwena
    Wilton, Daniel K.
    Quintes, Susanne
    Chabrol, Elodie
    Banerjee, Annbily
    Woodhoo, Ashwin
    Jenkins, Billy
    Rahman, Mary
    Turmaine, Mark
    Wicher, Grzegorz K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Mitter, Richard
    Greensmith, Linda
    Behrens, Axel
    Raivich, Gennadij
    Mirsky, Rhona
    Jessen, Kristjan R.
    c-Jun Reprograms Schwann Cells of Injured Nerves to Generate a Repair Cell Essential for Regeneration2012In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 75, no 4, p. 633-647Article in journal (Refereed)
    Abstract [en]

    The radical response of peripheral nerves to injury (Wallerian degeneration) is the cornerstone of nerve repair. We show that activation of the transcription factor c-Jun in Schwann cells is a global regulator of Wallerian degeneration. c-Jun governs major aspects of the injury response, determines the expression of trophic factors, adhesion molecules, the formation of regeneration tracks and myelin clearance and controls the distinctive regenerative potential of peripheral nerves. A key function of c-Jun is the activation of a repair program in Schwann cells and the creation of a cell specialized to support regeneration. We show that absence of c-Jun results in the formation of a dysfunctional repair cell, striking failure of functional recovery, and neuronal death. We conclude that a single glial transcription factor is essential for restoration of damaged nerves, acting to control the transdifferentiation of myelin and Remak Schwann cells to dedicated repair cells in damaged tissue.

  • 7. Aspelund, Aleksanteri
    et al.
    Tammela, Tuomas
    Antila, Salli
    Nurmi, Harri
    Leppanen, Veli-Matti
    Zarkada, Georgia
    Stanczuk, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Francois, Mathias
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Saharinen, Pipsa
    Immonen, Ilkka
    Alitalo, Kari
    The Schlemm's canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel2014In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, no 9, p. 3975-3986Article in journal (Refereed)
    Abstract [en]

    In glaucoma, aqueous outflow into the Schlemm's canal (SC) is obstructed. Despite striking structural and functional similarities with the lymphatic vascular, system, it is unknown whether the SC is a blood or lymphatic vessel. Here, we demonstrated the expression of lymphatic endothelial cell markers by the SC in murine and zebrafish models as well as in human eye tissue. The initial stages of SC development involved induction of the transcription factor PROX1 and the lymphangiogenic receptor tyrosine kinase VEGFR-3 in venous endothelial cells in postnatal mice. Using gene deletion and function-blocking antibodies in mice, we determined that the lymphangiogenic growth factor VEGF-C and its receptor, VEGFR-3, are essential for SC development. Delivery of VEGF-C into the adult eye resulted in sprouting, proliferation, and growth of SC endothelial cells, whereas VEGF-A obliterated the aqueous outflow system. Furthermore, a single injection of recombinant VEGF-C induced SC growth and was associated with trend toward a sustained decrease in intraocular pressure in adult mice. These results reveal the evolutionary conservation of the lymphatic-like phenotype of the SC, implicate VEGF-C and VEGFR-3 as critical regulators of SC lymphangiogenesis, and provide a basis for further studies on therapeutic manipulation of the SC with VEGF-C in glaucoma treatment.

  • 8.
    Babateen, Omar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    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.
    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.
    Uhrbom, Lene
    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.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Etomidate, propofol and diazepam potentiate GABA-evoked GABAA currents in a cell line derived from Human glioblastoma2015In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 748, p. 101-107Article in journal (Refereed)
    Abstract [en]

    GABAA receptors are pentameric chloride ion channels that are opened by GABA. We have screened a cell line derived from human glioblastoma, U3047MG, for expression of GABAA receptor subunit isoforms and formation of functional ion channels. We identified GABAA receptors subunit α2, α3, α5, β1, β2, β3, δ, γ3, π, and θ mRNAs in the U3047MG cell line. Whole-cell GABA-activated currents were recorded and the half-maximal concentration (EC50) for the GABA-activated current was 36μM. The currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and enhanced by the benzodiazepine diazepam (1μM) and the general anesthetics etomidate and propofol (50μM). In line with the expressed GABAA receptors containing at least the α3β3θ subunits, the receptors were highly sensitive to etomidate (EC50=55nM). Immunocytochemistry identified expression of the α3 and β3 subunit proteins. Our results show that the GABAA receptors in the glial cell line are functional and are modulated by classical GABAA receptor drugs. We propose that the U3047MG cell line may be used as a model system to study GABAA receptors function and pharmacology in glial cells.

  • 9.
    Bandopadhayay, Pratiti
    et al.
    Departments of Cancer Biology and Pediatric Neuro-Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology/Oncology, Boston Children's Hospital; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
    Bergthold, Guillaume
    Departments of Cancer Biology, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology/Oncology, Boston Children's Hospital; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
    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. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schumacher, Steven E.
    Zeid, Rhamy
    Masoud, Sabran
    Yu, Furong
    Vue, Nujsaubnusi
    Gibson, William J.
    Paolella, Brenton R.
    Mitra, Siddhartha S.
    Cheshier, Samuel H.
    Qi, Jun
    Liu, Kun-Wei
    Wechsler-Reya, Robert
    Weiss, William A.
    Department of Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, California.
    Swartling, Fredrik J.
    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.
    Kieran, Mark W.
    Bradner, James E.
    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
    Beroukhim, Rameen
    Departments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; Center for Cancer Genome Characterization, Dana-Farber Cancer Institute, Boston; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts;.
    Cho, Yoon-Jae
    Departments of Neurology and Neurological Sciences and Neurosurgery, Stanford University School of Medicine; Stanford Cancer Institute, Stanford University Medical Center, Stanford.
    BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma2014In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 20, no 4, p. 912-925Article in journal (Refereed)
    Abstract [en]

    Purpose:

    MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma.

    Experimental Design:

    We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice.

    Results:

    Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index.

    Conclusion:

    JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.

  • 10. 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)
  • 11. Benedito, Rui
    et al.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Notch as a hub for signaling in angiogenesis2013In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 319, no 9, p. 1281-1288Article, review/survey (Refereed)
  • 12. Bentley, Katie
    et al.
    Franco, Claudio Areias
    Philippides, Andrew
    Blanco, Raquel
    Dierkes, Martina
    Gebala, Veronique
    Stanchi, Fabio
    Jones, Martin
    Aspalter, Irene M.
    Cagna, Guiseppe
    Weström, Simone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Vestweber, Dietmar
    Gerhardt, Holger
    The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis2014In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 16, no 4, p. 309-321Article in journal (Refereed)
    Abstract [en]

    Endothelial cells show surprising cell rearrangement behaviour during angiogenic sprouting; however, the underlying mechanisms and functional importance remain unclear. By combining computational modelling with experimentation, we identify that Notch/VEGFR-regulated differential dynamics of VE-cadherin junctions drive functional endothelial cell rearrangements during sprouting. We propose that continual flux in Notch signalling levels in individual cells results in differential VE-cadherin turnover and junctional-cortex protrusions, which powers differential cell movement. In cultured endothelial cells, Notch signalling quantitatively reduced junctional VE-cadherin mobility. In simulations, only differential adhesion dynamics generated long-range position changes, required for tip cell competition and stalk cell intercalation. Simulation and quantitative image analysis on VE-cadherin junctional patterning in vivo identified that differential VE-cadherin mobility is lost under pathological high VEGF conditions, in retinopathy and tumour vessels. Our results provide a mechanistic concept for how cells rearrange during normal sprouting and how rearrangement switches to generate abnormal vessels in pathologies.

  • 13.
    Bergström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Modeling Neural Stem Cell and Glioma Biology2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is focused on neural stem cell (NSC) and glioma biology. I discuss how NSCs interact with extracellular matrix (ECM) proteins in the stem cell niche, and investigate the consequences of deregulated Platelet-derived growth factor (PDGF) signaling for embryonic NSCs in transgenic mice. Furthermore I present cell cultures of human glioblastoma multiforme (GBM) that models human disease, taking into account the heterogeneity of GBM. Finally, interactions between brain tumors and mast cells are studied using the glioma cultures.

    In paper I, the importance of NSC interactions with the ECM in the stem cell niche during development is discussed. Contacts between NSCs and the ECM in the subventricular zone (SVZ) are emerging as important regulatory mechanisms. We show that early postnatal neural stem and progenitor cells (NSPC) attach to collagen I, and that the adhesion is explained by higher expression of collagen receptor integrins compared to adult NSPC. Further, blood vessels in the SVZ express collagen I, indicating a possible functional relationship.

    Growth factors, e.g. PDGF, regulate NSC proliferation and differentiation. Aberrant activation of growth factor signaling pathways also plays a role in brain tumor formation. Paper II demonstrates that transgenic mice expressing PDGF-B at high levels in embryonic NSCs displayed mild neurological defects but no hyperplasia or brain tumors. This suggests that a high level of PDGF is not sufficient to induce brain tumors from NSCs without further mutations.

    Paper III presents a novel panel of human glioma stem cell (GSC) lines from GBM that display NSC markers in vitro and form secondary orthotopic tumors in vivo. GBM has recently been categorized in molecular subclasses and we demonstrate, for the first time, that these subclasses can be retained in vitro by stem cell culture conditions. We have thus generated models for research and drug development aiming at a focused treatment depending on GBM subtype.

    Interactions with the immune system are integral parts of tumorigenesis. Mast cells are found in glioma and in paper IV we demonstrate that the grade-dependent infiltration of mast cells is in part mediated by macrophage migration inhibitory factor and phosphorylation of STAT5.

     

     

    List of papers
    1. Temporally Regulated Collagen/Integrin Interactions Confer Adhesive Properties to Early Postnatal Neural Stem Cells
    Open this publication in new window or tab >>Temporally Regulated Collagen/Integrin Interactions Confer Adhesive Properties to Early Postnatal Neural Stem Cells
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-204940 (URN)
    Available from: 2013-08-13 Created: 2013-08-13 Last updated: 2018-01-11
    2. Enlarged lateral ventricles and aberrant behavior in mice overexpressing PDGF-B in embryonic neural stem cells
    Open this publication in new window or tab >>Enlarged lateral ventricles and aberrant behavior in mice overexpressing PDGF-B in embryonic neural stem cells
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    2010 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 316, no 17, p. 2779-2789Article in journal (Refereed) Published
    Abstract [en]

    Platelet-derived growth factor (PDGF) is important in central nervous system (CNS) development, and aberrant expression of PDGF and its receptors has been linked to developmental defects and brain tumorigenesis. We previously found that neural stem and progenitor cells in culture produce PDGF and respond to it by autocrine and/or paracrine signaling. We therefore aimed to examine CNS development after PDGF overexpression in neural stem cells in vivo. Transgenic mice were generated with PDGF-B under control of a minimal nestin enhancer element, which is specific for embryonic expression and will not drive adult expression in mice. The resulting mouse showed increased apoptosis in the developing striatum, which suggests a disturbed regulation of progenitor cells. Later in neurodevelopment, in early postnatal life, mice displayed enlarged lateral ventricles. This enlargement remained into adulthood and it was more pronounced in male mice than in transgenic female mice. Nevertheless, there was an overall normal composition of cell types and numbers in the brain and the transgenic mice were viable and fertile. Adult transgenic males, however, showed behavioral aberrations and locomotor dysfunction. Thus, a tightly regulated expression of PDGF during embryogenesis is required for normal brain development and function in mice.

    Keywords
    Transgenic, PDGF, neural stem cell, nestin
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-138074 (URN)10.1016/j.yexcr.2010.07.009 (DOI)000282357300007 ()20643125 (PubMedID)
    Available from: 2010-12-16 Created: 2010-12-16 Last updated: 2017-12-11Bibliographically approved
    3. Modeling Human Glioblastoma Subtypes in vitro using Stem Cell Culture Conditions
    Open this publication in new window or tab >>Modeling Human Glioblastoma Subtypes in vitro using Stem Cell Culture Conditions
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-204943 (URN)
    Available from: 2013-08-13 Created: 2013-08-13 Last updated: 2018-01-11
    4.
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  • 14.
    Bergström, Tobias
    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.
    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.
    Neural stem cells: Brain building blocks and beyond2012In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 117, no 2, p. 132-142Article, review/survey (Refereed)
    Abstract [en]

    Neural stem cells are the origins of neurons and glia and generate all the differentiated neural cells of the mammalian central nervous system via the formation of intermediate precursors. Although less frequent, neural stem cells persevere in the postnatal brain where they generate neurons and glia. Adult neurogenesis occurs throughout life in a few limited brain regions. Regulation of neural stem cell number during central nervous system development and in adult life is associated with rigorous control. Failure in this regulation may lead to e. g. brain malformation, impaired learning and memory, or tumor development. Signaling pathways that are perturbed in glioma are the same that are important for neural stem cell self-renewal, differentiation, survival, and migration. The heterogeneity of human gliomas has impeded efficient treatment, but detailed molecular characterization together with novel stem cell-like glioma cell models that reflect the original tumor gives opportunities for research into new therapies. The observation that neural stem cells can be isolated and expanded in vitro has opened new avenues for medical research, with the hope that they could be used to compensate the loss of cells that features in several severe neurological diseases. Multipotent neural stem cells can be isolated from the embryonic and adult brain and maintained in culture in a defined medium. In addition, neural stem cells can be derived from embryonic stem cells and induced pluripotent stem cells by in vitro differentiation, thus adding to available models to study stem cells in health and disease.

  • 15.
    Bergström, Tobias
    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.
    Holmqvist, Karin
    Tararuk, Tatsiana
    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.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    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.
    Developmentally regulated collagen/integrin interactions confer adhesive properties to early postnatal neural stem cells2014In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1840, no 8, p. 2526-2532Article in journal (Refereed)
    Abstract [en]

    Background:

    It is becoming increasingly apparent that the extracellular matrix acts as an important regulator of the neural stem niche. Previously we found that neural stem and progenitor cells (NSPCs) derived from the early postnatal subventricular zone of mice adhere to a collagen/hyaluronan hydrogel, whereas NSPCs from the adult and embryonic brain do not.

    Methods:

    To examine the specific adhesive properties of young stem cells in more detail, NSPCs isolated from embryonic, postnatal day 6 (P6), and adult mouse brains were cultured on collagen I.

    Results:

    Early postnatal NSPCs formed paxillin-positive focal adhesions on collagen I, and these adhesions could be prevented by an antibody that blocked integrin beta 1. Furthermore, we found the corresponding integrin alpha subunits alpha 2 and alpha 11 levels to be highest at the postnatal stage. Gene ontology analysis of differentially expressed genes showed higher expression of transcripts involved in vasculature development and morphogenesis in P6 stem cells, compared to adult.

    Conclusions:

    The ability to interact with the extracellular matrix differs between postnatal and adult NSPCs.

    General significance:

    Our observations that the specific adhesive properties of early postnatal NSPCs, which are lost in the adult brain, can be ascribed to the integrin subunits expressed by the former furthering our understanding of the developing neurogenic niche. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.  

  • 16.
    Bergström, Tobias
    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
    Tararuk, Tatsiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Temporally Regulated Collagen/Integrin Interactions Confer Adhesive Properties to Early Postnatal Neural Stem CellsManuscript (preprint) (Other academic)
  • 17.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Institutionen för medicinsk biokemi och biofysik, Karolinska Institutet.
    Double function at the blood-brain barrier2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 509, no 7501, p. 432-433Article in journal (Other academic)
  • 18.
    Betsholtz, Christer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Keller, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    PDGF, Pericytes and the Pathogenesis of Idiopathic Basal Ganglia Calcification (IBGC)2014In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 24, no 4, p. 387-395Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factors (PDGFs) are important mitogens for various types of mesenchymal cells, and as such, they exert critical functions during organogenesis in mammalian embryonic and early postnatal development. Increased or ectopic PDGF activity may also cause or contribute to diseases such as cancer and tissue fibrosis. Until recently, no loss-of-function (LOF) mutations in PDGF or PDGF receptor genes were reported as causally linked to a human disease. This changed in 2013 when reports appeared on presumed LOF mutations in the genes encoding PDGF-B and its receptor PDGF receptor-beta (PDGF-R) in familial idiopathic basal ganglia calcification (IBGC), a brain disease characterized by anatomically localized calcifications in or near the blood microvessels. Here, we review PDGF-B and PDGF-R biology with special reference to their functions in brain-blood vessel development, pericyte recruitment and the regulation of the blood-brain barrier. We also discuss various scenarios for IBGC pathogenesis suggested by observations in patients and genetically engineered animal models of the disease.

  • 19.
    Boije, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Investigations of Proneural Glioblastoma to Identify Novel Therapeutic Targets2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Malignant glioma is a highly lethal and destructive disease with no proper cure. We have investigated some of the hallmarks of cancer in connection to glioma and found ways to disrupt these and prevent tumor growth. The work is done within the context of a glioma subtype distinguished by activation of PDGF signaling termed the proneural subtype. In two of the studies we have investigated mechanisms regulating the glioma cells themselves, and in the other two we have focused on the tumor stroma.

    In the first study, glioma-initiating cells were isolated in defined serum free culture medium from PDGF-B driven murine glioma and shown to be independent of EGF and FGF2 for self-renewal and proliferation. When cultured in serum the GICs displayed an aberrant differentiation pattern that was reversible. Specific depletion of the transduced PDGF-B caused a loss of self-renewal and tumorigenicity and induced oligodendrocyte differentiation.

    The transcription factor S-SOX5 has previously been shown to have a tumor suppressive effect on PDGF-B induced murine glioma, and to induce cellular senescence in PDGF-B stimulated cells in vitro. We found that S-SOX5 had a negative effect on proliferation of newly established human glioma cells cultured under stem cell conditions. We also revealed a connection between alterations causing up-regulation of SOX5 with the proneural subgroup and a tendency towards co-occurrence with PDGFRA alterations.

    Angiogenesis, the formation of new blood vessels from existing ones, is an important hallmark for glioma malignancy. We found that the anti-angiogenic protein HRG had a negative effect on glioma progression in PDGF-B induced experimental tumors and that HRG was able to completely prevent formation of glioblastomas.

    Subsequently it was shown that HRG could skew pro-tumorigenic tumor associated macrophages into an anti-tumorigenic phenotype. Stromal cells had not previously been fully investigated in gliomas. We observed a correlation between tumor malignancy and increased numbers of tumor-associated macrophages as well as pericytes in PDGF-B induced gliomas. There was also a correlation between tumor grade and vessel functionality that had not previously been shown.

    Our results offer further understanding of gliomagenesis and present possible future therapies.

    List of papers
    1. PDGF-B Can sustain self-renewal and tumorigenicity of experimental glioma-derived cancer-initiating cells by preventing oligodendrocyte differentiation
    Open this publication in new window or tab >>PDGF-B Can sustain self-renewal and tumorigenicity of experimental glioma-derived cancer-initiating cells by preventing oligodendrocyte differentiation
    2011 (English)In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 13, no 6, p. 492-503Article in journal (Refereed) Published
    Abstract [en]

    According to the cancer stem cell (CSC)/cancer-initiating cell hypothesis, glioma development is driven by a sub-population of cells with unique tumor-regenerating capacity. We have characterized sphere-cultured glioma-derived cancer-initiating cells (GICs) from experimental gliomas induced by platelet-derived growth factor-B (PDGF-B) in neonatal Gtv-a Arf(-/-) mice. We found that the GICs can maintain their stem cell-like characteristics in absence of exogenous epidermal growth factor and fibroblast growth factor 2 and that this culture condition was highly selective for tumor-initiating cells where as few as five GICs could induce secondary tumor formation after orthotopic transplantation. Addition of FBS to the medium caused the GICs to differentiate into cells coexpressing glial fibrillary acidic protein and Tuj1, and this differentiation process was reversible, suggesting that the GICs are highly plastic and able to adapt to different environments without losing their tumorigenic properties. On inhibition of virally transduced PDGF-B by small interfering RNA treatment, the GICs stopped proliferating, lost their self-renewal ability, and started to uniformly express CNPase, a marker of oligodendrocyte precursor cells and mature oligodendrocytes. Most importantly, PDGF-B depletion completely abrogated the tumor-initiating capacity of the GICs. Our findings suggest that interfering with PDGF-controlled differentiation could be a therapeutic avenue for patients diagnosed with the PDGF-driven proneural subtype of human glioblastoma.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-158264 (URN)10.1593/neo.11314 (DOI)000295448800001 ()21677873 (PubMedID)
    Available from: 2011-09-05 Created: 2011-09-05 Last updated: 2017-12-08Bibliographically approved
    2. Upregulation of SOX5 can be linked to proneural glioblastoma and perturbs glioma cell proliferation
    Open this publication in new window or tab >>Upregulation of SOX5 can be linked to proneural glioblastoma and perturbs glioma cell proliferation
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cell and Molecular Biology
    Research subject
    Experimental Pathology
    Identifiers
    urn:nbn:se:uu:diva-158377 (URN)
    Available from: 2011-09-06 Created: 2011-09-06 Last updated: 2018-01-12
    3. Histidine-rich glycoprotein can prevent development of mouse experimental glioblastoma
    Open this publication in new window or tab >>Histidine-rich glycoprotein can prevent development of mouse experimental glioblastoma
    Show others...
    2009 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 4, no 12, p. e8536-Article in journal (Refereed) Published
    Abstract [en]

    Extensive angiogenesis, formation of new capillaries from pre-existing blood vessels, is an important feature of malignant glioma. Several antiangiogenic drugs targeting vascular endothelial growth factor (VEGF) or its receptors are currently in clinical trials as therapy for high-grade glioma and bevacizumab was recently approved by the FDA for treatment of recurrent glioblastoma. However, the modest efficacy of these drugs and emerging problems with anti-VEGF treatment resistance welcome the development of alternative antiangiogenic therapies. One potential candidate is histidine-rich glycoprotein (HRG), a plasma protein with antiangiogenic properties that can inhibit endothelial cell adhesion and migration. We have used the RCAS/TV-A mouse model for gliomas to investigate the effect of HRG on brain tumor development. Tumors were induced with platelet-derived growth factor-B (PDGF-B), in the presence or absence of HRG. We found that HRG had little effect on tumor incidence but could significantly inhibit the development of malignant glioma and completely prevent the occurrence of grade IV tumors (glioblastoma).

     

    National Category
    Cell and Molecular Biology
    Research subject
    Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-109484 (URN)10.1371/journal.pone.0008536 (DOI)000273180200017 ()20046875 (PubMedID)
    Available from: 2009-10-15 Created: 2009-10-15 Last updated: 2018-01-12Bibliographically approved
    4. Malignancy of PDGF-BB driven glioma correlates with increased infiltration of pro-angiogenic macrophages and mesenchymal cells
    Open this publication in new window or tab >>Malignancy of PDGF-BB driven glioma correlates with increased infiltration of pro-angiogenic macrophages and mesenchymal cells
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cell and Molecular Biology
    Research subject
    Experimental Pathology
    Identifiers
    urn:nbn:se:uu:diva-158378 (URN)
    Available from: 2011-09-06 Created: 2011-09-06 Last updated: 2018-01-12
  • 20.
    Boije, Maria
    et al.
    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.
    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.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Upregulation of SOX5 can be linked to proneural glioblastoma and perturbs glioma cell proliferationManuscript (preprint) (Other academic)
  • 21.
    Boije, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Sobocki, Caroline
    Jiang, Yiwen
    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.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Rolny, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Malignancy of PDGF-BB driven glioma correlates with increased infiltration of pro-angiogenic macrophages and mesenchymal cellsManuscript (preprint) (Other academic)
  • 22.
    Bolin, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Lau, Jasmine
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Chen, Justin
    Persson, Anders I.
    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.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    A glial origin for medulloblastoma and inhibition of MYCN stabilization2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8Article in journal (Other academic)
  • 23.
    Caglayan, Demet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Lundin, Erika
    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.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ferletta, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Sox21 inhibits glioma progression in vivo by forming complexes with Sox2 and stimulating aberrant differentiation2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 6, p. 1345-1356Article in journal (Refereed)
    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 S100, 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. What's new? Glioma formation is driven by brain tumor-initiating cells with stem cell-like properties. Here the authors show for the first time that the transcription factor Sox21 can act as a suppressor gene in gliomagenesis. Induced expression of Sox21 in human glioma cells results in reduced tumor growth and prolonged survival of xenotranplanted mice. Sox21 reduces the stem-cell like properties of the tumor cells, leading to abnormal differentiation, induced apoptosis, and decreased proliferation. The results point to a shift in balance between the counteracting and widely distributed Sox2 and Sox21, revealing the Sox2/Sox21 axis as a target for novel therapy of gliomas.

  • 24.
    Caglayan, Demet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Lundin, Erika
    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.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ferletta, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Sox21 inhibits glioma progression in vivo by reducing Sox2 and stimulating aberrant differentiation2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 6, p. 1345-1356Article in journal (Refereed)
    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.

  • 25.
    Caglayan, Demet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Moriarity, Branden
    Department of Genetics, Cell biology and Development, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. .
    Tschida, Barbara Ryan
    Department of Genetics, Cell biology and Development, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. .
    Kastemar, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Largaespada, David
    Department of Genetics, Cell biology and Development, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. .
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Induction of Glioblastoma Multiforme and Gliomatosis Cerebri with a Sleeping Beauty gene transfer system, implications for T regulatory cell involvement during glioma formation.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.

  • 26. Carneiro, Miguel
    et al.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Di Palma, Federica
    Albert, Frank W.
    Alfoeldi, Jessica
    Barrio, Alvaro Martinez
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rafati, Nima
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sayyab, Shumaila
    Turner-Maier, Jason
    Younis, Shady
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Afonso, Sandra
    Aken, Bronwen
    Alves, Joel M.
    Barrell, Daniel
    Bolet, Gerard
    Boucher, Samuel
    Burbano, Hernan A.
    Campos, Rita
    Chang, Jean L.
    Duranthon, Veronique
    Fontanesi, Luca
    Garreau, Herve
    Heiman, David
    Johnson, Jeremy
    Mage, Rose G.
    Peng, Ze
    Queney, Guillaume
    Rogel-Gaillard, Claire
    Ruffier, Magali
    Searle, Steve
    Villafuerte, Rafael
    Xiong, Anqi
    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.
    Young, Sarah
    Forsberg-Nilsson, Karin
    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.
    Good, Jeffrey M.
    Lander, Eric S.
    Ferrand, Nuno
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication2014In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 345, no 6200, p. 1074-1079Article in journal (Refereed)
    Abstract [en]

    The genetic changes underlying the initial steps of animal domestication are still poorly understood. We generated a high-quality reference genome for the rabbit and compared it to resequencing data from populations of wild and domestic rabbits. We identified more than 100 selective sweeps specific to domestic rabbits but only a relatively small number of fixed (or nearly fixed) single-nucleotide polymorphisms (SNPs) for derived alleles. SNPs with marked allele frequency differences between wild and domestic rabbits were enriched for conserved noncoding sites. Enrichment analyses suggest that genes affecting brain and neuronal development have often been targeted during domestication. We propose that because of a truly complex genetic background, tame behavior in rabbits and other domestic animals evolved by shifts in allele frequencies at many loci, rather than by critical changes at only a few domestication loci.

  • 27. Casazza, Andrea
    et al.
    Fu, Xi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Johansson, Irja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Capparuccia, Lorena
    Andersson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Giustacchini, Alice
    Squadrito, Mario Leonardo
    Venneri, Mary Anna
    Mazzone, Massimiliano
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Carmeliet, Peter
    De Palma, Michele
    Naldini, Luigi
    Tamagnone, Luca
    Rolny, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Systemic and Targeted Delivery of Semaphorin 3A Inhibits Tumor Angiogenesis and Progression in Mouse Tumor Models2011In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 31, no 4, p. 741-749Article in journal (Refereed)
    Abstract [en]

    Objective-The role of semaphorins in tumor progression is still poorly understood. In this study, we aimed at elucidating the regulatory role of semaphorin 3A (SEMA3A) in primary tumor growth and metastatic dissemination. Methods and Results-We used 3 different experimental approaches in mouse tumor models: (1) overexpression of SEMA3A in tumor cells, (2) systemic expression of SEMA3A following liver gene transfer in mice, and (3) tumor-targeted release of SEMA3A using gene modified Tie2-expressing monocytes as delivery vehicles. In each of these experimental settings, SEMA3A efficiently inhibited tumor growth by inhibiting vessel function and increasing tumor hypoxia and necrosis, without promoting metastasis. We further show that the expression of the receptor neuropilin-1 in tumor cells is required for SEMA3A-dependent inhibition of tumor cell migration in vitro and metastatic spreading in vivo. Conclusion-In sum, both systemic and tumor-targeted delivery of SEMA3A inhibits tumor angiogenesis and tumor growth in multiple mouse models; moreover, SEMA3A inhibits the metastatic spreading from primary tumors. These data support the rationale for further investigation of SEMA3A as an anticancer molecule.

  • 28.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Blood vessels as targets in tumor therapy2012In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 117, no 2, p. 178-186Article, review/survey (Refereed)
    Abstract [en]

    The landmark papers published by Judah Folkman in the early 1970s on tumor angiogenesis and therapeutic implications promoted the rapid development of a very dynamic field where basic scientists, oncologists, and pharmaceutical industry joined forces to determine the molecular mechanisms in blood vessel formation and find means to exploit this knowledge in suppressing tumor vascularization and growth. A wealth of information has been collected on angiogenic growth factors, and in 2004 the first specific blood vessel-targeted cancer therapy was introduced: a neutralizing antibody against vascular endothelial growth factor (VEGF). Now (2011) we know that suppression of tumor angiogenesis may be a double-edged sword and that the therapy needs to be further refined and individualized. This review describes the hallmarks of tumor vessels, how different angiogenic growth factors exert their function, and the perspectives for future development of anti-angiogenic therapy.

  • 29.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Introduction to symposium on vascular biology, metabolism and cancer2013In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 273, no 2, p. 112-113Article in journal (Refereed)
  • 30.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Receptor Talk and Tumor Cell Walk in Glioblastoma2012In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 22, no 1, p. 1-2Article in journal (Other academic)
    Abstract [en]

    In this issue of Cancer Cell, Lu et al. describe unconventional molecular interactions in glioblastoma cells that provide a mechanism for how anti-vascular endothelial growth factor therapy may promote mesenchymal transition of glioblastoma cells and increase tumor invasion.

  • 31.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Signal transduction by vascular endothelial growth factor receptors2012In: Vascular pharmacology, ISSN 1537-1891, E-ISSN 1879-3649, Vol. 56, no 5-6, p. 308-308Article in journal (Other academic)
  • 32.
    Claesson-Welsh, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Gerhardt, Holger
    Introduction to the ECR special angiogenesis issue2013In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 319, no 9, p. 1239-1239Article in journal (Other academic)
  • 33.
    Claesson-Welsh, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    VEGFA and tumour angiogenesis2013In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 273, no 2, p. 114-127Article, review/survey (Refereed)
    Abstract [en]

    In this review we summarize the current understanding of signal transduction downstream of vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2, and the relationship between these signal transduction pathways and the hallmark responses of VEGFA, angiogenesis and vascular permeability. These physiological responses involve a number of effectors, including extracellular signal-regulated kinases (ERKs), Src, phosphoinositide 3 kinase (PI3K)/Akt, focal adhesion kinase (FAK), Rho family GTPases, endothelial NO and p38 mitogen-activated protein kinase (MAPK). Several of these factors are involved in the regulation of both angiogenesis and vascular permeability. Tumour angiogenesis primarily relies on VEGFA-driven responses, which to a large extent result in a dysfunctional vasculature. The reason for this remains unclear, although it appears that certain aspects of the VEGFA-stimulated angiogenic milieu (high level of microvascular density and permeability) promote tumour expansion. The high degree of redundancy and complexity of VEGFA-driven tumour angiogenesis may explain why tumours commonly develop resistance to anti-angiogenic therapy targeting VEGFA signal transduction.

  • 34.
    Corell, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Wicher, Grzegorz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Katarzyna J., Radomska
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Trier Kjær, Marcel
    Syddansk Universitet, IMM-Neurobiology Reseach, Denmark .
    Dağlıkoca, E. Duygu
    Bogazici University, Deptartment of Molecular Biology and Genetics, Turkey .
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fex Svenningsen, Åsa
    Syddansk Universitet, IMM-Neurobiology Reseach, Denmark .
    The function of GABA and its B-receptor in Schwann cell developmentManuscript (preprint) (Other academic)
  • 35. Cvijovic, Marija
    et al.
    Almquist, Joachim
    Hagmar, Jonas
    Hohmann, Stefan
    Kaltenbach, Hans-Michael
    Klipp, Edda
    Krantz, Marcus
    Mendes, Pedro
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Nielsen, Jens
    Pagnani, Andrea
    Przulj, Natasa
    Raue, Andreas
    Stelling, Joerg
    Stoma, Szymon
    Tobin, Frank
    Wodke, Judith A. H.
    Zecchina, Riccardo
    Jirstrand, Mats
    Bridging the gaps in systems biology2014In: Molecular Genetics and Genomics, ISSN 1617-4615, E-ISSN 1617-4623, Vol. 289, no 5, p. 727-734Article, review/survey (Refereed)
    Abstract [en]

    Systems biology aims at creating mathematical models, i.e., computational reconstructions of biological systems and processes that will result in a new level of understanding-the elucidation of the basic and presumably conserved "design" and "engineering" principles of biomolecular systems. Thus, systems biology will move biology from a phenomenological to a predictive science. Mathematical modeling of biological networks and processes has already greatly improved our understanding of many cellular processes. However, given the massive amount of qualitative and quantitative data currently produced and number of burning questions in health care and biotechnology needed to be solved is still in its early phases. The field requires novel approaches for abstraction, for modeling bioprocesses that follow different biochemical and biophysical rules, and for combining different modules into larger models that still allow realistic simulation with the computational power available today. We have identified and discussed currently most prominent problems in systems biology: (1) how to bridge different scales of modeling abstraction, (2) how to bridge the gap between topological and mechanistic modeling, and (3) how to bridge the wet and dry laboratory gap. The future success of systems biology largely depends on bridging the recognized gaps.

  • 36.
    Dieterich, Lothar C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Huang, Hua
    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.
    Golenhofen, Nikola
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    alpha B-crystallin/HspB5 regulates endothelial-leukocyte interactions by enhancing NF-kappa B-induced up-regulation of adhesion molecules ICAM-1, VCAM-1 and E-selectin2013In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 16, no 4, p. 975-983Article in journal (Refereed)
    Abstract [en]

    alpha B-crystallin is a small heat shock protein, which has pro-angiogenic properties by increasing survival of endothelial cells and secretion of vascular endothelial growth factor A. Here we demonstrate an additional role of alpha B-crystallin in regulating vascular function, through enhancing tumor necrosis factor alpha (TNF-alpha) induced expression of endothelial adhesion molecules involved in leukocyte recruitme